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Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials

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Abstract

The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2−) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2− early breast cancer.

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Acknowledgments

We thank many pathologists who submitted tumor blocks and slides, and the patients, physicians, nurses and data managers who participated in the TEXT and SOFT clinical trials. We thank Stefania Andrighetto and Elvira Bianca Benini of the IBCSG Central Pathology Office and Wilbur Helfer of the IBCSG Coordinating Center. TEXT and SOFT received financial support for trial conduct from Pfizer, the International Breast Cancer Study Group, and the US National Cancer Institute. Pfizer and Ipsen provided drug supply. Support for the coordinating group, IBCSG: Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research (SAKK), Cancer Research Switzerland/Oncosuisse, the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK), US National Cancer Institute (NCI) (US NIH CA75362), Susan G. Komen for the Cure Promise Grant (KG080081), Breast Cancer Research Foundation. Grant support of cooperative groups: Australia and New Zealand Breast Cancer Trials Group (NHMRC 351161 and 510788); SWOG (US NIH CA32102); Alliance/CALGB (US NIH U10-CA180821); ECOG-ACRIN (US NIH CA21115 and CA16116); NSABP/NRG (US NIH U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974); NCIC-CTG (US NIH CA077202 and CCSRI 015469 and 021039); ICR-CTSU on behalf of the National Cancer Research Institute (NCRI) Breast Clinical Studies Group United Kingdom (NCRI-BCSG—ICR-CTSU Partnership) was supported by CRUK, CRUKE/03/022, CRUKE/03/023, A15955, NIHR RM/ICR Biomedical Research Centre, and by NIHR Cambridge Biomedical Research Centre.

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Authors and Affiliations

  1. Department of Biostatistics and Computational Biology, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Mailstop CLS-11007, Boston, MA, 02215, USA

    Meredith M. Regan

  2. Institute of Oncology of Southern Switzerland, Swiss Group for Clinical Cancer Research (SAKK), Lugano Viganello, Switzerland

    Olivia Pagani

  3. Peter MacCallum Cancer Center, St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia

    Prudence A. Francis

  4. Australia & New Zealand Breast Cancer Trials Group (ANZBCTG), University of Newcastle, Callaghan, NSW, Australia

    Prudence A. Francis

  5. The University of Chicago Medical Center and Alliance for Clinical Trials in Oncology, Chicago, IL, USA

    Gini F. Fleming

  6. Tom Baker Cancer Centre and NCIC Clinical Trials Group, Calgary, AB, Canada

    Barbara A. Walley

  7. International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Bern, Switzerland

    Roswitha Kammler

  8. International Breast Cancer Study Group Central Pathology Office, Department of Pathology, European Institute of Oncology, Milan, Italy

    Patrizia Dell’Orto & Leila Russo

  9. Pathological Department, National Institute of Oncology, Budapest, Hungary

    János Szőke

  10. Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru

    Franco Doimi

  11. Division of Pathology, Salvatore Maugeri Foundation, Pavia, Italy

    Laura Villani

  12. Struttura Operativa Complessa di Anatomia Patologica, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy

    Stefano Pizzolitto

  13. Kantonsspital St. Gallen, Swiss Group for Clinical Cancer Research (SAKK), St. Gallen, Switzerland

    Christian Öhlschlegel

  14. University of Insubria-Ospedale di Circolo and Fondazione Macchi, Varese, Italy

    Fausto Sessa

  15. Department of Pathology, Vall d’Hebron University Hospital, SOLTI Group, Barcelona, Spain

    Vicente Peg Cámara

  16. Pathology Department, Hospital Universitario «12 de Octubre», i+12, Universidad Complutense Madrid, SOLTI Group, Madrid, Spain

    José Luis Rodríguez Peralto

  17. Laboratoire Anatomopathologie, Institut Bergonié, Bordeaux, France

    Gaëtan MacGrogan

  18. EORTC, Brussels, Belgium

    Gaëtan MacGrogan

  19. Division of Medical Senology, European Institute of Oncology, Milan, Italy

    Marco Colleoni

  20. Program for Breast Health, European Institute of Oncology, Milan, Italy

    Aron Goldhirsch

  21. International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA, USA

    Karen N. Price

  22. University of Sydney, Sydney, Australia

    Alan S. Coates

  23. International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Richard D. Gelber

  24. Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Richard D. Gelber

  25. Frontier Science and Technology Research Foundation, Boston, MA, USA

    Richard D. Gelber

  26. International Breast Cancer Study Group Central Pathology Office, European Institute of Oncology, University of Milan, Milan, Italy

    Giuseppe Viale

Authors
  1. Meredith M. Regan
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  2. Olivia Pagani
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  3. Prudence A. Francis
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  4. Gini F. Fleming
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  11. Laura Villani
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  14. Fausto Sessa
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  18. Marco Colleoni
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  19. Aron Goldhirsch
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  21. Alan S. Coates
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  22. Richard D. Gelber
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  23. Giuseppe Viale
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Consortia

SOFT and TEXT Investigators and International Breast Cancer Study Group

Corresponding author

Correspondence to Meredith M. Regan.

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Conflicts of interest

Dr. Francis reports uncompensated presentation of results of SOFT and TEXT for Pfizer at an international meeting. The remaining authors declare that they have no conflict of interest.

Additional information

The affiliation of authors Olivia Pagani, Prudence A. Francis, János Szőke, Franco Doimi, Laura Villani, Stefano Pizzolitto, Christian Öhlschlegel, Fausto Sessa, Marco Colleoni, Aron Goldhirsch, and Alan S. Coates includes the International Breast Cancer Study Group.

Clinicaltrials. gov: NCT00066690, NCT00066703.

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Regan, M.M., Pagani, O., Francis, P.A. et al. Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials. Breast Cancer Res Treat 154, 275–286 (2015). https://doi.org/10.1007/s10549-015-3612-z

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