Skip to main content

Advertisement

SpringerLink
Log in

Molecular subtype profiling of invasive breast cancers weakly positive for estrogen receptor

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The estrogen receptor (ER) is a key predictive biomarker in the treatment of breast cancer. There is uncertainty regarding the use of hormonal therapy in the setting of weakly positive ER by immunohistochemistry (IHC). We report intrinsic subtype classification on a cohort of ER weakly positive early-stage breast cancers. Consecutive cases of breast cancer treated by primary surgical resection were retrospectively identified from 4 centers that engage in routine external proficiency testing for breast biomarkers. ER-negative (Allred 0 and 2) and ER weakly positive (Allred 3–5) cases were included. Gene expression profiling was performed using qRT-PCR. Intrinsic subtype prediction was made based upon the PAM50 gene expression signature. 148 cases were included in the series: 60 cases originally diagnosed as ER weakly positive and 88 ER negative. Of the cases originally assessed as ER weakly positive, only 6 (10 %) were confirmed to be of luminal subtype by gene expression profiling; the remaining 90 % of cases were classified as basal-like or HER2-enriched subtypes. This was not significantly different than the fraction of luminal cases identified in the IHC ER-negative cohort (5 (5 %) luminal, 83(95 %) non-luminal). Recurrence-free, and overall, survival rates were similar in both groups (p = 0.4 and 0.5, respectively) despite adjuvant hormonal therapy prescribed in the majority (59 %) of weakly positive ER cases. Weak ER expression by IHC is a poor correlate of luminal subtype in invasive breast cancer. In the setting of highly sensitive and robust IHC methodology, cutoffs for ER status determination and subsequent systemic therapy should be revisited.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Beatson GT (1896) On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 148(3803):162–165

    Article  Google Scholar 

  2. Wolff AC, Dowsett M (2011) Estrogen receptor: a never ending story? J Clin Oncol 29(22):2955–2958

    Article  PubMed  Google Scholar 

  3. McGuire WL (1973) Estrogen receptors in human breast cancer. J Clin Invest 52(1):73–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Early Breast Cancer Trialists’ Collaborative Group (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of tamoxifen: patient-level meta-analysis of randomized trials. Lancet 378(9793):771–784

    Article  Google Scholar 

  5. Dowsett M (2006) Estrogen receptor: methodology matters. J Clin Oncol 24(36):5626–5628

    Article  CAS  PubMed  Google Scholar 

  6. Gown AM (2004) Unmasking the mysteries of antigen or epitope retrieval and formalin fixation. Am J Clin Pathol 121(2):172–174

    Article  PubMed  Google Scholar 

  7. Sabattini E, Bisgaard K, AScani S, Poggi S, Piccioli M, Ceccarelli C, Pieri F, Fraternali-Orcioni G, Pileri SA (1998) The EnVision++ system: a new immunohistochemical method for diagnostics and research. Critical comparison with the APAAP, ChemMate, CSA, LABC, and SABC techniques. J Clin Pathol 51(7):506–511

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Cheang MC, Treaba DO, Speers CH, Olivotto IA, Bajdik CD, Chia SK, Goldstein LC, Gelmon KA, Huntsman D, Gilks CB, Nielsen TO, Gown AM (2006) Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 24(36):5637–5644

    Article  CAS  PubMed  Google Scholar 

  9. Terry J, Tolakovic EE, Garrat J et al (2009) Implementation of a Canadian external quality assurance program for breast cancer biomarkers: an initiative of Canadian Quality Control in immunohistochemistry (cIQc) and Canadian Association of Pathologists (CAP) National Standards Committee/immunohistochemistry. Appl Immunohistochem Mol Morphol 17(5):375–382

    Article  PubMed  Google Scholar 

  10. Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-biding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481

