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Estrogen, progesterone, and HER2/neu receptor discordance between primary and metastatic breast tumours—a review

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Abstract

Discordance in estrogen (ER), progesterone (PR), and HER2/neu status between primary breast tumours and metastatic disease is well recognized. In this review, we highlight how receptor discordance between primary tumours and paired metastasis can help elucidate the mechanism of metastasis but can also effect patient management and the design of future trials. Discordance rates and ranges were available from 47 studies (3384 matched primary and metastatic pairs) reporting ER, PR, and HER2/neu expression for both primary and metastatic sites. Median discordance rates for ER, PR, and HER2/neu were 14 % (range 0–67 %, IQR 9–25 %), 21 % (range 0–62 %, IQR 15–41 %), and 10 % (range 0–44 %, IQR 4–17 %), respectively. Loss of receptor expression was more common (9.17 %) than gain (4.51 %). Discordance rates varied amongst site of metastasis with ER discordance being highest in bone metastases suggesting that discordance is a true biological phenomenon. Discordance rates vary for both the biomarker and the metastatic site. Loss of expression is more common than gain. This can affect patient management as it can lead to a reduction in both the efficacy and availability of potential therapeutic agents. Future studies are recommended to explore both the mechanisms of discordance as well as its impact on patient outcome and management.

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Acknowledgments

Early data from this study were presented at the 2013 ASCO meeting (Journal of Clinical Oncology ASCO Annual Meeting Proceedings, 2013. E11574) SABCS 2013; ASBS (2013); EBCC-9 (2014)

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Authors and Affiliations

  1. Division of Surgical Oncology, University of Ottawa, Ottawa, Canada

    C. Yeung & A. Arnaout

  2. Division of Medical Oncology, Department of Medicine, Ottawa Hospital Cancer Centre and University of Ottawa, Ottawa, Canada

    J. Hilton, M. Clemons, I. Kuchuk & X. Zhu

  3. Ottawa Hospital Research Institute, Ottawa, Canada

    J. Hilton, M. Clemons, S. Mazzarello, B. Hutton, F. Haggar, C. L. Addison & A. Arnaout

  4. Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada

    K. Gelmon

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Electronic supplementary material

Appendix 1: Quality assessment and statistical analysis of included studies.

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Appendix 2: Quality assessment and statistical analysis of included studies

Quality assessment

Once the final group of articles was agreed upon, two of three authors (CY, FH, IK) independently examined the quality of each article using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool [95]. QUADAS-2 is the current version of the QUADAS, the tool used to evaluate the risk of bias and applicability of diagnostic accuracy studies in systematic reviews. It consists of four key domains: patient selection, index test, reference standard, and flow and timing. Each is assessed in terms of risk of bias and the first three in terms of concerns regarding applicability. Signalling questions are included to assist in judgments about the risk of bias (Supplemental Table 2). Risk of bias was judged as “low” if the answers to all signal questions for a domain were “yes”; it was judged as “high” if any signal question in a domain was answered “no”, or as “unclear” if insufficient information was provided. Concern for applicability is assessed in three key areas: patient selection, index test, and reference standard. Concern for applicability was assigned as “low”, “high”, or “unclear” with criteria analogous to those used for risk of bias. If a study is judged as “low” on all domains relating to bias or applicability, then it is considered appropriate to have an overall judgement of “low risk of bias” or “low concern regarding applicability” for that study [95]. If a study is judged “high” or “unclear” on one or more domains, then it may be judged “at risk of bias” or as having “concerns regarding applicability.”

Statistical analysis

To generate summary estimates of the rates of loss of receptor status, gain of receptor status, and total discordance rate, we had planned to pursue random effects meta-analyses of each of these proportions of interest, summarizing findings with pooled proportions and corresponding 95 % confidence intervals if studies were considered clinically homogeneous and if summary estimates were not associated with significant statistical heterogeneity (i.e. an I 2 value of >50 %). Following collection of study level data, we noted that a majority of included studies failed to report the raw data required for meta-analysis (i.e. numbers of events and sample size) and were instead reporting only percentages of each outcome observed. Given this limitation, we decided to provide summary medians and ranges of the proportions of each outcome instead. We explored these quantities both overall and within individual sites of metastasis. For each summary estimate reported, we conservatively report the median and range to be based on the total number of samples that are clear from the individual studies contributing to these estimates.

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Yeung, C., Hilton, J., Clemons, M. et al. Estrogen, progesterone, and HER2/neu receptor discordance between primary and metastatic breast tumours—a review. Cancer Metastasis Rev 35, 427–437 (2016). https://doi.org/10.1007/s10555-016-9631-3

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