Understanding the clinical behavior of relapsed colon cancers with microsatellite instability relative to BRAF mutations
Authors: D. Roda, S. Roselló, A. Cervantes
Journal: Annals of Oncology (2019)

When a physician approaches a new patient with colon cancer, whether it is localized or metastatic, they have to consider that this cancer is not a single disease, but rather a heterogeneous group of diseases that, despite involving the same organ, are driven by different pathogenesis and diverse molecular alterations. Our clinical decisions depend on not only pathological stage and tumor location but also specific molecular markers with prognostic or predictive value [1.Dienstmann R. Vermeulen L. Guinney J. et al.Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer.Nat Rev Cancer. 2017; 17: 79-92Crossref PubMed Scopus (474) Google Scholar, 2.Smeby J. Sveen A. Merck M.A. et al.CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer.Ann Oncol. 2018; 29: 2227-2234Abstract Full Text Full Text PDF Scopus (51) Google Scholar]. For this reason, it is important that we know how different molecular subgroups behave clinically. In the current issue of Annals of Oncology, Taieb et al. [3.Taieb J. Shi Q. Pederson L. et al.Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant adjuvant treatment: results of an ACCENT pooled analysis of 7 studies.Ann Oncol. 2019; 30: 1466-1471Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] report an analysis of 2630 stage III colon cancer patients who recurred after surgical resection with curative intent plus adjuvant chemotherapy to evaluate the relevance of microsatellite instability/deficient mismatch repair (MSI/dMMR) to predict survival after recurrence (SAR). Because BRAF mutations occur more often in patients with MSI, particularly when hypermethylation of the MLH1 gene promoter is present, the authors also analyzed the impact of BRAF on SAR. The authors of this article should be congratulated for making this important effort in helping us to better understand the clinical behavior of relapsed colon cancers with MSI, with or without BRAF mutations. This large sample of patients comes from seven randomized adjuvant trials, which were published between 2004 and 2014. All these trials were multicenter and carried out on both sides of the Atlantic. Despite the fact that 4861 participants in these trials recurred, only 54% could complete the molecular analysis. This limitation was mainly due to the lack of tumor samples or because the patient informed consents could not be obtained. This selection bias certainly limits the interpretation of the data. On the other hand, the main strengths of this analysis are the otherwise large numbers, the multinational origin of the patients and the quality of the ACCENT database of the trials from which patients were extracted. This report shows that SAR is better for stage III colon cancer patients who relapse after adjuvant chemotherapy with MSI/dMMR than for patients with proficient MMR or microsatellite stable (MSS) phenotype. Currently, patients with MSI/dMMR may be treated with checkpoint inhibitors [4.Le D.T. Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (6099) Google Scholar]. However, these studies were performed before there was the opportunity to be treated with checkpoint inhibitors. The finding of a prolonged SAR in the ACCENT report contrasts with another retrospective series containing more than 3000 patients which reported worse outcomes for patients with dMMR who were included in four first-line advanced disease trials [5.Venderbosch S. Nagtegaal I.D. Maughan T. et al.Mismatch repair status and BRAF mutation status in metastatic colorrectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies.Clin Cancer Res. 2014; 20: 5322-5330Crossref PubMed Scopus (424) Google Scholar]. Different conclusions in these two reports may be related to their retrospective nature and the different way they were designed, as well as to differences between adjuvant and advanced disease trials. The expected observation in Taieb’s article is the bad prognosis related to the presence BRAF mutations in primary tumors in both MSI and MSS, although a trend for better SAR is seen for BRAF mutant tumors with MSI. But a question remains unanswered: how can we use this information for MSI and BRAF mutant colon cancer patients? This question is even more relevant if MSI and BRAF are recognized not only as prognostic but also as predictive factors. Although checkpoint inhibitors have Food and Drug Administration regulatory approval for tumor agnostic MSI metastatic colon cancer [6.Marcus L. Lemery S.J. Keegan P. Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors.Clin Cancer Res. 2019; 25: 3753-3758Crossref PubMed Scopus (509) Google Scholar], randomized trials in MSI advanced colon cancer are underway to determine the duration of treatment, the optimal timing of immunotherapy compared with chemotherapy as well as the potential of combinations to improve the benefits of antiPD-1 antibodies. Moreover, the proportion of patients with MSI tumors presenting with concurrent BRAF mutations widely varies in several reports from 24% to 34% [4.Le D.T. Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (6099) Google Scholar, 5.Venderbosch S. Nagtegaal I.D. Maughan T. et al.Mismatch repair status and BRAF mutation status in metastatic colorrectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies.Clin Cancer Res. 2014; 20: 5322-5330Crossref PubMed Scopus (424) Google Scholar, 7.Overman M.J. Lonardi S. Wong K.Y.M. et al.Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer.JCO. 2018; 36: 773-779Crossref PubMed Scopus (1096) Google Scholar], but there is no clear indication if BRAF mutations may modify or not the sensitivity of MSI colon cancers to checkpoint inhibitors. A similar era is emerging for BRAF mutant tumors. The data recently presented on the safety cohort of the BEACON trial for advanced colon cancer patients bearing BRAF mutant tumors indicates better outcomes including a response rate of 48% and encouraging overall survival in the second- or third-line setting for patients allocated to a triple combination of cetuximab (an epidermal growth factor receptor inhibitor), encorafenib (a BRAF inhibitor) and binimetinib (a MET inhibitor) versus chemotherapy with irinotecan or FOLFIRI plus cetuximab [8.Kopetz S. Grothey A. van Cutsem E. et al.BEACON CRC: a randomized, 3-Arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E–mutant metastatic colorectal cancer.Ann Oncol. 2019; 30 (LBA 06)Abstract Full Text Full Text PDF Scopus (9) Google Scholar]. These results not only raise hope for patients with poor prognosis BRAF mutations but also confirm that BRAF mutational status, as a relevant predictive biomarker, has to be known before setting a treatment plan for any advanced colon cancer patients. The molecular landscape of colon cancer is moving forward to the clinic and it is far from being only RAS centered. Apart from MSI/dMMR and BRAF, HER2 amplification [9.Siena S. Sartore-Bianchi A. Marsoni S. et al.Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer.Ann Oncol. 2018; 29: 1108-1119Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar] and some low-prevalence gene rearrangements [10.Pietrantonio F. Di Nicolantonio F. Schrock A.B. et al.ALK, ROS1, and NTRK rearrangements in metastatic colorectal cancer.J Natl Cancer Inst. 2017; 109https://doi.org/10.1093/jnci/djx089Crossref PubMed Scopus (148) Google Scholar] are becoming relevant. We should be ready to adapt to those changes. Precision oncology is becoming stronger for colorectal cancer patients. Fondo de Investigaciones Sanitarias. Instituto de Salud Carlos III. Ministerio de Economía y Competitividad. DR was supported by Joan Rodes contract 16/00040. PI15/02180 to AC. PI18/01909 to AC and DR.