    CAS  PubMed  Google Scholar 

  11. Hammond ME, Hayes DF, Dowsett M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795

    Article  PubMed Central  PubMed  Google Scholar 

  12. Nadji M, Gomez-Fernandez C, Ganjei-Azar P, Morales AR (2005) Immunohistochemistry of estrogen and progesterone receptors reconsidered: experience with 5993 breast cancers. Am J Clin Pathol 123(1):21–27

    Article  PubMed  Google Scholar 

  13. Khoshnoud MR, Löfdahl B, Fohlin H et al (2011) Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen. Breast Cancer Res Treat 126(2):421–430

    Article  CAS  PubMed  Google Scholar 

  14. Iwamoto T, Booser D, Valero V et al (2012) Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1–10 % ER-positive by immunohistochemistry. J Clin Oncol 30(7):729–734

    Article  PubMed  Google Scholar 

  15. Allred DC, Carlson RW, Berry DA et al (2009) NCCN task force report: estrogen receptor and progesterone receptor testing in breast cancer by immunohistochemistry. J Natl Compr Canc Netw 7(S6):s1–s21

    CAS  PubMed  Google Scholar 

  16. Rhodes A, Jasani B, Barnes DM et al (2000) Reliability of immunohistochemical demonstration of estrogen receptors in routine practice: inter-laboratory variance in the sensitivity of detection and evaluation of scoring systems. J Clin Pathol 53:125–130

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Parker RL, Huntsman DG, Lesack DW et al (2002) Assessment of inter-laboratory variation in immunohistochemical determination of estrogen receptor using a breast cancer tissue microarray. Am J Clin Pathol 117:723–728

    Article  PubMed  Google Scholar 

  18. Cm Perou, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752

    Article  Google Scholar 

  19. Sørlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874

    Article  PubMed Central  PubMed  Google Scholar 

  20. Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci 100:8418–8423

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Hu Z, Fan C, Oh DS et al (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genom 7:96

    Article  Google Scholar 

  22. Won JR, Gao D, Chow C et al (2013) A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard. Mod Pathol 26(11):1438–1450

    Article  CAS  PubMed  Google Scholar 

  23. Park Y, Moryama A, Kithara T, Yoshida Y, Urita T, Kato R (2012) Triple-negative breast cancer and poly(ADP-ribose) polymerase inhibitors. Anticancer Agents Med Chem 12(6):672–677

    Article  CAS  PubMed  Google Scholar 

  24. Parker JS, Mullins M, Cheang MC et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167

    Article  PubMed Central  PubMed  Google Scholar 

  25. Chia SK, Bramwell VH, Tu D et al (2012) A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen. Clin Cancer Res 18(16):4465–4472

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Perez T, Makretsov N, Garatt J, Torlakovic E, Gilks CB, Mallett S. Modeling Canadian quality control test program for steroid hormone receptors in breast cancer: diagnostic accuracy study. Appl Immunohistochem Mol Morphol [Epub ahead of print] PMID2620083

  27. Mullins M, Perreard L, Quackenbush JF et al (2007) Agreement in breast cancer classification between microarray and quantitative reverse transcription PCR from fresh-frozen and formalin-fixed, paraffin-embedded tissues. Clin Chem 53:1273–1279

    Article  CAS  PubMed  Google Scholar 

  28. Bernard PS (2012) Personalized medicine for breast cancer. In: Ginsburg G (ed) Genomic and personalized medicine, 2nd edn. Elsevier, Amsterdam, pp 707–713

    Google Scholar 

  29. Perreard L, Fan C, Quackenbush JF et al (2006) Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay. Breast Cancer Res 8:R23

    Article  PubMed Central  PubMed  Google Scholar 

  30. Nielsen TO, Parker JS, Leung S et al (2010) A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor positive breast cancer. Clin Cancer Res 16(21):5222–5232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Lin CM, Jaswal J, Vandenberg T, Tuck A, Brackstone M (2013) Weakly hormone receptor-positive breast cancer and use of adjuvant hormonal therapy. Curr Oncol 20(6):e612–e613

