|
1
|
Kang D, Li J, Li Y, Xu J, Yang J, Zhang Z. Prognostic significance of KRAS, NRAS, BRAF, and PIK3CA mutations in stage II/III colorectal cancer: A retrospective study and meta-analysis. PLoS One 2025; 20:e0320783. [PMID: 40279317 PMCID: PMC12027030 DOI: 10.1371/journal.pone.0320783] [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: 10/12/2024] [Accepted: 02/25/2025] [Indexed: 04/27/2025] Open
Abstract
The prognostic significance of KRAS and BRAF mutations is well-established in metastatic colorectal cancer (CRC) but remains uncertain in early-stage tumors. This study retrospectively analyzed 47 stage II/III CRC patients undergoing curative surgery to assess the association of mutations in KRAS, NRAS, BRAF, and PIK3CA with overall survival (OS) and disease-free survival (DFS). Additionally, a meta-analysis was conducted to validate the prognostic relevance of these gene mutations. We included post hoc analyses of phase III randomized controlled trials (RCTs) in stage II/III patients receiving adjuvant therapy after curative resection in the meta-analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated using a random-effect model in the overall population, stratified subgroups adjusted for microsatellite instability (MSI) status, and within MSI-high (MSI-H) and microsatellite-stable (MSS) populations. In the retrospective cohort, mutations in KRAS, NRAS, BRAF, and PIK3CA were identified in 29.8%, 4.3%, 8.5%, and 14.9% of patients, respectively. No significant association between individual genes and survival was observed. However, in MSS patients, concurrent mutations were significantly associated with shorter OS and DFS (log-rank test, P < 0.05). The meta-analysis incorporated 13 eligible studies, including 15,034 patients. Pooled analyses revealed that KRAS and BRAF mutations were significantly linked to poor OS (KRAS: HR = 1.25, 95%CI: 1.06-1.47, P = 0.008; BRAF: HR = 1.43, 95%CI: 1.26-1.63, P < 0.001) and DFS (KRAS: HR = 1.36, 95%CI: 1.21-1.53, P < 0.001; BRAF: HR = 1.21, 95%CI: 1.02-1.44, P = 0.032). The prognostic impact of BRAF mutation increased with MSI adjustment compared those without MSI adjustment. In MSS tumors, KRAS-mutant patients demonstrated significantly shorter DFS (HR = 1.63, 95%CI: 1.25-2.13, P < 0.001), while BRAF-mutant patients exhibited reduced OS (HR = 1.53, 95%CI: 1.24-1.89, P < 0.001) and DFS (HR = 1.72, 95%CI: 1.20-2.46, P = 0.003) compared to wildtype patients. Conversely, no significant survival differences were found between mutant and wildtype patients in the MSI-H population. Although PIK3CA mutation was nominally associated with OS (HR = 0.86, 95%CI: 0.75-1.00, P = 0.046), the pooled result lacked robustness. In conclusion, KRAS and BRAF mutations had a negative prognostic impact on MSS stage II/III CRC patients receiving adjuvant therapy following curative resection. These patients may benefit from more effective adjuvant treatment strategies.
Collapse
Affiliation(s)
- Di Kang
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Jing Li
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Yangyang Li
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Jingquan Xu
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Jianlei Yang
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| | - Zili Zhang
- Department of General Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, China
| |
Collapse
|
|
2
|
Nielsen AT, Saqi IK, Justesen TF, Madsen MT, Gögenur I, Orhan A. The prognostic impact of tumor mutations and tumor-infiltrating lymphocytes in patients with localized pMMR colorectal cancer - A systematic review and meta-analysis. Crit Rev Oncol Hematol 2025; 211:104714. [PMID: 40188978 DOI: 10.1016/j.critrevonc.2025.104714] [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: 02/09/2025] [Revised: 03/21/2025] [Accepted: 03/28/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND Tumor mutations and the composition of the tumor microenvironment have prognostic and therapeutic significance in colorectal cancer (CRC). However, immunotherapy remains a challenge for patients with proficient mismatch repair (pMMR) CRC. In this paper, the association between tumor-infiltrating lymphocytes (TILs) and tumor mutations on survival outcomes in patients with localized pMMR CRC was examined. METHODS A systematic review of the literature and a meta-analysis were conducted in accordance with the PRISMA guidelines. The literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The outcomes of interest were overall survival, disease-free survival, and cancer-specific survival. The risk of bias was assessed through the Newcastle-Ottawa Scale and the quality of the cumulative evidence was evaluated through the modified GRADE approach. FINDINGS In total, 8498 articles were screened for eligibility and 44 articles were included in the meta-analysis with 33,704 patients in total. Patients with high infiltration of any TILs showed significantly improved overall survival (HR = 0.57, 95 % CI: 0.49-0.67, I2: 0 %), especially for the subgroup of CD3 + (HR = 0.52, 95 % CI: 0.38-0.71, I2: 0 %) and CD8 + (HR = 0.60, 95 % CI: 0.37-0.99, I2: 10 %) TILs. Patients with BRAF mutation (HR = 2.68, 95 % CI: 1.47-4.89, I2: 83 %) and KRAS mutation (HR = 1.25, 95 % CI: 1.18-1.33, I2: 0 %) showed decreased overall survival. INTERPRETATION High infiltration of TILs, especially CD3 + and CD8 + , was associated with significantly improved survival, while BRAF and KRAS mutations were correlated with worse survival outcomes for patients with non-metastatic pMMR CRC.
Collapse
Affiliation(s)
- Amalie Thomsen Nielsen
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark.
| | - Ida Kolukisa Saqi
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark
| | | | | | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Adile Orhan
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, Køge, Denmark
| |
Collapse
|
|
3
|
Yildirim HC, Gunenc D, Almuradova E, Sutcuoglu O, Yalcin S. A Narrative Review of RAS Mutations in Early-Stage Colorectal Cancer: Mechanisms and Clinical Implications. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:408. [PMID: 40142219 PMCID: PMC11944112 DOI: 10.3390/medicina61030408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/19/2025] [Accepted: 02/22/2025] [Indexed: 03/28/2025]
Abstract
Colorectal cancer (CRC) is the third-most common cancer globally and a leading cause of cancer-related deaths. While the prognostic and predictive roles of RAS mutations in advanced CRC are well-established, their significance in early-stage CRC remains a topic of debate. Studies have been conducted for many years on clinical and pathological parameters that may be associated with RAS mutation, and there are inconsistent results in this regard. Currently, the only biomarker used in early-stage CRC is microsatellite status. KRAS mutations are detected in 40-50% of patients with colorectal cancer. RAS activating mutations cause loss of EGFR regulation by acting on the RAS/RAF/MAPK signaling pathways. In advanced colorectal cancer, these mechanisms cause a decrease in the effectiveness of EGFR inhibitors. However, studies on patients with early-stage colorectal cancer have inconsistent results. This review highlights the prognostic and clinical significance of KRAS mutations in early-stage CRC, particularly in MSS tumors. In the MSS group, KRAS mutations were associated with shorter TTR and OS compared to DWT patients. In contrast, in the MSI-H group, KRAS mutations showed no prognostic effect in TTR and OS. However. KRAS mutations were associated with shorter SAR in both MSI-H and MSS groups of patients. The findings underscore the need for routine molecular profiling, including KRAS and MSI status, to refine risk stratification and guide adjuvant therapy decisions. Further studies are warranted to explore targeted therapeutic approaches for KRAS-mutant CRC in the adjuvant setting.
Collapse
Affiliation(s)
- Hasan Cagri Yildirim
- Department of Medical Oncology, Nigde Training and Research Hospital, 51100 Nigde, Turkey
| | - Damla Gunenc
- Department of Medical Oncology, Ege University Faculty of Medicine, 35040 Izmir, Turkey;
| | | | - Osman Sutcuoglu
- Department of Medical Oncology, Etlik City Hospital, 06170 Ankara, Turkey;
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey;
| |
Collapse
|
|
4
|
Pappas L, Quintanilha JCF, Huang RSP, Parikh AR. Genomic alterations associated with early-stage disease and early recurrence in patients with colorectal cancer. Oncologist 2025; 30:oyae269. [PMID: 39531357 PMCID: PMC11883158 DOI: 10.1093/oncolo/oyae269] [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: 04/18/2024] [Accepted: 08/28/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The molecular characterization of early-stage (1-3) colorectal cancer (CRC) remains incomplete, as opposed to metastatic disease, where comprehensive genomic profiling (CGP) is routinely performed. This study aimed to characterize the genomics of stages 1-3 versus IV CRC, and the genomics of patients recurring within 1 year of diagnosis. PATIENTS AND METHODS Patients from a de-identified CRC clinico-genomic database who received Foundation Medicine testing (FoundationOne/FoundationOne CDx) during routine clinical care at approximately 280 US cancer clinics between March 2014 and June 2023 were included. Genomic alterations (GA) were compared by Fisher's exact test. RESULTS A total of 4702 patients were included; 1902 with stages 1-3 and 2800 with stage 4 disease. Among patients with stages 1-3 disease, 546 recurred within 1 year. Patients staged 1-3 had higher prevalence of microsatellite instability (MSI-H, 11.4% vs 4.5%, P < .001), tumor mutational burden (TMB) ≥ 10 Mut/Mb (14.6% vs 6.8%, P < .001), GA in RNF43 (11.2% vs 5.7%, P < .001), MSH6 (3.9% vs 1.7%, P < .001), MLH1 (2.3% vs 0.7%, P < .001), and MSH2 (1.5% vs 0.6%, P < .01) compared to those with stage 4 disease. Patients who recurred within 1 year had higher prevalence of MSI-H (13.2% vs 4.4%, P < .001), TMB ≥ 10 Mut/Mb (16.2% vs 6.9%, P < .001), BRAF V600E (17.2% vs 7.9%, P < .003), GA in RNF43 (13.7% vs 5.3%, P < .001), MSH6 (4.2% vs 1.6%, P = .035), and BRCA1/2 (6.2% vs 3.0%, P = .030). On recurrence, more patients received targeted therapy when CGP was performed before versus after first-line therapy (43% vs 19%, P < .001). CONCLUSIONS Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies.
Collapse
Affiliation(s)
- Leontios Pappas
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | | | | | - Aparna R Parikh
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| |
Collapse
|
|
5
|
Lecuelle J, Truntzer C, Basile D, Laghi L, Greco L, Ilie A, Rageot D, Emile JF, Bibeau F, Taïeb J, Derangere V, Lepage C, Ghiringhelli F. Machine learning evaluation of immune infiltrate through digital tumour score allows prediction of survival outcome in a pooled analysis of three international stage III colon cancer cohorts. EBioMedicine 2024; 105:105207. [PMID: 38880067 PMCID: PMC11233898 DOI: 10.1016/j.ebiom.2024.105207] [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: 12/18/2023] [Revised: 05/18/2024] [Accepted: 06/03/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables. METHODS We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression. FINDINGS CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS. INTERPRETATION In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination. FUNDING This research received no external funding.
Collapse
Affiliation(s)
- Julie Lecuelle
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
| | - Caroline Truntzer
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France
| | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Molecular Gastroenterology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Luana Greco
- Molecular Gastroenterology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Alis Ilie
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
| | - David Rageot
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France
| | - Jean-François Emile
- Paris-Saclay University, Versailles SQY University (UVSQ), EA4340-BECCOH, Assistance Publique-Hôpitaux de Paris (AP-HP), Ambroise Paré Hospital, Smart Imaging, Service de Pathologie, Boulogne, France
| | - Fréderic Bibeau
- Service d'Anatomie et Cytologie Pathologiques, CHU Côte de Nacre, Normandie Université, Caen, France; Department of Pathology, Besançon University Hospital, Besançon, France
| | - Julien Taïeb
- Institut du Cancer Paris Cancer Research for Personalized Medicine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France; Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique, Sorbonne Université, Université Sorbonne Paris Cité, Université de Paris, Paris, France; Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, AP-HP Centre, Université Paris Cité, Paris, France
| | - Valentin Derangere
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France; University of Burgundy Franche-Comté, Dijon, France
| | - Come Lepage
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; University of Burgundy Franche-Comté, Dijon, France; Fédération Francophone de Cancérologie Digestive, Centre de Randomisation Gestion Analyse, EPICAD LNC 1231, Dijon, France; Service d'Hépato-gastroentérologie et Oncologie digestive, CHU de Dijon, France
| | - François Ghiringhelli
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France; Cancer Biology Transfer Platform, Centre Georges-François Leclerc, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France; University of Burgundy Franche-Comté, Dijon, France; Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France.
| |
Collapse
|
|
6
|
Orlandi E, Giuffrida M, Trubini S, Luzietti E, Ambroggi M, Anselmi E, Capelli P, Romboli A. Unraveling the Interplay of KRAS, NRAS, BRAF, and Micro-Satellite Instability in Non-Metastatic Colon Cancer: A Systematic Review. Diagnostics (Basel) 2024; 14:1001. [PMID: 38786299 PMCID: PMC11120454 DOI: 10.3390/diagnostics14101001] [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: 03/21/2024] [Revised: 04/30/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
Microsatellite Instability (MSI-H) occurs in approximately 15% of non-metastatic colon cancers, influencing patient outcomes positively compared to microsatellite stable (MSS) cancers. This systematic review focuses on the prognostic significance of KRAS, NRAS, and BRAF mutations within MSI-H colon cancer. Through comprehensive searches in databases like MEDLINE, EMBASE, and others until 1 January 2024, we selected 8 pertinent studies from an initial pool of 1918. These studies, encompassing nine trials and five observational studies involving 13,273 patients, provided insights into disease-free survival (DFS), survival after recurrence, and overall survival. The pooled data suggest that while KRAS and BRAF mutations typically predict poorer outcomes in MSS colorectal cancer, their impact is less pronounced in MSI contexts, with implications varying across different stages of cancer and treatment responses. In particular, adverse effects of these mutations manifest significantly upon recurrence rather than affecting immediate DFS. Our findings confirm the complex interplay between genetic mutations and MSI status, emphasizing the nuanced role of MSI in modifying the prognostic implications of KRAS, NRAS, and BRAF mutations in colon cancer. This review underscores the importance of considering MSI alongside mutational status in the clinical decision-making process, aiming to tailor therapeutic strategies more effectively for colon cancer patients.
