No Benefit From Adjuvant Chemotherapy in High Risk Premenopausal Luminal A Breast Cancer Patients

In a prospective-retrospective analysis of the Danish Breast Cancer Cooperative Group (DBCG) 77B phase III study, in which premenopausal women were randomised to adjuvant cyclophosphamide-based chemotherapy vs. no chemotherapy, patients whose invasive breast cancers were of the luminal A subtype, as defined by immunohistochemistry (IHC), had comparable 10-year disease-free survival (DFS) rates regardless of whether or not they received adjuvant chemotherapy. The results are presented in the oral session at San Antonio Breast Cancer Symposium (8–12 December 2015, San Antonio, Texas, USA).

Several studies have shown distinct clinical profiles of intrinsic breast cancer subtypes. The luminal A subtype has a favourable prognosis with higher survival rate and lower recurrence in comparison to other breast cancer subtypes (luminal B, HER2 and basal-like). In addition, there is mounting evidence suggesting that intrinsic breast cancer subtypes differ in their responsiveness to adjuvant chemotherapy. Based on these data, the study authors hypothesized that luminal A breast cancer patients derive no benefit from adjuvant chemotherapy whereas other intrinsic subtypes do.

Randomised breast cancer trials with a no chemotherapy arm and available tissues are rare, but represent the best materials to test for markers predicting chemotherapy benefit. The 77B clinical trial from the DBCG offers a unique opportunity to test such hypotheses, as it randomised 1146 premenopausal women, who had positive axillary lymph nodes or tumours larger than 5 cm to two chemotherapy arms (single-agent oral cyclophosphamide, or CMF regimen), and two no chemotherapy arms (levamisole, or no agent). All arms included radiotherapy but no endocrine therapy.

Dr Torsten Nielsen, who is a professor of pathology at the University of British Columbia in Vancouver, Canada and the study team performed a full intrinsic subtype analysis on the 709 breast cancers available from DBCG77B on tissue microarrays using previously published, locked-down IHC methods and intrinsic subtype definitions based on ER, PR, HER2, Ki67 and basal markers (Prat, et al. JCO 2014). Biomarker scoring was performed in Vancouver by researchers with no access to the clinical database. A full statistical plan was prespecified in the Material Transfer Agreement and executed accordingly by the DBCG Statistical Office.

Ten-year invasive DFS was the primary end point in DBCG77B; overall survival (OS) was also a predefined endpoint. The primary hypothesis was to assess interaction between benefit of chemotherapy and subtype (luminal A vs non-luminal A).

In total, 709 patients had tissue available and completed IHC intrinsic subtyping. The effect of chemotherapy in this subset of patients was similar to the original trial: hazard ratio (HR) 0.56, favouring chemotherapy for 10-year IDFS.

IHC classified 165 as luminal A, 319 luminal B, 58 HER2E and 91 as triple negative (including 82 core basal). Patients with luminal A breast tumours did not benefit from chemotherapy (HR = 1.07, p = 0.86), whereas patients with non-luminal A subtypes did (HR = 0.50, p < 0.001). This heterogeneity was statistically significant (p = 0.048). A similar trend for 25-year OS was seen, although not significant.

The study was supported by the Canadian Breast Cancer Foundation, the IM Daehnfeldt Foundation, and the Danish Research Council.

Reference

Nielsen TO, Jensen ‎ M-B, Gao D, et al. High risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from DBCG77B randomized trial. Presented at San Antonio Breast Cancer Symposium; San Antonio, Texas, USA: 8–12 December 2015.