{"id":30533,"date":"2020-07-28T15:22:10","date_gmt":"2020-07-28T14:22:10","guid":{"rendered":"http:\/\/touchoncology.com\/?p=30533"},"modified":"2020-09-21T09:04:01","modified_gmt":"2020-09-21T08:04:01","slug":"glimmers-of-hope-new-strategies-for-overcoming-treatment-resistance-in-patients-with-braf-v600e-mutated-metastatic-colorectal-cancer","status":"publish","type":"post","link":"https:\/\/touchoncology.com\/colorectal-cancer\/journal-articles\/glimmers-of-hope-new-strategies-for-overcoming-treatment-resistance-in-patients-with-braf-v600e-mutated-metastatic-colorectal-cancer\/","title":{"rendered":"Glimmers of Hope\u2014New Strategies for Overcoming Treatment Resistance in Patients with\u00a0BRAF V600E-mutated Metastatic Colorectal Cancer"},"content":{"rendered":"

Colorectal cancer (CRC) is a commonly diagnosed malignancy and the second-leading cause of cancer death in the USA, with 147,950 estimated new cases and 53,200 estimated deaths in 2020.1<\/span> Despite CRC screening, approximately 20% of patients are diagnosed with metastatic CRC (mCRC), which carries a 14.2% 5-year survival rate.2<\/span><\/p>\n

Over the last two decades, mCRC treatment has become more personalized, with a better understanding of tumor heterogeneity, including microsatellite instability (MSI) and mutations in genes such as\u00a0KRAS<\/span>,\u00a0NRAS<\/span>, and\u00a0BRAF<\/span>. The availability of molecularly tailored treatments has reshaped the therapeutic landscape for many patients with mCRC. Approximately 8\u201312% of mCRCs contain a mutation in\u00a0BRAF<\/span>, also known as v-raf murine sarcoma viral oncogene homolog B.3\u20136<\/span>\u00a0BRAF is a signal transduction protein involved in the mitogen-activated protein kinase (MAPK) pathway.3<\/span>\u00a0Here we review the prognostic and therapeutic implications of\u00a0BRAF<\/span>-mutated CRC.<\/p>\n

BRAF<\/span>\u00a0pathway and mutations in malignancies<\/p>\n

The\u00a0BRAF<\/span>\u00a0gene is located on chromosome 7 (7q34). It encodes the BRAF protein, a serine\/threonine protein kinase, which plays a role in the regulatory MAPK\/extracellular signal-regulated kinase (ERK) signaling pathway during cell growth, proliferation, differentiation, and apoptosis.7,8<\/span>\u00a0Mutations in\u00a0BRAF<\/span> result in downstream phosphorylation of mitogen-activated extracellular signal-regulated kinase (MEK) and ERK, leading to activation of the MAPK pathways. This oncogenic mutation stimulates cell proliferation and metastasis (Figure 1<\/em>)<\/span>.<\/p>\n

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 <\/p>\n

BRAF<\/span>\u00a0mutations have been identified with varying incidence in multiple malignancies, including melanoma, CRC, hairy cell leukemia, lung cancer, ovarian cancer, Langerhans cell histiocytosis, and papillary thyroid carcinoma.9\u201314<\/span>\u00a0The BRAF inhibitors, dabrafenib, encorafenib, and vemurafenib, are US Food and Drug Administration (FDA)-approved therapies for patients with\u00a0BRAF<\/span>-mutated melanoma. Median progression-free survival (PFS) of patients with melanoma treated with these inhibitors ranges from 5\u201310 months.15\u201318<\/span><\/p>\n

