SAN ANTONIO – The use of multigene sequencing as a therapeutic decision tool improved the outcomes for patients with metastatic breast cancer when the genomic alterations identified were ranked in the I/II tiers of the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), according to results from the SAFIR02-BREAST trial presented at the San Antonio Breast Cancer Symposium, held December 7-10, 2021.
Next-generation genome analysis technologies allow researchers to simultaneously sequence multiple genes and to establish the mutational profile of a patient’s tumors. This can help with targeting the identified alterations with therapeutics that may not be the standard of care for that disease, with the goal of improving patient outcomes.
“Multigene sequencing has been widely implemented but its clinical impact and the best framework for its use are unclear,” said presenter Fabrice André, MD, PhD, research director at Gustave Roussy Cancer Campus. “The main purpose of our study was to test whether genomic analyses are useful for patients with metastatic breast cancer, and how we can best analyze the results.”
The phase II SAFIR02-BREAST trial enrolled patients with metastatic, HER2-negative breast cancer to evaluate whether targeted therapies guided by genomics improve progression-free survival (PFS) compared to maintenance chemotherapy. Patient 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 this trial and the SAFIR-PI3K trial that compared a combination of the PI3Kα-specific inhibitor alpelisib (Piqray) and the estrogen receptor antagonist fulvestrant with maintenance chemotherapy in patients with PIK3CA-mutated metastatic breast cancer.
Genomic analysis through next-generation sequencing and SNP array was performed on 1,462 patients. The investigators assigned 238 patients whose disease was stable after six to eight cycles of chemotherapy and who carried known genomic alterations to either the appropriate targeted therapies matched to their genomic alteration (157) or maintenance chemotherapy (81).
The drugs included in the study were vistusertib, AZD4547, capivasertib, sapitinib, selumetinib (Koselugo), vandetanib (Caprelsa), bicalutamide (Casodex), olaparib (Lynparza), and alpelisib, and were matched to the following targets respectively: m-TOR, EGFR, AKT, HER2 or EGFR, MEK, VEGF or EGFR, androgen receptor, and PARP.
Genomic alterations in the patients’ tumors were classified using the ESCAT scale, which ranks the likelihood of genomic alterations to serve as therapeutic targets, based on the strength of evidence from clinical studies. The investigators assessed the efficacy of the therapies in relation to their ESCAT ranking.
In 115 patients presenting an ESCAT I/II genomic alteration, the median PFS was 9.1 and 2.8 months in the matched targeted therapy and maintenance chemotherapy arms, respectively. On the contrary, there was no significant difference in PFS 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, suggesting that the ESCAT classification was highly predictive of the benefits of targeted therapies matched to genomic alterations.
“Our study showed that genomic analysis improves the outcome of patients with metastatic breast cancer if they carry alterations classified as ESCAT I/II,” commented André. “These findings suggest that genomics should be a part of the pathway of care, but it has no impact if the results are not interpreted using a validated framework of actionability of the gene alterations identified.”
In addition to testing for known genetic alterations, multigene sequencing also allows researchers to discover new ones. André and colleagues identified 21 gene amplifications or deletions associated with metastatic evolution, poor prognosis, and drug resistance or sensitivity.
“The general implication of our study is that precision medicine can improve patient outcome if it is interpreted with the right tools,” André added.
According to the authors, the main limitation of this study is the limited number of targeted therapies matched to the genomic alterations found.
This study was funded by Fondation ARC, Breast Cancer Research Foundation, Agence Nationale de la Recherche (IHU-B).
André declares grants or advisory board/speaker honoraria (compensated to the hospital) from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lilly, and Novartis.
Abstract
GS1-10
Clinical utility of molecular tumor profiling: Results from the randomized trial SAFIR02-BREAST
Background: While studies have shown feasibility and reported preliminary evidence of utility, there is no evidence that multigene sequencing improves outcome in patients with metastatic cancer. The aim of the present study was to assess the clinical utility of multigene sequencing and DNA copy number analyses. Methods: In SAFIR02-BREAST (NCT: 02299999) and SAFIR-PI3K (NCT: 03386162), open-label multicentric phase II randomized trials, patients were selected if they had a Her2-negative metastatic breast cancer eligible to 1st or 2nd line chemotherapy. Patients underwent a pre-treatment biopsy of metastatic disease when feasible, followed by genomic analysis by next generation sequencing and SNParray. After 6 to 8 cycles of induction chemotherapy, patients without progressive disease and presenting an actionable genomic alteration, were randomized between targeted therapies matched to genomic alterations or maintenance chemotherapy. The primary objective was to evaluate whether targeted therapies guided by genomics improves progression-free survival (PFS) as compared to maintenance chemotherapy, in a pooled analyses of SAFIR02-BREAST and SAFIR-PI3K populations. A hierarchical testing was applied. The efficacy of targeted therapies matched to genomic alterations was first tested in patients presenting an ESCAT I/II alteration (ESMO Scale of Actionability of Molecular Targets). If a p value <0.1 was observed in the first step, analyses were then performed in the Intent-to-treat population. Results: Out of the 1462 patients included, 238 (16%) were subsequently randomized between maintenance chemotherapy (n=81) and targeted therapy (n=157). In 115 patients presenting an ESCAT I/II genomic alteration, the median PFS was 9.1 months (90%CI: 7.1-9.8) and 2.8 (90%CI: 2.1-4.8) in matched targeted therapy and maintenance chemotherapy arms respectively (adjusted HR for stratification factors =0.41;90%CI: 0.27-0.61, p<0.001). In the overall population, there was no significant difference in the duration of PFS between the two arms (adjusted HR: 0.77 (95%CI: 0.56- 1.06, p=0.109). ESCAT classification was highly predictive for the benefit of targeted therapies matched to genomic alterations (interaction test, p= 0.004). Targeted therapies matched to genomic alterations were not effective in patients without 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 as 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, high HRD was associated with longer PFS in patients with BRCA mutation treated with olaparib (HR: 0.32 [95%CI: 0.12;0.83], p=0.013). Conclusion: SAFIR02/PI3K trials report that the clinical use of multigene sequencing must be driven by a framework of actionability, and identifies new genomic alterations associated with metastatic evolution and drug resistance or sensitivity.
COI Statement
André declares grants or advisory board/speaker honoraria (compensated to the hospital) from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lilly, and Novartis.