ABSTRACT
Loss of function in epigenetic acting genes together with driver alterations in the PIK3CA pathway have been shown significantly associated with poor outcome in cervical squamous cell cancer. More recently, a CoxBoost analysis identified 16 gene alterations and 30 high level activated proteins to be of high interest, due to their association with either good or bad outcome, in the context of treatment received by chemoradiation. The objectives here were to review and confirm the significance of these molecular alterations as suggested by literature reports and to pinpoint alternate treatments options for poor-responders to chemoradiation.
Subject(s)
Breast Neoplasms , Carcinoma, Squamous Cell , Uterine Cervical Neoplasms , Female , Humans , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/therapy , Biomarkers , ChemoradiotherapyABSTRACT
Cancer progression is driven in part by genomic alterations1. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations2, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14-0.89; gBRCA2: HR = 0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.
