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Cartwright D, Kidd AC, Ansel S, Ascierto ML, Spiliopoulou P. Oncogenic Signalling Pathways in Cancer Immunotherapy: Leader or Follower in This Delicate Dance? Int J Mol Sci 2025; 26:4393. [PMID: 40362630 DOI: 10.3390/ijms26094393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/01/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.
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Affiliation(s)
- Douglas Cartwright
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Andrew C Kidd
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | - Sonam Ansel
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
| | | | - Pavlina Spiliopoulou
- School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK
- Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK
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Nguyen LTT, Thompson EK, Bhimani N, Duong MC, Nguyen HG, Bullock M, Gild ML, Glover A. Prognostic Significance of Key Molecular Markers in Thyroid Cancer: A Systematic Literature Review and Meta-Analysis. Cancers (Basel) 2025; 17:939. [PMID: 40149275 PMCID: PMC11940365 DOI: 10.3390/cancers17060939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/28/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Thyroid cancer (TC) involves diverse genetic alterations, with their prognostic significance often debated. Objectives: This study evaluates the impact of BRAF, TERT promoter, TP53, and PI3K pathway mutations detected via Next-Generation Sequencing (NGS) on overall survival (OS) and disease-free survival (DFS) in follicular-derived TC patients. Methods: A comprehensive search was conducted in MEDLINE, Scopus, and EMBASE databases from 2013 to 2023 for studies using NGS on TC patients. Hazard ratios (HR) and 95% confidence intervals (CI) for OS and DFS were extracted from original studies or estimated from Kaplan-Meier curves (KMC). A random-effects model, weighted by inverse variance, was used to calculate pooled HRs. Publication bias was assessed using Egger's regression test and visual funnel plot analysis. Results: Of the 3921 initial studies, nine studies involving 1075 patients were included in the meta-analysis. BRAF mutations showed no significant effect on OS (HR = 1.11, 95% CI: 0.66-1.88) or DFS (HR = 1.23, 95% CI: 0.66-2.29). In contrast, TERT promoter mutations were strongly associated with worse OS (HR = 1.90, 95% CI: 1.17-3.09) and DFS (HR = 2.76, 95% CI: 1.86-4.10). TP53 and PI3K pathway mutations were linked to shorter OS (HR = 2.87, 95% CI: 1.44-5.86 and HR = 2.17, 95% CI: 1.05-4.15, respectively), though their impact on DFS remains unclear due to limited data. Conclusions: These findings highlight TERT promoter mutations as strong prognostic markers for both OS and DFS, while TP53 and PI3K mutations indicate higher mortality risk.
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Affiliation(s)
- Linh T. T. Nguyen
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
- Department of Endocrinology, The 108 Military Central Hospital, Hanoi 100000, Vietnam
| | - Emma K. Thompson
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia; (E.K.T.); (N.B.)
| | - Nazim Bhimani
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia; (E.K.T.); (N.B.)
- Specialty of Surgery, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
| | - Minh C. Duong
- School of Population Health, University of New South Wales, Sydney, NSW 2033, Australia;
| | - Huy G. Nguyen
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Martyn Bullock
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
| | - Matti L. Gild
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
- Department of Endocrinology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW 2065, Australia
| | - Anthony Glover
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia; (E.K.T.); (N.B.)
- Specialty of Surgery, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
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Ji L, Chen J, He L, Zhang F, Deng Z, Lin J, Qi Z, Luo X, Giuliano AE, Cui X, Lin SL, Cui Y. Reversal of endocrine resistance via N6AMT1-NEDD4L pathway-mediated p110α degradation. Oncogene 2025; 44:530-544. [PMID: 39623076 PMCID: PMC11832415 DOI: 10.1038/s41388-024-03238-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 02/19/2025]
Abstract
Approximately 70% of breast cancer (BC) cases are luminal-type (estrogen receptor-positive, ER+), suitable for endocrine therapy with tamoxifen as the most commonly used drug. However, about 30% of these patients develop tamoxifen resistance due to various mechanisms, primarily involving PI3K pathway activation through mutations or unknown pathways. Here, we discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110α protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110α inhibitor A66. Clinically, decreased N6AMT1 expression correlates with poor prognosis in luminal BC patients. In TamR BC organoids, combining tamoxifen with A66 further reduced growth compared to either treatment alone. Mechanistically, increased p110α levels result from inhibited degradation by E3 ubiquitin ligase NEDD4L. These findings suggest N6AMT1 as a potential luminal breast cancer biomarker and highlight the N6AMT1-p110α pathway as a therapeutic target to sensitize cells to tamoxifen.
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Affiliation(s)
- Likeng Ji
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiongyu Chen
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Lifang He
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Fan Zhang
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zihao Deng
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiediao Lin
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zhaochang Qi
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Xi Luo
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Armando E Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stanley Li Lin
- Department of Cell Biology, Shantou University Medical College, Shantou, Guangdong, China
| | - Yukun Cui
- Shantou Key Laboratory of Precision Diagnosis and Treatment in Women's Cancer, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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Yan M, Zong Z, Guo W, Li X, Li J, Xia X, Wang X, Kong Y, Li F. PIK3CA gene mutation status associated with poor prognosis of breast cancer: a retrospective cohort study. BMC Cancer 2025; 25:365. [PMID: 40016671 PMCID: PMC11869396 DOI: 10.1186/s12885-025-13486-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/09/2025] [Indexed: 03/01/2025] Open
Abstract
PURPOSE PIK3CA gene mutations have been identified in various malignancies, but the prevalence of specific mutations and their role in breast cancer development remain uncertain. This study aimed to investigate the clinicopathological significance and prognostic impact of PIK3CA mutations in breast cancer. METHODS Five common PIK3CA mutations (H1047R and H1047L in exon 20, and E542K, E545K, and E545D in exon 9) were identified in breast cancer patients using amplification refractory mutation system (ARMS) allele-specific PCR. The study examined the relationships between these mutations and clinicopathologic factors, such as age, HR status, Her2 status, lymph node involvement, distant metastasis, clinicopathologic stage, and progression-free survival (PFS). RESULTS A total of 40 female breast cancer patients were included in this study. Twenty mutations were detected, with 12 located in exon 20 and 8 in exon 9. The most frequent mutation was H1047R in exon 20, present in 11 patients (14.8%). PIK3CA mutations were more commonly observed in patients with HR + breast cancer (P < 0.05). No significant correlation was found between PIK3CA mutations and age, Her2 status, lymph node involvement, distant metastasis, clinicopathologic stage, or Ki-67 expression. Database analysis from the cBioPortal online database showed that the median PFS (95%CI) of the PIK3CA unaltered group [22.93 (17.25-48.30) months] was higher than that of the altered group [12.98 (8.18-18.14) months]. In this study, PIK3CA mutant-type group [13.00 (10.56-15.45) months] had lower median PFS than that of the wild-type group [25.00 (13.46-36.55) months] in all breast cancer patients, the difference was significant (P = 0.004). Further, compared with PIK3CA wild-type, mutant-type was associated with poor PFS in HR + and Her2 + breast cancer patients (P < 0.05). In addition, positive H1047R mutation in PIK3CA was associated with poor PFS of breast cancer (P < 0.05). CONCLUSIONS Our data and public database research show that the PIK3CA mutation is a significant gene change in breast cancer, and the PIK3CA mutation was associated with a shorter PFS in all, HR + and Her2 + breast cancer patients. This research confirmed the important role of PIK3CA in breast cancer.
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Affiliation(s)
- Min Yan
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China.
- Second Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Zhiqiang Zong
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
- Second Clinical Medical College, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Wenyue Guo
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Xinyu Li
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Jingjing Li
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Xi Xia
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Xiaolei Wang
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Yuan Kong
- Department of Surgery, Division of Life Sciences and Medicine, the First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, 230001, Anhui, China.
| | - Fanfan Li
- Department of Oncology, the Second Afliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China.
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Khanyile R, Chipiti T, Hull R, Dlamini Z. Radiogenomic Landscape of Metastatic Endocrine-Positive Breast Cancer Resistant to Aromatase Inhibitors. Cancers (Basel) 2025; 17:808. [PMID: 40075655 PMCID: PMC11899325 DOI: 10.3390/cancers17050808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 02/11/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Breast cancer poses a significant global health challenge and includes various subtypes, such as endocrine-positive, HER2-positive, and triple-negative. Endocrine-positive breast cancer, characterized by estrogen and progesterone receptors, is commonly treated with aromatase inhibitors. However, resistance to these inhibitors can hinder patient outcomes due to genetic and epigenetic alterations, mutations in the estrogen receptor 1 gene, and changes in signaling pathways. Radiogenomics combines imaging techniques like MRI and CT scans with genomic profiling methods to identify radiographic biomarkers associated with resistance. This approach enhances our understanding of resistance mechanisms and metastasis patterns, linking them to specific genomic profiles and common metastasis sites like the bone and brain. By integrating radiogenomic data, personalized treatment strategies can be developed, improving predictive and prognostic capabilities. Advancements in imaging and genomic technologies offer promising avenues for enhancing radiogenomic research. A thorough understanding of resistance mechanisms is crucial for developing effective treatment strategies, making radiogenomics a valuable integrative approach in personalized medicine that aims to improve clinical outcomes for patients with metastatic endocrine-positive breast cancer.
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Affiliation(s)
- Richard Khanyile
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (R.K.); (T.C.); (R.H.)
- Department of Medical Oncology, Steve Biko Academic Hospital and University of Pretoria, Pretoria 0001, South Africa
| | - Talent Chipiti
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (R.K.); (T.C.); (R.H.)
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (R.K.); (T.C.); (R.H.)
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (R.K.); (T.C.); (R.H.)
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6
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Feng Y, Song Q, Yan L, Li R, Yang M, Bu P, Lian J. Predicting breast cancer prognosis using PR and PIK3CA biomarkers: a comparative analysis of diagnostic groups. BMC Cancer 2025; 25:68. [PMID: 39806274 PMCID: PMC11727184 DOI: 10.1186/s12885-025-13449-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 01/03/2025] [Indexed: 01/16/2025] Open
Abstract
PURPOSE To evaluate the prognostic significance of progesterone receptor (PR) expression and the PIK3CA mutation status in HR+/HER2 - breast cancer patients, with the goal of screening patients who may derive the greatest benefit from PI3K-targeted therapy. METHODS A retrospective analysis was conducted on 152 HR+/HER2 - breast cancer patients stratified by PR expression levels and PIK3CA mutation status. The study population was divided into groups on the basis of a median PR threshold of 50% and further subdivided by PIK3CA mutation status. To evaluate the variability of clinicopathologic features among these groups, t tests and ANOVA were employed. The influence of these variables on survival was analyzed via Cox regression. Additionally, a risk prediction model was developed using the PR expression level and PIK3CA mutation status. The prognostic utility of this model was examined via both Kaplan‒Meier (KM) survival curves and receiver operating characteristic (ROC) analyses. These methods have also been utilized to explore the associations between clinicopathologic parameters and clinical outcomes with respect to survival prediction and prognosis. RESULTS Significant differences in age, ER expression, and Ki67, HER2, and PIK3CA mutation status were detected between the groups (P < 0.05). Specifically, elevated PR expression was correlated with lower levels of Ki67 and low HER2 expression. The presence of a PIK3CA mutation was significantly linked to survival outcomes according to both univariate and multivariate Cox regression analyses. Moreover, ROC analysis revealed that models incorporating both PR expression and PIK3CA mutation status achieved the highest level of diagnostic precision (AUC = 0.82). CONCLUSION PR expression and PIK3CA mutation status are significant prognostic markers in HR+/HER2 - breast cancer patients. Assessing these biomarkers in combination can enhance prognostic stratification, potentially guiding more informed clinical decision-making.
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Affiliation(s)
- Yuting Feng
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi Province, 030013, People's Republic of China
- School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Qingzhen Song
- Department of General Medicine, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi Province, People's Republic of China
| | - Lei Yan
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Ruoqi Li
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Mengqin Yang
- School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Peng Bu
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi Province, 030013, People's Republic of China.
| | - Jing Lian
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi Province, 030013, People's Republic of China.
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Moore HN, Goncalves MD, Johnston AM, Mayer EL, Rugo HS, Gradishar WJ, Zylla DM, Bergenstal RM. Effective Strategies for the Prevention and Mitigation of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia: Optimizing Patient Care. Clin Breast Cancer 2025; 25:1-11. [PMID: 39462728 DOI: 10.1016/j.clbc.2024.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/29/2024]
Abstract
Hyperglycemia is a common adverse event (AE) associated with phosphatidylinositol-3-kinase inhibitors (PI3Kis) and considered an on-target effect. Presence of hyperglycemia is associated with poor outcomes in patients with cancer, and there is need for further refinement of hyperglycemia prevention and mitigation strategies in patients receiving PI3Kis. In this review, the authors highlight effective strategies for preventing PI3Ki-induced hyperglycemia before and during treatment as well as hyperglycemia management. Prior to initiating treatment with PI3Ki, identify baseline risk factors of patients at increased risk for developing hyperglycemia, which include older age, obesity, and glycosylated hemoglobin (HbA1c) 5.7%-6.4% (prediabetes or Type 2 diabetes). To prevent new-onset hyperglycemia, optimize blood glucose, and recommend a low-carbohydrate (60-130 g/day) diet along with regular exercise to all patients prior to initiating the PI3Ki. Prophylactic metformin may be considered in all patients starting a PI3Ki with HbA1c ≤6.4%. Although existing recommendations support monitoring fasting blood glucose (FBG) once weekly (twice-weekly for intermediate-risk, daily for high-risk patients) and HbA1c every 3 months upon initiation of PI3Ki, more frequent FBG monitoring may be considered for prompt detection of hyperglycemia. Experts also recommend considering postprandial glucose monitoring because it is an early indicator of glucose intolerance. If hyperglycemia develops, metformin (first-line) and/or sodium glucose co-transporter 2 inhibitors or thiazolidinediones (second-/third-line) are the preferred agents; consider early referral to an endocrinologist. In conclusion, hyperglycemia is a common but manageable AE associated with PI3Kis. Multidisciplinary approach to the prevention, monitoring, and management of hyperglycemia optimizes patient care and allows patients to maintain therapy on PI3Ki.
