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Mu P, Mo S, He X, Zhang H, Lv T, Xu R, He L, Xia F, Zhou S, Chen Y, Wang Y, Shen L, Wan J, Huang L, Lu W, Liang X, Li X, Lu P, Peng J, Hua G, Hu K, Zhang Z, Wang Y. Unveiling radiobiological traits and therapeutic responses of BRAF V600E-mutant colorectal cancer via patient-derived organoids. J Exp Clin Cancer Res 2025; 44:92. [PMID: 40069844 PMCID: PMC11895145 DOI: 10.1186/s13046-025-03349-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/21/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Radiotherapy (RT) is an essential treatment for colorectal cancer (CRC), yet the factors influencing radiosensitivity remain unclear. In the quest to enhance the therapeutic efficacy in CRC, the interplay between genetic mutations and RT sensitivity has emerged as a pivotal yet enigmatic area. METHODS We harness the fidelity of patient-derived organoids (PDOs) to dissect the molecular landscape of radiosensitivity, with a particular emphasis on BRAFV600E mutations. To further investigate, a cohort of 9 BRAFV600E-mutant and 10 BRAF wild-type PDOs is constructed to systematically assess the radiobiological traits of BRAFV600E-mutant CRC, including morphology, cell viability, and DNA damage, while also evaluating their responses to chemotherapy and chemoradiotherapy. RESULTS Our systematic investigation unveils a profound correlation between BRAFV600E mutation status and radioresistance, which is validated by clinical treatment responses. Intriguingly, BRAFV600E-mutant PDOs exhibit reduced sensitivity to conventional chemotherapy, yet demonstrate an enhanced response to combined chemoradiotherapy, characterized by increased apoptosis. The results are validated through in vivo analyses using patient-derived organoid xenograft mouse models and aligned with patient clinical outcomes. CONCLUSIONS This study outlines the distinct radiobiological profile of BRAFV600E-mutant CRC, underscoring the critical role of radiotherapy in comprehensive treatment strategies. This work not only advances our molecular understanding of CRC but also paves the way for precision medicine, offering valuable insights for therapeutic decision-making in the clinical management of BRAFV600E-mutant CRC.
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Affiliation(s)
- Peiyuan Mu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Shaobo Mo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Xingfeng He
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Tao Lv
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Ruone Xu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Luoxi He
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Shujuan Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Yajie Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Yaqi Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Juefeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Lili Huang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Weiqing Lu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
| | - Xinyue Liang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China
- Cancer institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Xiaomeng Li
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Urology Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Ping Lu
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Junjie Peng
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Guoqiang Hua
- D1Med Technology (Shanghai) Inc, Shanghai, 201802, China
| | - Kewen Hu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China.
- Cancer institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China.
| | - Yan Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, 200032, China.
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, 200032, China.
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Milan N, Navarria F, Cecchin E, De Mattia E. Somatic pharmacogenomics in the treatment prognosis of locally advanced rectal cancer patients: a narrative review of the literature. Expert Rev Clin Pharmacol 2024; 17:683-719. [PMID: 39046146 DOI: 10.1080/17512433.2024.2375449] [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: 01/23/2024] [Accepted: 06/28/2024] [Indexed: 07/25/2024]
Abstract
INTRODUCTION Standard treatment for patients with locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (nCRT) with fluoropyrimidines, followed by surgical excision. The newly introduced therapeutic strategies propose intensified regimens or more conservative approaches based on risk stratification algorithms that currently include clinicoradiological criteria but not molecular variables. How to better stratify patients is a burning clinical question, and pharmacogenomics may prove useful in identifying new genetic markers that could be incorporated into clinical algorithms to personalize nCRT. An emerging area could be the evaluation of somatic mutations as potential genetic markers that correlate with patient prognosis. Tumor mutations in the RAS/BRAF genes, as well as microsatellite instability (MSI) status, are currently used in treatment selection for colorectal cancer (CRC); however, their clinical value in LARC is still unclear. AREA COVERED This literature review discusses the relevant findings on the prognostic role of mutations in the key oncogenes RAS, KRAS, BRAF, PIK3CA, SMAD4 and TP53, including MSI status in LARC patients treated with nCRT. EXPERT OPINION KRAS proved to be the most promising marker, consistently associated with poorer disease-free survival and overall survival. Therefore, KRAS could be a good candidate for integration into the risk stratification algorithm to develop a personalized treatment.
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Affiliation(s)
- Noemi Milan
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Federico Navarria
- Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
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Zhang H, Li X, Sun W, Qin H, Li H, Yan H, Wang H, Zhang X, Zhang S, Wang H. PTEN and P-4E-BP1 might be associated with postoperative recurrence of rectal cancer patients undergoing concurrent radiochemotherapy. BMC Cancer 2024; 24:582. [PMID: 38741069 PMCID: PMC11089754 DOI: 10.1186/s12885-024-12339-x] [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: 10/10/2023] [Accepted: 05/03/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Local recurrence after surgery and radiochemotherapy seriously affects the prognosis of locally advanced rectal cancer (LARC) patients. Studies on molecular markers related to the radiochemotherapy sensitivity of cancers have been widely carried out, which might provide valued information for clinicians to carry out individual treatment. AIM To find potential biomarkers of tumors for predicting postoperative recurrence. METHODS In this study, LARC patients undergoing surgery and concurrent radiochemotherapy were enrolled. We focused on clinicopathological factors and PTEN, SIRT1, p-4E-BP1, and pS6 protein expression assessed by immunohistochemistry in 73 rectal cancer patients with local recurrence and 76 patients without local recurrence. RESULTS The expression of PTEN was higher, while the expression of p-4E-BP1 was lower in patients without local recurrence than in patients with local recurrence. Moreover, TNM stage, lymphatic vessel invasion (LVI), PTEN and p-4E-BP1 might be independent risk factors for local recurrence after LARC surgery combined with concurrent radiochemotherapy. CONCLUSIONS This study suggests that PTEN and p-4E-BP1 might be potential biomarkers for prognostic prediction and therapeutic targets for LARC.
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Affiliation(s)
- Heng Zhang
- Department of Oncology, Tianjin Union Medical Center, Nankai University, No.190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P. R. China
| | - Xiaofan Li
- Department of Oncology, People's Hospital of Rongcheng, Shandong, Rongcheng, P. R. China
| | - Wanjun Sun
- Department of Oncology, Tianjin Union Medical Center, Nankai University, No.190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P. R. China
| | - Haoren Qin
- Department of Oncology, Tianjin Union Medical Center, Nankai University, No.190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P. R. China
| | - Haipeng Li
- Department of Oncology, Tianjin Union Medical Center, Nankai University, No.190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P. R. China
| | - Hao Yan
- Department of Oncology, Tianjin Union Medical Center, Nankai University, No.190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P. R. China
| | - Huaqing Wang
- Department of Oncology, Tianjin Union Medical Center, Nankai University, No.190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P. R. China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Nankai University, Tianjin, P. R. China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Nankai University, Tianjin, P. R. China
| | - Hui Wang
- Department of Oncology, Tianjin Union Medical Center, Nankai University, No.190 Jieyuan Road, Hongqiao District, Tianjin, 300121, P. R. China.
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Predictive and Prognostic Value of Oncogene Mutations and Microsatellite Instability in Locally-Advanced Rectal Cancer Treated with Neoadjuvant Radiation-Based Therapy: A Systematic Review and Meta-Analysis. Cancers (Basel) 2023; 15:cancers15051469. [PMID: 36900260 PMCID: PMC10001009 DOI: 10.3390/cancers15051469] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/17/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Markers of pathological complete response (pCR) to preoperative radiation-based therapy in locally advanced rectal cancer (LARC) are strongly needed. This meta-analysis aimed at elucidating the predictive/prognostic role of tumor markers in LARC. We systematically reviewed the impact of RAS, TP53, BRAF, PIK3CA, and SMAD4 mutations and MSI status on response (pCR, downstaging) and prognosis (risk of recurrence, survival) in LARC according to PRISMA guidelines and the PICO model. PubMed, Cochrane Library, and Web of Science Core Collection were systematically searched to identify relevant studies published before October 2022. KRAS mutations were significantly associated with the risk of not achieving pCR after preoperative treatment (summary OR = 1.80, 95% CI: 1.23-2.64). This association was even more significant in patients not receiving cetuximab (summary OR = 2.17, 95% CI: 1.41-3.33) than in patients receiving cetuximab (summary OR = 0.89, 95% CI: 0.39-20.05). MSI status was not associated with pCR (summary OR = 0.80, 95% CI: 0.41-1.57). No effect of KRAS mutation or MSI status on downstaging was detected. Meta-analysis of survival outcomes was not possible due to the large heterogeneity among studies in endpoint assessment. The minimum number of eligible studies to assess the predictive/prognostic role of TP53, BRAF, PIK3CA, and SMAD4 mutations was not reached. KRAS mutation, but not MSI status, proved to be a detrimental marker for response to preoperative radiation-based therapy in LARC. Translating this finding into the clinic could improve the management of LARC patients. More data are needed to clarify the clinical impact of TP53, BRAF, PIK3CA, and SMAD4 mutations.