BRAF<\/span>\u00a0mutations\u00a0in colorectal cancer<\/p>\n

Most\u00a0BRAF<\/span> mutations in CRC appear in primary tumors located in the proximal colon and first two-thirds of the transverse colon.\u00a0BRAF<\/span>-mutated tumors tend to be larger than average, are associated with serrated polyp morphology, and have higher rates of distant metastases.19<\/span>\u00a0Eighty percent of hyperplastic microvascular polyps harbor\u00a0BRAF<\/span>\u00a0mutations, and these polyps present in the proximal colon as sessile serrated adenomas.19<\/span>\u00a0These types of polyps have high malignant potential and are under-detected by conventional colonoscopies, leading to their ability to progress without being detected.19<\/span>\u00a0BRAF<\/span>-mutated CRCs metastasize readily to the peritoneum and distant lymph nodes, but less readily to the lungs.\u00a0BRAF<\/span> mutations occur more commonly in mCRCs that are microsatellite instable. Women and individuals over the age of 65 years are more likely to have mCRCs that harbor mutated BRAF<\/span>.5,20<\/span><\/p>\n

In response to the binding of extracellular growth factors, receptor tyrosine kinases activate RAS, which activates and induces the formation of RAF dimers to propagate and transduce downstream signaling to promote cell proliferation and differentiation. Mutations in\u00a0BRAF<\/span>\u00a0fall into one of three categories based on the biochemical and signaling properties of their encoded proteins. Class 1 contains the most common\u00a0BRAF<\/span> mutation known as BRAF<\/span>\u00a0V600E, which is the product of a thymine to adenine base transversion at codon 600 of exon 15 of\u00a0BRAF<\/span>. This mutation, which leads to a substitution of valine for glutamate at position 600 of the encoded protein, is observed in approximately 10% of all patients with mCRC and accounts for around 80% of all\u00a0BRAF<\/span>\u00a0mutations.21<\/span>\u00a0The resulting aberrant protein exhibits high kinase activity and can signal independently of RAS activation.21<\/span>\u00a0BRAF<\/span>\u00a0mutations in classes 2 and 3 occur at different locations in the\u00a0BRAF<\/span>\u00a0gene, encoding non-V600E mutated proteins. These non-V600E\u00a0BRAF<\/span>\u00a0mutations are observed in mCRCs of approximately 2% of patients and account for around 20% of all\u00a0BRAF<\/span>\u00a0mutations (about 10% in each of class 2 and 3).21<\/span>\u00a0Class 2 mutations, like class 1, give rise to proteins that signal independently of RAS. In contrast, class 3\u00a0BRAF<\/span> mutations encode proteins that have enhanced binding to RAS and CRAF and lead to RAS-dependent signaling.6<\/span><\/p>\n

The activities of these different classes of\u00a0BRAF<\/span>\u00a0mutations correlate with differences in the clinical characteristics of\u00a0BRAF<\/span>-mutant mCRC and response to targeted therapy. Tumors with class 1\u00a0BRAF<\/span>\u00a0mutations (BRAF<\/span>\u00a0V600E-mutant) are typically found in right-sided, high-grade, MSI-high tumors and are associated with a worse patient prognosis compared with\u00a0BRAF<\/span>-wild type (WT) tumors. Patients with\u00a0BRAF<\/span>\u00a0V600E-mutated mCRC have a median overall survival of 4\u20136 months after failure of initial therapy, compared with 11\u201314 months for all patients with mCRC.22,23<\/span>\u00a0Class 2 and 3 (BRAF<\/span>\u00a0non-V600E mutant) tumors have been observed in younger patients with left-sided tumors, and the prognosis for these patients is similar to those with\u00a0BRAF<\/span>-WT tumors.6<\/span><\/p>\n