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Affiliation(s)
| | | | | | - Erica L Mayer
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Hope S Rugo
- Department of Medicine (Hematology/Oncology), University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
| | | | - Dylan M Zylla
- The Cancer Research Center, HealthPartners Institute, Minneapolis, MN
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Fanucci K, Giordano A, Erick T, Tolaney SM, Sammons S. Practical treatment strategies and novel therapies in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced breast cancer. ESMO Open 2024; 9:103997. [PMID: 39674130 PMCID: PMC11699375 DOI: 10.1016/j.esmoop.2024.103997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 12/16/2024] Open
Abstract
Mutations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway occur in 30%-40% of patients with advanced hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer. For most patients, endocrine therapy with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor is the first-line treatment. Recent studies indicate that adding inavolisib, a PI3Kα inhibitor, to palbociclib/fulvestrant benefits patients with endocrine-resistant HR+/HER2- metastatic breast cancer with a PIK3CA mutation. Alpelisib and capivasertib are both US Food and Drug Administration (FDA) approved in combination with fulvestrant in patients with endocrine-resistant HR+/HER2-, PIK3CA-mutant metastatic breast cancer, both with activity in the post-CDK4/6 setting. Capivasertib added to fulvestrant is the first AKT inhibitor to show a significant progression-free survival benefit with a trend for overall survival benefit and the only approved option for patients with phosphate and tensin homolog (PTEN) or AKT alterations. Toxicity profiles of all agents necessitate careful patient selection. Several mutant-selective and pan-mutant-selective novel inhibitors are under investigation with the potential to improve tolerability and efficacy.
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Affiliation(s)
- K Fanucci
- Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, USA; Harvard Medical School, Boston, USA. https://twitter.com/KristinaFanucci
| | - A Giordano
- Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, USA; Harvard Medical School, Boston, USA. https://twitter.com/antgiorda
| | - T Erick
- Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, USA. https://twitter.com/DrTimothyErick
| | - S M Tolaney
- Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, USA; Harvard Medical School, Boston, USA. https://twitter.com/stolaney1
| | - S Sammons
- Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, USA; Harvard Medical School, Boston, USA.
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9
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Frederick J, Virk RKA, Ye IC, Almassalha LM, Wodarcyk GM, VanDerway D, Gonzalez PC, Nap RJ, Agrawal V, Anthony NM, Carinato J, Li WS, Dunton CL, Medina KI, Kakkaramadam R, Jain S, Shahabi S, Ameer G, Szleifer IG, Backman V. Leveraging chromatin packing domains to target chemoevasion in vivo. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.14.623612. [PMID: 39605341 PMCID: PMC11601449 DOI: 10.1101/2024.11.14.623612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains (TADs). However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based mechanistic model that connects chromatin organization to cell fate decisions, specifically survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional efficiency through macromolecular crowding. The model accurately predicts chemoevasion in vitro, suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. Using live-cell chromatin imaging, we conducted a compound screen that identified several TPRs which synergistically enhanced chemotherapy-induced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft (PDX) model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a novel framework for enhancing cancer therapies, with broad potential across multiple cancer types.
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Affiliation(s)
- Jane Frederick
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Ranya K A Virk
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - I Chae Ye
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Luay M Almassalha
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Department of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Greta M Wodarcyk
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - David VanDerway
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Paola Carrillo Gonzalez
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Rikkert J Nap
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Vasundhara Agrawal
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Nicholas M Anthony
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - John Carinato
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Wing Shun Li
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Cody L Dunton
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Karla I Medina
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Rivaan Kakkaramadam
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Surbhi Jain
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Shohreh Shahabi
- Department of Obstetrics and Gynecology, Prentice Women's Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Guillermo Ameer
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Igal G Szleifer
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
- Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
| | - Vadim Backman
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
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10
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Nieto-Coronel T, Alette OG, Yacab R, Fernández-Figueroa EA, Lopez-Camarillo C, Marchat L, Astudillo-de la Vega H, Ruiz-Garcia E. PI3K Mutation Profiles on Exons 9 (E545K and E542K) and 20 (H1047R) in Mexican Patients With HER-2 Overexpressed Breast Cancer and Its Relevance on Clinical-Pathological and Survival Biological Effects. Int J Breast Cancer 2024; 2024:9058033. [PMID: 39444377 PMCID: PMC11496583 DOI: 10.1155/2024/9058033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 06/30/2024] [Accepted: 09/12/2024] [Indexed: 10/25/2024] Open
Abstract
Background: Trastuzumab resistance is associated with overexpressing the human epidermal growth factor receptor 2 (HER-2), which results from the altered phosphoinositide 3-kinase (PI3K) pathway in breast cancer patients. Objective: We quantified the frequency of PI3K enzyme single and double-point mutations in Mexican patients with HER-2 overexpressing breast cancer and its association with clinical-pathological variables. Methods: We embedded HER-2 breast samples in paraffin from 60 patients, extracted their DNA, and evaluated PI3K mutations in 49 HER-2-positive breast tumors. We focused on mutations for one exon 20 (H1047R) and two exon 9 PI3K (E545K, E542K) hotspots and characterized them as single and double-point mutations. The mean patient follow-up was 86 months. Results: Of 49 patients who tested positive for HER-2 breast cancer, 14.28% showed mutations in PI3K, 71.42% single-point, and 28.56% double-point mutations. We found single-point mutations in H1047R (42.85%) and E545K (28.57%). Only two patients exhibited double-point mutations: one in E542K/E545K and another in H1047R/E545K (14.28% each). Although we observed lower survival in patients with mutations in PI3K, we did not find a significant association between these factors (p = 0.191). However, single and double-point mutations in PI3K were significantly associated with the clinical stages of diagnosis and tumor size (p = 0.027 and p = 0.04, respectively). Conclusion: Single and double-point mutations in PI3K are related to tumor size and advanced clinical-pathological traits in Mexican patients with HER-2 overexpression, and future molecular studies are necessary to understand these findings.
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Affiliation(s)
- T. Nieto-Coronel
- Medical Oncology Unit, MyA Medic–Oncopalia Center, La Paz, Bolivia
| | - Ortega-Gómez Alette
- Translational Medicine Laboratory, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - R. Yacab
- Translational Medicine Laboratory, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - E. A. Fernández-Figueroa
- Core B of Innovation in Precision Medicine, National Institute of Genomic Medicine, Mexico City, Mexico
| | - C. Lopez-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico
| | - L. Marchat
- Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, Mexico City, Mexico
| | - H. Astudillo-de la Vega
- Translational Research Laboratory in Cancer & Cellular Therapy, Hospital de Oncologia, Siglo XXI, IMSS-Instituto Mexicano del Seguridad Social, Mexico City, Mexico
| | - E. Ruiz-Garcia
- Translational Medicine Laboratory, Instituto Nacional de Cancerología, Mexico City, Mexico
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11
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Bardia A, Cortés J, Bidard FC, Neven P, Garcia-Sáenz J, Aftimos P, O’Shaughnessy J, Lu J, Tonini G, Scartoni S, Paoli A, Binaschi M, Wasserman T, Kaklamani V. Elacestrant in ER+, HER2- Metastatic Breast Cancer with ESR1-Mutated Tumors: Subgroup Analyses from the Phase III EMERALD Trial by Prior Duration of Endocrine Therapy plus CDK4/6 Inhibitor and in Clinical Subgroups. Clin Cancer Res 2024; 30:4299-4309. [PMID: 39087959 PMCID: PMC11443208 DOI: 10.1158/1078-0432.ccr-24-1073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/24/2024] [Accepted: 07/30/2024] [Indexed: 08/02/2024]
Abstract
PURPOSE Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with estrogen receptor-positive (ER+), HER2- metastatic breast cancer and tumors harboring estrogen receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration and in clinical subgroups with prior ET+CDK4/6i ≥12 months. PATIENTS AND METHODS EMERALD, an open-label phase III trial, randomly assigned patients with ER+, HER2- metastatic breast cancer who had received 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post hoc exploratory analyses without adjustment for multiple testing. RESULTS In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, the median PFS for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% confidence interval, 0.26-0.63). In this population, the median PFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3 catalytic subunit α mutation), 8.6 versus 1.9 (tumor protein p53 gene mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1D538G-mutated tumors), and 9.0 versus 1.9 (ESR1Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population. CONCLUSIONS The duration of prior ET+CDK4/6i ≥12 months in metastatic breast cancer was associated with a clinically meaningful improvement in PFS for elacestrant compared with SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors.
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Affiliation(s)
- Aditya Bardia
- University of California Los Angeles (UCLA) Health Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California.
| | - Javier Cortés
- International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, Spain; and IOB Madrid, Hospital Beata Maria Ana, and Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain.
| | | | - Patrick Neven
- Universitaire Ziekenhuizen (UZ)—Leuven Cancer Institute, Leuven, Belgium.
| | - José Garcia-Sáenz
- Instituto de Investigación Sanitaria Hospital Clinico San Carlos (IdISSC), Madrid, Spain.
| | - Phillipe Aftimos
- Institut Jules Bordet—Université Libre de Bruxelles, Brussels, Belgium.
| | - Joyce O’Shaughnessy
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas.
| | - Janice Lu
- Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.
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12
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Čerina Pavlinović D, Dedić Plavetić N, Belac Lovasić I, Šeparović R, Flam J, Pancirov M, Bajić Ž, Tomić S, Vrdoljak E. Associations between PIK3CA Mutations and Disease Free Survival in Patients with HR+, HER2- Tumors Treated with Adjuvant Hormonal Therapy: A Real-World Study in Croatia. Breast J 2024; 2024:5648845. [PMID: 39742376 PMCID: PMC11416163 DOI: 10.1155/2024/5648845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/29/2024] [Accepted: 09/03/2024] [Indexed: 01/03/2025]
Abstract
Introduction Disease recurrence in patients with the early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast tumor subtype is particularly challenging to manage due to its complex and very heterogeneous biological nature. Namely, due to primary and secondary resistance, one-quarter of patients with early-stage disease will experience disease recurrence. This variability in the timing of recurrence highlights the need to better identify key biomarkers that could predict therapeutic outcomes and guide personalized treatment strategies for these patients. Mutations in the phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene are highly prevalent (30-40%) in HR+/HER2- advanced breast cancer. They lead to activation of the PI3K/AKT/mTOR pathway, promoting cell growth, and proliferation, and are associated with poor prognosis in advanced breast cancer. Our aim was to examine the association between and impact of PIK3CA mutation status on disease-free survival (DFS) in HR+/HER2- early breast cancer patients. Methods This cohort study was multicentric and retrospective in nature and was conducted at five Croatian institutions from July 2020 to December 2021. The study included initially early and locally advanced operable HR+/HER2- breast cancer patients who were diagnosed with disease recurrence during adjuvant hormonal treatment or within the first six years of follow-up. Results A total of 186 patients were included, 40.9% of whom tested positive for the PIK3CA mutation. Primary and adjuvant treatment, particularly adjuvant endocrine treatment, were similar between the two groups. After adjustment for 14 relevant covariates, we found that patients with a positive PIK3CA status and the H1047 PIK3CA mutation had a significantly lower hazard of disease recurrence than patients with no PIK3CA mutation (HR 0.65; 95% CI 0.45; 0.95; p=0.024; false discovery rate, FDR <10%). Conclusions This study highlights the potential impact of PIK3CA mutations on disease recurrence during or following adjuvant endocrine therapy and potentially opens the door for further investigation of possibly more personalized treatment strategies.
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Affiliation(s)
- Dora Čerina Pavlinović
- Department of OncologyUniversity Hospital Center SplitSchool of MedicineUniversity of Split, Split, Croatia
| | - Natalija Dedić Plavetić
- Department of OncologyUniversity Hospital Center ZagrebSchool of MedicineUniversity of Zagreb, Zagreb, Croatia
| | | | - Robert Šeparović
- Department of Medical OncologySestre Milosrdnice University Hospital CentreUniversity Hospital for Tumors, Zagreb, Croatia
| | - Josipa Flam
- Department of Radiotherapy and OncologyUniversity Hospital Center OsijekSchool of MedicineUniversity of Osijek, Osijek, Croatia
| | - Marija Pancirov
- Department of OncologyUniversity Hospital Center SplitSchool of MedicineUniversity of Split, Split, Croatia
| | - Žarko Bajić
- Research Unit “Dr. Mirko Grmek”Psychiatric Clinic “Sveti Ivan”, Zagreb, Croatia
| | - Snježana Tomić
- Department of PathologyUniversity Hospital Center SplitSchool of MedicineUniversity of Split, Split, Croatia
| | - Eduard Vrdoljak
- Department of OncologyUniversity Hospital Center SplitSchool of MedicineUniversity of Split, Split, Croatia
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13
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Chang L, Liu D, Zhao X, Dai L, Ren X, Hao Q, Liu P, Wu H, Ma X, Kang H. Can neoadjuvant systemic therapy provide additional benefits for T1 HER2+ breast cancer patients: a subgroup analysis based on different high-risk signatures. Clin Transl Oncol 2024; 26:2323-2338. [PMID: 38592638 DOI: 10.1007/s12094-024-03472-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 03/21/2024] [Indexed: 04/10/2024]
Abstract
INTRODUCTION Neoadjuvant systemic therapy (NAST) is vital in the management of HER2-positive (HER2+) breast cancer. Nevertheless, the indications for NAST in tumors <2 cm remain controversial. METHOD A total of 7961 patients were screened from the Surveillance, Epidemiology, and End Result database. Independent prognostic factors were identified using multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were used to simulate whether NAST would provide a survival benefit with different high-risk characteristics. Nomograms were constructed, and an internal validation cohort was employed. RESULTS Of the 7961 included patients, 1137 (14.3%) underwent NAST. In the total population, NAST was associated with poorer overall survival (OS) and breast cancer-specific survival (BCSS) (OS: P = 0.00093; BCSS: P < 0.0001). Multivariate Cox analysis confirmed that NAST markedly affected the prognosis of enrolled patients. Besides, a direct association between T, N, age, subtype, and prognosis was observed. Subgroup analyses yielded in these three subgroups, T1c, hormone receptor-negative, and 61-69 years of age, NAST and AST had comparable OS, while NAST possessed worse BCSS. Notably, even in the N3, we still did not observe any additional benefit of NAST. The calculated C-index of 0.72 and 0.73 confirmed the predictability of the nomograms. The AUCs exhibit consistency in the training and validation cohorts. CONCLUSION Our findings suggest that NAST does not provide additional benefit to patients with T1 HER2+ breast cancer, even in the presence of lymph node metastasis, T1c, or hormone receptor negativity. This study facilitates the implementation of individualized management strategies.