Collapse
Affiliation(s)
- Elena Orlandi
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Mario Giuffrida
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
| | - Serena Trubini
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Enrico Luzietti
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
| | - Massimo Ambroggi
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Elisa Anselmi
- Department of Oncology-Hematology, Piacenza General Hospital, 29121 Piacenza, Italy; (S.T.); (M.A.); (E.A.)
| | - Patrizio Capelli
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
| | - Andrea Romboli
- Department of General Surgery, Piacenza General Hospital, 29121 Piacenza, Italy; (M.G.); (E.L.); (P.C.); (A.R.)
| |
Collapse
|
|
7
|
Lawler T, Parlato L, Warren Andersen S. The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis. Front Oncol 2024; 14:1349572. [PMID: 38737895 PMCID: PMC11082351 DOI: 10.3389/fonc.2024.1349572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Background Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes. Methods We systematically searched PubMed for original research articles published between April 2013-January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC. Results In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in KRAS (OR, 95% CI: 0.91, 0.85-0.98), BRAF (0.63, 0.51-0.78), APC (0.70, 0.58-0.84), and NRAS (0.88, 0.78-1.00) but more likely to include mutations in PTEN (1.68, 1.04-2.73) and TP53 (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and BRAF (0.77, 0.64-0.92) and APC mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with PIK3CA mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent. Discussion A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.
Collapse
Affiliation(s)
- Thomas Lawler
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Shaneda Warren Andersen
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
| |
Collapse
|
|
8
|
Huo JT, Tuersun A, Yu SY, Zhang YC, Feng WQ, Xu ZQ, Zhao JK, Zong YP, Lu AG. Leveraging a KRAS-based signature to predict the prognosis and drug sensitivity of colon cancer and identifying SPINK4 as a new biomarker. Sci Rep 2023; 13:22230. [PMID: 38097680 PMCID: PMC10721872 DOI: 10.1038/s41598-023-48768-0] [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: 07/20/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023] Open
Abstract
KRAS is one of the leading mutations reported in colon cancer. However, there are few studies on the application of KRAS related signature in predicting prognosis and drug sensitivity of colon cancer patient. We identified KRAS related differentially expressed genes (DEGs) using The Cancer Genome Atlas (TCGA) database. A signature closely related to overall survival was recognized with Kaplan-Meier survival analysis and univariate cox regression analysis. Then we validated this signature with overall expression score (OE score) algorithm using both scRNA-seq and bulk RNA-seq data. Based on this signature, we performed LASSO cox regression to establish a prognostic model, and corresponding scores were calculated. Differences in genomic alteration, immune microenvironment, drug sensitivity between high- and low-KRD score groups were investigated. A KRAS related signature composed of 80 DEGs in colon cancer were recognized, among which 19 genes were selected to construct a prognostic model. This KRAS related signature was significantly correlated with worse prognosis. Furthermore, patients who scored lower in the prognostic model presented a higher likelihood of responding to chemotherapy, targeted therapy and immunotherapy. Furthermore, among the 19 selected genes in the model, SPINK4 was identified as an independent prognostic biomarker. Further validation in vitro indicated the knockdown of SPINK4 promoted the proliferation and migration of SW48 cells. In conclusion, a novel KRAS related signature was identified and validated based on clinical and genomic information from TCGA and GEO databases. The signature was proved to regulate genomic alteration, immune microenvironment and drug sensitivity in colon cancer, and thus might serve as a predictor for individual prognosis and treatment.
Collapse
Affiliation(s)
- Jian-Ting Huo
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Abudumaimaitijiang Tuersun
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Su-Yue Yu
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Yu-Chen Zhang
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Wen-Qing Feng
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Zhuo-Qing Xu
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China
| | - Jing-Kun Zhao
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China.
| | - Ya-Ping Zong
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China.
| | - Ai-Guo Lu
- Department of General Surgery, Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200020, People's Republic of China.
| |
Collapse
|
|
9
|
Baranov E, Nowak JA. Pathologic Evaluation of Therapeutic Biomarkers in Colorectal Adenocarcinoma. Surg Pathol Clin 2023; 16:635-650. [PMID: 37863556 DOI: 10.1016/j.path.2023.05.002] [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: 10/22/2023]
Abstract
Molecular testing is an essential component of the pathologic evaluation of colorectal carcinoma providing diagnostic, prognostic, and predictive therapeutic information. Mismatch repair status evaluation is required for all tumors. Advanced and metastatic tumors also require determination of tumor mutational burden, KRAS, NRAS, and BRAF mutation status, ERBB2 amplification status, and NTRK and RET gene rearrangement status to guide therapy. Multiple assays, including immunohistochemistry, microsatellite instability testing, MLH1 promoter methylation, and next-generation sequencing, are typically needed. Pathologists must be aware of these requirements to optimally triage tissue. Advances in colorectal cancer molecular diagnostics will continue to drive refinements in colorectal cancer personalized therapy.
Collapse
Affiliation(s)
- Esther Baranov
- Department of Pathology, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Jonathan A Nowak
- Department of Pathology, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
| |
Collapse
|
|
10
|
Kunt N, Araz M, Yildirim MS, Findik S, Kocak MZ, Eryilmaz MK, Artac M. The Effect of RAS/BRAF Mutation Status on Prognosis and Relapse Pattern in Early Stage Colon Cancers. J Gastrointest Cancer 2023; 54:1316-1321. [PMID: 37191843 DOI: 10.1007/s12029-023-00943-2] [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] [Accepted: 05/07/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE It is known that the RAS and BRAF mutations are predictive for targeted therapies in treating metastatic colon cancer and negatively affect the prognosis of the disease. However, there are limited studies in early-stage colon cancer about the relationship of this mutational condition with the prognosis and relapse pattern of the disease. In this study, we evaluated the effects of mutational status on the clinical pattern of recurrence and survival in early-stage colon cancer in addition to classical risk factors. METHODS Patients with early-stage colon cancer at the first time of diagnosis and developing recurrence or metastasis on following up were included in this study. Patients were divided into two groups according to the at the time of relapse RAS/BRAF mutation status: mutant or non-mutant/wild types. Then, mutation analysis was performed again from the early-stage tissue of the patients if available. The relationship between early-stage mutation status and progression-free survival (PFS), overall survival (OS), and relapse pattern was analyzed. RESULTS The number of patients with mutant and non-mutations in the early stage was 39 and 40, respectively. Mutant and non-mutant patients with stage 3 disease were similar (69% and 70%, respectively). OS (47.27 months vs. 67.53 months; p = 0.02) and PFS (25.12 vs. 38.13 months; p = 0.049) were statistically significantly lower in mutant patients, respectively. Most patients had distant metastases on both sides at recurrence (61.5% vs. 62.5%, respectively). There was no significant difference between mutant and non-mutant patients regarding distant metastasis and local recurrence rates (p = 0.657). A discordance of 11.4% between early-stage and late-stage tissue mutation status. CONCLUSION The presence of mutation in early-stage colon cancer is associated with shorter OS and PFS. The mutational status did not have a significant effect on the recurrence pattern. Because of the discordance of early-stage and late-stage mutational status, it is recommended to perform mutation analysis from tissue at relapse.
Collapse
Affiliation(s)
- Nazli Kunt
- Department of Internal Medicine, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey.
| | - Murat Araz
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Mahmut Selman Yildirim
- Department of Medical Genetics, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Siddika Findik
- Department of Pathology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Mehmet Zahid Kocak
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Melek Karakurt Eryilmaz
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| | - Mehmet Artac
- Department of Oncology, Faculty of Medicine, Necmettin Erbakan University Meram, Saraykoy Akyokus Street 42080, Konya, Turkey
| |
Collapse
|
|
11
|
Fang L, Yao Y, Guan X, Liao Y, Wang B, Cui L, Han S, Zou H, Su D, Ma Y, Liu B, Wang Y, Huang R, Ruan Y, Yu X, Yao Y, Liu C, Zhang Y. China special issue on gastrointestinal tumors-Regulatory-immunoscore-A novel indicator to guide precision adjuvant chemotherapy in colorectal cancer. Int J Cancer 2023; 153:1904-1915. [PMID: 37085990 DOI: 10.1002/ijc.34539] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 04/23/2023]
Abstract
Novel biomarkers are essential to improve the treatment efficacy and overall survival of stage II and III colorectal cancer (CRC), allowing for personalized treatment decisions. Here, the densities of CD8+ and FOXP3+ T cells in the tumor and invasive margin were processed by immunohistochemistry and digital pathology to form a scoring system named regulatory-Immunoscore (RIS). Cox proportional hazards regression models were used to determine the risk factors associated with time to recurrence. Harrell's concordance index and the time-dependent area under the curve were used to assess model performance. A total of 1213 stage I-III DNA mismatch repair-proficient colorectal cancer (pMMR CRC) patients were randomly assigned to a training set (n = 642) and a validation set (n = 571). From the Cox multivariable analysis, the association of RIS with survival was independent of patient age, sex and anatomy-based tumor risk parameters (P < .0001). For stage II patients, chemotherapy was significantly associated with better recurrence time in patients with low (95% confidence interval [CI]: 0.11-0.54, P = .001) and intermediate (95% CI = 0.25-0.57, P < .001) RIS values. In stage III patients treated with adjuvant chemotherapy, a treatment duration of 6 or more months was significantly associated with better recurrence time in patients with intermediate RIS values (95% CI = 0.38-0.90, P = .016) when compared with duration under 6 months. Therefore, these findings suggest that RIS is reliable for predicting recurrence risk and treatment responsiveness for patients with stage I-III pMMR CRC.
Collapse
Affiliation(s)
- Lin Fang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Yang Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Xin Guan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yuanyu Liao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Bojun Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Luying Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Shuling Han
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Haoyi Zou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Dan Su
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yue Ma
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Biao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yao Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Rui Huang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Yuli Ruan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Xuefan Yu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Chao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| |
Collapse
|
|
12
|
Wu Z, Qin X, Zhang Y, Luo J, Luo R, Cai Z, Wang H. Effect of BRAF mutation on the prognosis for patients with colorectal cancer undergoing cytoreductive surgery for synchronous peritoneal metastasis. Gastroenterol Rep (Oxf) 2023; 11:goad061. [PMID: 37886242 PMCID: PMC10598839 DOI: 10.1093/gastro/goad061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 08/02/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023] Open
Abstract
Background KRAS/BRAF mutations (mutKRAS/mutBRAF) are unfavorable prognostic factors for colorectal cancer (CRC) metastases to the liver and lungs. However, their effects on the prognosis for patients with synchronous peritoneal metastasis (S-PM) of CRC after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are controversial. In the study, we aimed to determine the effects of mutKRAS/mutBRAF on the prognosis for patients with S-PM who received CRS. Methods A total of 142 patients diagnosed with S-PM between July 2007 and July 2019 were included in this study. The demographics, mutKRAS/mutBRAF status, overall survival (OS), and progression-free survival (PFS) of the patients were evaluated. The Kaplan-Meier method and log-rank test were used to estimate the difference in survival between groups. Results Among 142 patients, 68 (47.9%) showed mutKRAS and 42 (29.5%) showed mutBRAF. The median OS values were 8.4 and 34.3 months for patients with mutBRAF and BRAF wild-type, respectively (P < 0.01). However, KRAS status was not significantly associated with median OS (P = 0.76). Multivariate analysis revealed carcinoembryonic antigen, CRS, HIPEC, and mutBRAF as independent predictors for OS. Based on these findings, a nomogram was constructed. The C-index was 0.789 (95% confidence interval, 0.742-0.836), indicating good predictive ability of the model. Furthermore, the 1- and 2-year survival calibration plots showed good agreement between the predicted and actual OS rates. The area under curves of the 1- and 2-year survival predictions based on the nomogram were 0.807 and 0.682, respectively. Additionally, mutBRAF was significantly associated with lower PFS (P < 0.001). Conclusions mutBRAF is an independent prognostic risk factor for S-PM. The established nomogram predicted the OS of patients with CRC having S-PM with high accuracy, indicating its usefulness as a valuable prognostic tool for the designated patient cohort.
