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.

While studies have shown feasibility and reported preliminary evidence of utility, there is no evidence that multigene sequencing improves outcomes in patients with metastatic breast cancer. The aim of phase 2 SAFIR02-BREAST study (NCT02299999) was to assess the clinical utility of multigene sequencing and DNA copy number analyses. The trial enrolled patients with metastatic, HER2-negative breast cancer to evaluate whether targeted therapies guided by genomics improve progression-free survival (PFS), compared with maintenance chemotherapy. 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 researchers performed a pooled analysis of this trial and the phase 2 SAFIR-PI3K trial (NCT03386162) that compared a combination of the PI3Kα-specific inhibitor alpelisib and the estrogen-receptor antagonist fulvestrant with maintenance chemotherapy in patients with PIK3CA-mutated metastatic breast cancer. 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 [1]. If a P<0.1 was observed in the first step, analyses were then performed in the intention-to-treat population. Dr. Fabrice André (Institut Gustave Roussy, France) presented the results of SAFIR02-BREAST [2]. Out of the 1,462 patients included, 238 (16%) had stable disease after 6 to 8 cycles of chemotherapy and carried known genomic alterations. These patients 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 and 2.8 in matched targeted therapy and maintenance chemotherapy arms, respectively (HR 0.41, P<0.001). In the overall population, there was no significant difference in the duration of PFS between the 2 arms (HR 0.77, P=0.109), 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 Dr. 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, like ESCAT, of the gene alterations identified.”

  1. Mateo J, et al. Ann Oncol. 2018;29:1895-1902.
  2. André F, et al. Clinical utility of molecular tumor profiling: Results from the randomized trial SAFIR02-BREAST. SABCS 2021 Virtual Meeting, abstract GS1-10.

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