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Affiliation(s)
- Lidan Chang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Dandan Liu
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xuyan Zhao
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Luyao Dai
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xueting Ren
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Qian Hao
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Peinan Liu
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Hao Wu
- Department of Biophysics, School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China
| | - Xiaobin Ma
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Huafeng Kang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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14
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Klocker EV, Hasenleithner S, Bartsch R, Gampenrieder SP, Egle D, Singer CF, Rinnerthaler G, Hubalek M, Schmitz K, Bago-Horvath Z, Petzer A, Heibl S, Heitzer E, Balic M, Gnant M. Clinical applications of next-generation sequencing-based ctDNA analyses in breast cancer: defining treatment targets and dynamic changes during disease progression. Mol Oncol 2024. [PMID: 38867388 DOI: 10.1002/1878-0261.13671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 03/03/2024] [Accepted: 05/17/2024] [Indexed: 06/14/2024] Open
Abstract
The advancements in the detection and characterization of circulating tumor DNA (ctDNA) have revolutionized precision medicine and are likely to transform standard clinical practice. The non-invasive nature of this approach allows for molecular profiling of the entire tumor entity, while also enabling real-time monitoring of the effectiveness of cancer therapies as well as the identification of resistance mechanisms to guide targeted therapy. Although the field of ctDNA studies offers a wide range of applications, including in early disease, in this review we mainly focus on the role of ctDNA in the dynamic molecular characterization of unresectable locally advanced and metastatic BC (mBC). Here, we provide clinical practice guidance for the rapidly evolving field of molecular profiling of mBC, outlining the current landscape of liquid biopsy applications and how to choose the right ctDNA assay. Additionally, we underline the importance of exploring the clinical relevance of novel molecular alterations that potentially represent therapeutic targets in mBC, along with mutations where targeted therapy is already approved. Finally, we present a potential roadmap for integrating ctDNA analysis into clinical practice.
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Affiliation(s)
- Eva Valentina Klocker
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Samantha Hasenleithner
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Austria
| | - Rupert Bartsch
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria
| | - Simon P Gampenrieder
- Third Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Oncologic Center, Paracelsus Medical University Salzburg, Austria
| | - Daniel Egle
- Department of Gynecology, Breast Cancer Center Tirol, Medical University of Innsbruck, Austria
| | - Christian F Singer
- Department of Gynecology, Breast Cancer Center Vienna, Medical University of Vienna, Austria
| | - Gabriel Rinnerthaler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Michael Hubalek
- Department of Gynecology, Breast Health Center Schwaz, Austria
| | - Katja Schmitz
- Institute of Pathology, University Medical Center Göttingen, Germany
- Tyrolpath Obrist Brunhuber GmbH and Krankenhaus St. Vinzenz, Zams, Austria
| | | | - Andreas Petzer
- Department of Internal Medicine I for Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Barmherzige Schwestern, Elisabethinen, Ordensklinikum Linz GmbH, Austria
| | - Sonja Heibl
- Department of Internal Medicine IV, Klinikum Wels-Grieskirchen GmbH, Austria
| | - Ellen Heitzer
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Christian Doppler Laboratory for Liquid Biopsies for early Detection of Cancer, Medical University of Graz, Austria
| | - Marija Balic
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Austria
- Division of Hematology and Medical Oncology, University of Pittsburgh School of Medicine, PA, USA
| | - Michael Gnant
- Comprehensive Cancer Center, Medical University of Vienna, Austria
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15
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Schagerholm C, Robertson S, Toosi H, Sifakis EG, Hartman J. PIK3CA mutations in endocrine-resistant breast cancer. Sci Rep 2024; 14:12542. [PMID: 38822093 PMCID: PMC11143214 DOI: 10.1038/s41598-024-62664-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/20/2024] [Indexed: 06/02/2024] Open
Abstract
Around 75% of breast cancer (BC) patients have tumors expressing the predictive biomarker estrogen receptor α (ER) and are offered endocrine therapy. One-third eventually develop endocrine resistance, a majority with retained ER expression. Mutations in the phosphatidylinositol bisphosphate 3-kinase (PI3K) catalytic subunit encoded by PIK3CA is a proposed resistance mechanism and a pharmacological target in the clinical setting. Here we explore the frequency of PIK3CA mutations in endocrine-resistant BC before and during treatment and correlate to clinical features. Patients with ER-positive (ER +), human epidermal growth factor receptor 2 (HER2)-negative primary BC with an ER + relapse within 5 years of ongoing endocrine therapy were retrospectively assessed. Tissue was collected from primary tumors (n = 58), relapse tumors (n = 54), and tumor-free lymph nodes (germline controls, n = 62). Extracted DNA was analyzed through panel sequencing. Somatic mutations were observed in 50% (31/62) of the patients, of which 29% occurred outside hotspot regions. The presence of PIK3CA mutations was significantly associated with nodal involvement and mutations were more frequent in relapse than primary tumors. Our study shows the different PIK3CA mutations in endocrine-resistant BC and their fluctuations during therapy. These results may aid investigations of response prediction, facilitating research deciphering the mechanisms of endocrine resistance.
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Affiliation(s)
- Caroline Schagerholm
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum, Stockholm, Sweden.
| | - Stephanie Robertson
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum, Stockholm, Sweden
| | - Hosein Toosi
- Division of Computational Science and Technology, KTH Royal Institute of Technology and Science for Life Laboratory, Stockholm, Sweden
| | - Emmanouil G Sifakis
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum, Stockholm, Sweden
| | - Johan Hartman
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
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16
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Pankotai-Bodó G, Oláh-Németh O, Sükösd F, Pankotai T. Routine molecular applications and recent advances in breast cancer diagnostics. J Biotechnol 2024; 380:20-28. [PMID: 38122830 DOI: 10.1016/j.jbiotec.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
Cancer stands as one of the most common and lethal diseases, imposing a substantial burden on global mortality rates. Breast cancer is distinct from other forms of cancer in which it is the primary cause of death for women. Early detection of breast cancer can significantly lower the risk of mortality, improving the prognosis for those who are affected. The death rate of breast cancer has been steadily rising, according to epidemiological data, especially since the COVID-19 pandemic. This emphasizes the necessity of sensitive and precise technologies that can be utilized in early breast cancer diagnosis. In this process, biomarkers play a pivotal role by facilitating the early detection and diagnosis of breast cancer. Currently, a wide variety of cancer biomarkers have been identified, improving the accuracy of cancer diagnosis. These biomarkers can be applied in liquid biopsies as well as on solid tissues. In the context of breast cancer, biomarkers are particularly valuable for determining who is predisposed to the disease, predicting prognosis at the time of diagnosis, and selecting the best course of therapy. This review comprehensively explores the recently developed gene-based biomarkers from biofluids that are used in the context of breast cancer, as well as the conventional and cutting-edge techniques that have been employed for breast cancer diagnosis.
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Affiliation(s)
- Gabriella Pankotai-Bodó
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged H-6725, Hungary
| | - Orsolya Oláh-Németh
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged H-6725, Hungary; Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Genome Integrity and DNA Repair Core Group, Budapesti út 9, Szeged H-6728, Hungary
| | - Farkas Sükösd
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged H-6725, Hungary
| | - Tibor Pankotai
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Állomás utca 1, Szeged H-6725, Hungary; Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Genome Integrity and DNA Repair Core Group, Budapesti út 9, Szeged H-6728, Hungary; Competence Centre of the Life Sciences Cluster of the Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Dugonics tér 13, Szeged H-6720, Hungary.
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17
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Debouki-Joudi S, Ben Kridis W, Trifa F, Ayadi W, Khabir A, Sellami-Boudawara T, Daoud J, Khanfir A, Mokdad-Gargouri R. A novel PIK3CA hot-spot mutation in breast cancer patients detected by HRM-COLD-PCR analysis. Breast Dis 2024; 43:213-221. [PMID: 38943378 PMCID: PMC11307001 DOI: 10.3233/bd-240005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2024]
Abstract
BACKGROUND The PI3K protein is involved in the PI3K/AKT/mTOR pathway. Deregulation of this pathway through PIK3CA mutation is common in various tumors. The aim of this work is to identify hotspot mutation at exons 9 and 20 in Tunisian patients with sporadic or hereditary breast cancer. METHODS Hotspot mutations in exon 9 and exon 20 of the PIK3CA gene were identified by QPCR-High Resolution Melting followed by COLD-PCR and sequencing in 63 (42 sporadic cases and 21 hereditary cases) tumor tissues collected from Tunisian patient with breast cancer. MCF7, and BT20 breast cancer cell lines harboring the PIK3CA hotspot mutations E545K and H1047R in exon 9 and exon 20 respectively, were used as controls in HRM experiments. RESULTS PIK3CA hotspot mutations were detected in 66.7% (28 out of 42) of sporadic BC cases, and in 14.3% (3 out of 21) of hereditary BC. The E545K and the H1048Y were the most prevalent mutations identified in patients with sporadic and hereditary BC, whereas the H1047R hotspot mutation was not found in our patients. Statistical analysis showed that PIK3CA mutation associated with an aggressive behavior in patients with sporadic BC, while it's correlated with age, tumor stage and tumor size in the group patients with hereditary breast cancer. CONCLUSIONS Our results showed a novel PIK3CA hotspot mutation in Tunisian breast cancer patients detected by HRM-COLD-PCR. Moreover, the absence of PIK3CA hotspot mutation associated with good prognosis.
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Affiliation(s)
- Saoussen Debouki-Joudi
- Department of Cancer Genetics, Laboratory of Molecular Biotechnology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Wala Ben Kridis
- Department of Medical Oncology, Habib Bourguiba University Hospital, University of Sfax, Sfax, Tunisia
| | - Fatma Trifa
- Department of Cancer Genetics, Laboratory of Molecular Biotechnology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Wajdi Ayadi
- Department of Cancer Genetics, Laboratory of Molecular Biotechnology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Abdelmajid Khabir
- Department of Anatomopathology, Habib Bourguiba University Hospital, University of Sfax, Sfax, Tunisia
| | - Tahia Sellami-Boudawara
- Department of Anatomopathology, Habib Bourguiba University Hospital, University of Sfax, Sfax, Tunisia
| | - Jamel Daoud
- Department of Radiotherapy, Habib Bourguiba University Hospital, University of Sfax, Sfax, Tunisia
| | - Afef Khanfir
- Department of Medical Oncology, Habib Bourguiba University Hospital, University of Sfax, Sfax, Tunisia
| | - Raja Mokdad-Gargouri
- Department of Cancer Genetics, Laboratory of Molecular Biotechnology of Eukaryotes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
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18
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Heinolainen K, Saarinen S, Vertuani S, Ellonen A, Karlsson A, Utriainen M, Carlqvist P, Mandelin J, Holm B. Characterization of clinicopathological features, treatment practices, and outcomes among Finnish advanced breast cancer patients in real-life clinical practice. J Cancer Res Clin Oncol 2023; 149:9139-9149. [PMID: 37178424 PMCID: PMC10374819 DOI: 10.1007/s00432-023-04723-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/22/2023] [Indexed: 05/15/2023]
Abstract
PURPOSE In recent years, several new targeted therapies have emerged for advanced breast cancer (aBC). However, real-life data specific to aBC and different breast cancer subtypes are scarce. This retrospective cohort study was designed to describe the distribution of aBC subtypes, incidence, treatment patterns, survival, and PIK3CA hotspot mutation frequency. METHODS The study included all patients in the Hospital District of Southwest Finland diagnosed with aBC between 2004 and 2013 and with a sample available in Auria Biobank. In addition to registry-based data collection, 161 HR+/HER2- aBCs were screened for PIK3CA mutations. RESULTS Altogether, 54.7% of the 444 patients included in the study had luminal B subtype. The smallest representations were in HR-/HER2+ (4.5%) and triple-negative (5.6%) subgroups. The percentage of aBC among all diagnosed breast cancers increased until 2010, after which it remained stable. The triple-negative cancers were associated with shorter median overall survival (5.5 months) compared to other subgroups (16.5-24.6 months). Most (84%) triple-negative cancers also metastasized during the first two years, whereas this was more evenly distributed over time in other subgroups. Of the HR+/HER2- tumors, 32.3% harbored a PIK3CA hotspot mutation. These patients, however, did not have inferior survival compared to patients with PIK3CA wild-type cancers. CONCLUSION This study described real-world aBC subgroups and indicated that the clinical outcomes of subgroups vary. Although PIK3CA hotspot mutations did not lead to inferior survival, they are relevant as possible treatment targets. Overall, these data could be utilized to further evaluate the subgroup-specific medical needs in breast cancer.
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Affiliation(s)
| | | | | | - Antti Ellonen
- Department of Oncology, Turku University Central Hospital, Turku, Finland
| | | | - Meri Utriainen
- Comprehensive Cancer Center, Helsinki University Central Hospital, Helsinki, Finland
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19
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Chung C, Yeung VTY, Wong KCW. Prognostic and predictive biomarkers with therapeutic targets in breast cancer: A 2022 update on current developments, evidence, and recommendations. J Oncol Pharm Pract 2023; 29:1343-1360. [PMID: 35971313 DOI: 10.1177/10781552221119797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To evaluate and validate the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in breast cancer. DATA SOURCES A literature search from January 2015 to March 2022 was performed using the key terms breast cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, predictive and/or prognostic biomarkers, and targeted therapies. STUDY SELECTION AND DATA EXTRACTION Relevant clinical trials, meta-analyses, seminal articles, and published evidence- and consensus-based clinical practice guidelines in the English language were identified, reviewed and evaluated. DATA SYNTHESIS Breast cancer is a biologically heterogeneous disease, leading to wide variability in treatment responses and survival outcomes. Biomarkers for breast cancer are evolving from traditional biomarkers in immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor type 2 (HER2) to genetic biomarkers with therapeutic implications (e.g. breast cancer susceptibility gene 1/2 [BRCA1/2], estrogen receptor α [ESR1] gene mutation, HER2 gene mutation, microsatellite instability [MSI], phosphatidylinositol 3-kinase catalytic subunit 3Cα [PIK3CA] gene mutation, neurotrophic tyrosine receptor kinase [NTRK] gene mutation). In addition, current data are most robust for biomarkers in immunotherapy (e.g. programmed cell death receptor ligand-1 [PD-L1], microsatellite instability-high [MSI-H] or deficient mismatch repair [dMMR]). Oncotype DX assay remains the best validated gene expression assay that is both predictive and prognostic whereas MammaPrint is prognostic for genomic risk. CONCLUSIONS Biomarker-driven therapies have the potential to confer greater therapeutic advantages than standard-of-care therapies. The purported survival benefits associated with biomarker-driven therapies should be weighed against their potential harms.
