Background Approximately 5% of patients with metastatic breast cancer survive more than 10 years. Long-term survival is mostly seen in patients with limited metastatic disease, often referred to as 'oligo'-metastatic disease. Oligo-metastatic breast cancer is variably defined as a maximum of 3-5 metastases beyond the regional lymph nodes. Some believe that oligo-metastatic cancer can be treated with curative intent using a multidisciplinary approach that targets the detected metastases, circulating micro-metastases, and any locoregional disease if present. Optimal patient selection is of vital importance.

Intensified alkylating chemotherapy in the treatment of breast cancer patients is controversial, as older studies have not shown a survival benefit in unselected groups of patients. More recent retrospective analyses, however, have suggested that patients with homologous recombination deficiency (HRD) derive significant benefit from intensified chemotherapy in comparison to conventional chemotherapy.

Trial design In this phase 3 trial patients with oligo-metastatic breast cancer and HRD start with 3 cycles of induction chemotherapy. Chemotherapy schedule includes anthracyclines and taxanes in treatment naïve patients and is personalized according to previously received (neo-)adjuvant chemotherapy in others. Patients with at least stable disease after 3 cycles are 1:1 randomized to receive another 3 cycles of conventional chemotherapy or progenitor cell mobilization with cyclophosphamide followed by 2 cycles of intensified chemotherapy (carboplatin 400 mg/m2 (day 1&2), thiotepa 250 mg/m2 (day 2), and cyclophosphamide 3000 mg/m2 (day 1)) and peripheral blood progenitor cell reinfusion. Following systemic treatment, all patients receive maximal local therapy of locoregional and distant disease with surgery and/or radiotherapy.

Eligibility criteria Eligible patients have histologically proven, HER2 negative, oligo-metastatic breast cancer (1-3 distant metastatic lesions), with or without locoregional disease, either as de novo disease or recurrence. All lesions must be amenable to surgery or radiotherapy with curative intent. The tumor has to be deficient in homologous recombination by array comparative genomic hybridization and no prior chemotherapy for metastatic disease is allowed.

Specific aim To study the difference in event-free survival (EFS) between intensified alkylating chemotherapy compared to standard chemotherapy as part of a multimodality treatment approach in patients with oligo-metastatic breast cancer harboring HRD.

Statistical methods and patient accrual Primary endpoint of the study is EFS at 3 years. Toxicity, time to recurrence, and overall survival will be evaluated as secondary endpoints. A total of 65 EFS events will provide 80% power to detect a hazard ratio of 2.0 between treatment arms at the 0.05 two-sided significance level. Assuming an accrual period of 48 months and a maximum follow-up time of 60 months, 86 patients are required. At the time of abstract submission, 33 patients were randomized.

Contact information Principal investigator: Dr. GS Sonke, Study coordinator: TG Steenbruggen, NCT01646034.

Citation Format: Steenbruggen TG, Vrancken Peeters M-JTFD, Scholten AN, Schot M, Wesseling J, Linn SC, Sonke GS. Intensified alkylating chemotherapy in patients with oligo-metastatic breast cancer harboring homologous recombination deficiency: The OLIGO study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-08.