Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer

Filippo Montemurro, Aleix Prat, Valentina Rossi, Giorgio Valabrega, Jeff Sperinde, Caterina Peraldo-Neia, Michela Donadio, Patricia Galván, Anna Sapino, Massimo Aglietta, José Baselga, Maurizio Scaltriti

Research output: Contribution to journalArticlepeer-review

Abstract

In 2009 a prospective, randomized Phase II trial (NCT00842998) was initiated to evaluate the activity of HER2-targeting agents without chemotherapy (CT) in HER2-positive metastatic breast cancer (MBC) patients. The primary tumors of the patients enrolled in this study offered a unique opportunity to identify biomarkers that could predict durable clinical benefit from CT-free anti-HER2 therapy.Patients with HER2-positive MBC were randomized to trastuzumab or lapatinib as first-line therapy. CT was added to anti-HER2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and in those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. Additionally, quantitative HER2 (H2T) and p95HER2 (p95) protein expression were evaluated by HERmark® and VeraTag® assay, respectively. Predictors of persistence on protocol (PP) were studied by Cox univariate and multivariate analysis.Nineteen patients were enrolled. Median overall survival was 43 months and median PP was 3.8 months (0.8-38.8+), with 4 patients (21.1%) persisting on single agent trastuzumab or lapatinib for longer than 12 mo (14.9-38.8 + mo). Seventeen patients were evaluable for PP. Gene expression analysis revealed that high expression of the 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were significantly associated with longer PP. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile correlated with reduced PP. Moreover, increasing H2T/p95 ratio was found to be significantly associated with longer PP (HR 0.56 per 2-fold increase in H2T/p95, P = 0.0015).Our data suggest that patients belonging to the "HER2-enriched" subtype and/or having high H2T/p95 protein expression ratio are exquisitely sensitive to anti-HER2 agents. MBC patients with these tumors could be candidates for studies aimed at establishing chemotherapy-free regimens.

Original languageEnglish
Pages (from-to)20-26
Number of pages7
JournalMolecular Oncology
Volume8
Issue number1
DOIs
Publication statusPublished - Feb 2014

Keywords

  • Chemotherapy-free
  • HER2-enriched
  • Lapatinib
  • Microarray
  • Signature
  • Trastuzumab

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

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