Background: Intrinsic breast cancer subtypes determined by the PAM50 assay are reported to be prognostic independent of standard clinicopathological variables. The CALGB (Alliance) 9741 adjuvant trial randomized treatment in a 2×2 factorial design to (i) 2-wk (dose dense; DD) vs 3-wk therapy and (ii) sequential vs concurrent doxorubicin, cyclophosphamide, paclitaxel (A>T>C vs AC>T). DD therapy improved disease-free survival and overall survival (OS) (Citron et al. JCO 2003.). A significant interaction between intrinsic breast cancer subtypes and the use of DD therapy was hypothesized. Methods: C9741 was conducted in collaboration with ECOG, NCCTG, and SWOG. Biospecimens were collected from 1652 of 2005 subjects. Multiplexed gene expression profiling (NanoString Technologies, Inc) generated PAM50 subtype calls (luminal A, luminal B, HER2-enriched, basal-like), risk of relapse (ROR) score, and proliferation score for 1321 cases (80%). Excluded samples were due to insufficient tumor (n = 181) or RNA (n = 150). The primary endpoint was relapse-free survival (RFS). The primary analysis to determine if the clinical benefit of DD therapy is dependent on intrinsic subtype was conducted as a test of interaction in a Cox proportional hazards model (3 degrees of freedom, df; alpha=0.05). Similar analyses were performed for ROR score and proliferation score as continuous measures of risk (1 df). PAM50 subtype, ROR score, and proliferation score were evaluated in separate multivariate models adjusting for number of positive nodes, menopausal status, dose density, and sequence of therapy. Results: Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete dataset (HR = 1.20; 95%CI 0.99–1.44) with a median follow-up of 12.3 yrs. Subtype analysis identified 32% luminal A (n = 417), 26% luminal B (n = 341), 20% HER2-enriched (n = 267), and 22% basal-like (n = 296). Intrinsic subtypes were prognostic of RFS (p < 0.0001) irrespective of treatment assignment with HRs relative to the luminal A subgroup of 1.50 (luminal B), 1.70 (HER2-enriched) and 1.66 (basal-like). No subtype specific treatment effect on RFS was identified (p = 0.44). ROR scores (range 0–100, median 60) were also prognostic of RFS (HR = 1.12 for a 10-unit change; 95% CI 1.07–1.18; p < 0.0001), but no association with DD therapy benefit was seen (p = 0.58). Similar results were obtained for the proliferation score, for OS as a secondary endpoint, and from multivariate models with clinical covariates. Conclusion: The prognostic value of PAM50 subtype, ROR score, and proliferation score remains highly significant in patients treated with contemporary adjuvant anthracycline and taxane based chemotherapy. Intrinsic subtype did not predict for improved survival with the 2-wk DD vs 3-wk treatment schedule; we hypothesize that this is because the prognostic differences by subtype outweighed the modest but significant clinical benefit of DD chemotherapy administration for the overall population. Planned clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize systemic therapy regimens based on the expected risk of distant recurrence. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-01.
Background: RNA profiling and mutational analyses in CALGB 40601 (NCT00770809) found significant impact on pathologic complete response (pCR) rates from tumor (intrinsic subtype, p53 mutation) and microenvironmental (immune cell) features. Integrated analysis across platforms is needed to better understand the roles of these different factors with respect to response to HER2-targeted therapies. Methods: We performed a comprehensive genomic analyses on pCR, defined as no invasive tumor in the breast, by integrating clinicopathological information with somatic mutation status, 422 segment-level DNA Copy Number Alterations (CNAs), and 510 gene expression signatures using mRNAseq and DNA exome sequencing from 213 pre-treatment tumors. Excluding 48 samples in the TL arm that was closed early due to futility, and 4 Normal-like tumors, the dataset consisted of 161 patients from TH and THL arms including 47 HER2-enriched (HER2E), 8 Basal-like, 54 Luminal A, and 52 Luminal B, all of whom received H. The main analysis was performed using the Elastic Net on multivariate logistic regression models for predicting pCR. The samples were divided into a training and a test set, then models were built to predict pCR by 10-fold cross-validation in the training set, then applying the best model onto the test set to construct ROC curves and evaluate prediction accuracy by calculating area under ROC (AUC). We also used the DawnRank, a network-based bioinformatics tool that integrates DNA and RNA data to identify driver genes, to find predictors of resistance to H-containing therapies. Results: Among clinicopathological factors, clinical estrogen/progesterone receptor (ER/PgR) status and intrinsic subtype by PAM50 were statistically associated with pCR, but treatment arm (TH vs THL) and stage were not. In the Elastic Net analysis, the models incorporating either gene signatures (AUC: 0.724) or CNAs (AUC: 0.777) were more predictive of response than mutation status model (AUC: 0.635). Gene signatures and CNAs were further combined with either mutation status (AUC: 0.773), clinical ER/PgR status (AUC: 0.787) or ER/PgR status plus intrinsic subtype (AUC: 0.784). The combination with the highest AUC comprised gene signatures, CNAs, and ER/PgR status, and demonstrated that CNAs at Chromosome (Chr.) 6p, 10q22, or 11q23, the signature of Correlation to HER2E, and a T-cell signature, positively predicted pCR and that Luminal and PgR gene signatures were negative predictors. The CN gain of Chr.6p, which contains the HLA genes, predicted for pCR and was associated with higher expression of HLA genes and B cell / IgG signatures. The CN loss of Chr.11q23 including CD3D, CD3E, and CD3G was also identified by DawnRank as a region associated with resistance. Conclusions: Tumor genetics (CNAs), tumor RNA subtype (HER2E, Luminal), and the microenvironment (immune cells) were independently predictive of response to H-containing therapies and biologically and clinically important for HER2-positive breast cancer, supporting integrated RNA- and DNA-based tumor assessments to clarify response to HER2-targeting. Support: U10CA031946/033601/180821/180882/180888. Citation Format: Tanioka M, Fan C, Carey LA, Hyslop T, Pitcher BN, Parker JA, Hoadley KA, Henry NL, Tolaney S, Dang C, Krop IE, Harris L, Berry DA, Mardis E, Perou CM, Winer EP, Hudis CA. Integrated analysis of multidimensional genomic data on CALGB 40601 (Alliance), a randomized neoadjuvant phase III trial of weekly paclitaxel (T) and trastuzumab (H) with or without lapatinib (L) for HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S3-05.
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