Collapse
Affiliation(s)
- Zhijie Wu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiusen Qin
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yuanxin Zhang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jian Luo
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Rui Luo
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Zonglu Cai
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Hui Wang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| |
Collapse
|
|
13
|
Cho WK, Yoo GS, Rim CH, Jeong JU, Chie EK, Ahn YC, Cho HM, Um JW, Suh YG, Chang AR, Lee JH. Differential Perspectives by Specialty on Oligometastatic Colorectal Cancer: A Korean Oligometastasis Working Group's Comparative Survey Study. Cancer Res Treat 2023; 55:1281-1290. [PMID: 37290481 PMCID: PMC10582548 DOI: 10.4143/crt.2023.479] [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: 03/20/2023] [Accepted: 06/05/2023] [Indexed: 06/10/2023] Open
Abstract
PURPOSE Despite numerous studies on the optimal treatments for oligometastatic disease (OMD), there is no established interdisciplinary consensus on its diagnosis or classification. This survey-based study aimed to analyze the differential opinions of colorectal surgeons and radiation oncologists regarding the definition and treatment of OMD from the colorectal primary. MATERIALS AND METHODS A total of 141 participants were included in this study, consisting of 63 radiation oncologists (44.7%) and 78 colorectal surgeons (55.3%). The survey consisted of 19 questions related to OMD, and the responses were analyzed using the chi-square test to determine statistical differences between the specialties. RESULTS The radiation oncologists chose "bone" more frequently compared to the colorectal surgeons (19.2% vs. 36.5%, p=0.022), while colorectal surgeons favored "peritoneal seeding" (26.9% vs. 9.5%, p=0.009). Regarding the number of metastatic tumors, 48.3% of colorectal surgeons responded that "irrelevant, if all metastatic lesions are amendable to local therapy", while only 21.8% of radiation oncologist chose same answer. When asked about molecular diagnosis, most surgeons (74.8%) said it was important, but only 35.8% of radiation oncologists agreed. CONCLUSION This study demonstrates that although radiation oncologists and colorectal surgeons agreed on a majority of aspects such as diagnostic imaging, biomarker, systemic therapy, and optimal timing of OMD, they also had quite different perspectives on several aspects of OMD. Understanding these differences is crucial to achieving multidisciplinary consensus on the definition and optimal management of OMD.
Collapse
Affiliation(s)
- Won Kyung Cho
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Gyu Sang Yoo
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Chai Hong Rim
- Department of Radiation Oncology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan,
Korea
| | - Jae-Uk Jeong
- Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun,
Korea
| | - Eui Kyu Chie
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul,
Korea
| | - Yong Chan Ahn
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Hyeon-Min Cho
- Department of Surgery, St. Vincent`s Hospital, College of Medicine, The Catholic University of Korea, Suwon,
Korea
| | - Jun Won Um
- Department of Surgery, Korea University Ansan Hospital, Korea University College of Medicine, Ansan,
Korea
| | - Yang-Gun Suh
- Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goyang,
Korea
| | - Ah Ram Chang
- Department of Radiation Oncology, Soonchunhyang University Seoul Hospital, Seoul,
Korea
| | - Jong Hoon Lee
- Department of Radiation Oncology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon,
Korea
| |
Collapse
|
|
14
|
Chang KJ, Kim DH, Lalani TK, Paroder V, Pickhardt PJ, Shaish H, Bates DDB. Radiologic T staging of colon cancer: renewed interest for clinical practice. Abdom Radiol (NY) 2023; 48:2874-2887. [PMID: 37277570 DOI: 10.1007/s00261-023-03904-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 03/27/2023] [Accepted: 03/28/2023] [Indexed: 06/07/2023]
Abstract
Radiologic imaging, especially MRI, has long been the mainstay for rectal cancer staging and patient selection for neoadjuvant therapy prior to surgical resection. In contrast, colonoscopy and CT have been the standard for colon cancer diagnosis and metastasis staging with T and N staging often performed at the time of surgical resection. With recent clinical trials exploring the expansion of the use of neoadjuvant therapy beyond the anorectum to the remainder of the colon, the current and future state of colon cancer treatment is evolving with a renewed interest in evaluating the role radiology may play in the primary T staging of colon cancer. The performance of CT, CT colonography, MRI, and FDG PET-CT for colon cancer staging will be reviewed. N staging will also be briefly discussed. It is expected that accurate radiologic T staging will significantly impact future clinical decisions regarding the neoadjuvant versus surgical management of colon cancer.
Collapse
Affiliation(s)
- Kevin J Chang
- Department of Radiology, Boston University Medical Center, Radiology- FGH 4001, 820 Harrison Ave, Boston, MA, 02118, USA.
| | - David H Kim
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Tasneem K Lalani
- Diagnostic Radiology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Viktoriya Paroder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Perry J Pickhardt
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Hiram Shaish
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - David D B Bates
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| |
Collapse
|
|
15
|
Wang J, Tao Z, Wang B, Xie Y, Wang Y, Li B, Cao J, Qiao X, Qin D, Zhong S, Hu X. Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma. Front Oncol 2023; 13:1152681. [PMID: 37333810 PMCID: PMC10272849 DOI: 10.3389/fonc.2023.1152681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 05/19/2023] [Indexed: 06/20/2023] Open
Abstract
Introduction Cuproptosis is a novel copper-dependent regulatory cell death (RCD), which is closely related to the occurrence and development of multiple cancers. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of colon adenocarcinoma (COAD) remains unclear. Methods Transcriptome, somatic mutation, somatic copy number alteration and the corresponding clinicopathological data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). Difference, survival and correlation analyses were conducted to evaluate the characteristics of CRGs in COAD patients. Consensus unsupervised clustering analysis of CRGs expression profile was used to classify patients into different cuproptosis molecular and gene subtypes. TME characteristics of different molecular subtypes were investigated by using Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA). Next, CRG Risk scoring system was constructed by applying logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis and multivariate cox analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were used to exam the expression of key Risk scoring genes. Results Our study indicated that CRGs had relatively common genetic and transcriptional variations in COAD tissues. We identified three cuproptosis molecular subtypes and three gene subtypes based on CRGs expression profile and prognostic differentially expressed genes (DEGs) expression profile, and found that changes in multilayer CRGs were closely related to the clinical characteristics, overall survival (OS), different signaling pathways, and immune cell infiltration of TME. CRG Risk scoring system was constructed according to the expression of 7 key cuproptosis-related risk genes (GLS, NOX1, HOXC6, TNNT1, GLS, HOXC6 and PLA2G12B). RT-qPCR and IHC indicated that the expression of GLS, NOX1, HOXC6, TNNT1 and PLA2G12B were up-regulated in tumor tissues, compared with those in normal tissues, and all of GLS, HOXC6, NOX1 and PLA2G12B were closely related with patient survival. In addition, high CRG risk scores were significantly associated with high microsatellite instability (MSI-H), tumor mutation burden (TMB), cancer stem cell (CSC) indices, stromal and immune scores in TME, drug susceptibility, as well as patient survival. Finally, a highly accurate nomogram was constructed to promote the clinical application of the CRG Risk scoring system. Discussion Our comprehensive analysis showed that CRGs were greatly associated with TME, clinicopathological characteristics, and prognosis of patient with COAD. These findings may promote our understanding of CRGs in COAD, providing new insights for physicians to predict prognosis and develop more precise and individualized therapy strategies.
Collapse
Affiliation(s)
- Jinyan Wang
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Zhonghua Tao
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Biyun Wang
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yizhao Xie
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ye Wang
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bin Li
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jianing Cao
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaosu Qiao
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Dongmei Qin
- Department of Pathology, Nanjing Jiangning Hospital, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Shanliang Zhong
- Center of Clinical Laboratory Science, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Xichun Hu
- Department of Breast and Urologic Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, China
| |
Collapse
|
|
16
|
Tsubaki M, Takeda T, Matsuda T, Kishimoto K, Takefuji H, Taniwaki Y, Ueda M, Hoshida T, Tanabe K, Nishida S. Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy. Cancer Cell Int 2023; 23:73. [PMID: 37069612 PMCID: PMC10108455 DOI: 10.1186/s12935-023-02884-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/01/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND KRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice. METHODS Cell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test. RESULTS In this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo. CONCLUSION Therefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.
Collapse
Affiliation(s)
- Masanobu Tsubaki
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Tomoya Takeda
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Takuya Matsuda
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Kana Kishimoto
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Honoka Takefuji
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Yuzuki Taniwaki
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Misa Ueda
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
| | - Tadafumi Hoshida
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan
- Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan
| | - Kazufumi Tanabe
- Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan
| | - Shozo Nishida
- Division of Pharmacotherapy, Kindai University Faculty of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.
| |
Collapse
|
|
17
|
Lian SY, Tan LX, Liu XZ, Yang LJ, Li NN, Feng Q, Wang P, Wang Y, Qiao DB, Zhou LX, Sun TT, Wang L, Wu AW, Li ZW. KRAS, NRAS, BRAF signatures, and MMR status in colorectal cancer patients in North China. Medicine (Baltimore) 2023; 102:e33115. [PMID: 36862900 PMCID: PMC9981427 DOI: 10.1097/md.0000000000033115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/08/2023] [Indexed: 03/04/2023] Open
Abstract
We assessed the clinicopathological features and prognostic values of KRAS, NRAS, BRAF, and DNA mismatch repair status in colorectal cancer (CRC) to provide real-world data in developing countries. We enrolled 369 CRC patients and analyzed the correlation between RAS/BRAF mutation, mismatch repair status with clinicopathological features, and their prognostic roles. The mutation frequencies of KRAS, NRAS, and BRAF were 41.7%, 1.6%, and 3.8%, respectively. KRAS mutations and deficient mismatch repair (dMMR) status were associated with right-sided tumors, aggressive biological behaviors, and poor differentiation. BRAF (V600E) mutations are associated with well-differentiated and lymphovascular invasion. The dMMR status predominated in young and middle-aged patients and tumor node metastasis stage II patients. dMMR status predicted longer overall survival in all CRC patients. KRAS mutations indicated inferior overall survival in patients with CRC stage IV. Our study showed that KRAS mutations and dMMR status could be applied to CRC patients with different clinicopathological features.
Collapse
Affiliation(s)
- Shen-Yi Lian
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Lu-Xin Tan
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xin-Zhi Liu
- Department of Colorectal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Lu-Jing Yang
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ning-Ning Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Qing Feng
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ping Wang
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yue Wang
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Dong-Bo Qiao
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Li-Xin Zhou
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ting-Ting Sun
- Department of Colorectal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Lin Wang
- Department of Colorectal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ai-Wen Wu
- Department of Colorectal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhong-Wu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| |
Collapse
|
|
18
|
Boutin M, Gill S. Controversies and management of deficient mismatch repair gastrointestinal cancers in the neoadjuvant setting. Ther Adv Med Oncol 2023; 15:17588359231162577. [PMID: 37007634 PMCID: PMC10064478 DOI: 10.1177/17588359231162577] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 02/17/2023] [Indexed: 03/31/2023] Open
Abstract
High microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) phenotype is a distinct molecular signature across gastrointestinal cancers characterized by high tumor mutational burden and high neoantigen load. Tumors harboring dMMR are highly immunogenic and heavily infiltrated by immune cells; consequently, they are uniquely vulnerable to therapeutic strategies enhancing immune antitumor response such as checkpoint inhibitors. The MSI-H/dMMR phenotype arose as a powerful predictor of response to immune checkpoint inhibitors with evidence supporting significantly improved outcomes in the metastatic setting. On the other hand, the genomic instability characteristic of MSI-H/dMMR tumors appears to be associated with decreased sensitivity to chemotherapy, and the benefits of standard adjuvant or neoadjuvant chemotherapy approaches in this subtype are being increasingly questioned. Here, we review the prognostic and predictive impact of MMR status in localized gastric and colorectal cancers, and highlight the emerging clinical data incorporating checkpoint inhibitors in the neoadjuvant setting.
Collapse
Affiliation(s)
- Mélina Boutin
- BC Cancer, University of British Columbia, Vancouver, BC, Canada
- Centre Intégré de Cancérologie de la Montérégie-Centre, Université de Sherbrooke, Greenfield Park, QC, Canada
| | | |
Collapse
|
|
19
|
Han F, Cheng C, Xu Q, Chen J, Yang Z, Liu J. DEPDC1B promotes colorectal cancer via facilitating cell proliferation and migration while inhibiting apoptosis. Cell Cycle 2023; 22:131-143. [PMID: 36016512 PMCID: PMC9769448 DOI: 10.1080/15384101.2022.2110439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/27/2022] [Accepted: 08/03/2022] [Indexed: 01/20/2023] Open
Abstract
Colorectal cancer (CRC) is a common malignant tumor with strong invasiveness. Given the reported involvement of DEP domain-containing protein 1B (DEPDC1B) in the progression of some cancers, its role in CRC was explored in this study. DEPDC1B expression in CRC was assessed based on database and tissue microarray (TMA). In addition, the knockdown and overexpression of DEPDC1B in CRC cell lines were constructed using small hairpin RNA (shRNA) interference. The biological function of DEPDC1B in CRC was evaluated in vitro and in vivo through loss/gain-of-function assays. The results demonstrated that DEPDC1B was highly expressed in CRC. Furthermore, DEPDC1B had the ability to promote CRC proliferation and migration coupled by cell apoptosis. In vivo results showed that DEPDC1B knockdown significantly inhibited the growth of xenograft tumors. Additionally, the results of antibody array indicated increased apoptosis-promoting proteins and decreased apoptosis-inhibiting proteins in DEPDC1B-knockdown CRC cells. In conclusion, DEPDC1B played a key driver role in CRC progression, and inhibition of its expression may be a potential target for precision medicine in CRC.