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Affiliation(s)
- Clement Chung
- Department of Pharmacy, Houston Methodist West Hospital, Houston, TX, USA
| | - Vanessa T Y Yeung
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong SAR
| | - Kenneth C W Wong
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong SAR
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20
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Neves Rebello Alves L, Dummer Meira D, Poppe Merigueti L, Correia Casotti M, do Prado Ventorim D, Ferreira Figueiredo Almeida J, Pereira de Sousa V, Cindra Sant'Ana M, Gonçalves Coutinho da Cruz R, Santos Louro L, Mendonça Santana G, Erik Santos Louro T, Evangelista Salazar R, Ribeiro Campos da Silva D, Stefani Siqueira Zetum A, Silva Dos Reis Trabach R, Imbroisi Valle Errera F, de Paula F, de Vargas Wolfgramm Dos Santos E, Fagundes de Carvalho E, Drumond Louro I. Biomarkers in Breast Cancer: An Old Story with a New End. Genes (Basel) 2023; 14:1364. [PMID: 37510269 PMCID: PMC10378988 DOI: 10.3390/genes14071364] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Breast cancer is the second most frequent cancer in the world. It is a heterogeneous disease and the leading cause of cancer mortality in women. Advances in molecular technologies allowed for the identification of new and more specifics biomarkers for breast cancer diagnosis, prognosis, and risk prediction, enabling personalized treatments, improving therapy, and preventing overtreatment, undertreatment, and incorrect treatment. Several breast cancer biomarkers have been identified and, along with traditional biomarkers, they can assist physicians throughout treatment plan and increase therapy success. Despite the need of more data to improve specificity and determine the real clinical utility of some biomarkers, others are already established and can be used as a guide to make treatment decisions. In this review, we summarize the available traditional, novel, and potential biomarkers while also including gene expression profiles, breast cancer single-cell and polyploid giant cancer cells. We hope to help physicians understand tumor specific characteristics and support decision-making in patient-personalized clinical management, consequently improving treatment outcome.
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Affiliation(s)
- Lyvia Neves Rebello Alves
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Débora Dummer Meira
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Luiza Poppe Merigueti
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
| | - Matheus Correia Casotti
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Diego do Prado Ventorim
- Instituto Federal de Educação, Ciência e Tecnologia do Espírito Santo (Ifes), Cariacica 29150-410, ES, Brazil
| | - Jucimara Ferreira Figueiredo Almeida
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
| | - Valdemir Pereira de Sousa
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Marllon Cindra Sant'Ana
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
| | - Rahna Gonçalves Coutinho da Cruz
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
| | - Luana Santos Louro
- Centro de Ciências da Saúde, Curso de Medicina, Universidade Federal do Espírito Santo (UFES), Vitória 29090-040, ES, Brazil
| | - Gabriel Mendonça Santana
- Centro de Ciências da Saúde, Curso de Medicina, Universidade Federal do Espírito Santo (UFES), Vitória 29090-040, ES, Brazil
| | - Thomas Erik Santos Louro
- Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM), Vitória 29027-502, ES, Brazil
| | - Rhana Evangelista Salazar
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Danielle Ribeiro Campos da Silva
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Aléxia Stefani Siqueira Zetum
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Raquel Silva Dos Reis Trabach
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
| | - Flávia Imbroisi Valle Errera
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Flávia de Paula
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Eldamária de Vargas Wolfgramm Dos Santos
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
| | - Elizeu Fagundes de Carvalho
- Instituto de Biologia Roberto Alcântara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro 20551-030, RJ, Brazil
| | - Iúri Drumond Louro
- Núcleo de Genética Humana e Molecular, Departamento de Ciências Biológicas, Universidade Federal do Espírito Santo (UFES), Vitória 29075-910, ES, Brazil
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Espírito Santo, Vitória 29047-105, ES, Brazil
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21
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Ye Y, Huang Z, Zhang M, Li J, Zhang Y, Lou C. Synergistic therapeutic potential of alpelisib in cancers (excluding breast cancer): Preclinical and clinical evidences. Biomed Pharmacother 2023; 159:114183. [PMID: 36641927 DOI: 10.1016/j.biopha.2022.114183] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 01/15/2023] Open
Abstract
The phosphoinositide 3-kinase (PI3K) signaling pathway is well-known for its important role in cancer growth, proliferation and migration. The activation of PI3K pathway is always connected with endocrine resistance and poor prognosis in cancers. Alpelisib, a selective inhibitor of PI3K, has been demonstrated to be effective in combination with endocrine therapy in HR+ PIK3CA-mutated advanced breast cancer in preclinical and clinical trials. Recently, the synergistic effects of alpelisib combined with targeted agents have been widely reported in PIK3CA-mutated cancer cells, such as breast, head and neck squamous cell carcinoma (HNSCC), cervical, liver, pancreatic and lung cancer. However, previous reviews mainly focused on the pharmacological activities of alpelisib in breast cancer. The synergistic therapeutic potential of alpelisib in other cancers has not yet been well reviewed. In this review, an extensive study of related literatures (published until December 20, 2022) regarding the anti-cancer functions and synergistic effects of alpelisib was carried out through the databases. Useful information was extracted. We summarized the preclinical and clinical studies of alpelisib in combination with targeted anti-cancer agents in cancer treatment (excluding breast cancer). The combinations of alpelisib and other targeted agents significantly improved the therapeutic efficacy both in preclinical and clinical studies. Unfortunately, synergistic therapies still could not effectively avoid the possible toxicities and adverse events during treatment. Finally, some prospects for the combination studies in cancer treatment were provided in the paper. Taken together, this review provided valuable information for alpelisib in preclinical and clinical applications.
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Affiliation(s)
- Yuhao Ye
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Zhiyu Huang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Maoqing Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Jiayue Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Yiqiong Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Chenghua Lou
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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22
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Bertucci A, Bertucci F, Gonçalves A. Phosphoinositide 3-Kinase (PI3K) Inhibitors and Breast Cancer: An Overview of Current Achievements. Cancers (Basel) 2023; 15:1416. [PMID: 36900211 PMCID: PMC10001361 DOI: 10.3390/cancers15051416] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/19/2023] [Accepted: 02/20/2023] [Indexed: 02/26/2023] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most altered pathways in human cancers, and it plays a central role in cellular growth, survival, metabolism, and cellular mobility, making it a particularly interesting therapeutic target. Recently, pan-inhibitors and then selective p110α subunit inhibitors of PI3K were developed. Breast cancer is the most frequent cancer in women and, despite therapeutic progress in recent years, advanced breast cancers remain incurable and early breast cancers are at risk of relapse. Breast cancer is divided in three molecular subtypes, each with its own molecular biology. However, PI3K mutations are found in all breast cancer subtypes in three main "hotspots". In this review, we report the results of the most recent and main ongoing studies evaluating pan-PI3K inhibitors and selective PI3K inhibitors in each breast cancer subtype. In addition, we discuss the future of their development, the various potential mechanisms of resistance to these inhibitors and the ways to circumvent them.
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Affiliation(s)
| | | | - Anthony Gonçalves
- Medical Oncology Department, CRCM, INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, 13009 Marseille, France
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23
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Potential Impact of PI3K-AKT Signaling Pathway Genes, KLF-14, MDM4, miRNAs 27a, miRNA-196a Genetic Alterations in the Predisposition and Progression of Breast Cancer Patients. Cancers (Basel) 2023; 15:cancers15041281. [PMID: 36831624 PMCID: PMC9954638 DOI: 10.3390/cancers15041281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023] Open
Abstract
Genome-wide association studies have reported link between SNPs and risk of breast cancer. This study investigated the association of the selected gene variants by predicting them as possible target genes. Molecular technique advances with the availability of whole-exome sequencing (WES), now offer opportunities for simultaneous investigations of many genes. The experimental protocol for PI3K, AKT-1, KLF-14, MDM4, miRNAs 27a, and miR-196a genotyping was done by ARMS-PCR and sanger sequencing. The novel and known gene variants were studied by Whole-exome sequencing using Illumina NovaSeq 6000 platform. This case control study reports significant association between BC patients, healthy controls with the polymorphic variants of PI3K C > T, AKT-1 G > A KLF 14 C > T, MDM4 A > G, miR-27a A > G, miR-196a-2 C > T genes (p < 0.05). MDM4 A > G genotypes were strongly associated with BC predisposition with OR 2.08 & 2.15, p < 0.05) in codominant and dominant models respectively. MDM4 A allele show the same effective (OR1.76, p < 0.05) whereas it remains protective in recessive model for BC risk. AKT1G > A genotypes were strongly associated with the BC susceptibility in all genetic models whereas PI3K C > T genotypes were associated with breast cancer predisposition in recessive model OR 6.96. Polymorphic variants of KLF-14 A > G, MDM4G > A, MiR-27aA >G, miR-196a-C > T were strongly associated with stage, tamoxifen treatment. Risk variants have been reported by whole exome sequencing in our BC patients. It was concluded that a strong association between the PI3K-AKT signaling pathway gene variants with the breast cancer susceptibility and progression. Similarly, KLF 14-AA, MDM4-GA, miR27a-GG and miR-196a-CT gene variants were associated with the higher risk probability of BC and were strongly correlated with staging of the BC patients. This study also reported Low, novel, and intermediate-genetic-risk variants of PI3K, AKT-1, MDM4G & KLF-14 by utilizing whole-exome sequencing. These variants should be further investigated in larger cohorts' studies.
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24
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Peixoto A, Cirnes L, Carvalho AL, Andrade MJ, Brito MJ, Borralho P, Coimbra N, Borralho PM, Carneiro AS, Castro L, Correia L, Dionísio MR, Faria C, Figueiredo P, Gomes A, Paixão J, Pinheiro M, Prazeres H, Ribeiro J, Salgueiro N, Schmitt FC, Silva F, Silvestre AR, Sousa AC, Almeida-Tavares J, Teixeira MR, André S, Machado JC. Evaluation of PIK3CA mutations in advanced ER+/HER2-breast cancer in Portugal - U-PIK Project. Front Mol Biosci 2023; 10:1082915. [PMID: 36825198 PMCID: PMC9941536 DOI: 10.3389/fmolb.2023.1082915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/05/2023] [Indexed: 02/10/2023] Open
Abstract
Background: Around 40% of ER+/HER2-breast carcinomas (BC) present mutations in the PIK3CA gene. Assessment of PIK3CA mutational status is required to identify patients eligible for treatment with PI3Kα inhibitors, with alpelisib currently the only approved tyrosine kinase inhibitor in this setting. U-PIK project aimed to conduct a ring trial to validate and implement the PIK3CA mutation testing in several Portuguese centers, decentralizing it and optimizing its quality at national level. Methods: Eight Tester centers selected two samples of patients with advanced ER+/HER2- BC and generated eight replicates of each (n = 16). PIK3CA mutational status was assessed in two rounds. Six centers used the cobas® PIK3CA mutation test, and two used PCR and Sanger sequencing. In parallel, two reference centers (IPATIMUP and the Portuguese Institute of Oncology [IPO]-Porto) performed PIK3CA mutation testing by NGS in the two rounds. The quality of molecular reports describing the results was also assessed. Testing results and molecular reports were received and analyzed by U-PIK coordinators: IPATIMUP, IPO-Porto, and IPO-Lisboa. Results: Overall, five centers achieved a concordance rate with NGS results (allele frequency [AF] ≥5%) of 100%, one of 94%, one of 93%, and one of 87.5%, considering the overall performance in the two testing rounds. NGS reassessment of discrepancies in the results of the methods used by the Tester centers and the reference centers identified one probable false positive and two mutations with low AF (1-3%, at the analytical sensitivity threshold), interpreted as subclonal variants with heterogeneous representation in the tissue sections processed by the respective centers. The analysis of molecular reports revealed the need to implement the use of appropriate sequence variant nomenclature with the identification of reference sequences (HGVS-nomenclature) and to state the tumor cell content in each sample. Conclusion: The concordance rates between the method used by each tester center and NGS validate the use of the PIK3CA mutational status test performed at these centers in clinical practice in patients with advanced ER+/HER2- BC.
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Affiliation(s)
- Ana Peixoto
- Serviço de Genética Laboratorial, Instituto Português de Oncologia do Porto Francisco Gentil (IPO Porto), Porto, Portugal
| | - Luís Cirnes
- IPATIMUP - Instituto de Patologia e Imunologia da Universidade do Porto, Porto, Portugal
| | - Ana Luísa Carvalho
- Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal
| | | | - Maria José Brito
- Unidade de Mama, Centro Clínico Champalimaud, Fundação Champalimaud, Lisboa, Portugal
| | - Paula Borralho
- Serviço de Anatomia Patológica, Hospital CUF Descobertas, Lisboa, Portugal
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| | - Nuno Coimbra
- Serviço de Anatomia Patológica, Instituto Português de Oncologia do Porto Francisco Gentil (IPO Porto), Porto, Portugal
| | - Pedro M. Borralho
- Novartis Farma - Produtos Farmacêuticos, S.A., Porto Salvo, Portugal
| | - Ana Sofia Carneiro
- Serviço de Anatomia Patológica, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal
| | - Lisandra Castro
- Departamento de Genética Molecular, SYNLAB Genética Médica, S.A., Porto, Portugal
| | - Lurdes Correia
- Serviço de Anatomia Patológica, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal
- Instituto de Anatomia Patológica, Lisboa, Portugal
| | | | - Carlos Faria
- Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | | | - Ana Gomes
- Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Joana Paixão
- Serviço de Anatomia Patológica, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal
| | - Manuela Pinheiro
- Serviço de Genética Laboratorial, Instituto Português de Oncologia do Porto Francisco Gentil (IPO Porto), Porto, Portugal
| | - Hugo Prazeres
- Serviço de Anatomia Patológica, IPO Coimbra, Coimbra, Portugal
| | - Joana Ribeiro
- Unidade de Mama, Centro Clínico Champalimaud, Fundação Champalimaud, Lisboa, Portugal
| | - Natália Salgueiro
- Departamento de Genética Molecular, SYNLAB Genética Médica, S.A., Porto, Portugal
| | - Fernando C. Schmitt
- IPATIMUP - Instituto de Patologia e Imunologia da Universidade do Porto, Porto, Portugal
- Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Fátima Silva
- Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Escola Superior de Tecnologia da Saúde de Coimbra, Coimbra, Portugal
- Associação Portuguesa de Técnicas de Anatomia Patológica, Porto, Portugal
| | - Ana Rita Silvestre
- Serviço de Anatomia Patológica, Hospital CUF Descobertas, Lisboa, Portugal
| | - Ana Carla Sousa
- GenoMed – Diagnósticos de Medicina Molecular, S.A., Lisboa, Portugal
| | - Joana Almeida-Tavares
- Serviço de Anatomia Patológica, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal
| | - Manuel R. Teixeira
- Serviço de Genética Laboratorial, Instituto Português de Oncologia do Porto Francisco Gentil (IPO Porto), Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Saudade André
- Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal
| | - José Carlos Machado
- IPATIMUP - Instituto de Patologia e Imunologia da Universidade do Porto, Porto, Portugal
- Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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25
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Arendt ML, Sakthikumar S, Melin M, Elvers I, Rivera P, Larsen M, Saellström S, Lingaas F, Rönnberg H, Lindblad-Toh K. PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia. Sci Rep 2023; 13:632. [PMID: 36635367 PMCID: PMC9837039 DOI: 10.1038/s41598-023-27664-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 01/05/2023] [Indexed: 01/13/2023] Open
Abstract
Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.
