Intrinsic subtypes and benefit from postmastectomy radiotherapy in node-positive premenopausal breast cancer patients who received adjuvant chemotherapy – results from two independent randomized trials

Abstract

Background: The study of the intrinsic molecular subtypes of breast cancer has revealed differences among them in terms of prognosis and response to chemotherapy and endocrine therapy. However, the ability of intrinsic subtypes to predict benefit from adjuvant radiotherapy has only been examined in few studies.

Methods: Gene expression-based intrinsic subtyping was performed in 228 breast tumors collected from two independent post-mastectomy clinical trials (British Columbia and the Danish Breast Cancer Cooperative Group 82b trials), where pre-menopausal patients with node-positive disease were randomized to adjuvant radiotherapy or not. All patients received adjuvant chemotherapy and a subgroup of patients underwent ovarian ablation. Tumors were classified into intrinsic subtypes: Luminal A, Luminal B, HER2-enriched, Basal-like and Normal-like using the research-based PAM50 classifier.

Results: In the British Columbia study, patients treated with radiation had an overall significant lower incidence of locoregional recurrence compared to the controls. For Luminal A tumors the risk of loco-regional recurrence was low and was further lowered by adjuvant radiation. These findings were validated in the DBCG 82b study. The individual data from the two cohorts were merged, the hazard ratio (HR) for loco-regional recurrence associated with giving radiation was 0.34 (0.19 to 0.61) overall and 0.12 (0.03 to 0.52) for Luminal A tumors.

Conclusions: In both postmastectomy trials, patients with Luminal A tumors turned out to have a significant lower incidence of loco-regional recurrence when randomized to adjuvant radiotherapy, leaving no indication to omit postmastectomy adjuvant radiation in pre-menopausal high-risk patients with Luminal A tumors. It was not possible to evaluate the effect of radiotherapy among the other subtypes because of limited sample sizes.

Acknowledgments

We thank Sherman Lau at the Genetic Pathology Evaluation Centre (Vancouver) for his assistance in RNA extraction of samples from the BC trial.

Disclosure statement

C.M.P. is equity stock holders of, and T.O. consults for BioClassifier LLC. C.M.P., T.O. and M.C.U.C. have filed a patent on the PAM50 assay. T.T, J.A., S.M, T.S. and J.O holds a patent for a gene signature associated with efficacy of radiotherapy in breast cancer (international patent publication no. WO 2013/132354A2). The patent is not related to the present work.

Additional information

Funding

This work was supported by funds from ReThink Breast Cancer Career Development Award for MCU Cheang, The Danish Council for Strategic Research (DBCG-TIBCAT) and CIRRO (Danish Center for Interventional Research in Radiation Oncology).