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Published on: October 11, 2017
Olaparib monotherapy as primary treatment in unselected triple negative breast cancer
H P Eikesdal1, S Yndestad1, A Elzawahry1
1Department of Oncology, Haukeland University Hospital, Bergen, Norway; K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
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 previous chemotherapy exposure.
Patients And Methods:
In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (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 mm). 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), in contrast to 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.
Trial Registration:
ClinicalTrials.gov identifier: NCT02624973.
Insights
PARP inhibitors show efficacy in treatment-naïve triple-negative breast cancer (TNBC) patients with homologous recombination deficiency (HRD). Olaparib response was observed in 56.3% of patients, particularly those with HR mutations or BRCA1 methylation.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- PARP inhibitors (PARPi) are effective for BRCA-mutated breast cancer.
- PARPi monotherapy is ineffective in metastatic triple-negative breast cancer (TNBC) wild type for BRCA1/2.
- Hypothesis: PARPi may be effective in primary TNBCs without prior chemotherapy.
Purpose of the Study:
- To evaluate the efficacy of olaparib in treatment-naïve primary TNBC.
- To identify predictive biomarkers for olaparib response in TNBC.
Main Methods:
- Phase II PETREMAC trial of olaparib in primary TNBC patients (>2 cm).
- Tumor biopsies for DNA sequencing, BRCA1 methylation, BRCAness, gene expression, RAD51 foci, TILs, and PD-L1 analysis.
- Olaparib administered for 10 weeks pre-chemotherapy.
Main Results:
- Objective response (OR) to olaparib in 56.3% (18/32) of patients.
- HR mutations (somatic or germline) observed in 55.6% of responders vs. 7.1% of non-responders (P=0.008).
- BRCA1 hypermethylation identified in 75% of non-mutated responders vs. 23.1% of non-responders (P=0.03).
- 88.9% of responders had HR mutations and/or BRCA1 methylation vs. 28.6% of non-responders (P=0.0008).
- Low RAD51 scores, high TILs, and high PD-L1 correlated with olaparib response.
Conclusions:
- Olaparib demonstrates significant clinical response in treatment-naïve TNBC.
- Homologous recombination deficiency (HRD), including BRCA1 methylation, predicts olaparib response beyond germline BRCA mutations.
- Biomarkers like RAD51, TILs, and PD-L1 may further refine treatment selection.
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