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Chang YK, Tseng HH, Leung CM, Lu KC, Tsai KW. Targeted Next-Generation Sequencing-Based Multiple Gene Mutation Profiling of Patients with Rectal Adenocarcinoma Receiving or Not Receiving Neoadjuvant Chemoradiotherapy. Int J Mol Sci 2022; 23:ijms231810353. [PMID: 36142267 PMCID: PMC9499649 DOI: 10.3390/ijms231810353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/24/2022] Open
Abstract
This study investigated whether oncogenic and tumor-suppressive gene mutations are involved in the differential outcomes of patients with rectal carcinoma receiving neoadjuvant chemoradiotherapy (nCRT). Genomic DNA was obtained from formalin-fixed paraffin-embedded (FFPE) specimens of patients with rectal carcinoma who received a complete nCRT course. Gene mutation status was examined in specimens from patients before and after nCRT by using the AmpliSeq platform. Our data revealed that the nonsynonymous p53, APC, KRAS, CDKN2A, and EGFR mutations were observed in 93.1%, 65.5%, 48.6%, and 31% of the patients with rectal adenocarcinoma, respectively. BRAF, FBXW7, PTEN, and SMAD4 mutations were observed in 20.7% of patients with rectal carcinoma. The following 12 gene mutations were observed more frequently in the patients exhibiting a complete response than in those demonstrating a poor response before nCRT: ATM, BRAF, CDKN2A, EGFR, FLT3, GNA11, KDR, KIT, PIK3CA, PTEN, PTPN11, SMAD4, and TP53. In addition, APC, BRAF, FBXW7, KRAS, SMAD4, and TP53 mutations were retained after nCRT. Our results indicate a complex mutational profile in rectal carcinoma, suggesting the involvement of BRAF, SMAD4, and TP53 genetic variants in the outcomes of patients with nCRT.
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Affiliation(s)
- You-Kang Chang
- Department of Radiation Oncology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei 23142, Taiwan
- College of Medicine, Tzu Chi University, Hualien City 97004, Taiwan
| | - Hui-Hwa Tseng
- Department of Anatomic Pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 97004, Taiwan
| | - Chung-Man Leung
- Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung 81341, Taiwan
| | - Kuo-Cheng Lu
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 97004, Taiwan
- Division of Nephrology, Department of Medicine, Fu-Jen Catholic University Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
| | - Kuo-Wang Tsai
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan
- Correspondence: ; Tel.: +886-2-266289779 (ext. 5796); Fax: +886-2-66281258
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Abstract
BACKGROUND The prognostic value of the KRAS proto-oncogene mutation in colorectal cancer has been debated. Herein, we analyzed the National Cancer Database (NCDB) to assess the role of KRAS mutation as a prognostic marker in patients with locally advanced rectal cancer (LARC). METHODS We identified LARC patients treated with neoadjuvant chemoradiation from 2004-2015 excluding those with stage I/IV disease and unknown KRAS status. Multivariable logistic regression identified variables associated with KRAS positivity. Propensity adjusted univariable and multivariable analyses identified predictors of survival. RESULTS Of the 784 eligible patients, 506 were KRAS-negative (KRAS -) and 278 were KRAS-positive (KRAS +). Median survival was 63.6 months and 76.3 months for KRAS + and KRAS - patients respectively, with propensity adjusted 3 and 5-year survival of 79.9% vs. 83.6% and 56.7% vs. 61.9% respectively (HR 1.56, p 1.074-2.272). Male sex, no insurance, and KRAS + disease were associated with poorer survival on unadjusted and propensity adjusted multivariable analyses. CONCLUSIONS Our analysis of KRAS + LARC suggest that KRAS + disease is associated with poorer overall survival. Given the inherent limitations of retrospective data, prospective validation is warranted.
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Peng J, Lv J, Peng J. KRAS mutation is predictive for poor prognosis in rectal cancer patients with neoadjuvant chemoradiotherapy: a systemic review and meta-analysis. Int J Colorectal Dis 2021; 36:1781-1790. [PMID: 33760952 DOI: 10.1007/s00384-021-03911-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/12/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE To investigate the association between KRAS mutation and prognosis in rectal cancer patients with neoadjuvant chemoradiotherapy. METHODS Literature was searched in the databases including Cochrane Library, EMBASE (Ovid), and MEDLINE (PubMed) from inception to December 16, 2020. The keywords "rectal cancer" or "rectal carcinoma" or "rectal adenocarcinoma" and "KRAS" and "neoadjuvant" were used for preliminary literature retrieval. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated for the KRAS mutation and clinical outcomes including overall survival (OS), disease-free survival (DFS), pathologic complete remission (pCR), downstaging of T stages and tumor stages, as well as improvements in tumor regression grading (TRG). Publication bias was assessed by the funnel plots. RESULTS A total of 16 articles were included for eligibility. The total number of patients was 3674 cases, with an incidence of KRAS gene mutation of 36.6% (1346/3674). Meta-analysis showed that the pooled OR for KRAS mutation on OS was 1.33 (95%CI: 113-1.56). Consistently, results also indicated that the KRAS mutant was related to the poor DFS (pooled OR=1.55, 95%CI: 1.19-2.02). However, KRAS mutation is not related to the PCR (pooled OR= 0.71, 95%CI: 0.44-1.14), downstaging in T stages (pooled OR= 0.66, 95%CI: 0.42-1.06), tumor stages (pooled OR= 1.18, 95%CI: 0.78-1.78, I2=12.9%), as well as improvement in TRG grades (pooled OR= 0.84, 95%CI: 0.59-1.20). CONCLUSION KRAS mutation is a predictor for the poor prognosis of neoadjuvant chemoradiotherapy in patients with rectal cancer, but it is not related to the responses of tumors after treatment.
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Affiliation(s)
- Junfu Peng
- Department of TCM Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Jun Lv
- Department of TCM, Aviation General Hospital, Beijing, China
| | - Jisheng Peng
- Department of TCM Gastroenterology, The Third Affiliated Hospital of Beijing University of Chinese Medicine, No. 51 Anwai Xiaoguan Street, Chaoyang District, Beijing, 100029, China.
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Biomarkers and cell-based models to predict the outcome of neoadjuvant therapy for rectal cancer patients. Biomark Res 2021; 9:60. [PMID: 34321074 PMCID: PMC8317379 DOI: 10.1186/s40364-021-00313-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022] Open
Abstract
Rectal cancer constitutes approximately one-third of all colorectal cancers and contributes to considerable mortality globally. In contrast to colon cancer, the standard treatment for localized rectal cancer often involves neoadjuvant chemoradiotherapy. Tumour response rates to treatment show substantial inter-patient heterogeneity, indicating a need for treatment stratification. Consequently researchers have attempted to establish new means for predicting tumour response in order to assist in treatment decisions. In this review we have summarized published findings regarding potential biomarkers to predict neoadjuvant treatment response for rectal cancer tumours. In addition, we describe cell-based models that can be utilized both for treatment prediction and for studying the complex mechanisms involved.
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Zhang Z, Shen L, Wang Y, Wang J, Zhang H, Xia F, Wan J, Zhang Z. MRI Radiomics Signature as a Potential Biomarker for Predicting KRAS Status in Locally Advanced Rectal Cancer Patients. Front Oncol 2021; 11:614052. [PMID: 34026605 PMCID: PMC8138318 DOI: 10.3389/fonc.2021.614052] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 03/18/2021] [Indexed: 12/21/2022] Open
Abstract
Background and Purpose Locally advanced rectal cancer (LARC) is a heterogeneous disease with little information about KRAS status and image features. The purpose of this study was to analyze the association between T2 magnetic resonance imaging (MRI) radiomics features and KRAS status in LARC patients. Material and Methods Eighty-three patients with KRAS status information and T2 MRI images between 2012.05 and 2019.09 were included. Least absolute shrinkage and selection operator (LASSO) regression was performed to assess the associations between features and gene status. The patients were divided 7:3 into training and validation sets. The C-index and the average area under the receiver operator characteristic curve (AUC) were used for performance evaluation. Results The clinical characteristics of 83 patients in the KRAS mutant and wild-type cohorts were balanced. Forty-two (50.6%) patients had KRAS mutations, and 41 (49.4%) patients had wild-type KRAS. A total of 253 radiomics features were extracted from the T2-MRI images of LARC patients. One radiomic feature named X.LL_scaled_std, a standard deviation value of scaled wavelet-transformed low-pass channel filter, was selected from 253 features (P=0.019). The radiomics-based C-index values were 0.801 (95% CI: 0.772-0.830) and 0.703 (95% CI: 0.620-0.786) in the training and validation sets, respectively. Conclusion Radiomics features could differentiate KRAS status in LARC patients based on T2-MRI images. Further validation in a larger dataset is necessary in the future.
