Genomically Driven Tumors and Actionability across Histologies:BRAF-Mutant Cancers as a Paradigm

Abstract

The diagnosis, classification, and management of cancer are traditionally dictated by the site of tumor origin, for example, breast or lung, and by specific histologic subtypes of site-oforigin cancers (e.g., non-small cell versus small cell lung cancer). However, with the advent of sequencing technologies allowing for rapid, low cost, and accurate sequencing of clinical samples, new observations suggest an expanded or different approach to the diagnosis and treatment of cancer-one driven by the unique molecular features of the tumor. We discuss a genomically driven strategy for cancer treatment using BRAF as an example. Several key points are highlighted: (i) molecular aberrations can be shared across cancers; (ii) approximately 15% of all cancers harbor BRAF mutations; and (iii) BRAF inhibitors, while approved only for melanoma, have reported activity across numerous cancers and related disease types bearing BRAF aberrations. However, BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy, striking a cautionary note. Yet, even in this case, emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors, albeit when administered in combination with other agents that impact resistance pathways. Taken together, these data suggest that molecular aberrations may be the basis for a new nosology for cancer. Mol Cancer Ther; 15(4); 533-47. Ó2016 AACR.

Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing

“…Among the 423 patients with alterations detected, 75.7% had a potentially actionable alteration. The rates of potentially actionable alterations in tissue, as reported in other studies, have varied widely (from about 20% to 93%), probably depending on the panel used, the definition of actionability (14) and the time period of the study (21–24). Of special interest was a patient with advanced gastric cancer who showed amplifications in EGFR in her ctDNA, a result that was confirmed by tissue NGS, and attained a rapid partial remission after two months of therapy with an anti-EGFR regimen combining an EGFR antibody and small molecule inhibitor.…”

“…Actionability implies that the protein product of a genomic abnormality can potentially be impacted by a specific targeted drug (14). A potentially actionable alteration was defined as a characterized alteration that was either the direct target (such as an EGFR inhibitor targeting an EGFR mutation), or a pathway component (such as an mTOR inhibitor for a PIK3CA mutation (since mTOR is downstream of PIK3CA)) that could be targeted by at least one approved (by the Food and Drug Administration–FDA) or investigational drug in a clinical trial.…”

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

“…Although less frequent, BRAF V600E mutations were found in 1.6% [7/442] of our CUP patients (Supplemental Table 3). Recent reports suggest that many cancer types, including CUP, with BRAF V600 mutations are targetable with vemurafenib (BRAF inhibitor) (43,44). BRAF alterations are also targetable with trametinib (MEK inhibitor) (42) or with dual suppression by both BRAF and MEK inhibitors (e.g.…”

Discrete cytosolic macromolecular BRAF complexes exhibit distinct activities and composition

“…BRAF is a therapeutic target of growing relevance across various clinical disciplines (Turski et al , ). Despite all the impressive therapeutic responses elicited by BRAF inhibitors reported since 2010, these drugs often fail to provide sustainable treatment options due to the emergence of drug resistance and side effects associated with the aforementioned “paradoxical ERK activation” observed in cells with elevated RAS activity (Samatar & Poulikakos, ; Yaktapour et al , ; Lavoie & Therrien, ).…”