Abstract
BackgroundThe PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer.MethodsProsigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF).ResultsIn total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (Pinteraction = 0.003 unadjusted, P = 0.001 adjusted) and OS (Pinteraction = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes.ConclusionThe Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.
Highlights
The prediction analysis of microarray 50 (PAM50)-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer
For the first co-primary objective, we examined the association between the continuous Prosigna ROR score and benefit of chemotherapy in the population including patients with estrogen receptor (ER)+/− and human epidermal growth factor receptor 2 (Her2)+/− breast cancer
By focusing on the more homogenous population of ER+, Her2− patients we did observe a benefit from chemotherapy in the high-risk population and no benefit in the low-risk population though we found no statistically significant heterogeneity of treatment effect according to ROR
Summary
The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. The early results of the first adjuvant Milan trial were published in 1976 [1], and showed a clear benefit from. The Milan trial included patients with high-risk (node-positive) breast cancer who were randomized after mastectomy; none of whom received radiotherapy or endocrine treatment. DBCG 77B included premenopausal patients with high-risk breast cancer who after mastectomy and radiotherapy and without endocrine treatment were randomized to observation, levamisole, single-agent cyclophosphamide, or CMF. Due to the results of these and other early clinical trials, adjuvant chemotherapy has been considered a standard in premenopausal patients with node-positive breast cancer since the National Institutes of Health Consensus Conference in 1980 [3]. In the EBCTCG analysis an additional incremental benefit was shown from adding an anthracycline to CMF, from substituting methotrexate with doxorubicin or epirubicin, and from giving taxanes concurrently or in sequence with anthracyclines [4, 5]
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