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Affiliation(s)
- ZhiYuan Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - LiJun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Yan Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Jiazhou Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - JueFeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
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do Canto LM, Barros-Filho MC, Rainho CA, Marinho D, Kupper BEC, Begnami MDFDS, Scapulatempo-Neto C, Havelund BM, Lindebjerg J, Marchi FA, Baumbach J, Aguiar S, Rogatto SR. Comprehensive Analysis of DNA Methylation and Prediction of Response to NeoadjuvantTherapy in Locally Advanced Rectal Cancer. Cancers (Basel) 2020; 12:cancers12113079. [PMID: 33105711 PMCID: PMC7690383 DOI: 10.3390/cancers12113079] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/09/2020] [Accepted: 10/16/2020] [Indexed: 12/19/2022] Open
Abstract
The treatment for locally advanced rectal carcinomas (LARC) is based on neoadjuvant chemoradiotherapy (nCRT) and surgery, which results in pathological complete response (pCR) in up to 30% of patients. Since epigenetic changes may influence response to therapy, we aimed to identify DNA methylation markers predictive of pCR in LARC patients treated with nCRT. We used high-throughput DNA methylation analysis of 32 treatment-naïve LARC biopsies and five normal rectal tissues to explore the predictive value of differentially methylated (DM) CpGs. External validation was carried out with The Cancer Genome Atlas-Rectal Adenocarcinoma (TCGA-READ 99 cases). A classifier based on three-CpGs DM (linked to OBSL1, GPR1, and INSIG1 genes) was able to discriminate pCR from incomplete responders with high sensitivity and specificity. The methylation levels of the selected CpGs confirmed the predictive value of our classifier in 77 LARCs evaluated by bisulfite pyrosequencing. Evaluation of external datasets (TCGA-READ, GSE81006, GSE75546, and GSE39958) reproduced our results. As the three CpGs were mapped near to regulatory elements, we performed an integrative analysis in regions associated with predicted cis-regulatory elements. A positive and inverse correlation between DNA methylation and gene expression was found in two CpGs. We propose a novel predictive tool based on three CpGs potentially useful for pretreatment screening of LARC patients and guide the selection of treatment modality.
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Affiliation(s)
- Luisa Matos do Canto
- Department of Clinical Genetics, University Hospital of Southern Denmark, 7100 Vejle, Denmark;
- International Research Center–CIPE, A.C. Camargo Cancer Center, Sao Paulo 04002-010, Brazil; (M.C.B.-F.); (F.A.M.)
| | - Mateus Camargo Barros-Filho
- International Research Center–CIPE, A.C. Camargo Cancer Center, Sao Paulo 04002-010, Brazil; (M.C.B.-F.); (F.A.M.)
- Department of Head and Neck Surgery, Hospital das Clinicas HCFMUSP, Sao Paulo 01246-903, Brazil
| | - Cláudia Aparecida Rainho
- Department of Chemical and Biological Sciences, Institute of Biosciences, Sao Paulo State University (Unesp), Botucatu 18618-689, Brazil;
| | - Diogo Marinho
- Institute of Biological Psychiatry, Psykiatrisk Center Sct. Hans, 4000 Roskilde, Denmark;
| | - Bruna Elisa Catin Kupper
- Colorectal Cancer Service, A.C. Camargo Cancer Center, Sao Paulo 04002-010, Brazil; (B.E.C.K.); (S.A.J.)
| | | | - Cristovam Scapulatempo-Neto
- Molecular Oncology Research Center, Barretos – 14784-400, and Diagnósticos da América (DASA), Barueri 06455010, Brazil;
| | - Birgitte Mayland Havelund
- Department of Oncology, University Hospital of Southern Denmark, 7100 Vejle, Denmark;
- Danish Colorectal Cancer Center South, 7100 Vejle, Denmark;
| | - Jan Lindebjerg
- Danish Colorectal Cancer Center South, 7100 Vejle, Denmark;
- Department of Pathology, University Hospital of Southern Denmark, 7100 Vejle, Denmark
| | - Fabio Albuquerque Marchi
- International Research Center–CIPE, A.C. Camargo Cancer Center, Sao Paulo 04002-010, Brazil; (M.C.B.-F.); (F.A.M.)
| | - Jan Baumbach
- TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany;
| | - Samuel Aguiar
- Colorectal Cancer Service, A.C. Camargo Cancer Center, Sao Paulo 04002-010, Brazil; (B.E.C.K.); (S.A.J.)
| | - Silvia Regina Rogatto
- Department of Clinical Genetics, University Hospital of Southern Denmark, 7100 Vejle, Denmark;
- Danish Colorectal Cancer Center South, 7100 Vejle, Denmark;
- Institute of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark
- Correspondence: ; Tel.: +45-7940-6669
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11
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Shinto E, Omata J, Sikina A, Sekizawa A, Kajiwara Y, Hayashi K, Hashiguchi Y, Hase K, Ueno H. Predictive immunohistochemical features for tumour response to chemoradiotherapy in rectal cancer. BJS Open 2020; 4:301-309. [PMID: 32026629 PMCID: PMC7093790 DOI: 10.1002/bjs5.50251] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 11/21/2019] [Indexed: 01/02/2023] Open
Abstract
Background Reduced expression of cluster of differentiation (CD) 133 and cyclo‐oxygenase (COX) 2, and increased density of CD8+ tumour‐infiltrating lymphocytes, are associated with a favourable tumour response to preoperative chemoradiotherapy (CRT). This study aimed to evaluate these markers in relation to tumour response after preoperative CRT in two rectal cancer cohorts. Methods Patients with low rectal cancer who underwent radical resection and preoperative short‐term CRT in 2001–2007 (retrospective cohort) and long‐term CRT in 2011–2017 (prospective cohort) were analysed. Pretreatment biopsies were stained immunohistochemically using antibodies to determine CD133 and COX‐2 expression, and increased CD8+ density. Outcome measures were tumour regression grade (TRG), tumour downstaging and survival. Results For 95 patients in the retrospective cohort, the incidence of TRG 3–4 was 67 per cent when two or three immunohistochemistry (IHC) features were present, but only 20 per cent when there were fewer features (P < 0·001). The incidence of tumour downstaging was higher in patients with at least two IHC features (43 versus 22 per cent with fewer features; P = 0·029). The 49 patients in the prospective cohort had similar rates to those in the retrospective cohort (TRG 3–4: 76 per cent for two or more IHC features versus 25 per cent with fewer features, P < 0·001; tumour downstaging: 57 versus 25 per cent respectively, P = 0·022). Local recurrence‐free survival rates in patients with more or fewer IHC features were similar in the retrospective and prospective cohort (P = 0·058 and P = 0·387 respectively). Conclusion Assessment of CD133, COX‐2 and CD8 could be useful in predicting a good response to preoperative CRT in patients with lower rectal cancer undergoing neoadjuvant therapy. Further studies are needed to validate the results in larger cohorts and investigate a survival benefit.
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Affiliation(s)
- E Shinto
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
| | - J Omata
- Department of Surgery, Self-Defense Forces Central Hospital, Tokyo, Japan
| | - A Sikina
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
| | - A Sekizawa
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
| | - Y Kajiwara
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
| | - K Hayashi
- Department of Radiology, National Defense Medical College, Tokorozawa, Japan
| | - Y Hashiguchi
- Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
| | - K Hase
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
| | - H Ueno
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan
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12
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Moosazadeh M, Sadough A, Afshari M, Barzegari S, Janbabaee G, Tabrizi R, Akbari M, Alizadeh-Navaei R, Hedayatizadeh-Omran A, Rostami-Maskopaee F. Prevalence of BRAF gene mutation in samples of primary and metastatic colorectal cancer: A meta-analysis. Eur J Cancer Care (Engl) 2019; 28:e13160. [PMID: 31482595 DOI: 10.1111/ecc.13160] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 06/23/2019] [Accepted: 08/01/2019] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Understanding the prevalence and biology of BRAF gene can improve the treatment methods of cancerous patients. This study aims to estimate the prevalence of BRAF gene mutation in samples of primary and metastatic colorectal cancer using meta-analysis method. METHODS We searched PubMed, Scopus, ScienceDirect, Ovid and Google Scholar motor engine using MeSH terms of relevant keywords. During the screening phase, titles, abstracts and full texts were reviewed and risk of bias was assessed for all selected papers based on Newcastle-Ottawa Scale (NOS) checklist. The results of the primary studies were combined using meta-analysis. RESULTS Of 95 eligible studies entered into the meta-analysis, prevalence of BRAF gene mutation had been assessed among 19,484 primary tumour samples as well as 12,256 metastatic samples. The total prevalence of BRAF gene mutation among primary tumour samples was estimated as of 10.16% (8.09-12.22) in the world, 0.41% (0-1.89) in EMRO region, 10.06% (7.54-12.59) in EURO region, 10.33% (7.24-13.43) in SEARO region and 11.33% (7.29-15.37) in WPRO region. The pooled estimates for BRAF gene mutation in metastatic samples were 6.53% (5.09-7.96), 8.07% (5.57-10.56), 5.38% (3.75-7.02) and 5.55% (1.72-9.38) for all regions, EURO, WPRO and PAHO regions respectively. CONCLUSION Our results showed evidences of BRAF gene mutation in one-tenth of primary colorectal tumour samples in EURO, PAHO, SEARO and WPRO regions which was considerably higher than that of the EMRO region.
