Sequential targeting of PARP with carboplatin inhibits primary tumour growth and distant metastasis in triple-negative breast cancer

Abstract

Background Patients with triple-negative breast cancer (TNBC) develop early recurrence. While PARP inhibitors (PARPi) have demonstrated potential in BRCA1/2-mutant (BRCAMUT) TNBC, durable responses will likely be achieved if PARPi are used in combination. It is plausible that sequential administration of a potent PARPi like talazoparib in combination with carboplatin can enhance primary tumour and metastasis inhibition in BRCAMUT and BRCA1/2 wild-type (BRCAWT) TNBCs, and decrease toxicity. Methods We evaluated the impact of the concurrent combination of talazoparib and carboplatin on cell survival in 13 TNBC cell lines. We compared the concurrent and sequential combination upon fork replication, migration and invasion. We also used three orthotopic xenograft models to evaluate primary tumour growth, distant metastasis, and toxicity. Results Concurrent talazoparib and carboplatin was synergistic in 92.3% of TNBC cell lines, independent of BRCA1/2-mutation status. The sequential combination decreased fork speed in normal cells, but not in TNBC cells. The talazoparib-first sequential combination resulted in a strong reduction in migration (70.4%, P < 0.0001), invasion (56.9%, P < 0.0001), lung micrometastasis (56.4%, P < 0.0001), and less toxicity in a BRCAWT model. Conclusion The sequential combination of talazoparib and carboplatin is an effective approach to inhibit micrometastatic disease, providing rationale for the use of this combination in early TNBC patients.

Recent advances in targeted strategies for triple-negative breast cancer

“…It demonstrated significantly higher pathologic complete response (pCR) rates in the evaluable and intent-to-treat populations (all TNBC patients) (45.8% and 49.2%), respectively, with a well-tolerated safety profile [ 36 ]. Sequential combination therapy with talazoparib and carboplatin suppressed primary cancer cell growth and distant metastases in patients with TNBC, laying the foundation for treating early-stage TNBC [ 37 ].…”

Establishment and verification of a nomogram to predict risk and prognostic factors of triple-negative breast cancer with organ metastasis based on the SEER cohort study

“…Among them, TNBC is clinically de ned as BC with negative ER, PR, and HER-2, which is the most aggressive and heterogeneous subtype, and there are about 200000 new cases every year, accounting for 15-20% of the total cases and 25% of all BC related deaths(Yin, Jiang, Xu, Jia, & Lin, 2023; Zhao et al, 2023). Moreover, its recurrence rate is high, the metastasis ability is strong, the prognosis is poor, and the survival rate is low (Beniey et al, 2023;Chu et al, 2023;Huang et al, 2023). A large number of researches show that TNBC is an invasive disease characterized by drug resistance and distant metastasis(Lawal, Wu, Chen, T, & .…”