Abstract Purpose/objectives: Women with recurrent triple-negative breast cancer (TNBC) who have recurrent disease have a poor prognosis. We know that recurrent TNBC has a high rate of homologous recombination deficiency (HRD). HRD cells are sensitive to cisplatin and radiation therapy (RT) independently, but their combination may enhance the sensitivity of HRD tumors. Materials/Methods: From April 2015 to September 2022, we enrolled 50 patients with locally recurrent or metastatic TNBC to a phase II trial (NCT02422498) of weekly cisplatin (25mg/m2) x12 and concurrent RT (50-60 Gy in 25 fractions or 37.5-48 Gy in 15 fractions). The primary end-point was the imaging response at 4-8 weeks after completion of therapy. Imaging response was a 50 reduction in the cross-sectional area of the index lesion. Fresh biopsies of all recurrent tumor masses were obtained in order to assess RAD51 function in viable cells, using ex-vivo irradiation for RAD51 foci in single cell suspensions from the tumor specimens. Tumors were categorized as HRD or HR-proficient (HRP) using the criteria established (PMID 28299801). All tumors with available material were subjected to whole genome sequencing (WGS) and categorized as HRD by criteria published recently (PMID 37587346). Results: The median age of enrolled patients was 50 (range 31-70). All patients had received at least two prior systemic therapies. 39 had local recurrence on the chest wall or regional nodes, with 25 having additional metastatic disease. 11 patients had only metastatic disease, with radiotherapy given to the dominant and painful site of disease. 1 patient was later determined to not have TNBC and was excluded from analysis. 42 of 49 patients had successful evaluation of HRD status, with 7 patients failing due to an inadequate cellular specimen on a limited core biopsy and the lack of any prior DNA for WGS. Of the 42 currently evaluated patients, 23 were HRD and 19 were HRP. For the patients with HRD tumors, the imaging response rate to cisplatin and RT was 78% (n=18, of which 10 showed a complete imaging response). In contrast, for HRP tumors the response rate was 21% (n=4, of which none showed a complete imaging response). The response of HRD tumors without radiotherapy, but to cisplatin alone was 24% (n=5) and only 1/15 HRP tumor showed a response to cisplatin alone. For the tumors where we had both RAD51 foci and WGS (n=29) the correlation of HRD calling was 27/29, with the two discordant tumors having evidence of BRCA2 reversion. HRD tumors were both sporadic biallelic and unknown germline at the time of recruitment to the study. Only 2 tumors were HRD without any detectable mutation in HR genes, suggesting that target gene mutation is the predominant cause of HRD. Further details of the whole genome signatures will be presented, with a mixture of BRCA1-like and BRCA2-like tumors observed (PMID 37587346). Although the study did not extend beyond the intitial treatment and response evaluation, follow-up durability of response was observed in the complete imaging responders. Conclusions: HRD status as determined by RAD51 focus formation or by WGS for genomic scars is the major determinant of imaging response of the index lesion (receiving cisplatin and RT). Even though these patients were heavily pre-treated, the imaging response and clinical benefit rate was reassuringly high for HRD patients, many of whom were non-germline cases. This trial supports the use of modern HRD testing as a method for selecting patients for HRD-directed therapies in future clinical trials. The incidence of HRD in recurrent TNBC is well above 50%, suggesting that many patients may benefit from newer agents for exploiting HRD in the future. Citation Format: S. N. Powell, A. J. Khan, R. Delsite, N. Riaz, J. S. Reis-Filho. Homologous Recombination Deficiency is the major determinant of response of Triple-Negative Breast Cancer to Cisplatin+Radiotherapy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-25.
Powell et al. (Tue,) studied this question.