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Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

Publication ,  Journal Article
Tanioka, M; Fan, C; Parker, JS; Hoadley, KA; Hu, Z; Li, Y; Hyslop, TM; Pitcher, BN; Soloway, MG; Spears, PA; Henry, LN; Tolaney, S; Dang, CT ...
Published in: Clin Cancer Res
November 1, 2018

Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy.Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures.Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC = 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ER+ features.Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer. Clin Cancer Res; 24(21); 5292-304. ©2018 AACR.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 1, 2018

Volume

24

Issue

21

Start / End Page

5292 / 5304

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Trastuzumab
  • Transcriptome
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoadjuvant Therapy
  • Mutation
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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Tanioka, M., Fan, C., Parker, J. S., Hoadley, K. A., Hu, Z., Li, Y., … Perou, C. M. (2018). Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer. Clin Cancer Res, 24(21), 5292–5304. https://doi.org/10.1158/1078-0432.CCR-17-3431
Tanioka, Maki, Cheng Fan, Joel S. Parker, Katherine A. Hoadley, Zhiyuan Hu, Yan Li, Terry M. Hyslop, et al. “Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.Clin Cancer Res 24, no. 21 (November 1, 2018): 5292–5304. https://doi.org/10.1158/1078-0432.CCR-17-3431.
Tanioka, Maki, et al. “Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.Clin Cancer Res, vol. 24, no. 21, Nov. 2018, pp. 5292–304. Pubmed, doi:10.1158/1078-0432.CCR-17-3431.
Tanioka M, Fan C, Parker JS, Hoadley KA, Hu Z, Li Y, Hyslop TM, Pitcher BN, Soloway MG, Spears PA, Henry LN, Tolaney S, Dang CT, Krop IE, Harris LN, Berry DA, Mardis ER, Winer EP, Hudis CA, Carey LA, Perou CM. Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer. Clin Cancer Res. 2018 Nov 1;24(21):5292–5304.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 1, 2018

Volume

24

Issue

21

Start / End Page

5292 / 5304

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Trastuzumab
  • Transcriptome
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoadjuvant Therapy
  • Mutation
  • Humans