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Originally published as JCO Early Release 10.1200/JCO.2007.10.7342 on April 23 2007 © 2007 American Society of Clinical Oncology.
Problems With the Progesterone Receptor in Practice?
Fox Chase Cancer Center, Philadelphia, PA
Dana-Farber Cancer Institute, Boston, MA The estrogen receptor (ER) has proven to be the best target for the treatment and prevention of breast cancer.1 The link between ER status and response to endocrine ablation originally was observed in women with metastatic breast cancer2 long before tamoxifen was first marketed in the United States in 1978. The development of tamoxifen for long-term adjuvant therapy3 and the evaluation of tamoxifen efficacy in worldwide randomized clinical trials led to a substantial increase in disease-free survival and overall survival, but only in the patients with ER-positive tumors.4,5 Unfortunately, as with all targets in cancer, not all ER-positive tumors respond, despite the fact that initially, the assay was rigorously quality controlled in cooperative groups. The solution seemed so easy because estrogen is necessary to induce the progesterone receptor (PgR), and therefore, those patients with ER+/PgR+ breast tumors should be more likely to respond to tamoxifen therapy.6,7 Extrapolation of these data from the metastatic breast cancer setting to adjuvant therapy has been less rewarding. There was initial promise that PgR status correlated well with disease-free and overall survivorship in stage II breast cancer.8 However, the Early Breast Cancer Trialists' Collaborative Group Overview analysis of randomized clinical trials has found strong correlation between ER status and response to adjuvant tamoxifen but no further benefit associated with positive PgR status.4,5 The development of therapeutic agents targeted specifically to block the aromatase enzyme, thereby creating a "no estrogen state," has introduced a new dimension in breast cancer therapeutics.9 A multitude of recent clinical studies have compared and contrasted several new aromatase inhibitors to adjuvant tamoxifen. In this issue of the Journal, Goss et al10 report an analysis of ER/PgR status and breast cancer responsiveness to extended adjuvant antihormonal therapy. Following the successful completion of 5 years of adjuvant tamoxifen treatment, the MA.17 trial evaluated 5 additional years of letrozole compared with a placebo control. Patients with ER+/PgR+ breast tumors constituted 73% of the patient population, whereas patients with ER+/PgR– tumors constituted 12% of the study population. The authors found that patients whose tumors are ER+/PgR+ are more likely to benefit from an additional 5 years of letrozole than are those with ER+/PgR– tumors. Should we be surprised? The authors contend that their result is controversial in light of the fact that a recent retrospective analysis of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial11 showed that patients with ER+/PgR– tumors are more likely to benefit from anastrozole than tamoxifen. However, the BIG (Breast International Group) 1-98 trial12 showed that the PgR status did not influence the magnitude of benefit of letrozole compared with tamoxifen. Patients with advanced breast cancer have a higher response rate to endocrine therapy if they have ER+/PgR+ tumors, compared with ER+/PgR– tumors.13,14 There is also a strong inverse relationship between S phase fraction (SPF) and steroid receptor classification. Tumors with both ER and PgR expression have low SPF, and SPF increases significantly with loss of PgR.15 What is the mechanism? We have known for nearly two decades that enhanced epidermal growth factor signaling reduces PgR levels16 and these ER+ tumor cells respond less completely to antiestrogen treatment than ER+/PgR+ tumor cells.17,18 These concepts have recently been confirmed and extended with reference to human epidermal growth factor receptor 2–neu19 and insulin-like growth factor receptor signaling.20 Laboratory studies also suggest that when drug resistance develops during long-term tamoxifen treatment21 and treatment is stopped, the undetected nascent tumors will still respond to either estrogen or tamoxifen for growth.22 These data explain the effectiveness of the letrozole after tamoxifen treatment was stopped in MA.17. The controversy arises when the sequential adjuvant study MA.17 is compared with adjuvant antihormone treatments that are initiated