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Acting on Rare Driver Alterations: Is Getting a Meaningful Response a Game of Chance or Scientific Rigor?

In this issue of JNCCN, Hamad et al (page 983) report an exceptional response to trastuzumab plus FOLFOX in a case of metastatic adenocarcinoma of the duodenum with ERRB2 (HER2/neu) amplification. This exceptional response is important to document for the oncology community as a whole, although it is difficult to attribute the complete pathologic response to trastuzumab alone, because it was used in combination with FOLFOX. Delineating the contribution of targeted approaches to pathologic response when used in combination with traditional chemotherapeutics is difficult outside the setting of a controlled trial. Nevertheless, it illustrates that rare but actionable driver alterations can be identified in uncommon cancers that lack clinical treatment guidelines for targeted therapy. The landscape of driver alterations in duodenal and ampullary carcinomas is incomplete at best. What we do know is that ERRB2 alterations have been reported with varying frequency in small bowel and ampullary adenocarcinomas, with missense mutations being the most frequent alteration in one study.1 Conversely, amplifications in ERBB2 are relatively rare in small bowel cancers and probably represent <3% of putative driver alterations in this histology.2,3 That ERRB2 alterations are the founder mutations in duodenal cancers has not been well established, and to what extent ERRB2 alterations are subject to intratumoral heterogeneity in these cancers is uncertain. If ERRB2 amplification is only present in a subclonal population, then targeting it would be unlikely to induce a complete pathologic response. So how did the authors overcome the many pitfalls in routine molecular biomarker testing and decide to take action and target this rare putative driver alteration? First, no other driver mutation was found in the molecular profiling that was performed by a relatively modest gene panel that included BRAF, HRAS, KRAS, NRAS, and PIK3CA gene sequencing and ALK by immunohistochemistry. Second, ERRB2 amplification was found in both the primary and metastatic lesions. Therefore, the amplification did not have other drivers to compete with and was less likely to be a subclonal alteration. These findings lend some support for ERRB2 amplification as the major driver alteration in this particular case. So, what factors are important in deciding that a putative driver alteration is actionable in the absence of clinical trial data? This question is becoming more frequent, with mainstream media promoting personalized medicine and growing demands from patients to be treated based on the results of next-generation sequencing assays. Whether the decision is to enroll in a clinical trial or to seek off-label use of an already approved drug, these situations are increasingly encountered by practitioners and patients alike. Identifying actionable driver alterations in routine clinical sequencing assays is not straightforward and can be particularly difficult in uncommon cancer types. Some driver alterations may have well-documented response rates in one histologic type but not in another, thereby making the extrapolation of results of targeted therapies trials from one histology to another not a sound approach. Clinical trials using a basket design have shown mixed results, with not all histologies responding to targeted therapy against a particular mutation. For instance, many BRAF V600E–mutant nonmelanoma histologies respond to vemurafenib; however, BRAF V600E–mutant colorectal cancers did not display any effectiveness with vemurafenib.4 This finding suggests that the overall cellular and genomic context in which a driver alteration occurs is important in determining its actionability. Additionally, a diverse repertoire of mutations can exist in some driver genes that lead to differing biologic consequences for each specific type of mutation. An example of this David R. Braxton, MD