The class of\u00a0BRAF<\/span>\u00a0mutation is clinically relevant because it has been shown to indicate prognosis, as well as effectiveness of the BRAF inhibitors, vemurafenib, dabrafenib, and encorafenib, and the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab and panitumumab.22,23<\/span>\u00a0Upon further examination of clinical characteristics of CRC tumors with non-V600E\u00a0BRAF<\/span>\u00a0mutations, patients with\u00a0RAS<\/span>-WT tumors and class 2\u00a0BRAF<\/span>-mutated CRC had shorter survival compared with those with\u00a0RAS<\/span>-WT and class 3\u00a0BRAF<\/span>-mutant CRC.25<\/span>\u00a0EGFR is a receptor tyrosine kinase in the MAPK pathway; RAS and\u00a0BRAF<\/span> operate downstream of EGFR.6<\/span>\u00a0While EGFR inhibitors improve overall survival in CRC, CRC tumors with activating\u00a0RAS<\/span>\u00a0mutations do not benefit from treatment with anti-EGFR antibodies.24<\/span>\u00a0Because class 1\u00a0BRAF<\/span>\u00a0mutations are\u00a0RAS<\/span>\u00a0activating, anti-EGFR antibody monotherapy is ineffective. Similarly, class 2\u00a0BRAF<\/span>-mutant CRCs rarely respond to EGFR therapy, suggesting that class 2\u00a0BRAF<\/span> mutations confer resistance.\u00a025<\/span>\u00a0Of 36 patients with non-V600E\u00a0BRAF<\/span>\u00a0mutations, patients with class 2 and 3 BRAF mutations did not have any objective response to anti-EGFR monotherapy.26<\/span>\u00a0Class 3 mutated CRCs that did not respond to anti-EGFR therapy have been shown to be linked to underlying activation of other receptor tyrosine kinases leading to RAS activation.25<\/span>\u00a0However, considering that a large portion of patients with class 3\u00a0BRAF<\/span>\u00a0mutations responded to anti-EGFR therapy, the main driver in these tumors is thought to be EGFR activation. These patients likely have tumors that are sensitive to EGFR inhibition.26<\/span><\/p>\n

Treatment in\u00a0BRAF<\/span>\u00a0V600E-mutated CRC<\/p>\n

Patients with\u00a0BRAF<\/span>\u00a0V600E-mutated CRC currently have shorter PFS on chemotherapy, an increased rate of disease recurrence after surgical resection, and poorer overall survival.20,27<\/span>\u00a0As mentioned above,\u00a0BRAF<\/span>\u00a0mutations in CRC confer resistance to anti-EGFR therapy,28\u201332<\/span>\u00a0and tend to be refractory to standard chemotherapy.33<\/span> Upfront intensive chemotherapy is often used, based on the phase III TRIBE trial results (ClinicalTrials.gov identifier: NCT00719797), which observed benefit of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)\/bevacizumab over fluorouracil, leucovorin, and irinotecan (FOLFIRI)\/bevacizumab in patients with
\nBRAF<\/span>-mutated mCRC.34<\/span>\u00a0In the TRIBE2 trial (ClinicalTrials.gov identifier: NCT02339116), which included 10%\u00a0BRAF<\/span>-mutated patients in each arm, the combination of FOLFOXIRI\/bevacizumab improved PFS during both upfront and pre-planned re-introduction after disease progression, as well as longer overall survival (27.6 versus 22.6 months, hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.67\u20130.98, p=0.033).35<\/span><\/p>\n

Although the\u00a0BRAF<\/span>\u00a0V600E mutation has been identified and successfully targeted in multiple other advanced cancers,\u00a0BRAF<\/span>-inhibitor monotherapy shows limited efficacy in cases of\u00a0BRAF<\/span> V600E-mutated mCRC. Vemurafenib is a small tyrosine kinase inhibitor that specifically targets the adenosine triphosphate-binding domain of BRAF<\/span>\u00a0V600E, and has been shown to decrease activation of the MAPK pathway in advanced malignancies with\u00a0BRAF<\/span>\u00a0mutations.4<\/span>\u00a0In mCRC, vemurafenib monotherapy is rarely effective at reducing tumor growth. This decreased efficacy is attributed to incomplete inhibition of MAPK signaling and a reflexive activation of EGFR, which promotes tumor progression through alternative pathways, bypassing\u00a0BRAF<\/span>.4<\/span>\u00a0The combination of vemurafenib plus trametinib (a MEK inhibitor) resulted in response rates as high as 76% in\u00a0BRAF<\/span>\u00a0V600E-mutated metastatic melanoma. In contrast, this same combination yielded only a 12% response rate in\u00a0BRAF<\/span>\u00a0V600E-mutated CRC.36<\/span>\u00a0In a phase IB study of 17 patients with\u00a0BRAF<\/span>\u00a0V600E-mutated mCRC, the addition of vemurafenib to a combination of irinotecan plus cetuximab yielded a 35% response rate and a median PFS of 7.7 months.4<\/span> Patients with radiographically observed responses and stable disease also exhibited reductions in the percentage of BRAF<\/span>\u00a0V600E cell-free DNA.4<\/span><\/p>\n

