Using genomics to match treatments improves outcomes

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.

The aim of the phase 2 SAFIR02-BREAST study (NCT02299999) was to assess the clinical utility of multigene sequencing and DNA copy number analyses. The study 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 who presented an actionable genomic alteration were randomised to 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 oestrogen-receptor antagonist fulvestrant with maintenance chemotherapy in patients with PIK3CA-mutated metastatic breast cancer.

The primary objective was to evaluate whether targeted therapies guided by genomics improves PFS compared with maintenance chemotherapy. A hierarchical testing was applied. The efficacy of targeted therapies was first tested in patients presenting an ESCAT I/II alteration [1]. If a P<0.1 was observed in the first step, subsequent analyses were performed in the intent-to-treat population. Prof. Fabrice André (Institut Gustave Roussy, France) presented the results of SAFIRE02-BREAST [2].

Out of the 1,462 patients enrolled, 238 (16%) had stable disease after 6–8 cycles of chemotherapy and carried known genomic alterations. These patients were subsequently randomised between maintenance chemotherapy (n=81) and targeted therapy (n=157). In the 115 patients presenting an ESCAT I/II genomic alteration, the median PFS was 9.1 months and 2.8 months in matched-targeted therapy and maintenance chemotherapy arms respectively (HR 0.41; 90% CI 0.27–0.61; P<0.001; see Figure). In the intent-to-treat 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.Figure: Progressive-free survival between ESCAT patients on maintenance chemotherapy versus targeted therapy [2].



 

 

 

 

 

 

PFS, progression-free survival; HR, hazard ratio; CI, confidence interval.

“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 Prof. André. “These findings suggest that genomics should be a part of the pathway of care, but it has no impact if the results of the identified gene alterations are not interpreted using a validated framework of actionability, like ESCAT.”

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. GS1-10, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January 202216 February 2024