Collapse
Affiliation(s)
- Fei Han
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chao Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qianqian Xu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jisong Chen
- The Second College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei, China
| | - Zhaohui Yang
- Department of Rehabilitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jun Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
20
|
Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM. Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment. Eur J Cancer 2022; 175:136-157. [PMID: 36115290 DOI: 10.1016/j.ejca.2022.07.020] [Citation(s) in RCA: 130] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/08/2022] [Accepted: 07/17/2022] [Indexed: 11/03/2022]
Abstract
Microsatellite unstable (MSI) colorectal cancers (CRCs) are due to DNA mismatch repair (MMR) deficiency and occurs in15% of non-metastatic diseases and 5% in the metastatic setting. Nearly 30% of MSI CRCs occur in a context of constitutional mutation of the MMR system (Lynch syndrome). Others are sporadic cancers linked to a hypermethylation of the MLH-1 promoter. The pathogenic alterations of MMR genes lead to the accumulation of frequent somatic mutational events and these tumours arbour a high antigen burden and are highly infiltrated with cytotoxic T-cell lymphocytes. Microsatellite instability/DNA mismatch repair deficiency (MSI/dMMR) status has prognostic and predictive implications in non-metastatic and metastatic CRCs. The prognostic value of MSI status in non-metastatic CRCs has been studied extensively, yet the data are more limited for its predictive value in terms of adjuvant chemotherapy efficacy. In both cases (metastatic and non-metastatic settings) treatment with immune check-point inhibitors (ICIs) have shown a remarkable effectiveness in the context of MSI/dMMR status. Indeed, recent data from prospective cohorts and randomised trials have shown a dramatical improvement of survival with immunotherapy (programmed death-ligand 1 [PD-(L)1] cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] blockage) in metastatic or non-metastatic MSI/dMMR CRC. In this review we report and discuss how and for whom to test for the MSI/dMMR phenotype, as well as the prognostic value of this phenotype and the new treatment recommendations options for this unique CRC population. Despite their efficacy, primary and secondary resistance to immune checkpoint inhibitors (ICIs) are observed in more than 50% MSI-H/dMMR CRC patients and in the future how to identify these patients and to overcome resistance will be an important challenge.
Collapse
Affiliation(s)
- Julien Taieb
- Université Paris-Cité, Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, SIRIC CARPEM, Paris, France.
| | - Magali Svrcek
- Sorbonne Université, Department of Pathology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer et SIRIC CURAMUS, Centre de Recherche Saint Antoine, Paris, France
| | - Romain Cohen
- Sorbonne Université, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer et SIRIC CURAMUS, Centre de Recherche Saint Antoine, Paris, France
| | - Debora Basile
- Department of Medical Oncology, San Giovanni di Dio Hospital, 88900 Crotone, Italy
| | - David Tougeron
- Université de Poitiers, Department of Gastroenterology and Hepatology, Poitiers University Hospital, Poitiers, France
| | - Jean-Marc Phelip
- University Hospital of Saint Etienne, Saint Etienne, France; Unité HESPER EA-7425 Université Jean Monnet/Claude Bernard Lyon 1, France
| |
Collapse
|
|
21
|
Neoadjuvant Chemotherapy Followed by Radiofrequency Ablation May Be a New Treatment Modality for Colorectal Liver Metastasis: A Propensity Score Matching Comparative Study. Cancers (Basel) 2022; 14:cancers14215320. [PMID: 36358739 PMCID: PMC9654097 DOI: 10.3390/cancers14215320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/15/2022] [Accepted: 10/27/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Most colorectal liver metastases (CRLM) are not candidates for liver resection. Radiofrequency ablation (RFA) plays a key role in selected CRLM patients. Neoadjuvant chemotherapy (NAC) followed by liver resection has been widely used for resectable CRLM. Whether NAC followed by radiofrequency ablation (RFA) can achieve a similar prognosis to NAC followed by hepatectomy remains is unclear. The present study aimed to provide a new treatment modality for CRLM patients. Methods: This comparative retrospective research selected CRLM patients from 2009 to 2022. They were divided into NAC + RFA group and NAC + hepatectomy group. The propensity score matching (PSM) was used to reduce bias. We used multivariate cox proportional hazards regression analysis to explore independent factors affecting prognosis. The primary study endpoint was the difference in the progression-free survival (PFS) between the two groups. Results: A total of 190 locally curable CRLM patients were in line with the inclusion criteria. A slight bias was detected in the comparison of basic clinical characteristics between the two groups. RFA showed a significant advantage in the length of hospital stay (median; 2 days vs. 7 days; p < 0.001). The 1- and 3-year PFS in the liver resection and the RFA groups was 57.4% vs. 86.9% (p < 0.001) and 38.8% vs. 55.3% (p = 0.035), respectively. The 1-year and 3-year OS in the liver resection and RFA groups was 100% vs. 96.7% (p = 0.191) and 73.8% vs. 73.6% (p = 0.660), respectively. Conclusions: NAC followed by RFA has rapid postoperative recovery, fewer complications, and better prognosis.
Collapse
|
|
22
|
Zhang Y, Chen Y, Huang J, Wu X, Tang R, Huang Q, Xu Y, Peng X, Fu K, Xiao S. Mucinous histology is associated with poor prognosis in locally advanced colorectal adenocarcinoma treated with postoperative first-line adjuvant chemotherapy: A systematic review and meta-analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:2075-2081. [PMID: 35768312 DOI: 10.1016/j.ejso.2022.06.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/04/2022] [Accepted: 06/19/2022] [Indexed: 12/27/2022]
Abstract
PURPOSE Postoperative adjuvant chemotherapy followed surgery is the standard management for localized advanced colorectal carcinoma (CRC). Mucinous adenocarcinoma (MAC) is a peculiar histological subtype of CRC, but the prognosis of MAC patients is controversial. The objective of this study is to assess the implication of MAC in survival of patients treated with surgery and firs-line adjuvant chemotherapy. METHODS Studies describing outcomes for advanced MAC and non-specific adenocarcinoma (AC) of CRC patients treated with first-line postoperative adjuvant chemotherapy followed surgery were searched in PubMed, Embase, Medline, EBSCO, Wiley, and Cochrane Library (January 1963-August 2021). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS) for MAC to AC were extracted. Random-effects model was used for calculating the pooled HRs and 95% confidence interval (CI). RESULTS This meta-analysis is comprised of 8 studies involving a total of 124,303 CRC patients treated with first-line adjuvant chemotherapy followed surgery. The pooled HR for MAC was 1.23 (95% CI, 1.07-1.41, p < 0.01, I2 = 80%), and the DFS (HR, 2.95, 95% CI, 1.22-7.14) of MAC patients were significantly poorer than AC patients. Similar results were also observed in stage III and FOLFOX regimen subgroups. CONCLUSION MAC was a risk factor for prognosis of localized advanced CRC patients treated with postoperative first-line adjuvant chemotherapy. Thus, the role of first-line adjuvant chemotherapy regimens should be further studied in these MAC patients.
Collapse
Affiliation(s)
- Yiwei Zhang
- The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yuqiao Chen
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Jia Huang
- The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaofeng Wu
- The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Rong Tang
- The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Qiulin Huang
- The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yunhua Xu
- The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiuda Peng
- The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Kai Fu
- Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Shuai Xiao
- The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| |
Collapse
|
|
23
|
Pelullo M, Zema S, De Carolis M, Cialfi S, Giuli MV, Palermo R, Capalbo C, Giannini G, Screpanti I, Checquolo S, Bellavia D. 5FU/Oxaliplatin-Induced Jagged1 Cleavage Counteracts Apoptosis Induction in Colorectal Cancer: A Novel Mechanism of Intrinsic Drug Resistance. Front Oncol 2022; 12:918763. [PMID: 35847908 PMCID: PMC9283835 DOI: 10.3389/fonc.2022.918763] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/02/2022] [Indexed: 11/23/2022] Open
Abstract
Colorectal cancer (CRC) is characterized by early metastasis, resistance to anti-cancer therapy, and high mortality rate. Despite considerable progress in the development of new treatment options that improved survival benefits in patients with early-stage or advanced CRC, many patients relapse due to the activation of intrinsic or acquired chemoresistance mechanisms. Recently, we reported novel findings about the role of Jagged1 in CRC tumors with Kras signatures. We showed that Jagged1 is a novel proteolytic target of Kras signaling, which induces Jagged1 processing/activation resulting in Jag1-ICD release, which favors tumor development in vivo, through a non-canonical mechanism. Herein, we demonstrate that OXP and 5FU cause a strong accumulation of Jag1-ICD oncogene, through ERK1/2 activation, unveiling a surviving subpopulation with an enforced Jag1-ICD expression, presenting the ability to counteract OXP/5FU-induced apoptosis. Remarkably, we also clarify the clinical ineffectiveness of γ-secretase inhibitors (GSIs) in metastatic CRC (mCRC) patients. Indeed, we show that GSI compounds trigger Jag1-ICD release, which promotes cellular growth and EMT processes, functioning as tumor-promoting agents in CRC cells overexpressing Jagged1. We finally demonstrate that Jagged1 silencing in OXP- or 5FU-resistant subpopulations is enough to restore the sensitivity to chemotherapy, confirming that drug sensitivity/resistance is Jag1-ICD-dependent, suggesting Jagged1 as a molecular predictive marker for the outcome of chemotherapy.