This regimen was further studied in the phase II SWOG S1406 study (ClinicalTrials.gov identifier: NCT02164916), which randomized patients with previously treated\u00a0BRAF<\/span>\u00a0V600E-mutated mCRC 1:1 to irinotecan plus cetuximab versus irinotecan plus cetuximab and vemurafenib. The primary endpoint of PFS was significantly longer in the arm that received vemurafenib: 4.3 versus 2.0 months (HR 0.48, 95% CI 0.31\u20130.75; p=0.001).22<\/span><\/p>\n

In addition to combined inhibition of EGFR and BRAF, the inhibition of the MAPK pathway has been explored through the combined inhibition of the MEK, EGFR, and BRAF. The phase III BEACON study (ClinicalTrials.gov identifier: NCT02928224) randomized patients with previously treated BRAF<\/span>\u00a0V600E-mutated mCRC 1:1:1 to triplet therapy with encorafenib (BRAF inhibitor), cetuximab (anti-EGFR antibody), and binimetinib (MEK inhibitor); doublet therapy with encorafenib and cetuximab; or the control arm of chemotherapy (FOLFIRI or irinotecan) with cetuximab (N=665).37<\/span> Patients treated with the triplet and doublet therapy had significantly longer median overall survival when compared with the control arm: 9.3 and 9.3 versus 5.9 months, respectively. The median overall response rate was also higher with the triplet (27%) and doublet (20%) therapy compared with the control arm of chemotherapy (2%, p<0.0001).37<\/span> As there was not a significant difference in overall survival between the triplet and doublet therapies, doublet therapy with encorafenib and cetuximab received FDA approval for patients with BRAF<\/span> V600E-mutated mCRC after prior therapy on April 8, 2020.38<\/span>\u00a0This study\u2019s quality-of-life assessment revealed the doublet and triplet regimens were not different, but both regimens provided improved patient-reported quality of life compared with the control arm.39<\/span>\u00a0The ongoing phase III ANCHOR trial is evaluating the triplet therapy in the
\nfirst-line setting (ClinicalTrials.gov Identifier: NCT03693170).<\/p>\n

Future approaches to treating\u00a0BRAF<\/span>-mutated CRC<\/p>\n

While\u00a0BRAF<\/span>\u00a0V600E mutations are currently a poor prognostic marker, the use of targeted therapies as well as high prevalence of MSI-high, which lends potential benefit from checkpoint inhibitors, are promising therapeutic avenues. Future clinical trials are accruing patients with\u00a0BRAF<\/span>-mutated CRC to test multi-agent combinations that inhibit various signaling proteins along the MAPK pathway. Novel targeted agents include ERK inhibitors, e.g., LTT462; BRAF inhibitors, e.g., LXH254; Src homology 2-containing phosphotyrosine phosphatase (SHP2) inhibitors, e.g., TNO155; WEE1 kinase inhibitors, e.g., AZD1775; and Wnt inhibitors, e.g., LGK974 (Table 1<\/span><\/em>). These novel agents are being combined together, added to traditional chemotherapy as well as immunotherapy, in the hope of overcoming the treatment resistance conferred by\u00a0BRAF<\/span>\u00a0mutations. One phase Ib clinical trial is utilizing combinations of targeted agents in the hope to prove the safety of combinations, as well as overcoming potential downstream resistance mechanisms (ClinicalTrials.gov identifier: NCT04294160). Novel combinations include a doublet BRAF inhibitor with ERK inhibitor; triplet arms that include a BRAF inhibitor, ERK inhibitor, and MEK inhibitor; and targeted agents plus immunotherapy or chemotherapy to review safety as well as efficacy. The utilization of concomitant MSI and\u00a0BRAF<\/span>\u00a0mutation testing may help predict response to checkpoint inhibition. Triplet combinations of BRAF inhibition, MEK inhibition, and programmed cell death protein 1 (PD-1) inhibition have been tested on\u00a0BRAF<\/span>-mutated melanomas in the phase III COMBI-i trial with acceptable safety profiles and promising response rates.40<\/span>\u00a0<\/span>This same combination is being testing in\u00a0BRAF<\/span>-mutated CRC (ClinicalTrials.gov identifier: NCT03668431). Given its recent FDA approval, encorafenib and cetuximab will likely form the backbone of future studies combining anti-BRAF\/EGFR therapy with chemotherapy and other targeted agents.<\/p>\n

