TY - JOUR

T1 - PAM50 breast cancer intrinsic subtypes and effect of gemcitabine in advanced breast cancer patients

AU - Jørgensen, Charlotte Levin Tykjær

AU - Nielsen, Torsten O

AU - Bjerre, Karsten D

AU - Liu, Shuzhen

AU - Wallden, Brett

AU - Balslev, Eva

AU - Nielsen, Dorte L

AU - Ejlertsen, Bent

PY - 2014/6

Y1 - 2014/6

N2 - BACKGROUND: In vitro studies suggest basal breast cancers are more sensitive to gemcitabine relative to other intrinsic subtypes. The main objective of this study was to use specimens from a randomized clinical trial to evaluate whether the basal-like subtype identifies patients with advanced breast cancer who benefit from gemcitabine plus docetaxel (GD) compared to single agent docetaxel (D).MATERIAL AND METHODS: From patients randomly assigned to GD or D, RNA was isolated from archival formalin-fixed, paraffin-embedded primary breast tumor tissue and used for PAM50 intrinsic subtyping by NanoString nCounter. Statistical analyses were prespecified as a formal prospective-retrospective clinical trial correlative study. Using time to progression (TTP) as primary endpoint, overall survival (OS) and response rate as secondary endpoints, relationships between subtypes and outcome after chemotherapy were analyzed by the Kaplan-Meier method, and Cox proportional hazards regression models. Data analysis was performed independently by the Danish Breast Cancer Cooperative Group (DBCG) statistical core and all statistical tests were two-sided.RESULTS: RNA from 270 patients was evaluable; 84 patients (31%) were classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like, and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was a significant independent prognostic factor for both TTP (p=0.014) and OS (p=0.0003). Response rate was not different by subtype, and PAM50 was not a predictor of TTP by treatment arm. PAM50 was however a highly significant predictor of OS following GD compared to D (pinteraction=0.0016). Patients with a basal-like subtype had a significant reduction in OS events [hazard ratio (HR)=0.29, 95% confidence interval (CI)=0.15-0.57; pinteraction=0.0006].CONCLUSION: A significantly improved and clinically important prolongation of survival was seen from the addition of gemcitabine to docetaxel in advanced basal-like breast cancer patients.

AB - BACKGROUND: In vitro studies suggest basal breast cancers are more sensitive to gemcitabine relative to other intrinsic subtypes. The main objective of this study was to use specimens from a randomized clinical trial to evaluate whether the basal-like subtype identifies patients with advanced breast cancer who benefit from gemcitabine plus docetaxel (GD) compared to single agent docetaxel (D).MATERIAL AND METHODS: From patients randomly assigned to GD or D, RNA was isolated from archival formalin-fixed, paraffin-embedded primary breast tumor tissue and used for PAM50 intrinsic subtyping by NanoString nCounter. Statistical analyses were prespecified as a formal prospective-retrospective clinical trial correlative study. Using time to progression (TTP) as primary endpoint, overall survival (OS) and response rate as secondary endpoints, relationships between subtypes and outcome after chemotherapy were analyzed by the Kaplan-Meier method, and Cox proportional hazards regression models. Data analysis was performed independently by the Danish Breast Cancer Cooperative Group (DBCG) statistical core and all statistical tests were two-sided.RESULTS: RNA from 270 patients was evaluable; 84 patients (31%) were classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like, and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was a significant independent prognostic factor for both TTP (p=0.014) and OS (p=0.0003). Response rate was not different by subtype, and PAM50 was not a predictor of TTP by treatment arm. PAM50 was however a highly significant predictor of OS following GD compared to D (pinteraction=0.0016). Patients with a basal-like subtype had a significant reduction in OS events [hazard ratio (HR)=0.29, 95% confidence interval (CI)=0.15-0.57; pinteraction=0.0006].CONCLUSION: A significantly improved and clinically important prolongation of survival was seen from the addition of gemcitabine to docetaxel in advanced basal-like breast cancer patients.

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Breast Neoplasms

KW - Carcinoma

KW - Deoxycytidine

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Middle Aged

KW - Multivariate Analysis

KW - Proportional Hazards Models

KW - RNA, Messenger

KW - Taxoids

U2 - 10.3109/0284186X.2013.865076

DO - 10.3109/0284186X.2013.865076

M3 - Journal article

C2 - 24359601

VL - 53

SP - 776

EP - 787

JO - Acta Oncologica

JF - Acta Oncologica

SN - 1100-1704

IS - 6

ER -