Collapse
Affiliation(s)
- Maria Pelullo
- CLN2S - Center for Life Nano- & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy
| | - Sabrina Zema
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Mariangela De Carolis
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Samantha Cialfi
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Maria Valeria Giuli
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Rocco Palermo
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Carlo Capalbo
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Giuseppe Giannini
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Isabella Screpanti
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy
- *Correspondence: Saula Checquolo, ; Diana Bellavia,
| | - Diana Bellavia
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
- *Correspondence: Saula Checquolo, ; Diana Bellavia,
| |
Collapse
|
|
24
|
Glaire MA, Ryan NAJ, Ijsselsteijn ME, Kedzierska K, Obolenski S, Ali R, Crosbie EJ, Bosse T, de Miranda NFCC, Church DN. Discordant prognosis of mismatch repair deficiency in colorectal and endometrial cancer reflects variation in antitumour immune response and immune escape. J Pathol 2022; 257:340-351. [PMID: 35262923 PMCID: PMC9322587 DOI: 10.1002/path.5894] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 02/01/2022] [Accepted: 03/07/2022] [Indexed: 12/04/2022]
Abstract
Defective DNA mismatch repair (dMMR) causes elevated tumour mutational burden (TMB) and microsatellite instability (MSI) in multiple cancer types. dMMR/MSI colorectal cancers (CRCs) have enhanced T-cell infiltrate and favourable outcome; however, this association has not been reliably detected in other tumour types, including endometrial cancer (EC). We sought to confirm this and explore the underpinning mechanisms. We first meta-analysed CRC and EC trials that have examined the prognostic value of dMMR/MSI and confirmed that dMMR/MSI predicts better prognosis in CRC, but not EC, with statistically significant variation between cancers (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.54-0.73 versus HR = 1.15, 95% CI = 0.72-1.58; PINT = 0.02). Next, we studied intratumoural immune infiltrate in CRCs and ECs of defined MMR status and found that while dMMR was associated with increased density of tumour-infiltrating CD3+ and CD8+ T-cells in both cancer types, the increases were substantially greater in CRC and significant only in this group (PINT = 4.3e-04 and 7.3e-03, respectively). Analysis of CRC and EC from the independent Cancer Genome Atlas (TCGA) series revealed similar variation and significant interactions in proportions of tumour-infiltrating lymphocytes, CD8+ , CD4+ , NK cells and immune checkpoint expression, confirming a more vigorous immune response to dMMR/MSI in CRC than EC. Agnostic analysis identified the IFNγ pathway activity as strongly upregulated by dMMR/MSI in CRC, but downregulated in EC by frequent JAK1 mutations, the impact of which on IFNγ response was confirmed by functional analyses. Collectively, our results confirm the discordant prognosis of dMMR/MSI in CRC and EC and suggest that this relates to differences in intratumoural immune infiltrate and tumour genome. Our study underscores the need for tissue-specific analysis of cancer biomarkers and may help inform immunotherapy use. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Mark A Glaire
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Neil AJ Ryan
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of Manchester, St Mary's HospitalManchesterUK
- Division of Evolution and Genomic Medicine, Faculty of Biology, Medicine and HealthUniversity of Manchester, St. Mary's HospitalManchesterUK
- The Academic Women's Health Unit, Translational Health SciencesBristol Medical School, University of BristolBristolUK
| | | | - Katarzyna Kedzierska
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Sofia Obolenski
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Reem Ali
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Emma J Crosbie
- Division of Cancer Sciences, Faculty of Biology, Medicine and HealthUniversity of Manchester, St Mary's HospitalManchesterUK
- Department of Obstetrics and GynaecologySt Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science CentreManchesterUK
| | - Tjalling Bosse
- Department of PathologyLeiden University Medical CenterLeidenThe Netherlands
| | - Noel FCC de Miranda
- Department of PathologyLeiden University Medical CenterLeidenThe Netherlands
| | - David N Church
- Cancer Genomics and Immunology Group, Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
- Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals Foundation NHS TrustOxfordUK
- Oxford NIHR Comprehensive Biomedical Research Centre, Oxford University Hospitals NHS Foundation TrustOxfordUK
| |
Collapse
|
|
25
|
Malla M, Parikh AR. Evolving Role of Circulating Tumor DNA and Emerging Targeted Therapy in Colorectal Cancer. Hematol Oncol Clin North Am 2022; 36:583-601. [DOI: 10.1016/j.hoc.2022.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
26
|
Kishigami F, Tanaka Y, Yamamoto Y, Ueno T, Kojima S, Sato K, Inoue S, Sugaya S, Ishihara S, Mano H, Kawazu M. Exploration of predictive biomarkers for postoperative recurrence of stage II/III colorectal cancer using genomic sequencing. Cancer Med 2022; 11:3457-3470. [PMID: 35343095 PMCID: PMC9487878 DOI: 10.1002/cam4.4710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/24/2022] [Accepted: 03/15/2022] [Indexed: 11/28/2022] Open
Abstract
Postoperative recurrence of colorectal cancer (CRC) eventually leads to therapeutic failure; therefore, treatment strategies based on accurate prediction of recurrence are urgently required. To identify biomarkers that can predict treatment outcomes, we compared the mutational profiles of surgically resected specimens from patients with recurrent cancer with those from patients with non‐recurrent cancer. Target sequencing, whole‐exome sequencing (WES), or whole‐genome sequencing (WGS) was performed on 89 and 58 tumors from recurrent and non‐recurrent cases, respectively. WGS revealed the driver mutations that were not detected with target sequencing or WES, including the structural variations affecting ZFP36L2. Loss of function of ZFP36L2 was frequently observed in primary tumors from recurrent cases. Furthermore, the recurrence‐free survival of patients with loss of function of ZFP36L2 was significantly shorter relative to patients with no loss of ZFP36L2 function. In summary, the study demonstrated that detailed genomic analysis could help improve precision medicine for CRC.
Collapse
Affiliation(s)
- Fumishi Kishigami
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.,Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Yosuke Tanaka
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoko Yamamoto
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Toshihide Ueno
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Shinya Kojima
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazuhito Sato
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Saori Sugaya
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Mano
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Masahito Kawazu
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| |
Collapse
|
|
27
|
Rodriquenz MG, Ciardiello D, Latiano TP, Maiorano BA, Martinelli E, Silvestris N, Ciardiello F, Maiello E. Exploring biological heterogeneity and implications on novel treatment paradigm in BRAF-mutant metastatic colorectal cancer. Crit Rev Oncol Hematol 2022; 173:103657. [PMID: 35337969 DOI: 10.1016/j.critrevonc.2022.103657] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/12/2022] [Accepted: 03/18/2022] [Indexed: 12/19/2022] Open
Abstract
Approximatively 8-15% of patients with metastatic colorectal cancer (mCRC) harbor mutation in BRAF gene. Recent advances in molecular biology enabled a better knowledge of the molecular heterogeneity within BRAF mutant (BRAFMT) CRCs, including high rate of overlapping with MSI-H status and detection of non-V600E mutations related to more favorable behavior. Treatment armamentarium has been rapidly growing in this subgroup and includes targeted combinations and immunotherapy for concomitant MSI-H patients, thereby making BRAFMT mCRC an innovative model for precision oncology. Nevertheless, duration of responses to targeted strategies remains unsatisfactory due to the development of secondary resistance, which is currently the field of major clinical research on BRAFMT mCRC. This review explores the molecular, clinical and therapeutic landscape of BRAFMT mCRC as well as an update on current treatment strategies and future perspectives in light of the heterogeneity of BRAF-mutated disease. Furthermore, a novel treatment algorithm for BRAFMT mCRC will be proposed.
Collapse
Affiliation(s)
- Maria Grazia Rodriquenz
- Oncology Unit, Foundation Casa Sollievo della Sofferenza IRCCS, 71013 San Giovanni Rotondo, Italy.
| | - Davide Ciardiello
- Oncology Unit, Foundation Casa Sollievo della Sofferenza IRCCS, 71013 San Giovanni Rotondo, Italy; Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Tiziana Pia Latiano
- Oncology Unit, Foundation Casa Sollievo della Sofferenza IRCCS, 71013 San Giovanni Rotondo, Italy
| | - Brigida Anna Maiorano
- Oncology Unit, Foundation Casa Sollievo della Sofferenza IRCCS, 71013 San Giovanni Rotondo, Italy; Medical Oncology Unit, Comprehensive Cancer Center, Foundation A. Gemelli Policlinic IRCCS, 00168 Rome, Italy
| | - Erika Martinelli
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy
| | - Fortunato Ciardiello
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy
| | - Evaristo Maiello
- Oncology Unit, Foundation Casa Sollievo della Sofferenza IRCCS, 71013 San Giovanni Rotondo, Italy
| |
Collapse
|
|
28
|
Larsen SG, Goscinski MA, Dueland S, Steigen SE, Hofsli E, Torgunrud A, Lund-Iversen M, Dagenborg VJ, Flatmark K, Sorbye H. Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients. Br J Cancer 2022; 126:726-735. [PMID: 34887523 PMCID: PMC8888568 DOI: 10.1038/s41416-021-01620-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. METHODS In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. RESULTS In total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis. CONCLUSIONS PM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.
Collapse
Affiliation(s)
- S. G. Larsen
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - M. A. Goscinski
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - S. Dueland
- grid.55325.340000 0004 0389 8485Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - S. E. Steigen
- grid.412244.50000 0004 4689 5540Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway
| | - E. Hofsli
- grid.52522.320000 0004 0627 3560The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway ,grid.5947.f0000 0001 1516 2393Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - A. Torgunrud
- grid.5947.f0000 0001 1516 2393Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - M. Lund-Iversen
- grid.5510.10000 0004 1936 8921Department of Clinical Pathology, University of Oslo, Oslo, Norway
| | - V. J. Dagenborg
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - K. Flatmark
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway ,grid.55325.340000 0004 0389 8485Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - H. Sorbye
- grid.7914.b0000 0004 1936 7443Department of Oncology, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
| |
Collapse
|
|
29
|
Lu L, Przybylla R, Shang Y, Dai M, Krohn M, Krämer OH, Mullins CS, Linnebacher M. Microsatellite Status and IκBα Expression Levels Predict Sensitivity to Pharmaceutical Curcumin in Colorectal Cancer Cells. Cancers (Basel) 2022; 14:1032. [PMID: 35205780 PMCID: PMC8870219 DOI: 10.3390/cancers14041032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 02/06/2023] Open
Abstract
Clinical utilization of curcumin in colorectal cancer (CRC) was revived as a result of the development of novel curcumin formulations with improved bioavailability. Additionally, identification of biomarkers for curcumin sensitivity would also promote successful clinical applications. Here, we wanted to identify such biomarkers in order to establish a predictive model for curcumin sensitivity. Thirty-two low-passage CRC cell lines with specified tumor characteristics were included. Curcumin suppressed cell proliferation, yet sensitivity levels were distinct. Most curcumin-sensitive CRC cell lines were microsatellite stable and expressed high levels of IκBα. The predictive capacity of this biomarker combination possessed a statistical significance of 72% probability to distinguish correctly between curcumin-sensitive and -resistant CRC cell lines. Detailed functional analyses were performed with three sensitive and three resistant CRC cell lines. As curcumin's mode of action, inhibition of NF-κB p65 activation via IκBα was identified. In consequence, we hypothesize that novel curcumin formulations-either alone or, more likely, in combination with standard therapeutics-can be expected to prove clinically beneficial for CRC patients with high IκBα expression levels.
Collapse
Affiliation(s)
- Lili Lu
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany; (L.L.); (R.P.); (Y.S.); (M.D.); (M.K.); (C.S.M.)
| | - Randy Przybylla
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany; (L.L.); (R.P.); (Y.S.); (M.D.); (M.K.); (C.S.M.)
| | - Yuru Shang
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany; (L.L.); (R.P.); (Y.S.); (M.D.); (M.K.); (C.S.M.)
| | - Meng Dai
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany; (L.L.); (R.P.); (Y.S.); (M.D.); (M.K.); (C.S.M.)
| | - Mathias Krohn
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany; (L.L.); (R.P.); (Y.S.); (M.D.); (M.K.); (C.S.M.)
| | | | - Christina Susanne Mullins
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany; (L.L.); (R.P.); (Y.S.); (M.D.); (M.K.); (C.S.M.)
| | - Michael Linnebacher
- Department of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany; (L.L.); (R.P.); (Y.S.); (M.D.); (M.K.); (C.S.M.)
| |
Collapse
|
|
30
|
Ren J, Xu L, Zhou S, Ouyang J, You W, Sheng N, Yan L, Peng D, Xie L, Wang Z. Clinicopathological Features Combined With Immune Infiltration Could Well Distinguish Outcomes in Stage II and Stage III Colorectal Cancer: A Retrospective Study. Front Oncol 2021; 11:776997. [PMID: 34926285 PMCID: PMC8678133 DOI: 10.3389/fonc.2021.776997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/15/2021] [Indexed: 01/01/2023] Open
Abstract
Background The Immunoscore predicts prognosis in patients with colorectal cancer (CRC). However, a few studies have incorporated the Immunoscore into the construction of comprehensive prognostic models in CRC, especially stage II CRC. We aimed to construct and validate multidimensional models integrating clinicopathological characteristics and the Immunoscore to predict the prognosis of patients with stage II–III CRC. Methods Patients (n = 254) diagnosed with stage II–III CRC from 2009 to 2016 were used to generate Cox models for predicting disease-free survival (DFS) and overall survival (OS). The variables included basic clinical indicators, blood inflammatory markers, preoperative tumor biomarkers, mismatch repair status, and the Immunoscore (CD3+ and CD8+ T-cell densities). Univariate and multivariate Cox proportional regressions were used to construct the prognostic models for DFS and OS. We validated the predictive accuracy and ability of the prognostic models in our cohort of 254 patients. Results We constructed two predictive prognostic models with C-index values of 0.6941 for DFS and 0.7138 for OS in patients with stage II–III CRC. The Immunoscore was the most informative predictor of DFS (11.92%), followed by pN stage, carcinoembryonic antigen (CEA), and vascular infiltration. For OS, the Immunoscore was the most informative predictor (8.59%), followed by pN stage, age, CA125, and CEA. Based on the prognostic models, nomograms were developed to predict the 3- and 5-year DFS and OS rates. Patients were divided into three risk groups (low, intermediate, and high) according to the risk scores obtained from the nomogram, and significant differences were observed in the recurrence and survival of the different risk groups (p < 0.0001). Calibration curve and time-dependent receiver operating characteristic (ROC) analysis showed good accuracy of our models. Furthermore, the decision curve analysis indicated that our nomograms had better net benefit than pathological TNM (pTNM) stage within a wide threshold probability. Especially, we developed a website based on our prognostic models to predict the risks of recurrence and death of patients with stage II–III CRC. Conclusions Multidimensional models including the clinicopathological characteristics and the Immunoscore were constructed and validated, with good accuracy and convenience, to evaluate the risks of recurrence and death of stage II–III CRC patients.