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Affiliation(s)
- Maja Louise Arendt
- Department of Veterinary Clinical Sciences, University of Copenhagen, Copenhagen, Denmark.
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
| | | | - Malin Melin
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Uppsala University, Uppsala, Sweden
| | | | | | | | - Sara Saellström
- Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Frode Lingaas
- Veterinary Faculty, Norwegian University of Life Sciences, Ås, Norway
| | - Henrik Rönnberg
- Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Kerstin Lindblad-Toh
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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26
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Bello Roufai D, Gonçalves A, De La Motte Rouge T, Akla S, Blonz C, Grenier J, Gligorov J, Saghatchian M, Bailleux C, Simon H, Desmoulins I, Tharin Z, Renaud E, Bertho M, Benderra MA, Delaloge S, Robert L, Cottu P, Pierga JY, Loirat D, Bertucci A, Renouf B, Bidard FC, Lerebours F. Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program. Oncogene 2023:10.1038/s41388-022-02585-3. [PMID: 36611120 DOI: 10.1038/s41388-022-02585-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 01/09/2023]
Abstract
SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA-mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8-52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95% CI = 1.1-2.1), >5 lines of prior treatments (HR = 1.4, 95% CI = 1.0-2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3-13.6). N = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.
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Affiliation(s)
- D Bello Roufai
- Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France.
| | - A Gonçalves
- Aix-Marseille Univ, CNRS, INSERM, Department of Medical Oncology, Institut Paoli Calmettes, CRCM, Marseille, France
| | | | - S Akla
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - C Blonz
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Sait-Herblain and Angers, France
| | - J Grenier
- Department of Medical Oncology, Institut du Cancer d'Avignon, Avignon, France
| | - J Gligorov
- Department of Medical Oncology, Hôpital Tenon, AP-HP, Paris, France.,INSERM U938, Institut Universitaire de Cancérologie, AP-HP Sorbonne Université, Paris, France
| | - M Saghatchian
- Breast Cancer Unit, American Hospital of Paris, Neuilly-sur-Seine, France
| | - C Bailleux
- Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France
| | - H Simon
- Department of Medical Oncology, University Hospital of Brest, Brest, France
| | - I Desmoulins
- Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France
| | - Z Tharin
- Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France
| | - E Renaud
- Department of Medical Oncology, University Hospital of Brest, Brest, France
| | - M Bertho
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Sait-Herblain and Angers, France
| | - M-A Benderra
- Department of Medical Oncology, Hôpital Tenon, AP-HP, Paris, France
| | - S Delaloge
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - L Robert
- Department of Medical Oncology, Centre Eugène Marquis, Rennes, France
| | - P Cottu
- Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France
| | - J Y Pierga
- Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France.,Paris Cité University, Paris, France
| | - D Loirat
- Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France
| | - A Bertucci
- Aix-Marseille Univ, CNRS, INSERM, Department of Medical Oncology, Institut Paoli Calmettes, CRCM, Marseille, France
| | - B Renouf
- Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France
| | - F C Bidard
- Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France.,UVSQ, Paris-Saclay University, Saint Cloud, France
| | - F Lerebours
- Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France
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Krajnak S, Trier JP, Heinzmann PF, Anic K, Heimes AS, Loewe A, Schmidt M, Battista MJ, Hasenburg A, Brenner W. Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells. EXCLI JOURNAL 2023; 22:114-130. [PMID: 36998707 PMCID: PMC10043427 DOI: 10.17179/excli2022-5064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 01/12/2023] [Indexed: 04/01/2023]
Abstract
In metastatic breast cancer (MBC), PIK3CA mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type PIK3CA) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by PIK3CA gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of PIK3CA-mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, PIK3CA wild-type BC cells. The p110α expression was downregulated or not affected in PIK3CA-mutated cell lines, and not significantly upregulated in PIK3CA wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, PIK3CA-mutated BC cells, providing a rationale for further efforts to evaluate this combination in vivo.
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Affiliation(s)
- Slavomir Krajnak
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Jannis Patrik Trier
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Pauline Friederike Heinzmann
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Katharina Anic
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Anne-Sophie Heimes
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Amelie Loewe
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Marcus Schmidt
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Marco Johannes Battista
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Annette Hasenburg
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
| | - Walburgis Brenner
- Clinic for Obstetrics and Women's Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- *To whom correspondence should be addressed: Walburgis Brenner,
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28
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Chow CY, Lie EF, Wu CH, Chow LW. Clinical implication of genetic composition and molecular mechanism on treatment strategies of HER2-positive breast cancers. Front Oncol 2022; 12:964824. [PMID: 36387174 PMCID: PMC9659858 DOI: 10.3389/fonc.2022.964824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/14/2022] [Indexed: 12/01/2022] Open
Abstract
The current clinical management model of HER2-positive breast cancers is commonly based on guidelines, which in turn are based on the design and outcome of clinical trials. While this model is useful to most practicing clinicians, the treatment outcome of individual patient is not certain at the start of treatment. As the understanding of the translational research of carcinogenesis and the related changes in cancer genetics and tumor microenvironment during treatment is critical in the selection of right choice of treatment to maximize the successful clinical outcome for the patient, this review article intends to discuss the latest developments in the genetic and molecular mechanisms of cancer progression and treatment resistance, and how they influence the planning of the treatment strategies of HER2-positive breast cancers.
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Affiliation(s)
- Christopher Y.C. Chow
- UNIMED Medical Institute, Hong Kong, Hong Kong SAR, China
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | | | - Cheng-Hsun Wu
- Department of Anatomy, China Medical University, Taichung, Taiwan
| | - Louis W.C. Chow
- UNIMED Medical Institute, Hong Kong, Hong Kong SAR, China
- Organisation for Oncology and Translational Research, Hong Kong, Hong Kong SAR, China
- *Correspondence: Louis W.C. Chow,
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29
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Lv W, Du C, Zhang Y, Wu F, Jin Y, Chen X, Liu X, Feng C, Ma X, Zhang S. Clinicopathological characteristics and prognostic analysis of PIK3CA mutation in breast cancer patients in Northwest China. Pathol Res Pract 2022; 238:154063. [PMID: 35994807 DOI: 10.1016/j.prp.2022.154063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 07/31/2022] [Accepted: 08/07/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Multiple studies on PIK3CA mutations in breast cancer (BC) had been performed, which showed the controversial results among different countries and races even those from the same country. The present study aimed to explore the PIK3CA gene mutation status in BC patients in Northwest China and reveal the relationship between PIK3CA mutations and clinicopathological features along with prognosis. MATERIALS AND METHODS 1002 BC patients from Northwest China were recruited in this study, genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissues, and hotspot mutations in the exon 9 and 20 of PIK3CA gene were detected by ARMS-PCR. RESULTS PIK3CA mutations were found in 31.2% (313/1002) of BC patients, among them 66.1% were mutations in exon 20% and 32.6% were mutations in exon 9. H1047R was the most common mutation type, accounting for 56.5% of the total mutated samples. Significant correlations were observed between PIK3CA mutation status and age (P = 0.035), histopathologic types (P = 0.004), pathological grade (P = 0.013), ER positivity (P < 0.001), PR positivity (P < 0.001), molecular subtypes (P = 0.004) and family history (P = 0.007). Cox multivariate analysis showed that patients with mutations in exon 9 or 20 had shorter DFS and OS than wild-type patients. Those with exon 9 mutations subgroup had the worst prognosis. Interestingly, patients with H1047L mutation had the best prognosis than others. CONCLUSION PIK3CA mutations could be used as an indicator of clinical outcome or targeted therapy for multiple breast cancer subgroups in Northwest China.
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Affiliation(s)
- Wei Lv
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Chong Du
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Yinbing Zhang
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Fei Wu
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Yaofeng Jin
- Department of Pathology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Xi Chen
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Xuan Liu
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Cong Feng
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China
| | - Xingcong Ma
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
| | - Shuqun Zhang
- Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710004, China.
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30
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Fillbrunn M, Signorovitch J, André F, Wang I, Lorenzo I, Ridolfi A, Park J, Dua A, Rugo HS. PIK3CA mutation status, progression and survival in advanced HR + /HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer 2022; 22:1002. [PMID: 36131248 PMCID: PMC9490901 DOI: 10.1186/s12885-022-10078-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 09/05/2022] [Indexed: 12/24/2022] Open
Abstract
Background Approximately 40% of hormone receptor positive/human epidermal receptor 2 negative (HR + /HER2-) metastatic breast cancer (mBC) patients harbor phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. However, associations between PIK3CA mutation status and clinical outcomes among patients with HR + /HER2- mBC have been heterogeneous across clinical trials. This meta-analysis was conducted to survey recently available trial data to assess the prognostic effects of PIK3CA among patients with HR + /HER2- mBC. Methods Randomized clinical trials reporting progression-free survival (PFS) or overall survival (OS) stratified by PIK3CA status in HR + /HER2- mBC were identified via systematic literature review. Trial arms receiving phosphatidylinositol 3-kinase (PI3K)-targeted therapies were excluded. Meta-regression analysis was used to estimate the association between PIK3CA status and PFS and OS among included studies. Results The analyzed data included 3,219 patients from 33 study arms across 11 trials (PIK3CA mutated: 1,386, wild type: 1,833). PIK3CA mutation was associated with shorter median PFS (difference [95% CI] (months): -1.8 [-3.4, -0.1], I2 = 35%) and shorter median OS (-8.4 [-13.4, -3.5], I2 = 58%, N = 1,545). Findings were similar for PFS rates at 6 months (odds ratio [95% CI]: 0.74 [0.59, 0.94], I2 = 42%, N = 3,160) and 12 months (0.76 [0.59, 0.99], I2 = 42%, N = 2,468) and directionally consistent but not statistically significant at 18 months (N = 1,726). Conclusions Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS and OS. These findings suggest a negative prognostic value of PIK3CA mutations in patients with HR + /HER2- mBC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10078-5.
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Affiliation(s)
| | | | | | - Iris Wang
- Novartis, East Hanover, New Jersey, USA
| | | | | | | | - Akanksha Dua
- Analysis Group, Inc., Boston, Massachusetts, USA
| | - Hope S Rugo
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA
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31
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KIF26B Is Overexpressed in Medulloblastoma and Promotes Malignant Progression by Activating the PI3K/AKT Pathway. Anal Cell Pathol (Amst) 2022; 2022:2552397. [PMID: 35866054 PMCID: PMC9296275 DOI: 10.1155/2022/2552397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 06/23/2022] [Accepted: 06/29/2022] [Indexed: 11/17/2022] Open
Abstract
Medulloblastoma is one of the most common malignant tumors of the central nervous system in children. Although KIF2B was reported as an oncogene in several malignant tumor types, its role in medulloblastoma has not been studied so far. The PCR results of our study showed that KIF26B is highly expressed in medulloblastoma, and its high expression is associated with a high clinical stage. Knockdown the expression of KIF26B could significantly impair the proliferation and migration of medulloblastoma cells. KIF26B promotes the malignant progression of medulloblastoma by affecting the expression of phosphorylation of key proteins in the PI3K/AKT signaling pathway. With the help of 740 Y-P, activating the pi3k signaling pathway can partially rescue the phenotype. Therefore, our experimental results suggest that KIF26B is a potential target for medulloblastoma.
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32
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Miller J, Armgardt E, Svoboda A. The efficacy and safety of alpelisib in breast cancer: A real-world analysis. J Oncol Pharm Pract 2022:10781552221096413. [PMID: 35450470 DOI: 10.1177/10781552221096413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Published trials of alpelisib + fulvestrant demonstrate efficacy and high rates of adverse effects as a first-line treatment option for metastatic breast cancer and as an option after cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i). The purpose of this analysis is to determine the real-world efficacy and safety of this regimen in heavily pretreated patients. This is a retrospective cohort analysis evaluating patients receiving alpelisib + fulvestrant for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer who previously received ≤ 2 lines of therapy in the metastatic setting and those who previously received ≥ 3 lines of therapy in the metastatic setting. Adverse effects, specifically hyperglycemia, rash, and diarrhea, were reported for the entire population. Thirty-three patients were included in this analysis. Progression-free survival (PFS), overall survival, time to change in therapy, and time to discontinuation were similar in the two groups. Forty-nine percent of patients discontinued alpelisib + fulvestrant due to progression of disease, and 27% of patients discontinued treatment due to adverse effects. Hyperglycemia, rash, and diarrhea occurred at high rates: 66.7%, 45.5%, and 72.7%, respectively. All three of these adverse effects required hospitalizations and pharmacological treatment. This analysis demonstrates that the outcomes of alpelisib + fulvestrant were worse in the real-world salvage setting in HR+, HER2- metastatic breast cancer as compared to the front-line setting. The real-world tolerability of this regimen is still of great concern.
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Affiliation(s)
- Jenn Miller
- 24560Northwestern Memorial Hospital, Chicago, IL, USA
| | - Emily Armgardt
- 88966Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Alison Svoboda
- 88966Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
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33
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Tankova T, Senkus E, Beloyartseva M, Borštnar S, Catrinoiu D, Frolova M, Hegmane A, Janež A, Krnić M, Lengyel Z, Marcou Y, Mazilu L, Mrinakova B, Percik R, Petrakova K, Rubovszky G, Tokar M, Vrdoljak E. Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer. Cancers (Basel) 2022; 14:1598. [PMID: 35406370 PMCID: PMC8997133 DOI: 10.3390/cancers14071598] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/18/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023] Open
Abstract
Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.
