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Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The
Francesco Schettini1,2, Silvia Paola Corona3,4, Fabiola Giudici3,5
1Translational genomics and targeted therapies in solid tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
Introduction:
Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.
Methods:
Patients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria.
Results:
27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p<0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to gBRCA status and type of response.
Conclusions:
Early-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.
Insights
Olaparib shows promise in treating triple-negative breast cancer (TNBC) regardless of BRCA mutations. Further research should combine biomarkers like TILs and PD-L1 to refine patient selection for olaparib-based therapies.
Area of Science:
- Oncology
- Pharmacology
- Biomarker Research
Background:
- Olaparib is effective in metastatic triple-negative breast cancer (TNBC) with germline BRCA mutations (gBRCA-mut).
- The OLTRE trial explored early response biomarkers to olaparib in gBRCA-wild-type (wt) TNBC and gBRCA-mut HER2-negative breast cancer.
Purpose of the Study:
- To investigate early response biomarkers to olaparib in TNBC.
- To assess olaparib's efficacy in gBRCA-wt TNBC and as a proof-of-concept in gBRCA-mut breast cancer.
Main Methods:
- Patients received 3 weeks of olaparib before neoadjuvant chemotherapy.
- Evaluated clinical and radiometabolic responses using RECIST1.1 and PERCIST criteria.
- Collected tumor biopsies and blood samples for biomarker analysis (TILs, PD-L1, immune cells).
Main Results:
- Olaparib induced partial clinical and radiometabolic responses in 16/35 and 15/27 patients, respectively.
- gBRCA-mut tumors showed higher tumor-infiltrating lymphocytes (TILs) and PD-L1 positivity.
- Clinical responders exhibited altered T-reg/T-eff ratios and changes in B and NK lymphocytes.
Conclusions:
- Early-stage TNBC may benefit from olaparib irrespective of gBRCA mutation status.
- Future trials should integrate TILs, PD-L1, and gBRCA status for personalized treatment strategies.
