Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Improvements in Clinical Outcomes for BRAFV600E-mutant Metastatic Colorectal Cancer Authors: Van K Morris,1 Tanios Bekaii-Saab2 Affiliations: 1University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Mayo Clinic College of Medicine and Science, Phoenix, Arizona Corresponding author: Name: Tanios Bekaii Saab Address: Mayo Clinic, 5881 E Mayo Blvd, Phoenix, Arizona, 85054 Tel: +014803422501 Email: [email protected] Running title: BRAFV600E-mutant metastatic colorectal cancer Acknowledgments Publication of this article was supported by Pfizer Inc (formerly Array BioPharma), who were given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion. All authors meet the authorship criteria of the International Committee of Medical Journal Editors, take responsibility for the integrity of the work and provided final approval of the version to be published. Medical writing support was provided by Alex Lowe, PhD of Touch Medical Communications and subsequently by JD Cox, PhD of Mayville Medical Communications (funded by Pfizer Inc). 1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Conflicts of interests TBS is a paid consultant for Imugen and a paid IDMC member for Exelixis, Astra Zeneca, Silajen and Armo. He is also a consultant for Array Biopharma, Bayer, Amgen, Incyte, Ipsen, Merck and Seattle Genetics. VKM is a consultant for Array Biopharma and Incyte, and has research support from EMD Serono, Astra Zeneca, Bristol Myers Squibb, and Array Biopharma. Max word count; current word count: 2000–10,000; Current: 4147 Max no. tables/figures: 0 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Abstract Although the last two decades have seen a broad improvement in overall survival, colorectal cancer (CRC) is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their CRC. Consequently, many patients present with metastatic CRC, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of CRC tumors and are associated with uninhibited cell proliferation, reduced apoptosis and resistance to standard therapeutic options. In CRC, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared to tumors with wildtype BRAF. Success in treating other BRAF V600E- mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic CRC. Consequently, combination therapy with inhibitors of BRAF, MEK, and epidermal growth factor receptor, which overcomes the innate treatment-resistant characteristics of BRAF V600E-mutant CRC, is now recommended by treatment guidelines. Keywords (Max 5): Colorectal cancer, biomarker, metastasis, MAPK signaling, BRAFV600E 3 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer Introduction Colorectal cancer (CRC) is a common cause of morbidity and mortality, and currently the second and third most common cancer worldwide in women and men respectively, accounting for 1.8 million new diagnoses and approximately 880,800 deaths in 2018.(1),(2),(3),(4) Given the inherent clinical challenges in diagnosing CRC including variable symptomatic presentation, natural history, rate of progression and tumor mutations, there is now a focus on the role of biomarkers in disease identification and predicting treatment responses.(5) Promising new treatments being explored for the treatment of CRC include inhibitors of critical oncoproteins in the MAPK signaling pathway, including MEK, BRAF and epidermal growth factor receptor (EGFR).(6) A key pathway in the pathogenesis of CRC is the mitogen-activated protein kinase (MAPK) signaling pathway.(7) Dysfunction of this pathway, including the RAS, RAF, and MEK kinases leads to increased cell proliferation and survival by the disruption of apoptosis.(7) Activating point mutations of the RAS family genes (H-RAS, K-RAS, and N-RAS) are common and comprise up to 30% of all human cancers.14 In this pathway, BRAF is a serine/threonine kinase downstream of EGFR and RAS.(7) Mutations in the BRAF gene most commonly result in a substitution of valine to glutamic acid at the 600th amino acid (BRAFV600; approximately 90% of BRAF mutations) and are mutually exclusive from KRAS/NRAS mutations.(6, 8, 9) BRAF mutations lead to a conformational change of RAF kinase, leading to the activation of BRAF kinase and the downstream MAPK pathway, subsequently driving increased tumor cell proliferation and anti-apoptotic behavior.(6) BRAFV600E mutations occur in approximately 10% of cases of CRC (estimates range from 5% to 21%),(6, 9-17) as well as being present in 51% of papillary thyroid cancers, 7% of non-small cell lung cancers and 40 to 60% of melanoma cases.(6, 8, 9, 14, 18-20) In recognition of the importance of BRAF V600E mutations in CRC, screening is recommended in the National Comprehensive Cancer Network (NCCN) guidelines.(21, 22) However, despite these recommendations, testing rates for BRAFV600E mutations may be as low 4 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer as 11.5% before first-line treatment initiation, once again highlighting the need for a more comprehensive screening effort.(23) Understanding the clinical impact of BRAFV600E mutations Due to their association with dysregulation of the MAPK pathway, the BRAFV600E mutation is an important prognostic biomarker and has predictive implications for patients with metastatic CRC.(6, 24, 25) In contrast, the less-common BRAFnon-V600 mutations, which are found in approximately 2% of patients with metastatic CRC, are associated with an improved disease prognosis compared with patients with BRAFV600E-mutant metastatic CRC.(26) The increasing incidence of BRAFV600E mutations with age in CRC may be a contributing factor to worse overall prognosis of patients with this mutation.(8) Additionally, mutations in BRAFV600E are associated with higher rates of bone, brain, and peritoneal involvement, a unique pattern of metastatic spread and worse health-related quality of life (HRQoL), relative to their BRAFV600E wildtype counterparts.(27-29) A number of studies have demonstrated worse prognosis with BRAF V600E-mutant compared with BRAF V600 wildtype CRC.(8, 30-33) In one study (n=229), patients with BRAF V600E-mutant/KRAS- wildtype CRC demonstrated significantly reduced overall survival (OS) compared with patients with BRAF V600-wildtype/KRAS-wildtype tumors (11.0 months vs 40.6 months; HR 4.25, 95% confidence interval [CI]: 2.08–8.67; p<0.001).(30) Similarly, a separate study (n=504) evaluating the detection of mutant BRAF V600E as part of daily clinical practice found that regardless of time of first-line intervention, there was a significant reduction in OS (14.0 months vs 34.6 months; HR: 5.43; 95% CI: 3.60–8.18; p<0.001), in addition to worsened progression-free survival (PFS) (4.1 months vs 11.6 months; HR: 4.07; 95% CI: 2.66–6.20; p<0.001) with BRAF V600E-mutant compared with BRAF V600- wildtype CRC.(31) Additionally, 5-year OS of patients with stage I–IV BRAFV600E-mutant CRC has been reported to be 47.5% compared with 60.7% in patients with wildtype tumors.(32) These findings are 5 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3809 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Improvements in clinical outcomes for BRAFV600E-mutant colorectal cancer supported by a recent real-world analysis (n=503) that observed a median OS of 18.2 months for BRAF V600E-mutant metastatic CRC compared with an OS of 41.1