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Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial.

Publication ,  Journal Article
Lesurf, R; Griffith, OL; Griffith, M; Hundal, J; Trani, L; Watson, MA; Aft, R; Ellis, MJ; Ota, D; Suman, VJ; Meric-Bernstam, F; Leitch, AM ...
Published in: Ann Oncol
May 1, 2017

BACKGROUND: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. PATIENTS AND METHODS: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. RESULTS: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. CONCLUSION: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. CLINICALTRIALS.GOV IDENTIFIERS: NCT00513292, NCT00353483.

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Published In

Ann Oncol

DOI

EISSN

1569-8041

Publication Date

May 1, 2017

Volume

28

Issue

5

Start / End Page

1070 / 1077

Location

England

Related Subject Headings

  • Treatment Outcome
  • Trastuzumab
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Neoadjuvant Therapy
  • Middle Aged
  • INDEL Mutation
  • Humans
 

Citation

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Lesurf, R., Griffith, O. L., Griffith, M., Hundal, J., Trani, L., Watson, M. A., … Mardis, E. R. (2017). Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial. Ann Oncol, 28(5), 1070–1077. https://doi.org/10.1093/annonc/mdx048
Lesurf, R., O. L. Griffith, M. Griffith, J. Hundal, L. Trani, M. A. Watson, R. Aft, et al. “Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial.Ann Oncol 28, no. 5 (May 1, 2017): 1070–77. https://doi.org/10.1093/annonc/mdx048.
Lesurf R, Griffith OL, Griffith M, Hundal J, Trani L, Watson MA, et al. Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial. Ann Oncol. 2017 May 1;28(5):1070–7.
Lesurf, R., et al. “Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial.Ann Oncol, vol. 28, no. 5, May 2017, pp. 1070–77. Pubmed, doi:10.1093/annonc/mdx048.
Lesurf R, Griffith OL, Griffith M, Hundal J, Trani L, Watson MA, Aft R, Ellis MJ, Ota D, Suman VJ, Meric-Bernstam F, Leitch AM, Boughey JC, Unzeitig G, Buzdar AU, Hunt KK, Mardis ER. Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial. Ann Oncol. 2017 May 1;28(5):1070–1077.
Journal cover image

Published In

Ann Oncol

DOI

EISSN

1569-8041

Publication Date

May 1, 2017

Volume

28

Issue

5

Start / End Page

1070 / 1077

Location

England

Related Subject Headings

  • Treatment Outcome
  • Trastuzumab
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Neoadjuvant Therapy
  • Middle Aged
  • INDEL Mutation
  • Humans