 <\/p>\n

\"\"<\/p>\n

 <\/p>\n

Radiological studies have also explored the use of imaging factors to predict which patients are more likely to have a\u00a0BRAF<\/span>\u00a0mutation in their tumors. One study (N=155) showed\u00a0BRAF<\/span>\u00a0mutations were more common in female patients (p=0.007), older patients (p=0.001), and right-sided tumors (p=0.001).38<\/span>\u00a0Radiologically significant factors seen in\u00a0BRAF<\/span>-mutated tumors, as opposed to\u00a0BRAF<\/span>-WT tumors, included right-sidedness (p=0.002); heterogeneous enhancement, possibly due to association between\u00a0BRAF<\/span>\u00a0and a mucinous histology (p=0.039); and lack of non-peritoneal metastases (p=0.043).41<\/span><\/p>\n

In addition to adenocarcinoma CRC,\u00a0BRAF<\/span>\u00a0V600E mutations have recently been identified in colon neuroendocrine tumors at rates as high as 28% and may benefit from targeted therapy as well.35<\/span>\u00a0This population has unique and complex biological differences compared with\u00a0BRAF<\/span>-mutated CRC adenocarcinoma as well as melanoma and will need to be tested in basket trials.<\/p>\n

Conclusion<\/p>\n

BRAF<\/span>\u00a0mutations in mCRC have traditionally portended a poor prognosis and decreased benefit from standard therapies. Although recent studies have shown improved overall survival and response rates with combined encorafenib and cetuximab, there is still a need to identify novel therapy combinations that can further extend survival outcomes of\u00a0BRAF<\/span>-mutated<\/span>\u00a0patient populations.<\/p>\n","protected":false},"excerpt":{"rendered":"

Colorectal cancer (CRC) is a commonly diagnosed malignancy and the second-leading cause of cancer death in the USA, with 147,950 estimated new cases and 53,200 estimated deaths in 2020.1 Despite CRC screening, approximately 20% of patients are diagnosed with metastatic CRC (mCRC), which carries a 14.2% 5-year survival rate.2 Over the last two decades, mCRC […]<\/p>\n","protected":false},"author":77781,"featured_media":29102,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_relevanssi_hide_post":"","_relevanssi_hide_content":"","_relevanssi_pin_for_all":"","_relevanssi_pin_keywords":"","_relevanssi_unpin_keywords":"","_relevanssi_related_keywords":"","_relevanssi_related_include_ids":"","_relevanssi_related_exclude_ids":"","_relevanssi_related_no_append":"","_relevanssi_related_not_related":"","_relevanssi_related_posts":"","_relevanssi_noindex_reason":"","rank_math_lock_modified_date":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-30533","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized","vocabulary_1-colorectal-cancer"],"acf":{"wpcf-article_introduction":"","wpcf-article_abstract":"BRAF<\/span>\u00a0V600E-mutated metastatic colorectal cancer is notoriously difficult to treat due to an aggressive tumor biology and resistance to chemotherapy. Single-agent BRAF inhibition has proven ineffective in this patient population. Approaches combining BRAF with epidermal growth factor receptor and mitogen-activated extracellular signal-regulated kinase inhibition are effective in overcoming resistance to BRAF monotherapy, and this treatment combination provides a superior overall survival benefit compared with irinotecan-based chemotherapy. Encorafenib plus cetuximab is now a US Food and Drug Administration-approved treatment option for patients with\u00a0BRAF<\/span>\u00a0V600E-mutated metastatic colorectal cancer after prior therapy. Ongoing clinical trials using immunotherapy and other targeted agents aim to further improve on these outcomes. We highlight the epidemiology and mutational landscape of\u00a0BRAF<\/span>-mutated colorectal cancer, as well as novel treatment options for patients with this subtype of metastatic colorectal cancer.","wpcf-article_keywords":"Colorectal cancer, BRAF, BRAF-V600E mutation, targeted therapy","wpcf-article_citation_override":"Oncology & Hematology Review (US)<\/i>. 2020;16(1):31-5 DOI: https:\/\/doi.org\/10.17925\/OHR.2020.16.1.31<\/a>","wpcf-compliance-with-ethics":"This article involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.","wpcf-article_disclosure":"Samantha A Armstrong, Rita Malley, and Benjamin A Weinberg have no financial or non-financial relationships or activities to declare in relation to this article.","wpcf-review_process":"Double-blind peer review.","wpcf-authorship":"The named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.","wpcf-article_correspondence":"Benjamin A Weinberg, Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007, USA.\r\nE: baw12@gunet.georgetown.edu Twitter: @benweinbergmd","wpcf-article_support":"No funding was received for the publication of this article.","wpcf-open_access":"This article is freely accessible at touchONCOLOGY.com \u00a9 Touch Medical Media 2020.","wpcf-article_pdf":"http:\/\/touchoncology.com\/wp-content\/uploads\/sites\/2\/2020\/08\/touchONC_US_16.1_p31-35.pdf","wpcf-article_pdf-gated":true,"wpcf-article_doi":"","wpcf-old_nid":"","wpcf-article_image":"","wpcf-editor_choice":false,"wpcf-old_author_ids":"","wpcf-article_references":"

