The use of multigene sequencing and SNP array as a therapeutic decision tool improved the outcomes of patients with metastatic breast cancer if the patients carried alterations classified in the I/II tiers of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), according to findings from the SAFIR02-Breast trial presented by André et al during the 2021 San Antonio Breast Cancer Symposium (Abstract GS1-10). The clinical use of multigene sequencing must be driven by a validated framework of actionability of the gene alterations identified, according to the study authors.
The aim of the study was to assess the clinical utility of multigene sequencing and DNA copy number analyses in patients with metastatic breast cancer and how to best analyze the results.
Study Methodology
The researchers analyzed data from 1,462 patients with metastatic, HER2-negative breast cancer enrolled in the phase II SAFIR02-Breast trial to evaluate whether targeted therapies guided by genomics improved progression-free survival compared to maintenance chemotherapy. Patients who had received more than two lines of chemotherapy or one of the targeted therapies evaluated in the trial were not eligible to participate.
The researchers performed a pooled analysis of the SAFIR02-Breast trial and the SAFIR-PI3K trial, which compared a combination of the PI3K inhibitor alpelisib and the estrogen receptor antagonist fulvestrant with maintenance chemotherapy in patients with PIK3CA-mutated breast cancer.
They then applied hierarchical testing to the patients. The efficacy of targeted therapies matched to genomic alterations was first tested in patients presenting an ESCAT I/II alteration. If a P value of < .1 was observed in the first step, analyses were then performed in the intent-to-treat population. Of the 1,462 patients included in the trial, the researchers assigned 238 patients with stable disease after six to eight cycles of chemotherapy and who carried known genomic alterations to either the appropriate targeted therapies matched to their genomic alteration (n = 157) or to maintenance chemotherapy (n = 81).
The drugs included in the study were vistusertib, AZD4547, capivasertib, sapitnib, selumetinib, vandetanib, bicalutamide, olaparib, and alpelisib. The drugs were matched to the following targets, respectively: m-TOR, EGFR, AKT, HER2 or EGFR, MEK, VEGF or EGFR, androgen receptor, and PARP.
KEY POINTS
- The use of multigene sequencing and SNP array as a therapeutic decision tool improved the outcomes of patients with metastatic breast cancer if the patients carried alterations classified in the I/II tiers of the ESCAT.
- In 115 patients presenting with an ESCAT I/II genomic alteration, the median progression-free survival was 9.1 months, and was 2.8 months in the matched targeted therapy and maintenance chemotherapy arms, respectively, of the study.
- There was no significant difference in progression-free survival between the two arms in the overall population, and targeted therapies were not effective when matched to alterations that did not rank as ESCAT I/II.
Results
The researchers found that in 115 patients presenting an ESCAT I/II genomic alteration, the median progression-free survival was 9.1 months (90% confidence interval [CI] = 7.1–9.8) and 2.8 months (90% CI: 2.1–4.8) in the matched targeted therapy and maintenance chemotherapy arms, respectively (adjusted hazard ratio [HR] for stratification factors = 0.41, 90% CI = 0.27–0.61, P < .001). In the overall population, there was no significant difference in the duration of progression-free survival between the two arms (adjusted HR = 0.77, 95% CI = 0.56–1.06, P = .109).
ESCAT classification was highly predictive for the benefit of targeted therapies matched to genomic alterations (interaction test, P = .004). Targeted therapies matched to genomic alterations were not effective in patients without an ESCAT I/II alteration (HR = 1.15, 95% CI = 0.76–1.75). The SNP array analyses (n = 926) identified 21 genes altered more frequently in metastases compared to primary tumors (TCGA+ METABRIC). Of these, focal TERT amplifications were associated with a poor outcome. Focal CDK4 amplifications were observed after resistance to CDK4 inhibitors. Finally, the researchers found that high homologous recombination deficiency was associated with longer progression-free survival in patients with a BRCA mutation treated with olaparib (HR = 0.32, 95% CI = 0.12–0.83, P = .013).
“[The] SAFIR02/PI3K trials report that the clinical use of multigene sequencing must be driven by a framework of actionability, and identify new genomic alterations associated with metastatic evolution and drug resistance or sensitivity,” concluded the study authors.
Clinical Significance
“Our study showed that genomic analysis improves the outcome of patients with metastatic breast cancer if they carry alterations classified as ESCAT I/II,” said first study author Fabrice André, MD, PhD, Director of Research and Professor of Medical Oncology at Institut Gustave Roussy in Villejuif, France, in a statement. “These findings suggest that genomics should be a part of the pathway of care, but [have] no impact if the results are not interpreted using a validated framework of actionability of the genetic alterations identified….The general implication of our study is that precision medicine can improve patient outcomes if it is interpreted with the right tools.”
Disclosure: Dr. André declares grants or advisory board/speaker honoraria from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lilly, and Novartis. Funding for this study was provided by Fondation ARC, the Breast Cancer Research Foundation, and Agence Nationale de la Recherche (IHU-B).