immediately after surgery. Unlike either the comparative ATAC or BIG 1-98 study populations, the MA.17 study investigates responsiveness in an enriched population after tamoxifen. The enrichment is evidenced by the high proportion of ER+/PgR+ tumors (73%) compared to either the ATAC (62%) or BIG 1-98 studies (63%). In other words, the ER+/PgR– tumors are more likely to recur during tamoxifen treatment. A patient can only be included in MA.17 if tamoxifen therapy is successful. The controversy really centers on the apparent conflict in outcomes of subgroup analyses between ATAC and BIG 1-98. Based on a small study of neoadjuvant therapy23 in which aromatase inhibitors performed better than tamoxifen in a growth factor–rich environment, the analysis of the ATAC data according to ER/PgR status11 supported the hypothesis that PgR– status could be used to select a cohort of patients with ER+ disease who would benefit most from adjuvant aromatase inhibitors. The observation in BIG 1-98 that the degree of benefit from letrozole compared with tamoxifen did not differ according to PgR status at this point seemed to be counterintuitive. Central pathology review of ER and PgR in tumor samples for 58% of randomized cases24 (subsequently increased to 79% [M. Regan, personal communication, January 2007]) confirmed this lack of enhanced effectiveness of letrozole compared with tamoxifen for the ER+/PgR– cohort in BIG 1-98. In fact, the benefit of letrozole compared with tamoxifen was numerically larger for the ER+/PgR+ cohort compared with the ER+/PgR– cohort based on the centrally reviewed receptor values. Furthermore, 2.3% of the BIG 1-98 cases enrolled on the basis of locally determined receptor-positive breast cancer were found to have no expression of either ER or PgR on central review. This small cohort of false-positive receptor cases had a substantially worse disease-free survival compared with the centrally reviewed receptor-positive cohort, and did not benefit from letrozole compared with tamoxifen. Thus, misclassification of true receptor status can influence observed results. Obtaining quality-controlled quantification of ER and PgR values is essential to assure that patients enrolled in endocrine therapy trials have the targeted disease and also that those cared for outside of clinical trials receive proper adjuvant therapy. Recently, Dowsett and Allred25 presented time-to-recurrence results according to a centrally reviewed assessment of ER and PgR conducted on 32% of patients enrolled on the monotherapy arms in the ATAC trial. In contrast to the original ATAC report, which was based on data provided on the case report forms,11 the centrally reviewed ER+/PgR– cohort did not demonstrate a differentially greater benefit of anastrozole. Notably, the centrally reviewed cases were highly selected according to geographic region, with almost 80% of United Kingdom cases included, but with less that 10% of the cases from the United States and other non-United Kingdom centers submitted for central review. It is possible, therefore, that the method of PgR determination in different parts of the world could have influenced the results. It is also quite reasonable to conclude that the apparent differences in outcome between ATAC and BIG 1-98 reported initially are due primarily to the play of chance. The importance of PgR– status to predict markedly superior response to aromatase inhibitor compared with tamoxifen may have been exaggerated in the original ATAC subgroup analyses. The current report from MA.17 shows that the ER+/PgR+ cohort benefits more from letrozole following tamoxifen than the ER+/PgR– cohort, while BIG 1-98 suggests little difference in the magnitude of the letrozole effect according to PgR status. We fully support the recommendation of Goss et al10 who, in their study in this issue of the Journal, "caution against using these results for clinical decision-making." AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Richard Gelber, Novartis Testimony: N/A Other: N/A AUTHOR CONTRIBUTIONS Conception and design: V. Craig Jordan, Richard D. Gelber Administrative support: V. Craig Jordan Collection and assembly of data: V. Craig Jordan Data analysis and interpretation: V. Craig Jordan Manuscript writing: V. Craig Jordan, Richard D. Gelber Final approval of manuscript: V. Craig Jordan, Richard D. Gelber ACKNOWLEDGMENTS V. Craig Jordan is supported by the Department of Defense Breast Program under award no. BC050277 Center of Excellence (views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense), SPORE in Breast Cancer CA 89018, R01 GM067156, FCCC Core Grant NIH P30 CA006927, the Avon Foundation, and the Weg Fund of Fox Chase Cancer Center. Richard D. Gelber is supported in part by Grant No. U24 CA-075362 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NOTES published online ahead of print at www.jco.org on April 23, 2007. REFERENCES
