Precision Medicine in Breast Cancer Must Consider Target Actionability

Precision cancer medicine aims to tailor treatment by basing decisions on the characteristics of an individual patient's tumor. Recent advances in DNA sequencing and cancer genomics have enabled the study of how different genomic alterations impact disease trajectory and govern sensitivity to targeted therapies. Multigene panels are common in clinical practice with frameworks, including the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT), having been developed to help prioritize alterations as actionable targets based on clinical evidence; however, it remains unclear how to best interpret sequencing results to guide treatment. To address this, Andre, Filleron, Kamal, and colleagues conducted the randomized, multicenter phase II SAFIR02-BREAST clinical trial, comparing targeted therapies matched to genomic alterations with chemotherapy in the maintenance setting for patients with HER2-negative metastatic breast cancer. The primary objective was to assess whether targeted therapy improved progression-free survival (PFS) as compared to maintenance chemotherapy, with secondary objectives being overall survival and response rates, safety, and correlation of molecular characteristics with efficacy endpoints. Of the 1,462 patients who received genomic profiling, 646 patients (44%) presented with a targetable genomic alteration, and 238 patients (16%) were subsequently randomized to receive targeted therapy (n = 157) or chemotherapy (n = 81). In patients presenting with an ESCAT tier I/II genomic alteration (48%)—the highest levels of actionability indicative of a matched drug having either established or preliminary clinical evidence of efficacy—targeted therapy led to a significantly longer PFS than chemotherapy (9.1 months vs. 2.8 months). Notably, targeted therapies matched to genomic alterations ranking lower on the ESCAT scale, indicating hypothetical actionability at best, had no significant difference in PFS compared with chemotherapy. In summary, this work demonstrates that genomic alterations can effectively guide targeted treatment to improve patient outcomes if there is prior clinical evidence of target actionability.

Andre F, Filleron T, Kamal M, Mosele F, Arnedos M, Dalenc F, et al. Genomics to select treatment for patients with metastatic breast cancer. Nature 2022 Sep 7 [Epub ahead of print].

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