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Affiliation(s)
- Mahmood Moosazadeh
- Health Sciences Research center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Azita Sadough
- Traditional Medicine and History of Medical science Research center, Faculty of Iranian medicine, Babol University of Medical Science, Babol, Iran
| | - Mahdi Afshari
- Department of Community Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Saeed Barzegari
- Department of Health Information Management, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghasem Janbabaee
- Gastrointestinal Cancer Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Reza Tabrizi
- Health Policy Research Center, Student Research Committee, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Akbari
- Health Policy Research Center, Student Research Committee, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Alizadeh-Navaei
- Gastrointestinal cancer research center, Mazandaran University of Medical Sciences, Sari, Iran
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13
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Bedin C, Crotti S, D'Angelo E, D'Aronco S, Pucciarelli S, Agostini M. Circulating Biomarkers for Response Prediction of Rectal Cancer to Neoadjuvant Chemoradiotherapy. Curr Med Chem 2019; 27:4274-4294. [PMID: 31060482 DOI: 10.2174/0929867326666190507084839] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 03/05/2019] [Accepted: 04/18/2019] [Indexed: 12/20/2022]
Abstract
Rectal cancer response to neoadjuvant Chemoradiotherapy (pCRT) is highly variable. In fact, it has been estimated that only about 21 % of patients show pathologic Complete Response (pCR) after therapy, while in most of the patients a partial or incomplete tumour regression is observed. Consequently, patients with a priori chemoradioresistant tumour should not receive the treatment, which is associated with substantial adverse effects and does not guarantee any clinical benefit. For Locally Advanced Rectal Cancer Patients (LARC), a standardized neoadjuvant treatment protocol is applied, the identification and the usefulness of prognostic or predictive biomarkers can improve the antitumoural treatment strategy, modifying the sequence, dose, and combination of radiotherapy, chemotherapy and surgical resection. For these reasons, a growing number of studies are actually focussed on the discovery and investigation of new predictive biomarkers of response to pCRT. In this review, we have selected the most recent literature (2012-2017) regarding the employment of blood-based biomarkers potentially predicting pCR in LARC patients and we have critically discussed them to highlight their real clinical benefit and the current limitations of the proposed methodological approaches.
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Affiliation(s)
- Chiara Bedin
- Nano-inspired Biomedicine Lab, Paediatric Research Institute-Città della Speranza, Padua, Italy
| | - Sara Crotti
- Nano-inspired Biomedicine Lab, Paediatric Research Institute-Città della Speranza, Padua, Italy
| | - Edoardo D'Angelo
- Nano-inspired Biomedicine Lab, Paediatric Research Institute-Città della Speranza, Padua, Italy
| | - Sara D'Aronco
- Nano-inspired Biomedicine Lab, Paediatric Research Institute-Città della Speranza, Padua, Italy,First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Science, University of
Padua, Padua, Italy
| | - Salvatore Pucciarelli
- First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Science, University of
Padua, Padua, Italy
| | - Marco Agostini
- Nano-inspired Biomedicine Lab, Paediatric Research Institute-Città della Speranza, Padua, Italy,First Surgical Clinic Section, Department of Surgical, Oncological and Gastroenterological Science, University of
Padua, Padua, Italy
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14
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Mutation in BRAF and SMAD4 associated with resistance to neoadjuvant chemoradiation therapy in locally advanced rectal cancer. Virchows Arch 2019; 475:39-47. [DOI: 10.1007/s00428-019-02576-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 04/04/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022]
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15
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Karagkounis G, Kalady MF. Molecular Biology: Are We Getting Any Closer to Providing Clinically Useful Information? Clin Colon Rectal Surg 2017; 30:415-422. [PMID: 29184477 DOI: 10.1055/s-0037-1606373] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Advances in molecular biology and biomarker research have significantly impacted our understanding and treatment of multiple solid malignancies. In rectal cancer, where neoadjuvant chemoradiation is widely used for locally advanced disease, most efforts have focused on the identification of predictors of response in an attempt to appropriately select patients for multimodality therapy. A variety of biomarkers have been studied, including genetic mutations, chromosomal copy number alterations, and single as well as multigene expression patterns. Also, as transanal resection of rectal tumors requires accurate preoperative detection of lymph node metastasis, the identification of biomarkers of regional nodal involvement has been another important field of active research. While preliminary results have been promising, lack of external validation means has a limited translation to clinical use. This review summarizes recent developments in rectal cancer biomarker research, highlighting the challenges associated with their adoption, and evaluating their potential for clinical use.
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Affiliation(s)
- Georgios Karagkounis
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Matthew F Kalady
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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16
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Gollins S, West N, Sebag-Montefiore D, Myint AS, Saunders M, Susnerwala S, Quirke P, Essapen S, Samuel L, Sizer B, Worlding J, Southward K, Hemmings G, Tinkler-Hundal E, Taylor M, Bottomley D, Chambers P, Lawrie E, Lopes A, Beare S. Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations. Br J Cancer 2017; 117:1286-1294. [PMID: 28859058 PMCID: PMC5672930 DOI: 10.1038/bjc.2017.294] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 07/27/2017] [Accepted: 08/01/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. METHODS In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. RESULTS Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73-88%) (four patients with clinical complete response declined surgery). Twenty-four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05-1.03, P=0.055). CONCLUSIONS This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss.
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Affiliation(s)
- Simon Gollins
- Department of Oncology, North Wales Cancer Treatment Centre, Bodelwyddan, Denbighshire LL18 5UJ, UK
| | - Nick West
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK
| | | | - Arthur Sun Myint
- Clatterbridge Cancer Centre, Clatterbridge Road, Wirral CH63 4JY, UK
| | - Mark Saunders
- The Christie NHS Foundation Trust, Withington, Manchester M20 4BX, UK
| | | | - Phil Quirke
- Pathology and Tumour Biology, Level 4 Wellcome Trust Brenner Building, St James University Hospital, Beckett Street, Leeds LS9 7TF, UK
| | | | - Leslie Samuel
- Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK
| | - Bruce Sizer
- Colchester General Hospital, Turner Road, Colchester CO4 5JL, UK
| | - Jane Worlding
- University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK
| | - Katie Southward
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK
| | - Gemma Hemmings
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK
| | - Emma Tinkler-Hundal
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK
| | - Morag Taylor
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK
| | - Daniel Bottomley
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK
| | - Philip Chambers
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK
| | - Emma Lawrie
- Cancer Research UK & UCL Cancer Trials Centre, University College London, 90 Tottenham Court Road, London W1T 4TJ, UK
| | - Andre Lopes
- Cancer Research UK & UCL Cancer Trials Centre, University College London, 90 Tottenham Court Road, London W1T 4TJ, UK
| | - Sandy Beare
- Cancer Research UK & UCL Cancer Trials Centre, University College London, 90 Tottenham Court Road, London W1T 4TJ, UK
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17
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Benevento I, De Felice F, Musio D, Tombolini V. The Addition of Target Therapy to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: A Review. Chemotherapy 2017; 62:314-322. [PMID: 28595169 DOI: 10.1159/000476056] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 04/25/2017] [Indexed: 12/18/2022]
Abstract
Currently, neoadjuvant fluoropyrimidine-based chemoradiotherapy (CRT) is standard practice in the management of locally advanced rectal cancer (LARC). In the last decade there has been a lively interest in the improvement of clinical outcomes by modifying this standard regimen by the addition of further agents. We review combinations of targeted therapies and conventional CRT currently under investigation in LARC patients.