1. Jensen EV, Jordan VC: The estrogen receptor: A model for molecular medicine—The Dorothy P: Landon AACR Prize for Translational Research. Clin Cancer Res 9: 1980-1989, 2003 2. McGuire WL, Carbone PP, Sears ME, et al: Estrogen receptors in human breast cancer: An overview, in: McGuire WL, Carbone PP, Volmer EP (eds): Estrogen Receptor in Human Breast Cancer. Raven Press, New York, NY, 1975, pp 1-7 3. Jordan VC: Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discov 2: 205-213, 2003[CrossRef][Medline] 4. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351: 1451-1467, 1998[CrossRef][Medline] 5. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365: 1687-1717, 2005[CrossRef][Medline] 6. Horwitz KB, McGuire WL, Pearson OH, et al: Predicting response to endocrine therapy in human breast cancer: A hypothesis. Science 189: 726-727, 1975 7. Elledge RM, Green S, Pugh R, et al: Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group Study. Int J Cancer 89: 111-117, 2000[CrossRef][Medline] 8. McGuire WL, Clark GM, Dressler LG, et al: Role of steroid hormone receptors as prognostic factors in primary breast cancer. NCI Monogr 19-23, 1986 9. Jordan VC, Brodie AMH: Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids 72: 7-25, 2007[CrossRef][Medline] 10. Goss PE, Ingle JN, Martino S, et al: Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status on the primary tumor. J Clin Oncol 25: 2006-2011, 2007 11. Dowsett M, Cuzick J, Wale C, et al: Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: An hypothesis-generating study. J Clin Oncol 23: 7512-7517, 2005 12. Thurlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353: 2747-2757, 2005 13. Bloom ND, Robin EH, Schreibman B, et al: The role of progesterone receptor in the management of advanced breast cancer. Cancer 45: 2992-2997, 1980[CrossRef][Medline] 14. Osborne CK, Yochmowitz MG, Knight WA, et al: The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer 46: 2884-2888, 1980[CrossRef][Medline] 15. Wenger CR, Beardslee S, Owens MA, et al: DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Res Treat 28: 9-20, 1993[CrossRef][Medline] 16. Cormier EM, Wolf MF, Jordan VC: Decrease in estradiol-stimulated progesterone receptor production in MCF-7 cells by epidermal growth factor and possible clinical implication for paracrine-regulated breast cancer growth. Cancer Res 49: 576-580, 1989 17. Cormier EM, Jordan VC: Contrasting ability of antiestrogens to inhibit MCF-7 growth stimulated by estradiol or epidermal growth factor. Eur J Cancer Clin Oncol 25: 57-63, 1989[CrossRef][Medline] 18. Robinson SP, Jordan VC: The paracrine stimulation of MCF-7 cells by MDA-MB-231 cells: Possible role in antiestrogen failure. Eur J Cancer Clin Oncol 25: 493-497, 1989[CrossRef][Medline] 19. Osborne CK, Bardou V, Hopp TA, et al: Role of the estrogen receptor coactivator AIB1 (SRC3) and HER2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95: 353-361, 2003 20. Cui X, Zhang P, Deng W, et al: Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: Progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol Endocrinol 17: 575-588, 2003 21. Jordan VC: Selective estrogen receptor modulation: Concept and consequences in cancer. Cancer Cell 5: 207-213, 2004[CrossRef][Medline] 22. Gottardis MM, Jordan VC: Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res 48: 5183-8187, 1988 23. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a Phase III randomized trial. J Clin Oncol 19: 3808-3816, 2001 24. Viale G, Regan M, Dell'Orto P, et al: Central review of ER, PgR and HER-2 in BIG 1-98 evaluating letrozole versus tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Breast Cancer Res Treat 94: S13, 2005 (suppl 1; abstr 44) 25. Dowsett M, Allred D, on behalf of the TransATAC Investigators: Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial. Breast Cancer Res Treat 100: S21, 2006 (suppl 1; abstr 48) Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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