Using Somatic Mutations to Guide Treatment Decisions

Abstract

Mutations and other somatic genomic abnormalities are commonly used to inform treatment decisions. Such molecularly based personalized treatment strategies were until recently limited to an assortment of rare tumor types or molecularly defined subtypes of common cancers. Lately, these strategies have expanded to other tumor types, in particular lung cancer and melanoma. Although the approach to genomic-based treatment decisions has been broadly embraced, provision of a targeted agent to a patient whose cancer harbors the genomic target rarely leads to cure, and sometimes responses are incomplete. Also, opportunity costs for patients and the expenses of ineffective treatments are great; therefore, improvements are needed in the effective clinical use of mutation data. Although patients do benefit from today's approach to interpreting mutation data, we propose that interpretive strategies considering both cellular and genomic context of mutations will provide a more accurate rationale for treatment decisions (Figure). Cellular context accounts for histologic etiology and how cell type-specific differences in cellular signaling impact treatment success. Genomic context includes 3 distinct considerations: (1) clonal diversity of cancer cell populations and resulting evolution induced by treatment, (2) the presence of resistance mutations or other genomic features that preclude effective targeting of a mutation 9treatment efficacy barriers), and (3) the driver or activation status of the mutation at the time of treatment.

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis

“…It is unclear as to why there is such a drastic difference in survival of POLE-mutated cancers arising at different primary sites, i.e., colorectal versus endometrial. These observations strengthen the view that effects of mutations on tumor characteristics or tumor response to therapeutics are tissue and context-dependent (44). While these tumors exhibit prominent host immune response in most cases, given the overall excellent outcomes in these women, it is not yet warranted to consider expensive immunotherapy regimens.…”

Clear cell and endometrioid carcinomas: are their differences attributable to distinct cells of origin?

“…Herein, we have provided correlative evidence on which to base a new model of how endometriosis‐associated ovarian carcinomas develop. The model is aligned with the burgeoning recognition of the importance of cell context in shaping oncogenic opportunity . Although functional evidence from in vitro and probably in vivo modelling of the events described here will be required to test its validity, the model offers a potential answer to one of the most vexing questions in gynaecological pathology: namely, how do two very different carcinomas with similar genetics emerge from the same precursor lesion?…”

Categorization of cancer through genomic complexity could guide research and management strategies

“…This study displayed that tumours derived from different tissues can share similar oncogenic mechanisms and the targetable functional driver events may act as a ‘tumour class’ independently of tissue origin . However, although we agree that the genomic context in which mutations are found, namely clonal dominance, presence or absence of resistance features, and the driver status of mutations at time of biopsy, is important, this strategy ignores the importance of cellular context in predicting the clinical relevance and druggability of mutations . Perhaps the best example of the latter is the stunning difference in response to targeting the BRAF V600E mutation between melanoma and colorectal cancer, wherein the signalling apparatus in epithelial cells permits immediate up‐regulation of EGFR in response to mutant BRAF inhibition, a response not seen in melanoma cells .…”