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Affiliation(s)
- Ilaria Benevento
- Department of Radiotherapy, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
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18
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Personalizing Therapy for Locally Advanced Rectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0355-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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19
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Yokoi K, Yamashita K, Ishii S, Tanaka T, Nishizawa N, Tsutsui A, Miura H, Katoh H, Yamanashi T, Naito M, Sato T, Nakamura T, Watanabe M. Comprehensive molecular exploration identified promoter DNA methylation of the CRBP1 gene as a determinant of radiation sensitivity in rectal cancer. Br J Cancer 2017; 116:1046-1056. [PMID: 28291773 PMCID: PMC5396119 DOI: 10.1038/bjc.2017.65] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/14/2017] [Accepted: 02/20/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Neoadjuvant chemoradiotherapy (NCRT) for advanced rectal cancer (RC) is a well-evidenced therapy; however, some RC patients have no therapeutic response. Patient selection for NCRT so that non-responsive patients are excluded has been subjective. To date, no molecular markers indicating radiation sensitivity have been reported. METHODS We irradiated six colorectal cancer (CRC) cell lines and identified HCT116 cells as radiation-sensitive and HCT15 and DLD-1 cells as radiation resistant. Using a microarray, we selected candidate radiation sensitivity marker genes by choosing genes whose expression was consistent with a radiation-resistant or sensitive cell phenotype. RESULTS Among candidate genes, cellular retinol binding protein 1 (CRBP1) was of particular interest because it was not only induced in HCT116 cells by tentative 10 Gy radiation treatments, but also its expression was increased in HCT116-derived radiation-resistant cells vs parental cells. Forced expression of CRBP1 decreased the viability of both HCT15 and DLD-1 cells in response to radiation therapy. We also confirmed that CRBP1 was epigenetically silenced by hypermethylation of its promoter DNA, and that the quantitative methylation value of CRBP1 significantly correlated with histological response in RC patients with NCRT (P=0.031). CONCLUSIONS Our study identified CRBP1 as a radiation-sensitive predictor in RC.
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Affiliation(s)
- K Yokoi
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - K Yamashita
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - S Ishii
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - T Tanaka
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - N Nishizawa
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - A Tsutsui
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - H Miura
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - H Katoh
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - T Yamanashi
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - M Naito
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - T Sato
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - T Nakamura
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
| | - M Watanabe
- Department of Surgery, Kitasato University School of Medicine, Kitasato, 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
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Abstract
Preoperative radiotherapy has an accepted role in reducing the risk of local recurrence in locally advanced resectable rectal cancer, particularly when the circumferential resection margin is breached or threatened, according to magnetic resonance imaging. Fluoropyrimidine-based chemoradiation can obtain a significant down-sizing response and a curative resection can then be achieved. Approximately, 20% of the patients can also obtain a pathological complete response, which is associated with less local recurrences and increased survival. Patients who achieve a sustained complete clinical response may also avoid radical surgery. In unresectable or borderline resectable tumors, around 20% of the patients still fail to achieve a sufficient down-staging response with the current chemoradiation schedules. Hence, investigators have aspired to increase pathological complete response rates, aiming to improve curative resection rates, enhance survival, and potentially avoid mutilating surgery. However, adding additional cytotoxic or biological agents have not produced dramatic improvements in outcome and often led to excess surgical morbidity and higher levels of acute toxicity, which effects on compliance and in the global efficacy of chemoradiation.
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Affiliation(s)
- Rob Glynne-Jones
- Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex, UK.
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21
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Ryan JE, Warrier SK, Lynch AC, Ramsay RG, Phillips WA, Heriot AG. Predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review. Colorectal Dis 2016; 18:234-46. [PMID: 26531759 DOI: 10.1111/codi.13207] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 09/17/2015] [Indexed: 02/08/2023]
Abstract
AIM Approximately 20% of patients treated with neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer achieve a pathological complete response (pCR) while the remainder derive the benefit of improved local control and downstaging and a small proportion show a minimal response. The ability to predict which patients will benefit would allow for improved patient stratification directing therapy to those who are likely to achieve a good response, thereby avoiding ineffective treatment in those unlikely to benefit. METHOD A systematic review of the English language literature was conducted to identify pathological factors, imaging modalities and molecular factors that predict pCR following chemoradiotherapy. PubMed, MEDLINE and Cochrane Database searches were conducted with the following keywords and MeSH search terms: 'rectal neoplasm', 'response', 'neoadjuvant', 'preoperative chemoradiation', 'tumor response'. After review of title and abstracts, 85 articles addressing the prediction of pCR were selected. RESULTS Clear methods to predict pCR before chemoradiotherapy have not been defined. Clinical and radiological features of the primary cancer have limited ability to predict response. Molecular profiling holds the greatest potential to predict pCR but adoption of this technology will require greater concordance between cohorts for the biomarkers currently under investigation. CONCLUSION At present no robust markers of the prediction of pCR have been identified and the topic remains an area for future research. This review critically evaluates existing literature providing an overview of the methods currently available to predict pCR to nCRT for locally advanced rectal cancer. The review also provides a comprehensive comparison of the accuracy of each modality.
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Affiliation(s)
- J E Ryan
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Epworth Healthcare, Melbourne, Victoria, Australia.,Austin Academic Centre, University of Melbourne, Parkville, Victoria, Australia
| | - S K Warrier
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - A C Lynch
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - R G Ramsay
- Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - W A Phillips
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.,Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - A G Heriot
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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Lee JW, Lee JH, Shim BY, Kim SH, Chung MJ, Kye BH, Kim HJ, Cho HM, Jang HS. KRAS Mutation Status Is Not a Predictor for Tumor Response and Survival in Rectal Cancer Patients Who Received Preoperative Radiotherapy With 5-Fluoropyrimidine Followed by Curative Surgery. Medicine (Baltimore) 2015; 94:e1284. [PMID: 26252300 PMCID: PMC4616597 DOI: 10.1097/md.0000000000001284] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
We evaluated the tumor response and survival according to the KRAS oncogene status in locally advanced rectal cancer. One hundred patients with locally advanced rectal cancer (cT3-4N0-2M0) received preoperative radiation of 50.4 Gy in 28 fractions with 5-fluorouracil and total mesorectal excision. Tumor DNA from each patient was obtained from pretreatment biopsy tissues. A Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation was found in 26 (26%) of the 100 patients. Downstaging (ypT0-2N0M0) rates after preoperative chemoradiotheray were not statistically different between the wild-type and mutant-type KRAS groups (30.8% vs 27.0%, P = 0.715, respectively). After a median follow-up time of 34 months, there was no statistically significant difference in the 3-year relapse-free survival (82.2% vs 82.6%, P = 0.512) and overall survival (94.7% vs 92.3%, P = 0.249) rates between wild-type and mutant-type KRAS groups, respectively. The KRAS mutation status does not influence the tumor response to the radiotherapy and survival in locally advanced rectal cancer patients who received preoperative chemoradiotherapy and curative surgery.
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Affiliation(s)
- Jeong Won Lee
- From the Department of Radiation Oncology, Seoul St. Mary's Hospital (JWL, HSJ); Department of Radiation Oncology (JHL, SHK, MJC); Department of Medical Oncology (BYS); Department of Colorectal Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (B-HK, HJK, HMC)
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Review of the development of DNA methylation as a marker of response to neoadjuvant therapy and outcomes in rectal cancer. Clin Epigenetics 2015. [PMID: 26203306 PMCID: PMC4511540 DOI: 10.1186/s13148-015-0111-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
There is much debate around the preoperative treatment of colorectal cancer and, in particular, neoadjuvant chemoradiotherapy in locally advanced rectal cancer. This treatment carries a significant risk of harmful side effects and has a highly variable response rate. Predictive biomarkers have been the subject of a great deal of study with the aim of pretreatment risk stratification in order to more accurately determine which patients will derive the most benefit and least harm from these treatments. The study of epigenetics in colorectal cancer is relatively recent, and distinct patterns of aberrant DNA methylation, in particular the cytosine-phosphate-guanine (CpG) island methylator phenotype (CIMP), have been demonstrated in colorectal cancer, and their characterisation and significance are under debate, particularly in rectal cancer. These patterns of DNA methylation have been associated with differences in response to therapy and treatment outcomes and therefore have the potential to be used as biomarkers in tailored therapy regimes for patients with rectal cancer. This review aims to summarise the current state of the art in rectal cancer, with particular regard to the determination of DNA methylation patterns, the CpG island methylator phenotype and its potential as a novel biomarker in rectal cancer treatment and prediction of outcomes and response after neoadjuvant chemoradiotherapy.