    \r\n \t
  1. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin<\/em>.<\/span>\u00a02020;70:145\u201364.<\/li>\r\n \t
  2. NIH. National Cancer Institute. Surveillance, Epidemiology, and End Results Program (SEER). Cancer stat facts: colorectal cancer. 2020. Available at: http:\/\/seer.cancer.gov\/statfacts\/html\/colorect.html<\/a>\u00a0(accessed May 7, 2020).<\/li>\r\n \t
  3. Cicenas J, Tamosaitis L, Kvederaviciute K, et al. KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma.\u00a0Med Oncol<\/em>.<\/span>\u00a02017;34:26.<\/li>\r\n \t
  4. Hong DS, Morris VK, El Osta B, et al. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with\u00a0BRAF<\/span>V600E<\/span> mutation. Cancer Discov<\/em>.<\/span>\u00a02016;6:1352\u201365.<\/li>\r\n \t
  5. Tie J, Gibbs P, Lipton L, et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation.\u00a0Int J Cancer<\/em>.<\/span>\u00a02011;128:2075\u201384.<\/li>\r\n \t
  6. Yaeger R, Cercek A, Chou JF, et al. BRAF mutation predicts for poor outcomes after metastasectomy in patients with metastatic colorectal cancer.\u00a0Cancer<\/span><\/em>. 2014;120:2316\u201324.<\/li>\r\n \t
  7. Hussain MR, Baig M, Mohamoud HS, et al. BRAF gene: from human cancers to developmental syndromes.\u00a0Saudi J Biol Sci<\/em>.<\/span>\u00a02015;22:359\u201373.<\/li>\r\n \t
  8. Peyssonnaux C, Eychene A. The Raf\/MEK\/ERK pathway: new concepts of activation.\u00a0Biol Cell<\/em>.\u00a0<\/span>2001;93:53\u201362.<\/li>\r\n \t
  9. Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent\u00a0BRAF<\/span>\u00a0mutations in Langerhans cell histiocytosis.\u00a0Blood<\/span><\/em>. 2010; 116:1919\u201323.<\/li>\r\n \t
  10. Bosmuller H, Fischer A, Pham DL, et al. Detection of the\u00a0BRAF\u00a0<\/span>V600E mutation in serous ovarian tumors: a comparative analysis of immunohistochemistry with a mutation-specific monoclonal antibody and allele-specific PCR.\u00a0Hum Pathol<\/span><\/em>. 2013;44:329\u201335.<\/li>\r\n \t
  11. Brose MS, Volpe P, Feldman M, et al.\u00a0BRAF<\/span>\u00a0and\u00a0RAS<\/span>\u00a0mutations in human lung cancer and melanoma.\u00a0Cancer Res<\/span><\/em>. 2002; 62:6997\u20137000.<\/li>\r\n \t
  12. Davies H, Bignell GR, Cox C, et al. Mutations of the\u00a0BRAF<\/span>\u00a0gene in human cancer.\u00a0Nature<\/span><\/em>. 2002;417:949\u201354.<\/li>\r\n \t
  13. Kimura ET, Nikiforova MN, Zhu Z, et al. High prevalence of\u00a0BRAF<\/span>\u00a0mutations in thyroid cancer: genetic evidence for constitutive activation of the RET\/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.\u00a0Cancer Res<\/span><\/em>. 2003;63:1454\u20137.<\/li>\r\n \t
  14. Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the\u00a0BRAF<\/span>\u00a0V600E mutation.\u00a0Blood<\/span><\/em>. 2012;119:3330\u20132.<\/li>\r\n \t
  15. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med<\/span><\/em>. 2011;364:2507\u201316.<\/li>\r\n \t
  16. Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with\u00a0BRAF<\/span>-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial.\u00a0Lancet Oncol<\/em>.<\/span>\u00a02018;19:1315\u201327.<\/li>\r\n \t
  17. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma.\u00a0N Engl J Med<\/span><\/em>. 2010;363:809\u201319.<\/li>\r\n \t