Collapse
Affiliation(s)
- Jiazi Ren
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Linfeng Xu
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.,School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Siyu Zhou
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jian Ouyang
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Weiqiang You
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Nengquan Sheng
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Li Yan
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Du Peng
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Xie
- Shanghai Center for Bioinformation Technology, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Zhigang Wang
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| |
Collapse
|
|
31
|
Calvo-López T, Paz-Cabezas M, Llovet P, Ibañez MD, Sastre J, Alonso-Orduña V, Viéitez JM, Yubero A, Vera R, Asensio-Martínez E, Garcia-Alfonso P, Aranda E, Diaz-Rubio E, Perez-Villamil B. Association of miR-21 and miR-335 to microsatellite instability and prognosis in stage III colorectal cancer. Cancer Biomark 2021; 34:201-210. [PMID: 34958006 DOI: 10.3233/cbm-210353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND MicroRNAs (miRs) are frequently altered in colorectal cancer (CRC) and can be used as prognostic factors. OBJECTIVE To confirm in stage III CRC patients a reported miR signature that was associated to the presence of metastatic disease. To correlate miR expression with microsatellite instability (MSI) and mutations in RAS and BRAF. METHODS miR-21, miR-135a, miR-206, miR-335 and miR-Let-7a expression was analyzed by RT-qPCR in 150 patients out of the 329 patients used to analyze MSI and RAS and BRAF mutations. Association with disease free survival (DFS) and overall survival (OS) was analyzed. Data was confirmed by a multivariate analysis. RESULTS MiR-21 high expression (p= 0.034) and miR-335 low expression (p= 0.0061) were significantly associated with MSI-H. A positive trend (p= 0.0624) between miR-135a high expression and RAS mutations was found. Lower miR-21 expression levels are associated with DFS (HR = 2.654, 95% CI: 1.066-6.605, p= 0.036) and a trend with OS (HR = 2.419, 95% CI: 0.749-7.815, p= 0.140). MiR-21 high expression significantly improves DFS of the poor prognosis group (T4 or N2) (p= 0.03). CONCLUSIONS Association of increased expression of miR-21 and better prognosis in the poor prognostic group may be of interest and could be explored in future prospective clinical trials.
Collapse
Affiliation(s)
- Tania Calvo-López
- Genomics and Microarrays Lab, Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Mateo Paz-Cabezas
- Genomics and Microarrays Lab, Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Patricia Llovet
- Genomics and Microarrays Lab, Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Maria Dolores Ibañez
- Genomics and Microarrays Lab, Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Javier Sastre
- Genomics and Microarrays Lab, Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Vicente Alonso-Orduña
- Hospital Universitario Miguel Servet, Instituto de Investigacion Sanitaria de Aragon (IISA), Zaragoza, Spain
| | - J Ma Viéitez
- Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Alfonso Yubero
- Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain
| | - Ruth Vera
- Complejo Hospitalario de Navarra, Pamplona, Spain
| | | | | | - Enrique Aranda
- IMIBIC, CIBERONC, ISCIII, Hospital Universitario Reina Sofia, Cordoba, Spain
| | - Eduardo Diaz-Rubio
- Genomics and Microarrays Lab, Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| | - Beatriz Perez-Villamil
- Genomics and Microarrays Lab, Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clinico San Carlos, Madrid, Spain
| |
Collapse
|
|
32
|
Rasool M, Carracedo A, Sibiany A, Al-Sayes F, Karim S, Haque A, Natesan Pushparaj P, Asif M, Achakzai NM. Discovery of a novel and a rare Kristen rat sarcoma viral oncogene homolog (KRAS) gene mutation in colorectal cancer patients. Bioengineered 2021; 12:5099-5109. [PMID: 34369256 PMCID: PMC8806922 DOI: 10.1080/21655979.2021.1960715] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most important causes of morbidity and mortality in the developed world and is gradually more frequent in the developing world including Saudi Arabia. According to the Saudi Cancer Registry report 2015, CRC is the most common cancer in men (14.9%) and the second most prevalent cancer. Oncogenic mutations in the KRAS gene play a central role in tumorigenesis and are mutated in 30-40% of all CRC patients. To explore the prevalence of KRAS gene mutations in the Saudi population, we collected 80 CRC tumor tissues and sequenced the KRAS gene using automated sequencing technologies. The chromatograms presented mutations in 26 patients (32.5%) in four different codons, that is, 12, 13, 17, and 31. Most of the mutations were identified in codon 12 in 16 patients (61.5% of all mutations). We identified a novel mutation c.51 G>A in codon 17, where serine was substituted by arginine (S17R) in four patients. We also identified a very rare mutation, c.91 G>A, in which glutamic acid was replaced by lysine (E31K) in three patients. In conclusion, our findings further the knowledge about KRAS mutations in different ethnic groups is indispensable to fully understand their role in the development and progression of CRC.
Collapse
Affiliation(s)
- Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Angel Carracedo
- Genomic Medicine Group, University of Santiago De Compostela, Spain
| | | | - Faten Al-Sayes
- Faculty of Medicine, KAUH, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sajjad Karim
- Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Absarul Haque
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- King Fahd Medical Research Center, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Peter Natesan Pushparaj
- Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muhammad Asif
- ORIC, Department of Biotechnology, Buitems, Quetta, Pakistan
| | - Niaz M. Achakzai
- Department of Molecular Biology, City Medical Complex, Kabul, Afghanistan
- Department of Molecular Biology, DNA Section, Legal Medicine Directorate, Ministry of Public Health, Kabul, Afghanistan
| |
Collapse
|
|
33
|
Jin Z, Dixon JG, Fiskum JM, Parekh HD, Sinicrope FA, Yothers G, Allegra CJ, Wolmark N, Haller D, Schmoll HJ, de Gramont A, Kerr R, Taieb J, Van Cutsem E, Tweleves C, O’Connell M, Saltz LB, Sadahiro S, Blanke CD, Tomita N, Seitz JF, Erlichman C, Yoshino T, Yamanaka T, Marsoni S, Andre T, Mahipal A, Goldberg RM, George TJ, Shi Q. Clinicopathological and Molecular Characteristics of Early-Onset Stage III Colon Adenocarcinoma: An Analysis of the ACCENT Database. J Natl Cancer Inst 2021; 113:1693-1704. [PMID: 34405233 PMCID: PMC8634466 DOI: 10.1093/jnci/djab123] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/23/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. METHODS Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. RESULTS Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P < .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers. CONCLUSION Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.
Collapse
Affiliation(s)
- Zhaohui Jin
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Jesse G Dixon
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Jack M Fiskum
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Hiral D Parekh
- Cancer Specialists of North Florida, Jacksonville, FL, USA
| | | | - Greg Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Carmen J Allegra
- Department of Medicine, Shands Cancer Center, University of Florida, Gainesville, FL, USA
| | | | - Daniel Haller
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hans-Joachim Schmoll
- Department of Internal Medicine IV-Hematology-Oncology, University Clinic Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | | | - Julien Taieb
- Sorbonne Paris Cité, Paris Descartes University Georges Pompidou European Hospital, Paris, France
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - Christopher Tweleves
- University of Leeds and St. James’s Institute of Oncology, Tom Connors Cancer Research Center, University of Bradford, Bradford, UK
| | | | | | | | | | - Naohiro Tomita
- Cancer Treatment Center, Toyonaka Municipal Hospital, Toyonaka, Japan
| | | | | | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, Kanagawa, Japan
| | | | - Thierry Andre
- Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Richard M Goldberg
- West Virginia University Cancer Institute and the Mary Babb Randolph Cancer Center, Morgantown, WV, USA
| | - Thomas J George
- University of Florida, Health Cancer Center, Gainesville, FL, USA
| | - Qian Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
34
|
Oneda E, Zaniboni A. Adjuvant treatment of colon cancer with microsatellite instability - the state of the art. Crit Rev Oncol Hematol 2021; 169:103537. [PMID: 34801698 DOI: 10.1016/j.critrevonc.2021.103537] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 10/15/2021] [Accepted: 11/15/2021] [Indexed: 12/19/2022] Open
Abstract
Adjuvant chemotherapy with fluoropyrimidine (FP) plus oxaliplatin in stage III resected colorecatal cancer (RCRC) resulted in a 30% relative reduction of disease recurrence risk and mortality. The presence of altered mismatch repair genes identify tumors with microsatellite instability (MSI) that have a better prognosis than stable tumors, but data about adjuvant chemotherapy benefit in this subgroup are compelling. We investigate the role of adjuvant therapy in resected MSI RCRC. The standard treatment is the association of FP plus oxaliplatin, while it can avoided in low risk stage II, thanks to its good prognosis. We propose a practice strategy to approach MSI RCRC in line with the current knowledge. In consideration of the dramatic results in chemorefractory MSI metastatic CRC, there are assumptions that immunotherapy can become a potential alternative to classical systemic therapies also in the adjuvant setting. We await the results of ongoing studies to draw further conclusions."
Collapse
Affiliation(s)
- Ester Oneda
- Department of Clinical Oncology, Fondazione Poliambulanza, Bissolati street, 25124, Brescia, Italy.
| | - Alberto Zaniboni
- Department of Clinical Oncology, Fondazione Poliambulanza, Bissolati street, 25124, Brescia, Italy.
| |
Collapse
|
|
35
|
Repeat Local Treatment of Recurrent Colorectal Liver Metastases, the Role of Neoadjuvant Chemotherapy: An Amsterdam Colorectal Liver Met Registry (AmCORE) Based Study. Cancers (Basel) 2021; 13:cancers13194997. [PMID: 34638481 PMCID: PMC8507904 DOI: 10.3390/cancers13194997] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/02/2021] [Accepted: 10/03/2021] [Indexed: 01/10/2023] Open
Abstract
This cohort study aimed to evaluate efficacy, safety, and survival outcomes of neoadjuvant chemotherapy (NAC) followed by repeat local treatment compared to upfront repeat local treatment of recurrent colorectal liver metastases (CRLM). A total of 152 patients with 267 tumors from the prospective Amsterdam Colorectal Liver Met Registry (AmCORE) met the inclusion criteria. Two cohorts of patients with recurrent CRLM were compared: patients who received chemotherapy prior to repeat local treatment (32 patients) versus upfront repeat local treatment (120 patients). Data from May 2002 to December 2020 were collected. Results on the primary endpoint overall survival (OS) and secondary endpoints local tumor progression-free survival (LTPFS) and distant progression-free survival (DPFS) were reviewed using the Kaplan-Meier method. Subsequently, uni- and multivariable Cox proportional hazard regression models, accounting for potential confounders, were estimated. Additionally, subgroup analyses, according to patient, initial and repeat local treatment characteristics, were conducted. Procedure-related complications and length of hospital stay were compared using chi-square test and Fisher's exact test. The 1-, 3-, and 5-year OS from date of diagnosis of recurrent disease was 98.6%, 72.5%, and 47.7% for both cohorts combined. The crude survival analysis did not reveal a significant difference in OS between the two cohorts (p = 0.834), with 1-, 3-, and 5-year OS of 100.0%, 73.2%, and 57.5% for the NAC group and 98.2%, 72.3%, and 45.3% for the upfront repeat local treatment group, respectively. After adjusting for two confounders, comorbidities (p = 0.010) and primary tumor location (p = 0.023), the corrected HR in multivariable analysis was 0.839 (95% CI, 0.416-1.691; p = 0.624). No differences between the two cohorts were found with regards to LTPFS (HR = 0.662; 95% CI, 0.249-1.756; p = 0.407) and DPFS (HR = 0.798; 95% CI, 0.483-1.318; p = 0.378). No heterogeneous treatment effects were detected in subgroup analyses according to patient, disease, and treatment characteristics. No significant difference was found in periprocedural complications (p = 0.843) and median length of hospital stay (p = 0.600) between the two cohorts. Chemotherapy-related toxicity was reported in 46.7% of patients. Adding NAC prior to repeat local treatment did not improve OS, LTPFS, or DPFS, nor did it affect periprocedural morbidity or length of hospital stay. The results of this comparative assessment do not substantiate the routine use of NAC prior to repeat local treatment of CRLM. Because the exact role of NAC (in different subgroups) remains inconclusive, we are currently designing a phase III randomized controlled trial (RCT), COLLISION RELAPSE trial, directly comparing upfront repeat local treatment (control) to neoadjuvant systemic therapy followed by repeat local treatment (intervention).
Collapse
|
|
36
|
Tang D, Kroemer G, Kang R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol Cancer 2021; 20:128. [PMID: 34607583 PMCID: PMC8489073 DOI: 10.1186/s12943-021-01422-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023] Open
Abstract
Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
Collapse
Affiliation(s)
- Daolin Tang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| |
Collapse
|
|
37
|
Formica V, Sera F, Cremolini C, Riondino S, Morelli C, Arkenau HT, Roselli M. KRAS and BRAF Mutations in Stage II/III Colon Cancer: A Systematic Review and Meta-Analysis. J Natl Cancer Inst 2021; 114:517-527. [PMID: 34542636 DOI: 10.1093/jnci/djab190] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/09/2021] [Accepted: 09/15/2021] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer, however their impact in the adjuvant setting has not yet been established. METHODS We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS/BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS/OS (so-called 'multivariate') meta-analysis was performed. All statistical tests were 2-sided. RESULTS Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled HR = 1.36, 95% CI = 1.15-1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03-1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00-1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31-1.70, P < .001). MSI adjustment enhanced the effect of the mutations on outcome in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15-1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03-1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22-2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37-2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (P interaction = 0.02). This interaction was even more pronounced in the DFS/OS multivariate meta-analysis. CONCLUSIONS Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.