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Germline and somatic genetic predictors of pathological response in neoadjuvant settings of rectal and esophageal cancers: systematic review and meta-analysis. THE PHARMACOGENOMICS JOURNAL 2015; 16:249-65. [PMID: 26122021 DOI: 10.1038/tpj.2015.46] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 05/10/2015] [Accepted: 05/21/2015] [Indexed: 12/21/2022]
Abstract
Oncologists have pointed out an urgent need for biomarkers that can be useful for clinical application to predict the susceptibility of patients to preoperative therapy. This review collects, evaluates and combines data on the influence of reported somatic and germline genetic variations on histological tumor regression in neoadjuvant settings of rectal and esophageal cancers. Five hundred and twenty-seven articles were identified, 204 retrieved and 61 studies included. Among 24 and 14 genetic markers reported for rectal and esophageal cancers, respectively, significant associations in meta-analyses were demonstrated for the following markers. In rectal cancer, major response was more frequent in carriers of the TYMS genotype 2 R/2 R-2 R/3 R (rs34743033), MTHFR genotype 677C/C (rs1801133), wild-type TP53 and KRAS genes. In esophageal cancer, successful therapy appeared to correlate with wild-type TP53. These results may be useful for future research directions to translate reported data into practical clinical use.
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25
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Does the Addition of Cetuximab to Radiochemotherapy Improve Outcome of Patients with Locally Advanced Rectal Cancer? Long-Term Results from Phase II Trials. Gastroenterol Res Pract 2015; 2015:273489. [PMID: 25861256 PMCID: PMC4377474 DOI: 10.1155/2015/273489] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 03/03/2015] [Indexed: 12/21/2022] Open
Abstract
Purpose. The addition of cetuximab to radiochemotherapy (RCT) failed to improve complete response rates in locally advanced rectal cancer (LARC). We report the long-term results in patients treated within two sequential clinical trials. Methods. Patients receiving neoadjuvant RCT using capecitabine and irinotecan (CapIri) within a phase I/II trial or CapIri + cetuximab within a phase II trial were evaluated for analysis of disease-free survival (DFS) and overall survival (OS). KRAS exon 2 mutational status had been analyzed in patients receiving cetuximab. Results. 37 patients from the CapIri trial and 49 patients from the CapIri-cetuximab treatment group were evaluable. Median follow-up time was 75.2 months. The 5-year DFS rate was 82% (CapIri) and 79% (CapIri-cetuximab) (P = 0.62). The median OS was 127.4 months. 5-year OS was 73% for both groups (CapIri and CapIri-cetuximab) (P = 0.61). No significant difference in DFS (P = 0.86) or OS (P = 0.39) was noticed between patients receiving CapIri and those receiving CapIri-cetuximab with KRAS wild-type tumors. Conclusions. As the addition of cetuximab did not improve neither DFS nor OS it should not play a role in the perioperative treatment of patients with LARC, not even of patients with (K)RAS WT tumors.
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Stojsic J, Stankovic T, Stojkovic S, Milinkovic V, Dinic J, Milosevic Z, Milovanovic Z, Tanic N, Bankovic J. Prolonged survival after neoadjuvant chemotherapy related with specific molecular alterations in the patients with nonsmall-cell lung carcinoma. Exp Mol Pathol 2015; 98:27-32. [DOI: 10.1016/j.yexmp.2014.11.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 11/18/2014] [Indexed: 11/25/2022]
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Berardi R, Maccaroni E, Onofri A, Morgese F, Torniai M, Tiberi M, Ferrini C, Cascinu S. Locally advanced rectal cancer: the importance of a multidisciplinary approach. World J Gastroenterol 2014; 20:17279-17287. [PMID: 25516638 PMCID: PMC4265585 DOI: 10.3748/wjg.v20.i46.17279] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 07/09/2014] [Accepted: 07/29/2014] [Indexed: 02/07/2023] Open
Abstract
Rectal cancer accounts for a relevant part of colorectal cancer cases, with a mortality of 4-10/100000 per year. The development of locoregional recurrences and the occurrence of distant metastases both influences the prognosis of these patients. In the last two decades, new multimodality strategies have improved the prognosis of locally advanced rectal cancer with a significant reduction of local relapse and an increase in terms of overall survival. Radical surgery still remains the principal curative treatment and the introduction of total mesorectal excision has significantly achieved a reduction in terms of local recurrence rates. The employment of neoadjuvant treatment, delivered before surgery, also achieved an improved local control and an increased sphincter preservation rate in low-lying tumors, with an acceptable acute and late toxicity. This review describes the multidisciplinary management of rectal cancer, focusing on the effectiveness of neoadjuvant chemoradiotherapy and of post-operative adjuvant chemotherapy both in the standard combined modality treatment programs and in the ongoing research to improve these regimens.
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Abdul-Jalil KI, Sheehan KM, Toomey S, Schmid J, Prehn J, O'Grady A, Cummins R, O'Neill B, McNamara DA, Deasy J, Breathnach O, Grogan L, Rogers A, Doherty G, Winter D, Ryan J, El-Masry S, Gibbons D, Sheahan K, Gillen P, Kay EW, Hennessy BT. The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer: a pilot study. Ann Surg Oncol 2014; 21:2642-9. [PMID: 24700299 DOI: 10.1245/s10434-014-3658-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes. METHODS We genotyped 234 potentially clinically relevant nonsynonymous mutations in 33 PI3K and MAPK pathway-related genes, including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET, and NRAS, using the Sequenom platform. DNA samples were extracted from pretreatment LARC biopsy samples taken from 201 patients who were then treated with long-course neoadjuvant CRT followed by surgical resection. RESULTS Sixty-two mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (47 %), PIK3CA (14 %), STK11 (6.5 %), and CTNNB1 (6 %). Mutations were detected in BRAF, NRAS, AKT1, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK, and TNK2, but at frequencies of <5 %. As expected, a pathologic complete response (pCR) was associated with improved 5-year recurrence-free survival (RFS; hazard ratio, 0.074; 95 % CI 0.01-0.54; p = 0.001). Mutations in PI3K pathway-related genes (odds ratio, 5.146; 95 % CI 1.17-22.58; p = 0.030), but not MAPK pathway-related genes (p = 0.911), were associated with absence of pCR after neoadjuvant CRT. In contrast, in patients who did not achieve pCR, mutations in PI3K pathway-related genes were not associated with recurrence-free survival (p = 0.987). However, in these patients, codon 12 (G12D/G12 V/G12S) and 13 mutations in KRAS were associated with poor recurrence-free survival (hazard ratio, 1.579; 95 % confidence ratio, 1.00-2.48; p = 0.048). CONCLUSIONS Mutations in kinase signaling pathways modulate treatment responsiveness and clinical outcomes in LARC and may constitute rational targets for novel therapies.
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Preoperative Chemoradiation Therapy With Capecitabine/Oxaliplatin and Cetuximab in Rectal Cancer: Long-Term Results of a Prospective Phase 1/2 Study. Int J Radiat Oncol Biol Phys 2013; 87:992-9. [DOI: 10.1016/j.ijrobp.2013.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 09/04/2013] [Accepted: 09/08/2013] [Indexed: 12/14/2022]
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Berardi R, Maccaroni E, Mantello G, Onofri A, Mandolesi A, Bearzi I, Cascinu S. Locally advanced rectal cancer: new findings in anticancer therapy. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.73] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY Rectal cancer accounts for nearly a third of colorectal cancer cases, with a mortality of 4–10 cases per 100,000 per year, thus accounting for 9% of cancer deaths both in males and in females in western countries. Management of locally advanced rectal cancer has undergone and continues to undergo significant progress in the last two decades: in particular, new multimodality strategies have contributed to marked improvements in terms of reduction of both local and distant recurrence rates. This review focuses and summarizes the effectiveness of multimodality approaches in the standard treatment programs for locally advanced rectal cancer and also discusses the ongoing research to improve these regimens.
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Affiliation(s)
- Rossana Berardi
- Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Via Conca 71, 60126 Ancona, Italy
| | - Elena Maccaroni
- Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Via Conca 71, 60126 Ancona, Italy
| | - Giovanna Mantello
- Radiotherapy, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy
| | - Azzurra Onofri
- Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Via Conca 71, 60126 Ancona, Italy
| | - Alessandra Mandolesi
- Anatomia Patologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy
| | - Italo Bearzi
- Anatomia Patologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy
| | - Stefano Cascinu
- Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Via Conca 71, 60126 Ancona, Italy
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Lee YC, Lee YL, Chuang JP, Lee JC. Differences in survival between colon and rectal cancer from SEER data. PLoS One 2013; 8:e78709. [PMID: 24265711 PMCID: PMC3827090 DOI: 10.1371/journal.pone.0078709] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 09/16/2013] [Indexed: 12/20/2022] Open
Abstract
Background Little is known about colorectal cancer or colon and rectal cancer. Are they the same disease or different diseases? Objectives The aim of this epidemiology study was to compare the features of colon and rectal cancer by using recent national cancer surveillance data. Design and setting Data included colorectal cancer (1995–2008) from the Surveillance, Epidemiology, and End Results Program (SEER) database. Only adenocarcinoma was included for analysis. Patients A total of 372,130 patients with a median follow-up of 32 months were analyzed. Main outcome measures Mean survival of patients with the same stage of colon and rectal cancer was evaluated. Results Around 35% of patients had stage information. Among them, colon cancer patients had better survival than those with rectal cancer, by a margin of 4 months in stage IIB. In stage IIIC and stage IV, rectal cancer patients had better survival than colon cancer patients, by about 3 months. Stage IIB colorectal cancer patients had a poorer prognosis than those with stage IIIA and IIIB colorectal cancer. After adjustment of age, sex and race, colon cancer patients had better survival than rectal cancer of stage IIB, but in stage IIIC and IV, rectal cancer patients had better survival than colon cancer. Limitations The study is limited by its retrospective nature. Conclusion This was a population-based study. The prognosis of rectal cancer was not worse than that of colon cancer. Local advanced colorectal cancer had a poorer prognosis than local regional lymph node metastasis. Stage IIB might require more aggressive chemotherapy, and no less than that for stage III.