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Affiliation(s)
- Tsvetalina Tankova
- Department of Endocrinology, Medical University of Sofia, 2, Zdrave Str., 1431 Sofia, Bulgaria
| | - Elżbieta Senkus
- Department of Oncology & Radiotherapy, Medical University of Gdańsk, Smoluchowskiego 17, 80-214 Gdańsk, Poland;
| | - Maria Beloyartseva
- Institution N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 23 Kashirskoye Avenue, 115478 Moscow, Russia; (M.B.); (M.F.)
| | - Simona Borštnar
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000 Ljubljana, Slovenia;
| | - Doina Catrinoiu
- Department of Diabetology, Clinical Emergency Hospital of Constanta, Romania, Tomis Bvd. No. 145, 900591 Constanta, Romania; (D.C.); (L.M.)
- Faculty of Medicine, “Ovidius” University of Constanta, University Alley No. 1, 900470 Constanta, Romania
| | - Mona Frolova
- Institution N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, 23 Kashirskoye Avenue, 115478 Moscow, Russia; (M.B.); (M.F.)
| | - Alinta Hegmane
- Out-Patient Department of Medical Oncology, Riga East University Hospital, Oncology Center of Latvia, 4, Hipokrata Str., LV1079 Riga, Latvia;
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Disease, University Medical Center, Zaloska 7, 1000 Ljubljana, Slovenia;
| | - Mladen Krnić
- Department of Endocrinology, Clinical Hospital Center Split, School of Medicine, University of Split, Šoltanska 1, 21000 Split, Croatia;
| | - Zoltan Lengyel
- Szent János Hospital, Diós árok 1-3, 1125 Budapest, Hungary;
| | - Yiola Marcou
- Medical Oncology Department, The Bank of Cyprus Oncology Centre, 32 Acropoleos Avenue, Strovolos, Nicosia 2006, Cyprus;
| | - Laura Mazilu
- Department of Diabetology, Clinical Emergency Hospital of Constanta, Romania, Tomis Bvd. No. 145, 900591 Constanta, Romania; (D.C.); (L.M.)
- Faculty of Medicine, “Ovidius” University of Constanta, University Alley No. 1, 900470 Constanta, Romania
| | - Bela Mrinakova
- 1st Department of Oncology, Comenius University, Faculty of Medicine, Bratislava, Heydukova 10, 812 50 Bratislava, Slovakia;
- Slovak Republic Department of Medical Oncology, St. Elisabeth Cancer Institute, Heydukova 10, 812 50 Bratislava, Slovakia
| | - Ruth Percik
- Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel;
- Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Ramat Aviv, Tel Aviv 69978, Israel
| | - Katarina Petrakova
- Masaryk Memorial Cancer Institute, Žlutý kopec 543/7, Brno-Střed-Staré, 602 00 Brno, Czech Republic;
| | - Gábor Rubovszky
- National Institute of Oncology, Rath Gy. Str. 7-9, 1122 Budapest, Hungary;
| | - Margarita Tokar
- The Legacy Heritage Oncology Center and Dr. Larry Norton Institute, SorokaMedical Center, Yitzhack I. Rager Blvd 151, Be’er Sheva, Israel;
| | - Eduard Vrdoljak
- Department of Oncology, Clinical Hospital Center Split, School of Medicine, University of Split, Spinčićeva 1, 21000 Split, Croatia;
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Migliaccio I, Paoli M, Risi E, Biagioni C, Biganzoli L, Benelli M, Malorni L. PIK3CA co-occurring mutations and copy-number gain in hormone receptor positive and HER2 negative breast cancer. NPJ Breast Cancer 2022; 8:24. [PMID: 35181669 PMCID: PMC8857304 DOI: 10.1038/s41523-022-00382-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 01/11/2022] [Indexed: 12/31/2022] Open
Abstract
We aim to elucidate the prognostic value of PIK3CA mutations and copy number (CN) gain (PIK3CA-mut/gain) in hormone receptor-positive and HER2-negative (HR + /HER2−) breast cancer (BC). We analyzed primary HR + /HER2− BC from three publicly available datasets comprising over 2000 samples and assessed the associations with tumoral and clinical characteristics and outcome. Clinical benefit (CB) in alpelisib-treated patients from two studies including 46 patients was analyzed. About 8–10% of HR + /HER2− primary BC had PIK3CA-mut/gain. In two of the datasets analyzed, among patients with PIK3CA mutant tumors, those with mut/gain had significantly worse outcome compared to those with CN neutral (PIK3CA-mut/neut) and PIK3CA-mut/gain remained an independent prognostic factor. CB of alpelisib-treated patients with PIK3CA-mut/gain and PIK3CA-mut/neut tumors was comparable. PIK3CA CN might help clarifying the prognostic and predictive role of PIK3CA mutations. Further studies are warranted.
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Affiliation(s)
- Ilenia Migliaccio
- "Sandro Pitigliani" Translational Research Unit, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy.
| | - Marta Paoli
- Bioinformatics Unit, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy
| | - Emanuela Risi
- "Sandro Pitigliani" Department of Medical Oncology, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy
| | - Chiara Biagioni
- Bioinformatics Unit, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy.,"Sandro Pitigliani" Department of Medical Oncology, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy
| | - Laura Biganzoli
- "Sandro Pitigliani" Department of Medical Oncology, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy
| | - Matteo Benelli
- Bioinformatics Unit, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy
| | - Luca Malorni
- "Sandro Pitigliani" Translational Research Unit, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy.,"Sandro Pitigliani" Department of Medical Oncology, Hospital of Prato, Azienda USL Toscana Centro, 59100, Prato, Italy
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Rugo HS, Lacouture ME, Goncalves MD, Masharani U, Aapro MS, O'Shaughnessy JA. A multidisciplinary approach to optimizing care of patients treated with alpelisib. Breast 2022; 61:156-167. [PMID: 35016012 PMCID: PMC8749445 DOI: 10.1016/j.breast.2021.12.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/23/2021] [Accepted: 12/26/2021] [Indexed: 12/20/2022] Open
Abstract
PURPOSE The oral, α-specific phosphatidylinositol-3-kinase (PI3Kα) inhibitor alpelisib is the first PI3K inhibitor approved for the treatment of advanced breast cancer. As alpelisib is a relatively new therapeutic option, specific guidance and a multidisciplinary approach are needed to provide optimal patient care. The primary objective of this manuscript is to provide comprehensive guidance on minimizing and managing adverse events (AEs) for patients with advanced breast cancer who are receiving alpelisib. METHODS Clinical studies, prescribing information, published literature, and relevant guidelines were reviewed to provide recommendations on the prevention and management of alpelisib-associated AEs. RESULTS The most common AEs associated with alpelisib in the phase 3 SOLAR-1 trial were hyperglycemia and rash (which are considered on-target effects of PI3Kα inhibition) and gastrointestinal AEs, including diarrhea, nausea, and decreased appetite. These AEs require regular monitoring, early recognition, and prompt initiation of appropriate treatment. In addition, there are effective strategies to reduce the onset and severity of frequently observed AEs-in particular, onset of hyperglycemia and rash may be reduced by lifestyle changes (such as reduced intake of carbohydrates and regular exercise) and antihistamine prophylaxis, respectively. To reduce risk of severe hyperglycemia, it is essential to achieve adequate glycemic control prior to initiation of alpelisib treatment. CONCLUSION Overall, alpelisib-associated AEs are generally manageable with prompt recognition, regular monitoring, and appropriate intervention, preferably with a multidisciplinary approach.
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Affiliation(s)
- Hope S Rugo
- Department of Medicine (Hematology/Oncology), University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
| | - Mario E Lacouture
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Marcus D Goncalves
- Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
| | - Umesh Masharani
- Department of Medicine (Endocrinology), University of California San Francisco, San Francisco, CA, USA.
| | - Matti S Aapro
- Department of Oncology, Genolier Cancer Centre, Clinique de Genolier, Genolier, Switzerland.
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Chung WP, Huang WL, Liao WA, Hung CH, Chiang CW, Cheung CHA, Su WC. FTY720 in resistant human epidermal growth factor receptor 2-positive breast cancer. Sci Rep 2022; 12:241. [PMID: 34997132 PMCID: PMC8742024 DOI: 10.1038/s41598-021-04328-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/21/2021] [Indexed: 12/29/2022] Open
Abstract
The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo.
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Affiliation(s)
- Wei-Pang Chung
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Lun Huang
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.,Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-An Liao
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Hua Hung
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Wu Chiang
- Institute of Molecular Medicine, College of Medicine and Center for Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
| | - Chun Hei Antonio Cheung
- Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Wu-Chou Su
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. .,Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.
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Reinhardt K, Stückrath K, Hartung C, Kaufhold S, Uleer C, Hanf V, Lantzsch T, Peschel S, John J, Pöhler M, Bauer M, Bürrig FK, Weigert E, Buchmann J, Kantelhardt EJ, Thomssen C, Vetter M. PIK3CA-mutations in breast cancer. Breast Cancer Res Treat 2022; 196:483-493. [PMID: 36279023 PMCID: PMC9633529 DOI: 10.1007/s10549-022-06637-w] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/14/2022] [Indexed: 01/31/2023]
Abstract
PURPOSE Phosphatidylinositide-3-kinase (PI3K) regulates proliferation and apoptosis; somatic PIK3CA-mutations may activate these processes. Aim of this study was to determine the prevalence of PIK3CA-mutations in a cohort of early stage breast cancer patients and the association to the course of disease. PATIENTS AND METHODS From an unselected cohort of 1270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT01592825) 1123 tumours were tested for the three PIK3CA hotspot-mutations H1047R, E545K, and E542K by qPCR. Primary objectives were the prevalence of somatic PIK3CA-mutations and their association to tumour characteristics. Secondary objective was the association of PIK3CA-mutations to recurrence-free interval (RFI) and overall survival. RESULTS PIK3CA-mutation rate was 26.7% (300 of 1123). PIK3CA-mutations were significantly more frequent in steroid hormone-receptor (SHR)-positive HER2-negative (31.4%), and G1 and G2 tumours (32.8%). Overall, we did not observe a significant association of PIK3CA-mutations to RFI. In SHR-positive BCs with PIK3CA-mutations, a strong trend for impaired RFI was observed (adjusted HR 1.64, 95% CI 0.958-2.807), whilst in SHR-negative BCs PIK3CA-mutations were insignificantly associated with improved RFI (adjusted HR 0.49; 95% CI 0.152-1.597). Of note, we observed a significantly detrimental prognostic impact of PIK3CA-mutations on RFI in SHR-positive, HER2-negative BCs if only aromatase inhibitors were administered as adjuvant therapy (adjusted HR 4.44, 95% CI 1.385-13.920), whilst no impact was observed in tamoxifen treated patients. CONCLUSION This cohort study speficies the overall mutation rate of PIK3CA in early breast cancer. The impact of PIK3CA-mutations on RFI and OS was heterogeneous. Our results suggest that estrogen deprivation failes to be active in case of PIK3CA-mutation.
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Affiliation(s)
- Kristin Reinhardt
- Department of Gynaecology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
| | - Kathrin Stückrath
- Department of Gynaecology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
| | - Carolin Hartung
- Department of Gynaecology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
| | - Sandy Kaufhold
- Department of Gynaecology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
| | | | - Volker Hanf
- Department of Gynaecology, Nathanstift, Hospital Fuerth, Fürth, Germany
| | - Tillmann Lantzsch
- Department of Gynaecology, Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany
| | - Susanne Peschel
- Department of Gynaecology, St. Bernward Hospital, Hildesheim, Germany
| | - Jutta John
- Department of Gynaecology, Helios Hospital Hildesheim, Hildesheim, Germany
| | - Marleen Pöhler
- Department of Gynaecology, Asklepios Hospital Goslar, Goslar, Germany ,Present Address: Department of Gynaecology and Obstretrics, Hospital Wolfenbüttel, Wolfenbüttel, Germany
| | - Marcus Bauer
- Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | | | - Edith Weigert
- Institute of Pathology, Hospital Fürth, Fürth, Germany ,Present Address: Gemeinschaftspraxis Pathologie Amberg, Amberg, Germany
| | - Jörg Buchmann
- Institute of Pathology, Hospital Martha-Maria, Halle (Saale), Germany
| | - Eva Johanna Kantelhardt
- Department of Gynaecology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany ,Institute of Epidemiology, Biometry and Informatics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Christoph Thomssen
- Department of Gynaecology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
| | - Martina Vetter
- Department of Gynaecology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany
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Turner N, Dent RA, O'Shaughnessy J, Kim SB, Isakoff SJ, Barrios C, Saji S, Bondarenko I, Nowecki Z, Lian Q, Reilly SJ, Hinton H, Wongchenko MJ, Kovic B, Mani A, Oliveira M. Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial. Breast Cancer Res Treat 2021; 191:565-576. [PMID: 34860318 PMCID: PMC8831286 DOI: 10.1007/s10549-021-06450-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 11/12/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib-paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). METHODS Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS Overall, 146 patients were randomized to ipatasertib-paclitaxel and 76 to placebo-paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71-1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib-paclitaxel vs 1% with placebo-paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). CONCLUSION Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib-paclitaxel safety profile was consistent with each agent's known adverse effects. Trial registration NCT03337724.