    Article  PubMed Central  PubMed  Google Scholar 

  32. Prabhu JS, Korlimarla A, Desai K et al (2014) A majority of low (1–10%) ER positive breast cancers behave like hormone receptor negative tumors. J Cancer 5(2):156–165

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Deyarmin B, Kane JL, Valente AL, van Laar R, Gallagher C, Shriver CD, Ellseworth RE (2013) Effect of ASCO/CAP guidelines for determining ER status on molecular subtype. Ann Surg Oncol 20(1):87–93

    Article  PubMed  Google Scholar 

  34. Rakha EA, Lee AH, Roberts J, Villena Salinas NM, Hodi Z, Ellis IO, Reis-Filho JS (2012) Low-estrogen receptor-positive breast cancer: the impact of tissue sampling, choice of antibody, and molecular subtyping. J Clin Oncol 30(23):2929–2930

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the Canadian Breast Cancer Foundation—British Columbia/Yukon chapter for their support of this research. This work was supported by a grant from the Canadian Breast Cancer Foundation (British Columbia and Yukon).

Author information

Author notes

    Authors and Affiliations

    1. Department of Laboratory Medicine and Pathology, University of British Columbia, 899 W 12th Ave, Vancouver, BC, V5Z 1M9, Canada

      Brandon S. Sheffield, Xiu Qing Wang, C. Blake Gilks, Nickolas Myles, Tom Thomson, Malcolm M. Hayes, Torsten O. Nielsen & Stephen K. L. Chia

    2. Department of Pathology and Laboratory Medicine, University of Ottawa and The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada

      Zuzana Kos

    3. Genetic Pathology Evaluation Centre, University of British Columbia, 509-2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada

      Karama Asleh-Aburaya, Samuel Leung, Dongxia Gao, Jennifer Won, Christine Chow, C. Blake Gilks & Torsten O. Nielsen

    4. Department of Pathology, University of Utah/Huntsman Cancer Center, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA

      Rakesh Rachamadugu, Inge Stijleman & Philip S. Bernard

    5. Department of Laboratory Medicine and Pathology, Lions Gate Hospital, 231 East 15 Street, North Vancouver, BC, V7L 4P7, Canada

      Robert Wolber

    6. Department of Laboratory Medicine and Pathology, Vancouver General Hospital, 899 West 12th Ave, Vancouver, BC, V5Z 1M9, Canada

      C. Blake Gilks & Torsten O. Nielsen

    7. Department of Laboratory Medicine and Pathology, St. Paul’s Hospital, 1082 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada

      Nickolas Myles

    8. Department of Laboratory Medicine, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC, V5Z 4E6, Canada

      Tom Thomson & Malcolm M. Hayes

    9. Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Ave, Vancouver, BC, V5Z 4E6, Canada

      Stephen K. L. Chia

    Authors
    1. Brandon S. Sheffield
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zuzana Kos
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Karama Asleh-Aburaya
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xiu Qing Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Samuel Leung
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Dongxia Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Jennifer Won
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Christine Chow
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Rakesh Rachamadugu
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Inge Stijleman
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Robert Wolber
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. C. Blake Gilks
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Nickolas Myles
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Tom Thomson
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Malcolm M. Hayes
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Philip S. Bernard
      View author publications

      You can also search for this author in PubMed Google Scholar

    17. Torsten O. Nielsen
      View author publications

      You can also search for this author in PubMed Google Scholar

    18. Stephen K. L. Chia
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Stephen K. L. Chia.

    Additional information

    B. S. Sheffield and Z. Kos have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Sheffield, B.S., Kos, Z., Asleh-Aburaya, K. et al. Molecular subtype profiling of invasive breast cancers weakly positive for estrogen receptor. Breast Cancer Res Treat 155, 483–490 (2016). https://doi.org/10.1007/s10549-016-3689-z

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10549-016-3689-z

    Keywords

    Search

    Navigation