Impact of serum HER2, TIMP-1, and CAIX on outcome for HER2+ metastatic breast cancer patients: CCTG MA.31 (lapatinib vs. trastuzumab)

Diep Ho, Jessica Huang, Judith Anne W. Chapman, Kim Leitzel, Suhail M. Ali, Lois Shepherd, Wendy R. Parulekar, Catherine E. Ellis, Rocco J. Crescnzo, Liting Zhu, Shakeel Virk, Dora Nomikos, Samuel Aparicio, Karen A. Gelmon, Walter P. Carney, Allan Lipton

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Background: The lapatinib–taxane combination led to shorter PFS than trastuzumab–taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum HER2, CAIX, and TIMP-1. Methods: MA.31 accrued 652 patients; 537 (82%) were centrally confirmed HER2+. Biomarkers were categorized for univariate and multivariable predictive investigations with a median cut-point, ULN cut-points (15 ng/ml for HER2; 506 pg/ml for CAIX; 454 pg/ml for TIMP-1), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariable analysis examined continuous and categorical effects of biomarkers on PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. Results: Serum was banked for 472 (72%) of 652 patients. Higher serum HER2 (>median; >15; >30; or >100 ng/ml; p = 0.05–0.002); higher CAIX (>median; >506 pg/ml; p = 0.02; p = 0.001); and higher TIMP-1 (> median; > 454 pg/ml; p = 0.001; p = 0.02) had shorter univariate PFS. In multivariable analysis, higher continuous TIMP-1 was associated with significantly shorter PFS: HR = 1.001 (95% CI = 1.00–01.002; p = 0.004). Continuous serum HER2 and CAIX were not significantly associated with PFS. HER2 of 15 ng/ml or higher had shorter PFS (p = 0.02); higher categorical CAIX had shorter PFS (p = 0.01–0.08). Interaction terms of HER2, CAIX, and TIMP-1 with treatment were not significant; the predictive test power was low. Conclusions: Higher levels of serum TIMP-1, CAIX, and HER2 were significant prognostic biomarkers of shorter PFS. We found no significant interaction between serum biomarkers and response to lapatinib versus trastuzumab. Evaluation of TIMP-1 and CAIX-targeted therapy in addition to HER2-targeted therapy appears warranted in patients with elevated serum levels of these biomarkers.

Original languageEnglish (US)
Pages (from-to)571-580
Number of pages10
JournalBreast Cancer Research and Treatment
Issue number3
StatePublished - Aug 1 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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