Collapse
Affiliation(s)
- Vincenzo Formica
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Rome, Italy
| | - Francesco Sera
- Department of Statistics, Computer Science and Applications "G Parenti, " University of Florence, Florence, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.,Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Silvia Riondino
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Rome, Italy
| | - Cristina Morelli
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Rome, Italy
| | - Hendrik-Tobias Arkenau
- Sarah Cannon Research Institute, Cancer Institute, University College London, London, UK
| | - Mario Roselli
- Medical Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital, Rome, Italy
| |
Collapse
|
|
38
|
Beypinar I, Demir H, Sakin A, Taskoylu BY, Sakalar T, Ergun Y, Korkmaz M, Ates O, Eren T, Turhal S, Artac M. The Real-Life Data of BRAF Mutation on the Treatment of Colorectal Cancer: a TOG Study. J Gastrointest Cancer 2021; 52:932-939. [PMID: 32914373 DOI: 10.1007/s12029-020-00514-9] [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: 10/23/2022]
Abstract
PURPOSE Colorectal cancer is the third leading diagnosis accounting for nearly 10% of all new cancers worldwide. The distinct features among BRAF mutant colorectal cancers make these tumor groups hard to treat for oncologists. The median overall survival (OS) of these types of cancers is reported to be 9 to 14 months. METHODS The study was declared on the Turkish Oncology Study Group Conference and approved. The patients' data was received from the centers who confirmed to participate. The BRAF-mutated patients were included in the study. The demographic features (age, gender, etc.), type of mutation, tumor localizations, histology, microsatellite instability (MSI) status, metastasis patterns chemotherapeutic agents and progression, and death times were recorded. RESULTS Thirty-nine patients were enrolled in the study. Sixteen patients had concurrent KRAS mutations, while 7 had NRAS mutations. Most of the patients received doublet chemotherapies in combination with anti-VEGF agents in the first and second line of the treatment. There was a significant difference in OS according to the stage which showed a decreased survival in stage IV patients at the time of diagnosis. Concurrent KRAS mutation resulted in increased OS. The median OS was 47 and 24 months favoring the KRAS mutant group. The patients whose primary tumor operated had better survival when compared with other patients. The median OS of the operated group was 47 months, while the non-operated group was 24 months. Liver metastasis was related to worse prognosis at the time of diagnosis in univariate analysis. CONCLUSION In our study we found a high concurrent RAS mutation ratio in a BRAF mutant patient group which was different from prior studies. The concurrent mutations resulted in a favorable outcome in terms of OS which is also different from the current knowledge. More prospective studies are needed especially BRAF-mutated patient population and especially with concurrent RAS mutations.
Collapse
Affiliation(s)
- Ismail Beypinar
- Department of Medical Oncology, Eskişehir City Hospital, Eskişehir, Turkey.
| | - Hacer Demir
- Department of Medical Oncology, Afyonkarahisar Health Sciences University, Afyon, Turkey
| | - Abdullah Sakin
- Department of Medical Oncology, Yüzüncü Yıl University, Van, Turkey
| | | | - Teoman Sakalar
- Department of Medical Oncology, Kahramanmaraş Necip Fazıl City Hospital, Kahramanmaraş, Turkey
| | - Yakup Ergun
- Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Mustafa Korkmaz
- Meram Medicine Faculty, Department of Medical Oncology, Necmettin Erbakan University, Konya, Turkey
| | - Ozturk Ates
- Department of Medical Oncology, Abdurrahman Yurtaslan Training and Research Hospital, Ankara, Turkey
| | - Tulay Eren
- Training and Research Hospital, Dışkapı Training and Research Hospital, Ankara, Turkey
| | - Serdar Turhal
- Department of Medical Oncology, Anadolu Health Center, Istanbul, Turkey
| | - Mehmet Artac
- Meram Medicine Faculty, Department of Medical Oncology, Necmettin Erbakan University, Konya, Turkey
| |
Collapse
|
|
39
|
Dijkstra M, Nieuwenhuizen S, Puijk RS, Timmer FEF, Geboers B, Schouten EAC, Opperman J, Scheffer HJ, de Vries JJJ, Versteeg KS, Lissenberg-Witte BI, van den Tol MP, Meijerink MR. Primary Tumor Sidedness, RAS and BRAF Mutations and MSI Status as Prognostic Factors in Patients with Colorectal Liver Metastases Treated with Surgery and Thermal Ablation: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE). Biomedicines 2021; 9:biomedicines9080962. [PMID: 34440165 PMCID: PMC8395017 DOI: 10.3390/biomedicines9080962] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/16/2021] [Accepted: 08/03/2021] [Indexed: 01/10/2023] Open
Abstract
The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, and local tumor progression (LTP) following surgery and thermal ablation in patients with colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study included 520 patients, 774 procedures, and 2101 tumors undergoing local treatment (resection and/or thermal ablation) from 2000 to 2021. Outcomes following local treatment were analyzed for primary tumor sidedness of CRC, RAS, and BRAF mutations and MSI status. The Kaplan–Meier method was used to estimate local tumor progression-free survival (LTPFS), local control (LC), distant progression-free survival (DPFS), and overall survival (OS). Uni- and multivariable analyses were performed based on Cox proportional hazards model. The chi-square test was used to analyze complications. Complications (p = 0.485), OS (p = 0.252), LTPFS (p = 0.939), and LC (p = 0.423) was not associated with tumor-sidedness. Compared to right-sided colon cancer (CC) (reference HR 1.000), DPFS was superior for left-sided CC and rectal cancer (p = 0.018) with an HR for left-sided CC of 0.742 (95% CI, 0.596–0.923) and for RC of 0.760 (95% CI, 0.597–0.966). Regarding RAS mutations, no significant difference was found in OS (p = 0.116). DPFS (p = 0.001), LTPFS (p = 0.039), and LC (p = 0.025) were significantly lower in the RAS mutation group. Though no difference in LTPFS was found between RAS wildtype and RAS mutated CRLM following resection (p = 0.532), LTPFS was worse for RAS mutated tumors compared to RAS wildtype following thermal ablation (p = 0.037). OS was significantly lower in the BRAF mutation group (p < 0.001) and in the MSI group (p < 0.001) following local treatment, while both did not affect DPFS, LTPFS, and LC. This AmCORE based study suggests the necessity of wider margins to reduce LTP rates in patients with RAS mutated CRLM, especially for thermal ablation. Upfront knowledge regarding molecular biomarkers may contribute to improved oncological outcomes.
Collapse
Affiliation(s)
- Madelon Dijkstra
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
- Correspondence: ; Tel.: +31-20-444-4571
| | - Sanne Nieuwenhuizen
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| | - Robbert S. Puijk
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| | - Florentine E. F. Timmer
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| | - Bart Geboers
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| | - Evelien A. C. Schouten
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| | - Jip Opperman
- Department of Radiology and Nuclear Medicine, Noordwest Ziekenhuisgroep, Location Alkmaar, 1800 AM Alkmaar, The Netherlands;
| | - Hester J. Scheffer
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| | - Jan J. J. de Vries
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| | - Kathelijn S. Versteeg
- Department of Medical Oncology, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands;
| | - Birgit I. Lissenberg-Witte
- Department of Epidemiology and Data Science, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands;
| | - M. Petrousjka van den Tol
- Department of Surgery, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands;
| | - Martijn R. Meijerink
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, VU Medical Center Amsterdam, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands; (S.N.); (R.S.P.); (F.E.F.T.); (B.G.); (E.A.C.S.); (H.J.S.); (J.J.J.d.V.); (M.R.M.)
| |
Collapse
|
|
40
|
Loaiza‐Bonilla A, Benson AB, Grothey A, Karimi M, Klempner SJ, Lin D, Mahtani R, Soares HP. Use of Molecular Assays and Circulating Tumor DNA in Early-Stage Colorectal Cancer: A Roundtable Discussion of the Gastrointestinal Cancer Therapy Expert Group. Oncologist 2021; 26:651-659. [PMID: 33650740 PMCID: PMC8342566 DOI: 10.1002/onco.13738] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/10/2021] [Indexed: 12/16/2022] Open
Abstract
The use of genomic testing is rapidly emerging as an important clinical tool both for cancer diagnosis and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction and next-generation sequencing methods have made it possible to noninvasively screen for CRC through, for example, the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available that can detect circulating tumor DNA as a means for noninvasive minimal/molecular residual disease monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating therapy. The Gastrointestinal Cancer Therapy Expert Group (GICTEG) recently convened a virtual meeting to discuss current issues related to genomic testing in GI cancer, with the goal of providing guidance on the use of these tests for the practicing community oncologist, for whom GI cancer may be only one of many tumor types encountered. This article provides a summary of the discussion and highlights the key opinions of the GICTEG on this topic. IMPLICATIONS FOR PRACTICE: The Gastrointestinal Cancer Therapy Expert Group seeks to provide practical guidance and opinion on the treatment of gastrointestinal malignancies, including colorectal cancer (CRC), for the practicing community oncologist in situations for which guidelines from established bodies, such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology, may be less clear. In the present report, clinical guidance on the use of molecular assays for a range of clinical indications in CRC is presented, including the use of circulating tumor DNA to detect minimal/molecular residual disease in patients with successfully resected early-stage CRC.
Collapse
Affiliation(s)
- Arturo Loaiza‐Bonilla
- Department of Medical Oncology, Cancer Treatment Centers of AmericaPhiladelphiaPennsylvaniaUSA
| | - Al B. Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicagoIllinoisUSA
| | | | - Misagh Karimi
- Department of Medical Oncology & Therapeutics ResearchCity of Hope, Newport Beach, CaliforniaUSA
| | - Samuel J. Klempner
- Department of Medicine, Massachusetts General HospitalBostonMassachusettsUSA
| | - Daniel Lin
- Thomas Jefferson University HospitalPhiladelphiaPennsylvaniaUSA
| | | | | |
Collapse
|
|
41
|
Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
Collapse
Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
| |
Collapse
|
|
42
|
Chen K, Zhang Y, Qian L, Wang P. Emerging strategies to target RAS signaling in human cancer therapy. J Hematol Oncol 2021; 14:116. [PMID: 34301278 PMCID: PMC8299671 DOI: 10.1186/s13045-021-01127-w] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023] Open
Abstract
RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.
Collapse
Affiliation(s)
- Kun Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yalei Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ling Qian
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Peng Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
43
|
Yuan Y, Liu Y, Wu Y, Zhang J, Shen C, Zhang F, Wu C, Hu W. Clinical characteristics and prognostic value of the KRAS mutation in Chinese colorectal cancer patients. Int J Biol Markers 2021; 36:33-39. [PMID: 34044655 DOI: 10.1177/17246008211017152] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The KRAS mutations are high-frequency somatic mutations found in colorectal cancer patients from Western and Asian countries however, with the exception of exon 2 of KRAS, other prevalence and prognostic values have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of whole exon mutations of KRAS in Chinese colorectal cancer patients and to investigate their impact on prognosis. METHODS A total of 7189 tumor tissue samples (iCohort) were subjected to next-generation sequencing for detection of KRAS mutations. All pathologic or likely pathologic mutations of KRAS were considered. In addition, clinical features and prognostic dates were collected from 145 patients at The Third Affiliated Hospital of Soochow University, China (sCohort) and used droplet digital™ polymerase chain reaction to detect KRAS mutations. RESULTS In the iCohort, 2706 patients (37.6%) were confirmed harboring KRAS mutations. The most frequent of these mutations were G12D (32.19%), G12V (17.96%), and G13D (17.59%). In the sCohort, 51 colorectal cancer patients (35.17%) had KRAS mutations, among which KRAS G12D (64.71%), G13D (29.41%), and G14D (3.92%) were high-frequency. The KRAS mutations were associated with shorter median overall survival than wild-type tumors (69 vs. 55 months; HR 1.80; 95% Cl 1.22, 2.64; P=0.0003). In the Cox multivariate analysis, age (HR 1.562; 95% Cl 1.10, 2.22; P=0.013), tumor differentiation (HR 0.417; 95% Cl 0.19, 0.90; P=0.026), and KRAS mutation (HR 1.897; 95% Cl 0.19, 0.90; P=0.001) remained independent predictors of shorter overall survival. Among the common KRAS mutations, G12D was significantly associated with shorter overall survival (HR 2.17; 95% Cl 1.31, 3.58; P < 0.0001) compared with KRAS wild-type patients. CONCLUSIONS Our findings indicate that KRAS genes are frequently mutated, and over 30% harbored the KRAS G12D mutation subtype. We found that the KRAS G12D mutation is associated with inferior survival and is a biomarker of poor prognosis in Chinese patients. Our data emphasize the importance of molecular features in colorectal cancer patients, which could potentially be improved by G12D-specific related inhibitors.
Collapse
Affiliation(s)
- Ye Yuan
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yingting Liu
- Department of Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ye Wu
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Junling Zhang
- The Medical Department, 3D Medicines Inc., Shanghai, China
| | - Chunti Shen
- The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| |
Collapse
|
|
44
|
Abstract
Colorectal cancers (CRC) with B-RAF mutation carry a particularly poor prognosis. In this context, the value of first-line intensified chemotherapy associated with an anti-VEGF (Vascular endothelial growth factor) to treat metastatic CRC has recently been called into question. In patients with mutated B-RAF, the efficacy of first-line anti-EGFR (Epidermal Growth Factor Receptor) associated with chemotherapy for treatment of metastatic CRC is uncertain while that of anti-VEGF has been shown to be effective. The therapeutic pathways involving inhibition of B-RAF activity, although ineffective as monotherapy, have received marketing authorization when used in association with anti-EGFR for second-line treatment of metastatic CRC. Immunotherapy has provided very encouraging results in a recent phase III study in patients with microsatellite instability, irrespective of their B-RAF status. Finally, new therapies, targeting other RAF proteins and other specific receptors are currently under development. Surgery for liver metastases in patients with the B-RAF mutation should be considered whenever possible, after a complete search for peritoneal carcinomatosis and distant metastases, similarly to workup for patients without the B-RAF mutation.