  18. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF<\/span>-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.\u00a0Lancet<\/span><\/em>. 2012;380:358\u201365.<\/li>\r\n \t
  19. Kim SY, Kim TI. Serrated neoplasia pathway as an alternative route of colorectal cancer carcinogenesis.\u00a0Intest Res<\/em>.<\/span>\u00a02018;16:358\u201365.<\/li>\r\n \t
  20. Margonis GA, Buettner S, Andreatos N, et al. Association of\u00a0BRAF<\/span>\u00a0mutations with survival and recurrence in surgically treated patients with metastatic colorectal liver cancer.\u00a0JAMA Surg<\/em>. <\/span>2018;153:e180996.<\/li>\r\n \t
  21. Schirripa M, Biason P, Lonardi S, et al. Class 1, 2, and 3 BRAF<\/span>-mutated metastatic colorectal cancer: a detailed clinical, pathologic, and molecular characterization.\u00a0Clin Cancer Re<\/em>s<\/span>. 2019;25:3954\u201361.<\/li>\r\n \t
  22. Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF<\/span>-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol<\/em>.<\/span>\u00a02017;35(Suppl. 4):520.<\/li>\r\n \t
  23. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.\u00a0J Clin Oncol<\/em>.\u00a0<\/span>2010;28:4706\u201313.<\/li>\r\n \t
  24. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.\u00a0N Engl J Med<\/em>.<\/span>\u00a02013;369:1023\u201334.<\/li>\r\n \t
  25. Yaeger R, Kotani D, Mondaca S, et al. Response to anti-EGFR therapy in patients with BRAF non-V600-mutant metastatic colorectal cancer.\u00a0Clin Cancer Res<\/em>. 2<\/span>019;25:7089\u201397.<\/li>\r\n \t
  26. Johnson B, Loree JM, Morris VK, et al. Activity of EGFR inhibition in atypical (non-V600E) BRAF-mutated metastatic colorectal cancer.\u00a0J Clin Oncol<\/span><\/em>. 2019;37(Suppl. 4):596.<\/li>\r\n \t
  27. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer.\u00a0Cancer<\/span><\/em>. 2011;117:4623\u201332.<\/li>\r\n \t
  28. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS\/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies.\u00a0Cancer Res<\/em>.<\/span>\u00a02007;67:2643\u20138.<\/li>\r\n \t
  29. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type\u00a0BRAF<\/span>\u00a0is required for response to panitumumab or cetuximab in metastatic colorectal cancer.\u00a0J Clin Oncol<\/em>.<\/span>\u00a02008;26:5705\u201312.<\/li>\r\n \t
  30. Hsu HC, Thiam TK, Lu YJ, et al. Mutations of\u00a0KRAS\/NRAS\/BRAF<\/span>\u00a0predict cetuximab resistance in metastatic colorectal cancer patients.\u00a0Oncotarget<\/span><\/em>. 2016;7:22257\u201370.<\/li>\r\n \t
  31. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of\u00a0PTEN<\/span>,\u00a0BRAF<\/span>, and\u00a0EGFR<\/span>\u00a0status in determining benefit from cetuximab therapy in wild-type\u00a0KRAS<\/span>\u00a0metastatic colon cancer.\u00a0J Clin Oncol<\/em>.<\/span>\u00a02009;27:5924\u201330.<\/li>\r\n \t
  32. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.\u00a0N Engl J Med<\/span><\/em>. 2009;360:1408\u201317.<\/li>\r\n \t
  33. Souglakos J, Philips J, Wang R, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.\u00a0Br J Cancer<\/em>.<\/span>\u00a02009;101:465\u201372.<\/li>\r\n \t