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Affiliation(s)
- Nicholas Turner
- Breast Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK. .,Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK.
| | - Rebecca A Dent
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joyce O'Shaughnessy
- Department of Medical Oncology, Texas Oncology, Baylor University Medical Center, US Oncology, Dallas, TX, USA
| | - Sung-Bae Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Steven J Isakoff
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Carlos Barrios
- Latin American Cooperative Oncology Group, Oncology Research Service, Hospital São Lucas, PUCRS, Porto Alegre, RS, Brazil
| | - Shigehira Saji
- Department of Medical Oncology, Fukushima Medical University Hospital, Fukushima, Japan
| | - Igor Bondarenko
- Oncology and Medical Radiology Department, City Clinical Hospital No. 4, Dnipropetrovsk, Ukraine
| | - Zbigniew Nowecki
- Oncology Centre, Instytut im. Marii-Sklodowskiej, Warsaw, Poland
| | - Qinshu Lian
- Biostatistics, Genentech, Inc, South San Francisco, CA, USA
| | | | - Heather Hinton
- Product Development Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - Bruno Kovic
- Patient-Centered Outcomes Research, Product Development, Hoffmann-La Roche Limited, Mississauga, ON, Canada
| | - Aruna Mani
- Product Development Oncology, Genentech, Inc, South San Francisco, CA, USA
| | - Mafalda Oliveira
- Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Colombo J, Moschetta-Pinheiro MG, Novais AA, Stoppe BR, Bonini ED, Gonçalves FM, Fukumasu H, Coutinho LL, Chuffa LGDA, Zuccari DAPDC. Liquid Biopsy as a Diagnostic and Prognostic Tool for Women and Female Dogs with Breast Cancer. Cancers (Basel) 2021; 13:5233. [PMID: 34680380 PMCID: PMC8533706 DOI: 10.3390/cancers13205233] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/10/2021] [Accepted: 09/17/2021] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Breast cancer (BC) is the malignant neoplasm with the highest mortality rate in women and female dogs are good models to study BC. OBJECTIVE We investigated the efficacy of liquid biopsy to detect gene mutations in the diagnosis and follow-up of women and female dogs with BC. MATERIALS AND METHODS In this study, 57 and 37 BC samples were collected from women and female dogs, respectively. After core biopsy and plasma samples were collected, the DNA and ctDNA of the tumor fragments and plasma were processed for next generation sequencing (NGS) assay. After preprocessing of the data, they were submitted to the Genome Analysis ToolKit (GATK). RESULTS In women, 1788 variants were identified in tumor fragments and 221 variants in plasma; 66 variants were simultaneously detected in tumors and plasma. Conversely, in female dogs, 1430 variants were found in plasma and 695 variants in tumor fragments; 59 variants were simultaneously identified in tumors and plasma. The most frequently mutated genes in the tumor fragments of women were USH2A, ATM, and IGF2R; in female dogs, they were USH2A, BRCA2, and RRM2. Plasma of women showed the most frequent genetic variations in the MAP3K1, BRCA1, and GRB7 genes, whereas plasma from female dogs had variations in the NF1, ERBB2, and KRT17 genes. Mutations in the AKT1, PIK3CA, and BRIP genes were associated with tumor recurrence, with a highly pathogenic variant in PIK3CA being particularly prominent. We also detected a gain-of-function mutation in the GRB7, MAP3K1, and MLH1 genes. CONCLUSION Liquid biopsy is useful to identify specific genetic variations at the beginning of BC manifestation and may be accompanied over the entire follow-up period, thereby supporting the clinicians in refining interventions.
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Affiliation(s)
- Jucimara Colombo
- Laboratory of Molecular Investigation in Cancer (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José, São José do Rio Preto 15090-000, Brazil; (J.C.); (M.G.M.-P.); (A.A.N.); (B.R.S.); (E.D.B.); (F.M.G.)
| | - Marina Gobbe Moschetta-Pinheiro
- Laboratory of Molecular Investigation in Cancer (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José, São José do Rio Preto 15090-000, Brazil; (J.C.); (M.G.M.-P.); (A.A.N.); (B.R.S.); (E.D.B.); (F.M.G.)
| | - Adriana Alonso Novais
- Laboratory of Molecular Investigation in Cancer (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José, São José do Rio Preto 15090-000, Brazil; (J.C.); (M.G.M.-P.); (A.A.N.); (B.R.S.); (E.D.B.); (F.M.G.)
| | - Bruna Ribeiro Stoppe
- Laboratory of Molecular Investigation in Cancer (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José, São José do Rio Preto 15090-000, Brazil; (J.C.); (M.G.M.-P.); (A.A.N.); (B.R.S.); (E.D.B.); (F.M.G.)
| | - Enrico Dumbra Bonini
- Laboratory of Molecular Investigation in Cancer (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José, São José do Rio Preto 15090-000, Brazil; (J.C.); (M.G.M.-P.); (A.A.N.); (B.R.S.); (E.D.B.); (F.M.G.)
| | - Francine Moraes Gonçalves
- Laboratory of Molecular Investigation in Cancer (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José, São José do Rio Preto 15090-000, Brazil; (J.C.); (M.G.M.-P.); (A.A.N.); (B.R.S.); (E.D.B.); (F.M.G.)
| | - Heidge Fukumasu
- Laboratory of Comparative and Translational Oncology (LOCT), Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of Sao Paulo, Pirassununga 13635-900, Brazil;
| | - Luiz Lehmann Coutinho
- Luiz de Queiroz College of Agriculture (ESALQ), University of São Paulo, Piracicaba 13418-900, Brazil;
| | - Luiz Gustavo de Almeida Chuffa
- Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, Universidade Estadual Paulista, Botucatu 18618-689, Brazil;
| | - Debora Aparecida Pires de Campos Zuccari
- Laboratory of Molecular Investigation in Cancer (LIMC), Department of Molecular Biology, Faculdade de Medicina de São José, São José do Rio Preto 15090-000, Brazil; (J.C.); (M.G.M.-P.); (A.A.N.); (B.R.S.); (E.D.B.); (F.M.G.)
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Diao FY. Alpelisib: A Well-Tolerated Treatment Option for Patients with HR-Positive, HER2-Negative, PIK3CA-Mutated Advanced Breast Cancer. Glob Med Genet 2021; 9:1-3. [PMID: 35169775 PMCID: PMC8837412 DOI: 10.1055/s-0041-1736239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Fei-Yu Diao
- Department of General Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
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41
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Valencia GA, Rioja P, Morante Z, Araujo JM, Vallejos HD, Guerra H, Gomez HL. PIK3CA mutation in non-metastatic triple-negative breast cancer as a potential biomarker of early relapse: A case report. World J Clin Oncol 2021; 12:702-711. [PMID: 34513603 PMCID: PMC8394163 DOI: 10.5306/wjco.v12.i8.702] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/18/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Currently, the detection of PIK3CA mutations is of special interest in personalized medicine because it is frequently found in triple-negative breast cancer (TNBC). The PI3KCA mutation is an independent negative prognostic factor for survival in metastatic breast cancer, and its prognostic value in liquid biopsy as a biomarker of treatment and early relapse is under investigation, both for metastatic disease and neoadjuvant scenario with curative intent.
CASE SUMMARY A 54-year-old female patient with TNBC clinical stage IIIA, who, after receiving neoadjuvant chemotherapy (based on anthracyclines and taxanes), surgery, radiotherapy, and adjuvant capecitabine, was detected with a PI3KCA mutation in tissue and peripheral blood (ctDNA in liquid biopsy). After 10 mo, the patient had disease relapse of left cervical node disease.
CONCLUSION The detection of PIK3CA mutation in TNBC after neoadjuvant treatment might be associated with early relapse or rapid disease progression.
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Affiliation(s)
| | - Patricia Rioja
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru
| | - Zaida Morante
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru
| | - Jhajaira M Araujo
- Escuela de Medicina Humana, Universidad Privada San Juan Bautista, Lima 15067, Peru
| | - Heberth Daniel Vallejos
- Department of Medical Oncology, Russian Scientific Center of Radiology and Radiotherapy, Konkovo 117485, Moscow, Russia
| | - Henry Guerra
- Department of Pathology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru
| | - Henry L Gomez
- Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru
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Ghasemishahrestani Z, Melo Mattos LM, Tilli TM, Santos ALSD, Pereira MD. Pieces of the Complex Puzzle of Cancer Cell Energy Metabolism: An Overview of Energy Metabolism and Alternatives for Targeted Cancer Therapy. Curr Med Chem 2021; 28:3514-3534. [PMID: 32814521 DOI: 10.2174/0929867327999200819123357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/17/2020] [Accepted: 07/22/2020] [Indexed: 11/22/2022]
Abstract
Over the past decades, several advances in cancer cell biology have led to relevant details about a phenomenon called the 'Warburg effect'. Currently, it has been accepted that the Warburg effect is not compatible with all cancer cells, and thus the process of aerobic glycolysis is now challenged by the knowledge of a large number of cells presenting mitochondrial function. The energy metabolism of cancer cells is focused on the bioenergetic and biosynthetic pathways in order to meet the requirements of rapid proliferation. Changes in the metabolism of carbohydrates, amino acids and lipids have already been reported for cancer cells and this might play an important role in cancer progression. To the best of our knowledge, these changes are mainly attributed to genetic reprogramming which leads to the transformation of a healthy into a cancerous cell. Indeed, several enzymes that are highly relevant for cellular energy are targets of oncogenes (e.g. PI3K, HIF1, and Myc) and tumor suppressor proteins (e.g. p53). As a consequence of extensive studies on cancer cell metabolism, some new therapeutic strategies have appeared that aim to interrupt the aberrant metabolism, in addition to influencing genetic reprogramming in cancer cells. In this review, we present an overview of cancer cell metabolism (carbohydrate, amino acid, and lipid), and also describe oncogenes and tumor suppressors that directly affect the metabolism. We also discuss some of the potential therapeutic candidates which have been designed to target and disrupt the main driving forces associated with cancer cell metabolism and proliferation.
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Affiliation(s)
- Zeinab Ghasemishahrestani
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Larissa Maura Melo Mattos
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tatiana Martins Tilli
- Centro de Desenvolvimento Tecnologico em Saude, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil
| | - André Luis Souza Dos Santos
- Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcos Dias Pereira
- Departamento de Bioquimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Ciruelos EM, Rugo HS, Mayer IA, Levy C, Forget F, Delgado Mingorance JI, Safra T, Masuda N, Park YH, Juric D, Conte P, Campone M, Loibl S, Iwata H, Zhou X, Park J, Ridolfi A, Lorenzo I, André F. Patient-Reported Outcomes in Patients With PIK3CA-Mutated Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer From SOLAR-1. J Clin Oncol 2021; 39:2005-2015. [PMID: 33780274 PMCID: PMC8210974 DOI: 10.1200/jco.20.01139] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 01/08/2021] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
PURPOSE In the phase III SOLAR-1 trial (NCT02437318), the PI3Kα-selective inhibitor and degrader alpelisib significantly improved median progression-free survival when added to fulvestrant in patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed health-related quality of life using patient-reported outcome measures in these patients. MATERIALS AND METHODS In the PIK3CA-mutant cohort, 341 patients were randomly assigned 1:1 to receive alpelisib 300 mg daily or placebo plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Patient-reported outcomes were evaluated with the European Organisation for Research and Treatment of Cancer QoL of Cancer Patients and Brief Pain Inventory-Short Form questionnaires. Changes from baseline and time to 10% deterioration were analyzed using repeated measurement models and Cox models, respectively. RESULTS Global Health Status/QoL and functional status were maintained from baseline (mean changes < 10 points) in the alpelisib (overall change from baseline [95% CI], -3.50 [-8.02 to 1.02]) and placebo arms (overall change from baseline [95% CI], 0.27 [-4.48 to 5.02]). Overall treatment effect in Global Health Status/QoL was not significantly different between arms (-3.77; 95% CI, -8.35 to 0.80; P = .101). Time to 10% deterioration for Global Health Status/QoL was similar between arms (hazard ratio, 1.03; 95% CI, 0.72 to 1.48). Compared with placebo, deterioration in social functioning and in diarrhea, appetite loss, nausea or vomiting, and fatigue symptom subscales occurred with alpelisib. Numerical improvement in Worst Pain was observed with alpelisib versus placebo (42% v 32%, week 24; P = .090). CONCLUSION In SOLAR-1, there was no statistical difference in deterioration of Global Health Status/QoL between arms, whereas symptom subscales favored placebo for diarrhea, appetite loss, nausea or vomiting, and fatigue, known side effects of alpelisib. Treatment decisions must consider efficacy and tolerability; taken with clinical efficacy, these results support the benefit-risk profile of alpelisib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative PIK3CA-mutated advanced breast cancer.
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Affiliation(s)
- Eva Maria Ciruelos
- Department of Medical Oncology, Breast Cancer Unit, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Hope S. Rugo
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
| | - Ingrid A. Mayer
- Division of Hematology/Oncology, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN
| | - Christelle Levy
- Responsable de l'Institut Normand du Sein, Centre François Baclesse, Caen, France
| | - Frédéric Forget
- Oncologie CHA, Hôpital de Libramont, Vivalia, Libramont-Chevigny, Belgium
| | - Juan Ignacio Delgado Mingorance
- Oncology Department, University Hospital of Badajoz, Servicio Extremeño de Salud, Badajoz, Spain, and Hospital Infanta Cristina, Badajoz, Spain
| | - Tamar Safra
- Medical Oncology and Radiotherapy, Tel Aviv Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Norikazu Masuda
- Department of Surgery and Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yeon Hee Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dejan Juric
- Departments of Hematology/Oncology and Medicine, Massachusetts General Hospital, Boston, MA
| | - Pierfranco Conte
- Dipartimento Di Scienze Chirurgiche Oncologiche e Gastroenterologiche, Università di Padova and Oncologia Medica 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | | | - Sibylle Loibl
- German Breast Group, GBG Forschungs GmbH, Neu-Isenburg, Germany
- Center for Haematology and Oncology, Bethanien Hospital, Frankfurt, Germany
| | - Hiroji Iwata
- Department of Breast Oncology, Aichi Cancer Center, Nagoya, Japan
| | - Xiaolei Zhou
- RTI Health Solutions, Research Triangle Park, NC
| | - Jinhee Park
- Novartis Pharmaceuticals Corporation, East Hanover, NJ
| | - Antonia Ridolfi
- Global Medical Affairs Biostatistics, Novartis Pharma S.A.S., Rueil-Malmaison, France
| | | | - Fabrice André
- Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France
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Xiao W, Zhang G, Chen B, Chen X, Wen L, Lai J, Li X, Li M, Liu H, Liu J, Han-Zhang H, Lizaso A, Liao N. Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics. J Cancer 2021; 12:4408-4417. [PMID: 34093841 PMCID: PMC8176410 DOI: 10.7150/jca.52993] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/17/2021] [Indexed: 12/16/2022] Open
Abstract
Background: Comprehensive analysis of PI3K-AKT-mTOR pathway gene alterations in breast cancer may be helpful for targeted therapy. Methods: We performed targeted sequencing using a panel of 520 cancer-related genes to investigate gene alterations in the PI3K-AKT-mTOR pathway from 589 consecutive Chinese women diagnosed with stage I-III breast cancer. Analyses of overall survival (OS) were performed using the publicly available clinical and genomic data from METABRIC. Results: PI3K-AKT-mTOR pathway gene alterations were detected in 62.6% (369/589) of our cohort. The most commonly altered genes were PIK3CA (45%), PTEN (7.5%), AKT1 (5.9 %), PIK3R1 (2.7%), and PIK3CG (2%). Four PIK3CA mutations (E545K, H1047R, E542K, and H1047L) were detected in all the breast cancer molecular subtypes. Seven PIK3CA mutations (E545G, E418_L422delinsV, E726K, E110del, G1049R, G118D, and D350G) were only detected in HR+ subtypes. Two PIK3CA mutations (C420R and N345K) were only detected in non-triple-negative subtypes. Most cases with PTEN mutation were HR+/HER2- subtype (77.3%), followed by triple-negative subtype (18.2%). In the METABRIC breast cancer dataset, no significant OS difference was observed between the PIK3CA-mutant and wild-type groups. However, patients with multiple PIK3CA mutations (mOS: 131 vs. 159 months, P= 0.029), or PIK3CA mutations located in the C2 domain had significantly shorter OS (mOS, 130 vs. 154 months, P=0.020) than those without the mutations. Conclusions: Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of PIK3CA mutations have distinct prognostic impact.
