A new randomized phase III clinical trial has investigated the efficacy of intensified alkylating chemotherapy (IACT) compared to conventional-dose chemotherapy (CDCT) in patients with oligometastatic breast cancer (OMBC) harboring homologous recombination deficiency (HRD). The OLIGO study, conducted at the Netherlands Cancer Institute, was funded by the Dutch Cancer Society and published in the European Journal of Cancer in October 2024.
The primary aim of this single-center study was to determine if IACT could improve long-term outcomes in OMBC patients with HRD as part of a multimodality treatment approach. The researchers hypothesized that IACT might be particularly effective in this patient population due to the vulnerability of HRD tumors to alkylating agents.
The study enrolled 75 patients with HER2-negative OMBC harboring HRD, defined as either a deleterious germline BRCA1 or BRCA2 mutation or a BRCA-like profile based on molecular testing. Eligible patients had a maximum of three distant metastases amenable to local ablative therapy (LAT), with or without primary tumor and/or locoregional nodes. Patients were randomized 1:1 to receive either IACT or CDCT after completing three cycles of induction CDCT.
The demographic data showed a median age of 46 years at randomization. Thirty-one percent of patients had hormone receptor-positive disease, while 69% had triple-negative breast cancer. HRD status was based on germline BRCA1 mutations in 27% of patients, BRCA2 mutations in 11%, and BRCA-like profiles in the remaining 63%.
After a median follow-up of 52 months, the study found no significant difference in event-free survival (EFS) between the two groups. The median EFS was 28 months in the IACT group versus 25 months in the CDCT group (hazard ratio 0.78, 95% CI 0.42-1.42). Overall survival (OS) also showed no significant difference, with a median of 67 months in the IACT group and 36 months in the CDCT group (HR 0.74, 95% CI 0.37-1.48).
Notably, the entire study population experienced favorable long-term survival, with median OS exceeding five years. This outcome was better than initially anticipated when the study was designed in 2011, reflecting the evolving landscape of breast cancer treatment.
As expected, the IACT group experienced more grade 3 or higher toxicities (94% vs 64% in the CDCT group), primarily hematologic in nature. However, no grade 5 toxicities occurred in either group. Quality of life assessments showed a transient decrease in the IACT group at the end of chemotherapy, but scores recovered to baseline levels one year after study therapy.
The authors noted several limitations to the study. The accrual period was longer than anticipated, which resulted in a smaller sample size than initially planned. Additionally, the emergence of new treatments during the study period, such as immune checkpoint inhibitors and PARP inhibitors, may affect the generalizability of the results to the current OMBC population.
The researchers concluded that IACT did not improve outcomes compared to CDCT in patients with OMBC harboring study-defined HRD. They emphasized that the optimal therapy for patients with OMBC requires further investigation, particularly given the heterogeneity of the disease and the rapidly changing treatment landscape.
The potential clinical impact of this study is significant, as it suggests that the intensification of alkylating chemotherapy may not provide additional benefit in this specific patient population. However, the favorable long-term survival observed in both groups highlights the importance of optimizing treatment strategies for OMBC patients.
Moving forward, the authors call for future studies to focus on identifying prognostic biomarkers to guide patient selection and predictive biomarkers to inform treatment choices. They stress the need for intensive collaboration and innovative study designs to overcome the challenges posed by the rarity and heterogeneity of OMBC, as well as the rapidly evolving treatment options for metastatic breast cancer.
In conclusion, while this study does not support the use of IACT over CDCT in OMBC patients with HRD, it underscores the potential for long-term survival in this patient population and emphasizes the need for continued research to optimize individualized treatment approaches. Medical professionals should consider these findings when discussing treatment options with OMBC patients, while recognizing that the optimal systemic therapy for each individual requires further study in the context of current and emerging treatment modalities.
References
van Ommen-Nijhof A, Steenbruggen TG, Wiersma TG, et al. Intensified alkylating chemotherapy for patients with oligometastatic breast cancer harboring homologous recombination deficiency: Primary outcomes from the randomized phase III OLIGO study. Eur J Cancer. 2024;213:115083. doi:10.1016/j.ejca.2024.115083