Collapse
|
|
45
|
Zaanan A, Henriques J, Cohen R, Sefrioui D, Evrard C, de la Fouchardiere C, Lecomte T, Aparicio T, Svrcek M, Taieb J, André T, Vernerey D, Tougeron D, for the Association des Gastro-entérologues Oncologues (AGEO). Efficacy of Anti-EGFR in Microsatellite Instability Metastatic Colorectal Cancer Depending on Sporadic or Familial Origin. J Natl Cancer Inst 2021; 113:496-500. [PMID: 32415973 PMCID: PMC8023852 DOI: 10.1093/jnci/djaa072] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/07/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
Anti-epidermal growth factor receptor (EGFR) efficacy in patients with microsatellite instability (MSI) metastatic colorectal cancer (mCRC) according to sporadic vs familial origin is unknown. We retrospectively analyzed 128 patients with MSI mCRC treated with first-line chemotherapy ± anti-EGFR. Among them, 61 and 67 patients were respectively categorized as familial and sporadic based on mismatch repair protein immunostaining, BRAF mutational status, and MLH1 promoter methylation status. We observed that addition of anti-EGFR to chemotherapy was associated with a statistically significant improvement of progression-free survival for familial (median = 5.0 vs 10.2 months, hazard ratio [HR] = 0.47, 95% confidence interval [CI] = 0.23 to 0.94; P = .03) but not for sporadic (median = 4.4 vs 5.4 months, HR = 0.80, 95% CI = 0.39 to 1.60; P = .52) MSI mCRC patients. In multivariate analysis, the survival benefit of adding anti-EGFR to chemotherapy remained statistically significant for familial MSI cases (P = .04). These findings deserve to be confirmed in a prospective study and could help decision making in MSI mCRC without access or resistant to immunotherapy.
Collapse
Affiliation(s)
- Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, AP-HP Centre, Paris, France
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, MEPPOT, F-75006 Paris, France
| | - Julie Henriques
- Bourgogne Franche-Comté University, INSERM, Etablissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
- Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Besançon, France
| | - Romain Cohen
- Medical Oncology Department, Sorbonne University, Saint-Antoine Hospital, AP-HP, F-75012 Paris, France
| | - David Sefrioui
- Digestive Oncology Unit, Department of Hepatogastroenterology, Rouen University Hospital, Normandie Univ, UNIROUEN, Inserm, 1245, IRON Group, Rouen, France
| | - Camille Evrard
- Medical Oncology Department, Poitiers University Hospital, Poitiers, France
| | | | - Thierry Lecomte
- Department of Hepato-Gastroenterology and Digestive Oncology, Tours University Hospital, EA, 7501 GICC, University of Tours, Tours, France
| | - Thomas Aparicio
- Gastroenterology Department, Saint Louis Hospital, AP-HP, Université de Paris, Paris, France
- Gastroenterology Department, Avicenne Hospital, AP-HP, Bobigny, France
| | - Magali Svrcek
- Sorbonne University, Department of Pathology, Saint-Antoine Hospital, AP-HP, F-75012 Paris, France
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, AP-HP Centre, Paris, France
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, MEPPOT, F-75006 Paris, France
| | - Thierry André
- Medical Oncology Department, Sorbonne University, Saint-Antoine Hospital, AP-HP, F-75012 Paris, France
| | - Dewi Vernerey
- Bourgogne Franche-Comté University, INSERM, Etablissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
- Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Besançon, France
| | - David Tougeron
- Gastroenterology Department, Poitiers University Hospital and University of Poitiers, Poitiers, France
| | | |
Collapse
|
|
46
|
Sinicrope FA, Chakrabarti S, Laurent-Puig P, Huebner L, Smyrk TC, Tabernero J, Mini E, Goldberg RM, Zaanan A, Folprecht G, Van Laethem JL, Le Malicot K, Shi Q, Alberts SR, Taieb J. Prognostic variables in low and high risk stage III colon cancers treated in two adjuvant chemotherapy trials. Eur J Cancer 2021; 144:101-112. [PMID: 33341444 PMCID: PMC7855426 DOI: 10.1016/j.ejca.2020.11.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/15/2020] [Accepted: 11/07/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Stratification of patients with stage III colon cancer into low (T1-3N1) and high (T4 and/or N2) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group. MATERIALS & METHODS Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2. RESULTS Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAFV600E/pMMR, subgroups. Specifically, BRAFV600E/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; Padj<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; Padj<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; Padj<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours. CONCLUSION Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.
Collapse
Affiliation(s)
- Frank A Sinicrope
- Department of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN, USA.
| | - Sakti Chakrabarti
- Department of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN, USA
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM, CNRS, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France
| | - Luke Huebner
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Thomas C Smyrk
- Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Josep Tabernero
- Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), UVic, IOB-Quiron, Barcelona, Spain
| | - Enrico Mini
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Richard M Goldberg
- Department of Medicine, West Virginia University Cancer Center, Morgantown, WV, USA
| | - Aziz Zaanan
- Department of Gastroenterology and GI Oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France
| | - Gunnar Folprecht
- First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany
| | | | - Karine Le Malicot
- Department of Statistics, Fédération Francophone de Cancérologie Digestive, EPICAD INSERM, France
| | - Qian Shi
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA; Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA
| | - Steven R Alberts
- Department of Oncology, Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN, USA
| | - Julien Taieb
- Department of Gastroenterology and GI Oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France
| |
Collapse
|
|
47
|
Sztupinszki Z, Le Naour J, Vacchelli E, Laurent-Puig P, Delaloge S, Szallasi Z, Kroemer G. A major genetic accelerator of cancer diagnosis: rs867228 in FPR1. Oncoimmunology 2021; 10:1859064. [PMID: 33489470 PMCID: PMC7801119 DOI: 10.1080/2162402x.2020.1859064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Affiliation(s)
- Zsofia Sztupinszki
- Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA.,Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Julie Le Naour
- Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France.,Harvard Medical School, Boston, MA, USA.,Université Paris Sud, Paris Saclay, Faculty of Medicine Kremlin Bicêtre, France
| | - Erika Vacchelli
- Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Pierre Laurent-Puig
- Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France.,Institut du Cancer Paris CARPEM, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
| | - Suzette Delaloge
- Université Paris Sud, Paris Saclay, Faculty of Medicine Kremlin Bicêtre, France.,Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France
| | - Zoltan Szallasi
- Computational Health Informatics Program (CHIP), Boston Children's Hospital, Boston, MA, USA.,Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Guido Kroemer
- Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Institut Universitaire de France, Paris, France.,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.,Suzhou Institute for stems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.,Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
48
|
Ruffinelli JC, Santos Vivas C, Sanz-Pamplona R, Moreno V. New advances in the clinical management of RAS and BRAF mutant colorectal cancer patients. Expert Rev Gastroenterol Hepatol 2021; 15:65-79. [PMID: 32946312 DOI: 10.1080/17474124.2021.1826305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION In colorectal carcinogenesis, genetic alterations in RAS and BRAF oncogenes play an important role for cancer initiation and/or progression and represent a key focus in the search for targeted therapies. Despite many years of research and a great amount of studies, until very recently this pathway was considered extremely hard to downregulate to obtain a significant clinical impact in colorectal cancer patients. But better times are coming with the advent of new promising drugs and combinations strategies. AREAS COVERED In this review, we go over the biological characteristics of the MAPK pathway in colorectal tumors, while illustrating the clinical correlation of RAS and BRAF mutations, particularly its prognostic and predictive value. We also present newly data about recent improvements in the treatment strategy for patients harboring these types of tumors. EXPERT COMMENTARY With great advances in the knowledge of molecular basis of RAS and BRAF mutant colorectal cancer in conjunction with biotechnology development and the constant effort for improvement, in the near future many new therapeutic options would be available for the management of this group of patient with dismal prognosis.
Collapse
Affiliation(s)
- Jose Carlos Ruffinelli
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain
| | - Cristina Santos Vivas
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain.,Consortium for Biomedical Research in Oncology (CIBERONC) , Barcelona, Spain.,Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona , Barcelona, Spain
| | - Rebeca Sanz-Pamplona
- Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain.,Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) , Barcelona, Spain
| | - Victor Moreno
- Colorectal Cancer Group, ONCOBELL Program, Institut De Recerca Biomedica De Bellvitge (IDIBELL) , Barcelona, Spain.,Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona , Barcelona, Spain.,Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program (ODAP, Catalan Institute of Oncology (ICO), L'Hospitalet De Llobregat , Barcelona, Spain.,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) , Barcelona, Spain
| |
Collapse
|
|
49
|
Cohen R, Taieb J, Fiskum J, Yothers G, Goldberg R, Yoshino T, Alberts S, Allegra C, de Gramont A, Seitz JF, O'Connell M, Haller D, Wolmark N, Erlichman C, Zaniboni A, Lonardi S, Kerr R, Grothey A, Sinicrope FA, André T, Shi Q. Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials. J Clin Oncol 2020; 39:642-651. [PMID: 33356421 DOI: 10.1200/jco.20.01600] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
PURPOSE In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.
Collapse
Affiliation(s)
- Romain Cohen
- Sorbonne Université, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France.,Department of Health Science Research, Mayo Clinic, Rochester, MN
| | - Julien Taieb
- Sorbonne Paris Cité, Paris Descartes University Georges Pompidou European Hospital, Paris, France
| | - Jack Fiskum
- Department of Health Science Research, Mayo Clinic, Rochester, MN
| | - Greg Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA
| | | | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | | | - Carmen Allegra
- Department of Medicine and University of Florida Shands Cancer Center, FL
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | | | | | - Daniel Haller
- Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA
| | | | | | | | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Rachel Kerr
- University of Oxford, Oxford, United Kingdom
| | | | | | - Thierry André
- Sorbonne Université, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, Paris, France
| | - Qian Shi
- Department of Health Science Research, Mayo Clinic, Rochester, MN
| |
Collapse
|
|
50
|
Zanatto RM, Santos G, Oliveira JC, Pracucho EM, Nunes AJF, Lopes-Filho GJ, Saad SS. IMPACT OF KRAS MUTATIONS IN CLINICAL FEATURES IN COLORECTAL CANCER. ACTA ACUST UNITED AC 2020; 33:e1524. [PMID: 33331426 PMCID: PMC7743328 DOI: 10.1590/0102-672020200003e1524] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/29/2020] [Indexed: 01/04/2023]
Abstract
Background:
KRAS mutations are important events in colorectal carcinogenesis, as well as
negative predictors of response to EGFR inhibitors treatment.
Aim:
To investigate the association of clinical-pathological features with KRAS
mutations in colorectal cancer patients treated.
Methods:
Data from 69 patients with colorectal cancer either metastatic at diagnosis
or later, were retrospectively analyzed. The direct sequencing and
pyrosequencing techniques were related to KRAS exon 2. The mutation
diagnosis and its type were determined.
Results:
KRAS mutation was identified in 43.4% of patients. The most common was
c.35G>T (p.G12V), c.35G>A (p.G12D) and c.38G>A (p.G13D). No
correlation was found between KRAS mutation and age (p=0.646) or gender
(p=0.815). However, mutated group had higher CEA levels at admission
(p=0.048) and codon 13 mutation was associated with involvement of more than
one metastatic site in disease progression (p=0.029). Although there was no
association between primary tumor site and mutation diagnosis (p=0.568),
primary colon was associated with worse overall survival (p=0.009).
Conclusion:
The KRAS mutation was identified in almost half of patients. Mutated KRAS
group had higher levels of CEA at admission and the mutation at codon 13 was
associated with involvement of more than one metastatic site in the course
of the disease. Colon disease was associated with the worst overall
survival.
Collapse
Affiliation(s)
- Renato Morato Zanatto
- Department of Abdominal and Pelvic Surgery, Hospital Amaral Carvalho, Jaú, SP, Brazil
| | - Gianni Santos
- Department of Biostatistics, Federal University of São Paulo, São Paulo, SP, Brazil
| | - Júnea Caris Oliveira
- Department of Abdominal and Pelvic Surgery, Hospital Amaral Carvalho, Jaú, SP, Brazil
| | | | | | - Gaspar Jesus Lopes-Filho
- Department of Digestive Surgery, Federal University of São Paulo, São Paulo, SP, Brazil.,Postgraduate Program in Surgery, Federal University of São Paulo, São Paulo, SP, Brazil
| | - Sarhan Sydney Saad
- Department of Digestive Surgery, Federal University of São Paulo, São Paulo, SP, Brazil.,Postgraduate Program in Surgery, Federal University of São Paulo, São Paulo, SP, Brazil
| |
Collapse
|