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Affiliation(s)
- Yen-Chien Lee
- Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan, R.O.C
- Department of Oncology, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, R.O.C
| | - Yen-Lin Lee
- Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan, R.O.C
- Department of Oncology, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, R.O.C
| | - Jen-Pin Chuang
- Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan, R.O.C
- Department of Surgery, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, R.O.C
| | - Jenq-Chang Lee
- Department of Surgery, National Cheng Kung University Medical Center, Tainan, Taiwan, R.O.C
- * E-mail:
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Glynne-Jones R, Hadaki M, Harrison M. The status of targeted agents in the setting of neoadjuvant radiation therapy in locally advanced rectal cancers. J Gastrointest Oncol 2013; 4:264-84. [PMID: 23997939 DOI: 10.3978/j.issn.2078-6891.2013.037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 05/21/2013] [Indexed: 12/18/2022] Open
Abstract
Radiotherapy has a longstanding and well-defined role in the treatment of resectable rectal cancer to reduce the historically high risk of local recurrence. In more advanced borderline or unresectable cases, where the circumferential resection margin (CRM) is breached or threatened according to magnetic resonance imaging (MRI), despite optimized local multimodality treatment and the gains achieved by modern high quality total mesorectal excision (TME), at least half the patients fail to achieve sufficient downstaging with current schedules. Many do not achieve an R0 resection. In less locally advanced cases, even if local control is achieved, this confers only a small impact on distant metastases and a significant proportion of patients (30-40%) still subsequently develop metastatic disease. In fact, distant metastases have now become the predominant cause of failure in rectal cancer. Therefore, increasing the intensity and efficacy of chemotherapy and chemoradiotherapy by integrating additional cytotoxics and biologically targetted agents seems an appealing strategy to explore-with the aim of enhancing curative resection rates and improving distant control and survival. However, to date, we lack validated biomarkers for these biological agents apart from wild-type KRAS. For cetuximab, the appearance of an acneiform rash is associated with response, but low levels of magnesium appear more controversial. There are no molecular biomarkers for bevacizumab. Although some less invasive clinical markers have been proposed for bevacizumab, such as circulating endothelial cells (CECS), circulating levels of VEGF and the development of overt hypertension, these biomarkers have not been validated and are observed to emerge only after a trial of the agent. We also lack a simple method of ongoing monitoring of 'on target' effects of these biological agents, which could determine and pre-empt the development of resistance, prior to radiological and clinical assessessments or even molecular imaging. These shortcomings probably explain our current relative lack of success in the arena of combining these agents with chemoradiation.
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Gantt GA, Kalady MF. Molecular markers for targeted neoadjuvant rectal cancer therapy. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.35] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY Neoadjuvant chemoradiotherapy is the standard of care for locally advanced rectal cancer. While neoadjuvant chemoradiation has been demonstrated to improve oncological outcomes, there is a wide spectrum of responses to therapy. The ability to predict who will respond favorably or unfavorably to neoadjuvant therapy could prevent unnecessary morbidity and potentially lead to novel therapeutic targets. A number of individual biomarkers and multigene signatures have been investigated as potential means of predicting response to neoadjuvant chemoradiation. While promising, none of these predictive biomarkers have yet been introduced clinically. This review summarizes both individual and multigene biomarkers for rectal cancer response to neoadjuvant chemoradiation.
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Affiliation(s)
- Gerald A Gantt
- Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Matthew F Kalady
- Department of Stem Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
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Clancy C, Burke JP, Coffey JC. KRAS mutation does not predict the efficacy of neo-adjuvant chemoradiotherapy in rectal cancer: a systematic review and meta-analysis. Surg Oncol 2013; 22:105-11. [PMID: 23473635 DOI: 10.1016/j.suronc.2013.02.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 01/30/2013] [Accepted: 02/03/2013] [Indexed: 01/12/2023]
Abstract
INTRODUCTION The current management of locally advanced rectal cancer involves total mesorectal excision, which may be preceded by neo-adjuvant chemoradiotherapy (CRT). Individual patient response to CRT is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of the current study was to systematically appraise the effect of KRAS mutation on outcomes following CRT for rectal cancer. METHODS A comprehensive search for published studies examining the effect of KRAS mutation on outcome after neo-adjuvant CRT in rectal cancer was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data. RESULTS Data was retrieved from 8 series describing 696 patients. Neo-adjuvant treatment regimens varied in usage of chemotherapeutic agents and interval to surgery. KRAS mutation was present in an average of 33.2 ± 11.8% of patients with rectal cancer. KRAS mutation was not associated with decreased rates of pathological complete response (odds ratio (OR): 0.778, 95% confidence interval (CI): 0.424-1.428, P = 0.418), tumor down-staging (OR: 0.846, 95% CI: 0.331-2.162, P = 0.728) or an increase in cancer related mortality (OR: 1.239, 95% CI: 0.607-2.531, P = 0.555). CONCLUSIONS Based on these data, the presence of KRAS mutation does not affect tumor down-staging or cancer specific survival following neo-adjuvant CRT and surgery for rectal cancer.
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Affiliation(s)
- Cillian Clancy
- Department of Colorectal Surgery, University Hospital Limerick, Graduate Entry Medical School, University of Limerick, Ireland
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Personalized radiation therapy and biomarker-driven treatment strategies: a systematic review. Cancer Metastasis Rev 2013; 32:479-92. [DOI: 10.1007/s10555-013-9419-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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36
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Chargari C, Soria JC, Deutsch E. Controversies and challenges regarding the impact of radiation therapy on survival. Ann Oncol 2013; 24:38-46. [DOI: 10.1093/annonc/mds217] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Ree AH, Kristensen AT, Saelen MG, de Wijn R, Edvardsen H, Jovanovic J, Abrahamsen TW, Dueland S, Flatmark K. Tumor phosphatidylinositol-3-kinase signaling and development of metastatic disease in locally advanced rectal cancer. PLoS One 2012; 7:e50806. [PMID: 23226389 PMCID: PMC3511283 DOI: 10.1371/journal.pone.0050806] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Accepted: 10/25/2012] [Indexed: 02/02/2023] Open
Abstract
Background Recognizing EGFR as key orchestrator of the metastatic process in colorectal cancer, but also the substantial heterogeneity of responses to anti-EGFR therapy, we examined the pattern of composite tumor kinase activities governed by EGFR-mediated signaling that might be implicated in development of metastatic disease. Patients and Methods Point mutations in KRAS, BRAF, and PIK3CA and ERBB2 amplification were determined in primary tumors from 63 patients with locally advanced rectal cancer scheduled for radical treatment. Using peptide arrays with tyrosine kinase substrates, ex vivo phosphopeptide profiles were generated from the same baseline tumor samples and correlated to metastasis-free survival. Results Unsupervised clustering analysis of the resulting phosphorylation of 102 array substrates defined two tumor classes, both consisting of cases with and without KRAS/BRAF mutations. The smaller cluster group of patients, with tumors generating high ex vivo phosphorylation of phosphatidylinositol-3-kinase-related substrates, had a particularly aggressive disease course, with almost a half of patients developing metastatic disease within one year of follow-up. Conclusion High phosphatidylinositol-3-kinase-mediated signaling activity of the primary tumor, rather than KRAS/BRAF mutation status, was identified as a hallmark of poor metastasis-free survival in patients with locally advanced rectal cancer undergoing radical treatment of the pelvic cavity.
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Affiliation(s)
- Anne Hansen Ree
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
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Weber GF, Rosenberg R, Murphy JE, Meyer zum Büschenfelde C, Friess H. Multimodal treatment strategies for locally advanced rectal cancer. Expert Rev Anticancer Ther 2012; 12:481-94. [PMID: 22500685 DOI: 10.1586/era.12.3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
This review outlines the important multimodal treatment issues associated with locally advanced rectal cancer. Changes to chemotherapy and radiation schema, as well as modern surgical approaches, have led to a revolution in the management of this disease but the morbidity and mortality remains high. Adequate treatment is dependent on precise preoperative staging modalities. Advances in staging via endorectal ultrasound, computed tomography, MRI and PET have improved pretreatment triage and management. Important prognostic factors and their impact for this disease are under investigation. Here we discuss the different treatment options including modern tumor-related surgical approaches, neoadjuvant as well as adjuvant therapies. Further clinical progress will largely depend on the broader implementation of multidisciplinary treatment strategies following the principles of evidence-based medicine.
