Selective benefit of high-dose, platinum-containing, alkylating chemotherapy with stem cell rescue for patients with breast cancers with an expansive growth pattern on histology

Abstract

587 Background: Breast cancer (BC) cells lacking the DNA repair mechanism homologous recombination (HR), a feature of BRCA-deficient tumor cells, are hypersensitive to bifunctional alkylating agents. Metastatic BC patients whose tumors were scored as BRCA1-like with a BRCA1 Comparative Genomic Hybridization classifier had an impressive progression-free survival after platinum-containing (PC), high-dose alkylating (HDA) chemotherapy. BRCA1-like tumors showed an expansive growth (EG) pattern, were generally HER-2 negative and estrogen receptor (ER) negative (Vollebergh et al, Cancer Res. 2009, 69;[Suppl. 2]6050). To further investigate whether BRCA1-like tumors were chemosensitive in general, or were sensitive specifically to PC HDA chemotherapy, we studied outcome of stage III BC patients who had participated in a randomized trial of adjuvant 5 x FEC (5-fluorouracil, epirubicin, cyclophosphamide) versus 4 x FEC followed by high-dose CTC (cyclophosphamide, thiotepa, carboplatin) with autologous stem cell rescue (Rodenhuis et al, New Engl J Med. 2003). Methods: 162 Patients with an ER negative or low (<25% of tumor cells positive) and HER-2-negative tumor were selected from abovementioned trial. EG was used as a surrogate for ‘BRCA1-like'. Currently available whole slides of n = 99 patients were scored for EG. An interaction term was fitted to a multivariate proportional hazards model to evaluate whether effect of CTC treatment in terms of recurrence-free survival (RFS) was modified by EG. Results: While RFS after 5 x FEC was similar for the 15 patients with EG as compared to 38 without EG (33%, and 31% 10-year RFS, respectively), 10-year RFS after high dose CTC was better for the 16 patients with EG (81% (multivariate hazard rate [HR] of CTC versus FEC 0.11 [95% CI 0.02–0.53]) as opposed to the 30 without EG (53% [multivariate HR of CTC versus FEC 0.58 (95% CI 0.3–1.12)]); multivariate test for interaction p = 0.056). Conclusions: Using histological information, by determining the presence of an expansive growth pattern, we were able to identify a group of stage III breast cancer patients who selectively benefited from PC HDA chemotherapy. No significant financial relationships to disclose.