  34. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.\u00a0Lancet Oncol<\/em>.\u00a0<\/span>2015;16:1306\u201315.<\/li>\r\n \t
  35. Cremolini C, Antoniotti C, Lonardi S, et al. Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the first- and second-line treatment of unresectable mCRC. J Clin Oncol<\/em>. <\/span>2019;37(Suppl. 15):3508.<\/li>\r\n \t
  36. Corcoran RB, Atreya CE, Falchook GS, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in\u00a0BRAF <\/span>V600-mutant colorectal cancer.\u00a0J Clin Oncol<\/em>.<\/span>\u00a02015;33:4023\u201331.<\/li>\r\n \t
  37. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in\u00a0BRAF<\/span> V600E-mutated colorectal cancer. N Engl J Med<\/em>.<\/span>\u00a02019;381:1632\u201343.<\/li>\r\n \t
  38. Array BioPharma Inc. Braftovi\u00ae<\/span> (encorafenib) capsules. Prescribing information. 2020. Available at:\u00a0www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/210496s006lbl.pdf <\/a>(accessed May 7, 2020).<\/li>\r\n \t
  39. Kopetz S, Grothey A, Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for\u00a0BRAF<\/span>\u00a0V600E-mutant metastatic colorectal cancer: quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC).\u00a0J Clin Oncol<\/span><\/em>. 2020;38 (Suppl. 4):8.<\/li>\r\n \t
  40. Long GV, Lebbe C, Atkinson V, et al. The anti\u2013PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced\u00a0BRAF<\/span>\u00a0V600\u2013mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-i.\u00a0J Clin Oncol<\/em>. <\/span>2019;37(Suppl):9531.<\/li>\r\n \t
  41. Eurboonyanun K, Lahoud RM, Kordbacheh H, et al. Imaging predictors of BRAF mutation in colorectal cancer. Abdom Radiol (NY)<\/span><\/em>. 2020;45:2336\u201344.<\/li>\r\n<\/ol>","wpcf-article_received_date":"20200416","wpcf-article_accepted_date":"20200428","wpcf-article_published_online":"20200728","wpcf-podcast":"","wpcf-ogg":"","wpcf-article_end_page":"","wpcf-article_start_page":"","wpcf-acknowledgements":"The authors wish to acknowledge Marion L Hartley, Science Writer for Clinical Research at the Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, for her edits and suggestions during the composition of this manuscript.","wpcf-errata_pdf":"","wpcf-article_flipper_image":"","wpcf-corrected_online":null,"wpcf-supplementary_information":"","wpcf-article_highlight_pdf":"","data_availability":"","digital_features":""},"_links":{"self":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts\/30533"}],"collection":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/users\/77781"}],"replies":[{"embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/comments?post=30533"}],"version-history":[{"count":6,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts\/30533\/revisions"}],"predecessor-version":[{"id":32354,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/posts\/30533\/revisions\/32354"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/media\/29102"}],"wp:attachment":[{"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/media?parent=30533"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/categories?post=30533"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/touchoncology.com\/wp-json\/wp\/v2\/tags?post=30533"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}