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Affiliation(s)
- Georg F Weber
- Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA
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KRAS mutation status and clinical outcome of preoperative chemoradiation with cetuximab in locally advanced rectal cancer: a pooled analysis of 2 phase II trials. Int J Radiat Oncol Biol Phys 2012; 85:201-7. [PMID: 22672749 DOI: 10.1016/j.ijrobp.2012.03.048] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 03/13/2012] [Accepted: 03/13/2012] [Indexed: 12/19/2022]
Abstract
PURPOSE Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. METHODS AND MATERIALS We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m2 weekly and 1650 mg/m2/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m2 on 1 week before radiation, and 250 mg/m2 weekly thereafter. RESULTS Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. CONCLUSIONS In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with irinotecan plus capecitabine regimen was not associated with improved clinical outcome compared with chemoradiation without cetuximab.
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Cetuximab in preoperative treatment of rectal cancer - term outcome of the XERT trial. Radiol Oncol 2012; 46:252-7. [PMID: 23077464 PMCID: PMC3472951 DOI: 10.2478/v10019-012-0030-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 03/19/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Preoperative capecitabine-based chemoradiotherapy (CRT) is feasible for the treatment of resectable locally advanced rectal cancer (LARC). To try to improve efficacy, we conducted a phase II study in which the epidermal growth factor receptor-targeting monoclonal antibody cetuximab was added to capecitabine-based CRT. The results for long-term survival and for an analysis investigating the relationship between survival and patient and disease characteristics, including tumour KRAS mutation status, and surgery type, are presented. PATIENTS AND METHODS.: Patients with resectable LARC received capecitabine (1250 mg/m(2) twice daily, orally) for 2 weeks followed by cetuximab alone (400 mg/m(2) for 1 week) and then with CRT (250 mg/m(2)/week) comprising capecitabine (825 mg/m(2) twice daily) and radiotherapy to the small pelvis (45 Gy in 25 1.8-Gy fractions), five days a week for five weeks. Surgery was conducted six weeks following CRT, with post-operative chemotherapy with capecitabine (1250 mg/m(2) twice daily for 14 days every 21 days) three weeks later. RESULTS Forty-seven patients were enrolled and 37 underwent treatment. Twenty-eight of the patients (75.7%) had T3N+ disease. Thirty-six patients were evaluable for efficacy. The median follow-up time was 39.0 months (range 5.0--87.0). The three-year local control, disease-free survival, relapse-free survival and overall survival rates were 96.9% (95% CI 90.0--100), 72.2% (57.5--86.9), 74.3% (95% CI 59.8--88.8) and 68.1% (95% CI 36.7--99.4), respectively. There was no significant association between survival and gender, age, tumour location in the rectum, type of surgery, pathological T or N status, tumour regression grade or tumour KRAS mutation status, although sample sizes were small. CONCLUSIONS Preoperative cetuximab plus capecitabine-based CRT was feasible in patients with resectable LARC and was associated with an impressive three-year local control rate. The use of tumour KRAS mutation status as a biomarker for the efficacy of cetuximab-based regimens in this setting requires further investigation.
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Garcia-Aguilar J, Chen Z, Smith DD, Li W, Madoff RD, Cataldo P, Marcet J, Pastor C. Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer. Ann Surg 2011; 254:486-92; discussion 492-3. [PMID: 21865946 PMCID: PMC3202983 DOI: 10.1097/sla.0b013e31822b8cfa] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To identify a biomarker profile associated with tumor response to chemoradiation (CRT) in locally advanced rectal cancer. BACKGROUND Rectal cancer response to neoadjuvant CRT is variable. Whereas some patients have a minimal response, others achieve a pathologic complete response (pCR) and have no viable cancer cells in their surgical specimens. Identifying biomarkers of response will help select patients more likely to benefit from CRT. METHODS This study includes 132 patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by surgery. Tumor DNA from pretreatment tumor biopsies and control DNA from paired normal surgical specimens was screened for mutations and polymorphisms in 23 genes. Genetic biomarkers were correlated with tumor response to CRT (pCR vs non-pCR), and the association of single or combined biomarkers with tumor response was determined. RESULTS Thirty-three of 132 (25%) patients achieved a pCR and 99 (75%) patients had non-pCR. Three individual markers were associated with non-pCR; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutation (P = 0.0145), cyclin D1 G870A (AA) polymorphism (P = 0.0138), and methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (P = 0.0120). Analysis of biomarker combinations revealed that none of the 27 patients with both tumor protein p53 (p53) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations had a pCR. Further, in patients with both p53 and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations or the cyclin D1 G870A (AA) polymorphism or the methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (n = 52) the association with non-pCR was further strengthened; 51 of 52 (98%) of patients were non-pCR. These biomarker combinations had a validity of more than 70% and a positive predictive value of 97% to 100%, predicting that patients harboring these mutation/polymorphism profiles will not achieve a pCR. CONCLUSIONS A specific biomarker profile is strongly associated with non-pCR to CRT and could be used to select optimal oncologic therapy in rectal cancer patients. ClinicalTrials.org Identifier: NCT00335816.
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Schwaab J, Horisberger K, Ströbel P, Bohn B, Gencer D, Kähler G, Kienle P, Post S, Wenz F, Hofmann WK, Hofheinz RD, Erben P. Expression of Transketolase like gene 1 (TKTL1) predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy. BMC Cancer 2011; 11:363. [PMID: 21854597 PMCID: PMC3176245 DOI: 10.1186/1471-2407-11-363] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Accepted: 08/19/2011] [Indexed: 01/09/2023] Open
Abstract
Background For patients with locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R) and Transketolase-like-1 (TKTL1) are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab. Methods Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years) with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy) were analysed by quantitative PCR. Results Significantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers. Conclusion High TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.
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Affiliation(s)
- Juliana Schwaab
- III, Medizinische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
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Spolverato G, Pucciarelli S, Bertorelle R, De Rossi A, Nitti D. Predictive factors of the response of rectal cancer to neoadjuvant radiochemotherapy. Cancers (Basel) 2011; 3:2176-94. [PMID: 24212803 PMCID: PMC3757411 DOI: 10.3390/cancers3022176] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Revised: 04/08/2011] [Accepted: 04/11/2011] [Indexed: 02/07/2023] Open
Abstract
Locally advanced rectal cancer is currently treated with pre-operative radiochemotherapy (pRCT), but the response is not uniform. Identification of patients with higher likelihood of responding to pRCT is clinically relevant, as patients with resistant tumors could be spared exposure to radiation or DNA-damaging drugs that are associated with adverse side effects. To highlight predictive biomarkers of response to pRCT, a systematic search of PubMed was conducted with a combination of the following terms: "rectal", "predictive", "radiochemotherapy", "neoadjuvant", "response" and "biomarkers". Genetic polymorphisms in epithelial growth factor receptor (EGFR) and thymidylate synthase (TS) genes, the expression of several markers, such as EGFR, bcl-2/bax and cyclooxygenase (COX)-2, and circulating biomarkers, such as serum carcinoembryonic antigen (CEA) level, are promising as predictor markers, but need to be further evaluated. The majority of the studies did not support the predictive value of p53, while the values of Ki-67, TS and p21 is still controversial. Gene expression profiles of thousands of genes using microarrays, microRNA studies and the search for new circulating molecules, such as human telomerase reverse transcriptase mRNA and cell-free DNA, are providing interesting results that might lead to the identification of new useful biomarkers. Evaluation of biomarkers in larger, prospective trials are required to guide therapeutic strategies.
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Affiliation(s)
- Gaya Spolverato
- Department of Oncology and Surgical Sciences, Section of Surgery, University of Padova, Padova 35128, Italy; E-Mails: (G.S.); (S.P.); (D.N.)
| | - Salvatore Pucciarelli
- Department of Oncology and Surgical Sciences, Section of Surgery, University of Padova, Padova 35128, Italy; E-Mails: (G.S.); (S.P.); (D.N.)
| | | | - Anita De Rossi
- Istituto Oncologico Veneto-IRCCS, Padova 35128, Italy; E-Mail: (R.B.)
- Department of Oncology and Surgical Sciences, Section of Oncology, University of Padova, Padova 35128, Italy
| | - Donato Nitti
- Department of Oncology and Surgical Sciences, Section of Surgery, University of Padova, Padova 35128, Italy; E-Mails: (G.S.); (S.P.); (D.N.)
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