NSABP B-41, a Randomized Neoadjuvant Trial: Genes and Signatures Associated with Pathologic Complete Response

Clin Cancer Res. 2020 Aug 15;26(16):4233-4241. doi: 10.1158/1078-0432.CCR-20-0152. Epub 2020 May 5.

Abstract

Purpose: In NSABP B-41, pathologic complete response (pCR) was associated with prolonged survival among women with HER2-positive operable breast cancer treated with neoadjuvant chemotherapy and lapatinib, trastuzumab, or the combination. We used a large human breast cancer gene expression panel to select candidate prognostic biomarkers for pCR among women treated with trastuzumab in NSABP B-41.

Patients and methods: Eligible patients had a baseline preadjuvant treatment core biopsy sample, known pCR status, and no withdrawal of consent. We analyzed extracted RNA using the human nCounter Breast Cancer 360 gene expression panel. Gene counts were normalized to housekeeping genes and transformed into logarithmic scale with base 2. To screen for candidate genes and metagene signatures prognostic of pCR, we used univariate logistic regression. Variable selection was done by multivariable logistic regression with lasso regularization.

Results: Analyses of data from 130 patients revealed that a composite of gene expression from 19 genes and one gene signature appeared to predict pCR in women with HER2-positive early-stage breast cancer undergoing neoadjuvant chemotherapy with trastuzumab-containing regimens. The identified genes are involved in important pathways such as epithelial-mesenchymal transition, adhesion and migration, estrogen receptor signaling, DNA damage and repair, apoptosis, and proliferation. The AUC from a 10-fold cross-validation on predicting pCR, with these 20 genomic markers in a logistic regression model, was 0.73.

Conclusions: The expression level of ERBB2, ESR1, and a few other genomic markers was highly predictive of pCR after trastuzumab-containing regimens. These findings need to be validated and calibrated in future studies.

Publication types

  • Pragmatic Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Biomarkers, Tumor / genetics
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Chemotherapy, Adjuvant
  • DNA Damage / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Estrogen Receptor alpha / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lapatinib / administration & dosage
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasm Proteins / genetics*
  • Prognosis
  • Receptor, ErbB-2 / genetics*
  • Trastuzumab / administration & dosage*
  • Trastuzumab / adverse effects

Substances

  • Biomarkers, Tumor
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Neoplasm Proteins
  • Lapatinib
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab