Open Access Research article

Effect of continuous statistically standardized measures of estrogen and progesterone receptors on disease-free survival in NCIC CTG MA.12 Trial and BC Cohort

Judith-Anne W Chapman1*, Torsten O Nielsen2, Matthew J Ellis3, Phillip Bernard4, Stephen Chia5, Karen A Gelmon5, Kathleen I Pritchard6, Aurelie Le Maitre1, Paul E Goss7, Samuel Leung2, Lois E Shepherd1 and Vivien H C Bramwell8

Author Affiliations

1 NCIC Clinical Trials Group, Queen's University, Kingston, ON K7L3N6, Canada

2 Pathology Department, Vancouver Hospital, University of British Columbia, Vancouver, BC V5Z1M9, Canada

3 Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA

4 Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA

5 Division of Medical Oncology, BCCA - Vancouver Centre, Vancouver, BC V5Z4E6, Canada

6 Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON M4N3M5, Canada

7 Massachusetts General Hospital, Boston, MA 02114, USA

8 Department of Oncology, University of Calgary, Calgary, AB T2N4N2, Canada

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Breast Cancer Research 2013, 15:R71  doi:10.1186/bcr3465

Published: 23 August 2013

Abstract

Introduction

We hypothesized improved inter-laboratory comparability of estrogen receptor (ER) and progesterone receptor (PgR) across different assay methodologies with adjunctive statistical standardization, akin to bone mineral density (BMD) z-scores. We examined statistical standardization in MA.12, a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumours, and in a cohort of post-menopausal British Columbia (BC) tamoxifen-treated patients.

Methods

ER and PgR were centrally assessed for both patient groups with real time quantitative reverse transcription polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Effects on disease-free survival (DFS) were investigated separately for 345 MA.12 and 673 BC patients who had both qPCR and IHC assessments. Comparisons utilized continuous laboratory units and statistically standardized z-scores. Univariate categorization of ER/PgR was by number of standard deviations (SD) above or below the mean (z-score ≥1.0 SD below mean; z-score <1.0 SD below mean; z-score ≤1.0 SD above mean; z-score >1.0 SD above mean). Exploratory multivariate examinations utilized step-wise Cox regression.

Results

Median follow-up for MA.12 was 9.7 years; for BC patients, 11.8 years. For MA.12, 101 of 345 (29%) patients were IHC ER-PgR-. ER was not univariately associated with DFS (qPCR, P = 0.19; IHC, P = 0.08), while PgR was (qPCR, P = 0.09; IHC, P = 0.04). For BC patients, neither receptor was univariately associated with DFS: for ER, PCR, P = 0.36, IHC, P = 0.24; while for PgR, qPCR, P = 0.17, IHC, P = 0.31. Multivariately, MA.12 patients randomized to tamoxifen had significantly better DFS (P = 0.002 to 0.005) than placebo. Meanwhile, jointly ER and PgR were not associated with DFS whether assessed by qPCR or by IHC in all patients, or in the subgroup of patients with IHC positive stain, for pooled or separate treatment arms. Different results by type of continuous unit supported the concept of ER level being relevant for medical decision-making. For postmenopausal BC tamoxifen patients, higher qPCR PgR was weakly associated with better DFS (P = 0.06).

Conclusions

MA.12 pre-menopausal patients in a placebo-controlled tamoxifen trial had similar multivariate prognostic effects with statistically standardized hormone receptors when tumours were assayed by qPCR or IHC, for hormone receptor +/- and + tumours. The BC post-menopausal tamoxifen cohort did not exhibit a significant prognostic association of ER or PgR with DFS. Adjunctive statistical standardization is currently under investigation in other NCIC CTG endocrine trials.