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Affiliation(s)
- Weikai Xiao
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Guochun Zhang
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Bo Chen
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiaoqing Chen
- Department of Breast, Foshan Women and Children Hospital, Foshan, China
| | - Lingzhu Wen
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jianguo Lai
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xuerui Li
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Min Li
- Burning Rock Biotech, Guangzhou, China
| | - Hao Liu
- Burning Rock Biotech, Guangzhou, China
| | - Jing Liu
- Burning Rock Biotech, Guangzhou, China
| | | | | | - Ning Liao
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Martínez-Fernández P, Pose P, Dolz-Gaitón R, García A, Trigo-Sánchez I, Rodríguez-Zarco E, Garcia-Ruiz MJ, Barba I, Izquierdo-García M, Valero-Garcia J, Ruiz C, Lázaro M, Carbonell P, Gargallo P, Méndez C, Ríos-Martín JJ, Palmeiro-Uriach A, Camarasa-Lillo N, Forteza-Vila J, Calabria I. Comprehensive NGS Panel Validation for the Identification of Actionable Alterations in Adult Solid Tumors. J Pers Med 2021; 11:jpm11050360. [PMID: 33947144 PMCID: PMC8145002 DOI: 10.3390/jpm11050360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 01/08/2023] Open
Abstract
The increasing identification of driver oncogenic alterations and progress of targeted therapies addresses the need of comprehensive alternatives to standard molecular methods. The translation into clinical practice of next-generation sequencing (NGS) panels is actually challenged by the compliance of high quality standards for clinical accreditation. Herein, we present the analytical and clinical feasibility study of a hybridization capture-based NGS panel (Action OncoKitDx) for the analysis of somatic mutations, copy number variants (CNVs), fusions, pharmacogenetic SNPs and Microsatellite Instability (MSI) determination in formalin-fixed paraffin-embedded (FFPE) tumor samples. A total of 64 samples were submitted to extensive analytical validation for the identification of previously known variants. An additional set of 166 tumor and patient-matched normal samples were sequenced to assess the clinical utility of the assay across different tumor types. The panel demonstrated good specificity, sensitivity, reproducibility, and repeatability for the identification of all biomarkers analyzed and the 5% limit of detection set was validated. Among the clinical cohorts, the assay revealed pathogenic genomic alterations in 97% of patient cases, and in 82.7%, at least one clinically relevant variant was detected. The validation of accuracy and robustness of this assay supports the Action OncoKitDx's utility in adult solid tumors.
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Affiliation(s)
- Paula Martínez-Fernández
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Patricia Pose
- Servicio de Anatomía Patológica, Hospital Universitario de la Ribera, 46600 Alcira, Spain; (P.P.); (R.D.-G.)
| | - Raquel Dolz-Gaitón
- Servicio de Anatomía Patológica, Hospital Universitario de la Ribera, 46600 Alcira, Spain; (P.P.); (R.D.-G.)
| | - Arantxa García
- Servicio de Genética Molecular y Radiobiología, Centro Oncológico de Galicia, 15009 A Coruña, Spain;
| | - Inmaculada Trigo-Sánchez
- Servicio de Anatomía Patológica, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; (I.T.-S.); (E.R.-Z.); (J.J.R.-M.)
| | - Enrique Rodríguez-Zarco
- Servicio de Anatomía Patológica, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; (I.T.-S.); (E.R.-Z.); (J.J.R.-M.)
| | - MJose Garcia-Ruiz
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Ibon Barba
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Marta Izquierdo-García
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Jennifer Valero-Garcia
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Carlos Ruiz
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Marián Lázaro
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Paula Carbonell
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Pablo Gargallo
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
| | - Carlos Méndez
- Servicio de Oncología Médica, Centro Oncológico de Galicia, 15009 A Coruña, Spain;
| | - Juan José Ríos-Martín
- Servicio de Anatomía Patológica, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; (I.T.-S.); (E.R.-Z.); (J.J.R.-M.)
| | - Alberto Palmeiro-Uriach
- Laboratorio de Anatomía Patológica, Hospital General Universitario de Castellón, 12004 Castellón, Spain;
| | | | - Jerónimo Forteza-Vila
- Anatomía Patológica, Universidade de Santiago de Compostela, 15705 Santiago de Compostela, Spain;
| | - Inés Calabria
- Imegen-Health in Code Group, 46980 Paterna, Spain; (P.M.-F.); (M.G.-R.); (I.B.); (M.I.-G.); (J.V.-G.); (C.R.); (M.L.); (P.C.); (P.G.)
- Correspondence:
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Vitale SR, Martorana F, Stella S, Motta G, Inzerilli N, Massimino M, Tirrò E, Manzella L, Vigneri P. PI3K inhibition in breast cancer: Identifying and overcoming different flavors of resistance. Crit Rev Oncol Hematol 2021; 162:103334. [PMID: 33865994 DOI: 10.1016/j.critrevonc.2021.103334] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 04/03/2021] [Accepted: 04/06/2021] [Indexed: 02/07/2023] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is commonly deregulated in many human tumors, including breast cancer. Somatic mutations of the PI3K alpha catalytic subunit (PIK3CA) are the most common cause of pathway hyperactivation. Hence, several PI3K inhibitors have been investigated with one of them, alpelisib, recently approved for the treatment of endocrine sensitive, PIK3CA mutated, metastatic breast cancer. Unfortunately, all patients receiving a PI3K inhibitor eventually develop resistance to these compounds. Mechanisms of resistance include oncogenic PI3K alterations, pathway reactivation through upstream or downstream effectors and enhancement of parallel pro-survival pathways. We review the prognostic and predictive role of PI3K alterations in breast cancer, focusing on resistance to PI3K inhibitors and on biomarkers with potential clinical relevance. We also discuss combination strategies that may overcome resistance to PI3K inhibitors, thus increasing the efficacy of these drugs in breast cancer.
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Affiliation(s)
- Silvia Rita Vitale
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Federica Martorana
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Medical Oncology A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Stefania Stella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Gianmarco Motta
- Medical Oncology A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Nicola Inzerilli
- Medical Oncology A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Michele Massimino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Elena Tirrò
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy; Medical Oncology A.O.U. Policlinico "G. Rodolico - San Marco", Catania, Italy.
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Magri J, Gasparetto A, Conti L, Calautti E, Cossu C, Ruiu R, Barutello G, Cavallo F. Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies. Cells 2021; 10:108. [PMID: 33430127 PMCID: PMC7827209 DOI: 10.3390/cells10010108] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/24/2020] [Accepted: 01/05/2021] [Indexed: 12/13/2022] Open
Abstract
The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. Moreover, xCT is overexpressed in cancer stem cells. These features render xCT a promising target for cancer therapy, as has been widely reported in the literature and in our work on its immunotargeting. Interestingly, studies on the TP53 gene have revealed that both wild-type and mutant p53 induce the post-transcriptional down modulation of xCT, contributing to ferroptosis. Moreover, APR-246, a small molecule drug that can restore wild-type p53 function in cancer cells, has been described as an indirect modulator of xCT expression in tumors with mutant p53 accumulation, and is thus a promising drug to use in combination with xCT inhibition. This review summarizes the current knowledge of xCT and its regulation by p53, with a focus on the crosstalk of these two molecules in ferroptosis, and also considers some possible combinatorial strategies that can make use of APR-246 treatment in combination with anti-xCT immunotargeting.
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Affiliation(s)
| | | | | | | | | | | | - Giuseppina Barutello
- Correspondence: (G.B.); (F.C.); Tel.: +39-011-670-6458 (G.B.); +39-011-670-6457 (F.C.)
| | - Federica Cavallo
- Correspondence: (G.B.); (F.C.); Tel.: +39-011-670-6458 (G.B.); +39-011-670-6457 (F.C.)
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Donahue S, Santos Fulgencio G. PI3K Inhibitors and Adverse Events: Optimizing Patient Care for the Treatment of Advanced Breast Cancer. Clin J Oncol Nurs 2020; 24:673-680. [PMID: 33216054 DOI: 10.1188/20.cjon.673-680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Excessive activation of the PI3K pathway has been associated with malignant transformation and resistance to treatment in various cancer types. Various PI3K inhibitors have been evaluated in phase 3 clinical trials; however, most have been associated with modest clinical improvement and poor tolerability. The safety profile of PI3K inhibitors poses new challenges in treatment monitoring and management of common adverse events (AEs). OBJECTIVES The purpose of this article is to provide an overview of AEs associated with PI3K inhibitors, with a focus on alpelisib, as well as guidance on the prevention and management of AEs. METHODS The literature and results from phase 3 trials evaluating the efficacy and safety of endocrine therapy plus PI3K inhibitors in patients with advanced breast cancer were reviewed. FINDINGS AEs associated with PI3K inhibitors include hyperglycemia, diarrhea, nausea, rash, and decreased appetite. Prevention strategies are recommended to avoid the development or decrease the severity of these AEs. Patient education and multidisciplinary care are necessary for the optimal care of these patients.
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Affiliation(s)
- Sarah Donahue
- University of California San Francisco Helen Diller Family Comprehensive Cancer Center
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André F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, Rubovszky G, Yamashita T, Kaufman B, Lu YS, Inoue K, Pápai Z, Takahashi M, Ghaznawi F, Mills D, Kaper M, Miller M, Conte PF, Iwata H, Rugo HS. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol 2020; 32:208-217. [PMID: 33246021 DOI: 10.1016/j.annonc.2020.11.011] [Citation(s) in RCA: 338] [Impact Index Per Article: 67.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2- ABC. PATIENTS AND METHODS Men and postmenopausal women with HR+, HER2- ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan-Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien-Fleming efficacy boundary of P ≤ 0.0161. RESULTS In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. CONCLUSIONS Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2- ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. CLINICALTRIALS. GOV ID NCT02437318.
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Affiliation(s)
- F André
- Department of Medical Oncology, Institut Gustave Roussy, Villejuif and Paris Saclay University, Orsay, France.
| | - E M Ciruelos
- Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - D Juric
- Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, USA
| | - S Loibl
- Department of Medicine and Research, German Breast Group, GBG Forschungs GmbH, Neu-Isenburg, Germany
| | - M Campone
- Medical Oncology, Institut de Cancerologie de l'Ouest, Saint-Herblain, Nantes Cedex, France
| | - I A Mayer
- Hematology/Oncology, Vanderbilt University, Nashville, USA
| | - G Rubovszky
- Department of Medical Oncology and Clinical Pharmacology, National Institute of Oncology, Budapest, Hungary
| | - T Yamashita
- Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - B Kaufman
- Medical Oncology, Tel Aviv University, Sheba Medical Centre, Tel Hashomer, Israel
| | - Y-S Lu
- Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - K Inoue
- Breast Surgery, Saitama Cancer Center, Saitama, Japan
| | - Z Pápai
- Medical Oncology, Hungarian Defence Forces Medical Centre, Budapest, Hungary
| | - M Takahashi
- Breast Surgery, NHO Hokkaido Cancer Center, Sapporo, Japan
| | - F Ghaznawi
- Novartis Pharmaceuticals Corporation, East Hanover, USA
| | - D Mills
- Novartis Pharma AG, Basel, Switzerland
| | - M Kaper
- Novartis Pharmaceuticals Corporation, East Hanover, USA
| | - M Miller
- Novartis Pharmaceuticals Corporation, East Hanover, USA
| | - P F Conte
- Medical Oncology, Universita di Padova and Oncologia Medica 2, Istituto Oncologico Veneto IRCCS, Padua, Italy
| | - H Iwata
- Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan
| | - H S Rugo
- Breast Department, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA
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Jones VC, Dietze EC, Jovanovic-Talisman T, McCune JS, Seewaldt VL. Metformin and Chemoprevention: Potential for Heart-Healthy Targeting of Biologically Aggressive Breast Cancer. Front Public Health 2020; 8:509714. [PMID: 33194937 PMCID: PMC7658387 DOI: 10.3389/fpubh.2020.509714] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 09/24/2020] [Indexed: 12/14/2022] Open
Abstract
Currently, tamoxifen is the only drug approved for reduction of breast cancer risk in premenopausal women. The significant cardiovascular side effects of tamoxifen, coupled with lack of a survival benefit, potential for genotoxicity, and failure to provide a significant risk-reduction for estrogen receptor-negative breast cancer, all contribute to the low acceptance of tamoxifen chemoprevention in premenopausal women at high-risk for breast cancer. While other prevention options exist for postmenopausal women, there is a search for well-tolerated prevention agents that can simultaneously reduce risk of breast cancers, cardiovascular disease, and type-2 diabetes. Metformin is a well-tolerated oral biguanide hypoglycemic agent that is prescribed worldwide to over 120 million individuals with type-2 diabetes. Metformin is inexpensive, safe during pregnancy, and the combination of metformin, healthy lifestyle, and exercise has been shown to be effective in preventing diabetes. There is a growing awareness that prevention drugs and interventions should make the “whole woman healthy.” To this end, current efforts have focused on finding low toxicity alternatives, particularly repurposed drugs for chemoprevention of breast cancer, including metformin. Metformin's mechanisms of actions are complex but clearly involve secondary lowering of circulating insulin. Signaling pathways activated by insulin also drive biologically aggressive breast cancer and predict poor survival in women with breast cancer. The mechanistic rationale for metformin chemoprevention is well-supported by the scientific literature. Metformin is cheap, safe during pregnancy, and has the potential to provide heart-healthy breast cancer prevention. On-going primary and secondary prevention trials will provide evidence whether metformin is effective in preventing breast cancer.
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Affiliation(s)
- Veronica C Jones
- City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Eric C Dietze
- City of Hope Comprehensive Cancer Center, Duarte, CA, United States
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