Abstract
The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09–1.33), and for CEF (HR 1.04, 95% CI 0.92–1.18), Pinteraction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38–0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.
Highlights
IntroductionAdjuvant chemotherapy has for decades been a central treatment component for patients with early-stage breast cancer and moderate or high risk of recurrence.[1,2] Proven clinical utility of the prognostic ability by different tumor transcriptome analyses has facilitated a decrease in the use of adjuvant chemotherapy among patients with estrogen receptor (ER) positive breast cancers.[3,4,5] No benefit was observed in the Trial AssigningIndividuaLized Options for Treatment Rx (TAILORx) trial from adding chemotherapy to endocrine therapy among women with node-negative, ER positive breast cancer and a recurrence score of to 25.5 The 70-gene MammaPrint assay was used in the Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) trial and neither patients with low clinical and high genomic risk nor patients with high clinical and low genomic risk obtained substantial benefit from adjuvant chemotherapy.[6]Most patients with sufficient clinical and genomic risk to warrant adjuvant chemotherapy will receive alkylator-, anthracycline-, and taxane-based chemotherapy but genomic assays have identified patients who are unlikely to benefit from cyclophosphamide-based regimens
The Danish Breast Cancer Group (DBCG) 89D trial enrolled 980 Danish patients, among whom were treated per protocol (Supplementary Fig. 1)
Our study suggests a differential benefit from the addition of an anthracycline to CMF-based chemotherapy according to intrinsic molecular subtype as provided by Prosigna
Summary
Adjuvant chemotherapy has for decades been a central treatment component for patients with early-stage breast cancer and moderate or high risk of recurrence.[1,2] Proven clinical utility of the prognostic ability by different tumor transcriptome analyses has facilitated a decrease in the use of adjuvant chemotherapy among patients with estrogen receptor (ER) positive breast cancers.[3,4,5] No benefit was observed in the Trial AssigningIndividuaLized Options for Treatment Rx (TAILORx) trial from adding chemotherapy to endocrine therapy among women with node-negative, ER positive breast cancer and a recurrence score of to 25.5 The 70-gene MammaPrint assay was used in the Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) trial and neither patients with low clinical and high genomic risk nor patients with high clinical and low genomic risk obtained substantial benefit from adjuvant chemotherapy.[6]Most patients with sufficient clinical and genomic risk to warrant adjuvant chemotherapy will receive alkylator-, anthracycline-, and taxane-based chemotherapy but genomic assays have identified patients who are unlikely to benefit from cyclophosphamide-based regimens. IndividuaLized Options for Treatment Rx (TAILORx) trial from adding chemotherapy to endocrine therapy among women with node-negative, ER positive breast cancer and a recurrence score of to 25.5 The 70-gene MammaPrint assay was used in the Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) trial and neither patients with low clinical and high genomic risk nor patients with high clinical and low genomic risk obtained substantial benefit from adjuvant chemotherapy.[6]. 77B trial that randomized premenopausal high-risk patients with early breast cancer to adjuvant chemotherapy vs no chemotherapy.[7] A Basal-like subtype was associated with an 86% reduction in disease-free survival (DFS) event while no benefit was obtained by patients with an HER2-enriched subtype. Patients with a Luminal B subtype had a significant 52% reduction in DFS events while no significant benefit (39% improved DFS) was obtained by patients with a Luminal A subtype.[7]
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