Olaparib Monotherapy as Primary Treatment in Unselected Triple Negative Breast Cancer
Mené sur 32 patientes atteintes d'un cancer du sein triple négatif, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, de l'olaparib en traitement de première ligne, selon la présence de mutations au niveau des gènes BRCA ou de gènes impliqués dans la recombinaison homologue
Background : The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without prior chemotherapy exposure. Patients and methods : In the phase 2 PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks prior to chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing of (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples. Results : The median pretreatment tumor diameter was 60 mm (range 25-112). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders (OR 55.6%, 95% confidence interval [CI] 33.7-75.4) contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), contrasting 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response. Conclusion : Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations.