Precision medicine interpreted with ‘right tools’ beneficial in metastatic breast cancer
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Use of genomics to guide treatment selection improved outcomes for certain patients with metastatic breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
Researchers observed the greatest benefit with the multigene sequencing strategy when the genomic alterations identified were included in the top two tiers of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT).
In addition, results identified new genomic alterations associated with metastatic evolution, as well as drug sensitivity or resistance.
“The general implication of our study is that precision medicine can improve patient outcome if it is interpreted with the right tools,” Fabrice André, MD, PhD, research director at Gustave Roussy Cancer Campus in France, said in a press release.
Establishing the mutational profile of a tumor through next-generation genomic analysis allows clinicians to select targeted therapies that match detected alterations, increasing the likelihood of better outcomes.
Multigene sequencing has been widely adopted and prior research has shown preliminary evidence of clinical utility. However, it had not been established whether multigene sequencing improved outcomes for patients with metastatic breast cancer, according to study background.
André and colleagues conducted the randomized phase 2 SAFIR02-BREAST trial to evaluate the clinical utility of multigene sequencing and DNA copy number analyses.
The open-label trial included 1,462 patients with HER2-negative metastatic breast cancer eligible for first- or second-line chemotherapy.
When feasible, patients underwent pretreatment biopsy of metastatic disease, followed by genomic analysis by next-generation sequencing and single nucleotide polymorphism array.
Patients underwent six to eight cycles of induction chemotherapy.
The 238 patients who presented with an actionable genomic alteration and did not experience disease progression on chemotherapy proceeded to the randomized portion of the trial. Researchers randomly assigned these patients to maintenance chemotherapy (n = 81) or to one of nine targeted therapies matched to identified genomic alterations (n = 157). The targets included mammalian target of rapamycin, EGFR, AKT, HER2, MEK, VEGF, the androgen receptor and poly(ADP-ribose) polymerases (PARP).
Researchers initially tested the efficacy of targeted therapies among patients who presented with alterations in tier 1 or tier 2 of ESCAT, which ranks the likelihood that genomic alterations will serve as therapeutic targets based on available evidence. If they calculated a P value less than 0.1, they performed analyses in the intent-to-treat population.
Among the 115 patients who presented with ESCAT tier 1 or tier 2 genomic alterations, those assigned targeted therapy achieved significantly longer PFS than those assigned maintenance chemotherapy (9.1 months vs. 2.8 months; adjusted HR = 0.41; 90% CI, 0.27-0.61).
Researchers reported no significant difference in PFS between the targeted therapy and maintenance chemotherapy groups in the overall study population (adjusted HR = 0.77; 95% CI, 0.56-1.06).
ESCAT classification appeared highly predictive for the benefit of targeted therapies matched to identified genomic alterations (P = .004). However, targeted therapies did not appear effective for patients with genomic alterations not included in ESCAT tier 1 or tier 2 classification (HR = 1.15; 95% CI, 0.76-1.75).
Researchers conducted single nucleotide polymorphism array analyses of 926 patients’ tumors and identified 21 genes that more frequently were altered in metastases than primary tumors.
Results showed focal TERT amplifications appeared associated with poor outcomes and focal cyclin-dependent kinase (CDK) 4 amplifications occurred among patients who developed resistance to CDK 4/6 inhibitors. In addition, researchers identified an association between high homologous recombination deficiency and longer PFS among patients with BRCA mutations treated with the PARP inhibitor olaparib (Lynparza; AstraZeneca, Merck; HR = 0.32; 95% CI, 0.12-0.83).
“Our study showed that genomic analysis improves the outcome of patients with metastatic breast cancer if they carry alterations classified as ESCAT (tier 1 or tier 2),” André said. “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.”
Perspective
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Virginia Kaklamani, MD
I really cannot overstate how important this clinical trial is. This is the first trial we have in which we have used genomic alterations to actively change a patient’s treatment plan and found an improvement in outcomes. This is for early-stage breast cancer, which is even more important because the whole point is to try to prevent metastatic disease. What Dr. Andre showed so eloquently was the fact that, by finding changes in the tumor that were unique to that patient and by having targeted therapies available for that change, we were able to treat the patient with that specific targeted therapy instead of standard of care, which would’ve been chemotherapy. This resulted in improved outcomes. This is an approach we will be using more often in our practice so we can treat our patients based on their genomic alterations.
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André F, et al. Abstract GS1-10. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2021; San Antonio.
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