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Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14

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Abstract

Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker’s z-scores categorized: ≥1.0 standard deviation (SD) below mean; <1.0 SD below mean; ≤1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS-ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p ≤ 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18–0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z ≥ 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores ≤ −1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ ≥ 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology.

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Acknowledgments

This study was funded by the Avon Foundation (PEG, DCS). MA.14 was supported by Grant No. 16512 from Canadian Cancer Society Research Institute (MNP), and a grant from Novartis Pharmaceuticals Canada (MNP). The Canadian Cancer Society supports the work of the NCIC Clinical Trials Group through a program grant from the Canadian Cancer Society Research Institute. Paul Goss is funded in part by the Avon Foundation, New York.

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Authors and Affiliations

  1. Canadian Cancer Trials Group (Formerly, NCIC Clinical Trials Group), Queen’s University, 10 Stuart St, Kingston, ON, Canada

    Judith-Anne W. Chapman, Lei Han & Lois E. Shepherd

  2. Massachusetts General Hospital, Harvard University, Boston, MA, USA

    Dennis C. Sgroi, Paul E. Goss, Elizabeth Zarella, Shemeica Binns & Tanja Badovinac-Crnjevic

  3. bioTheranostics Inc, San Diego, CA, USA

    Yi Zhang, Catherine A. Schnabel & Mark G. Erlander

  4. Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada

    Kathleen I. Pritchard

  5. McGill University, Montreal, QC, Canada

    Michael N. Pollak

Authors
  1. Judith-Anne W. Chapman
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  2. Dennis C. Sgroi
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  3. Paul E. Goss
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  4. Elizabeth Zarella
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  5. Shemeica Binns
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  6. Yi Zhang
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  7. Catherine A. Schnabel
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  8. Mark G. Erlander
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  9. Kathleen I. Pritchard
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  10. Lei Han
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  11. Tanja Badovinac-Crnjevic
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  12. Lois E. Shepherd
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  13. Michael N. Pollak
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Correspondence to Judith-Anne W. Chapman.

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Conflicts of Interest

YZ and CAS were paid and have stock ownership in bioTheranostics, Inc.; ME had a consultant/advisory role in bioTheranostics, Inc.; TB-C has been paid by Roche. No other authors have conflicts to disclose.

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Chapman, JA.W., Sgroi, D.C., Goss, P.E. et al. Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14. Breast Cancer Res Treat 157, 101–108 (2016). https://doi.org/10.1007/s10549-016-3806-z

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  • DOI: https://doi.org/10.1007/s10549-016-3806-z

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