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Progesterone Receptor Testing: Not the Right Time to Be Buried

Chemotherapy and Pathology Units, Jules Bordet Institute, Brussels, Belgium

To the Editor:

Olivotto et al state that progesterone receptor (PgR) testing should be discontinued,¹ but we disagree with their conclusions for several reasons. It is well known that PgR is an estrogen receptor (ER) -regulated protein and that its expression indicates a functional ER pathway. In the 70% to 80% of breast cancer cases that are ER-positive, we think that PgR testing has some utility. While its prognostic role is not clearly defined, it does provide predictive information. ER-positive and PgR-negative tumors are, in fact, less responsive to endocrine therapy (particularly tamoxifen) than ER-positive and PgR-positive tumors in the metastatic setting.^2,3 Other authors have reported that the presence of both receptors is a marker of a greater probability of benefit from adjuvant tamoxifen than ER alone.^4,5 Consequently, PgR negativity can influence the therapeutic decision to offer adjuvant chemotherapy in addition to adjuvant endocrine therapy in selected patients. The observation in the Oxford Overview that the reduction of recurrence for patients with ER-positive/PgR-negative tumors after adjuvant tamoxifen is similar to that obtained in patients with ER-positive/PgR-positive tumors⁶ could be due to technical difficulties in measuring PgR in some of the earlier trials included in the meta-analysis.⁷ Moreover, recent preliminary data from the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial, presented by Dowsett at the 2003 San Antonio Breast Cancer Symposium, show no difference in disease-free survival between tamoxifen and anastrozole in the subgroup of patients with ER- and PgR-positive tumors, while anastrozole was found to be significantly superior to tamoxifen in the subgroup of ER-positive PgR-negative patients.⁸ While these are retrospective data that need to be confirmed, they are provocative. Furthermore, it is now known that human PgR proteins exist in two isoforms, PgR-A and PgR-B, which seem to have different functions as shown by in vitro and in vivo data,^9,10 even if they are transcribed from the same gene under the control of separate promoters.¹¹ The two isoforms were measured by immunoblotting of tumor lysates from node-positive patients treated with tamoxifen. A high ratio between the two isoforms (PgR-A/PgR-B) was found to identify a subgroup of patients with ER and PgR positive tumors resistant to tamoxifen in both univariate and multivariate analysis.¹² If confirmed, these data offer a new opportunity to better select patients who are good candidates for tamoxifen. For all the above reasons, it does not seem to be the right time to bury PgR testing, but instead, to start refining its purpose.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have 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. Consultant: M.J. Piccart. Novartis, Aventis, Pfizer, Johnson & Johnson, GlaxoSmithKline, Bristol-Myers Squibb. Honoraria: M.J. Piccart, AstraZeneca, Aventis, Novartis, Pfizer, Roche. For a detailed description of these 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 of Information for Contributors found in the front of every issue.

REFERENCES

1. Olivotto IA, Truong PT, Speers C, et al: Time to stop progesterone receptor testing in breast cancer management. J Clin Oncol 22:1769-1770, 2004[Free Full Text]

2. 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 immunohistochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group study. Int J Cancer 89:111-117, 2000[CrossRef][Medline]

3. Ravdin PM, Green S, Dorr TM, et al: Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen: Results of a prospective Southwest Oncology Group study. J Clin Oncol 10:1284-1291, 1992[Abstract/Free Full Text]

4. Bardou V-J, Arpino G, Elledge RM, et al: Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 21:1973-1979, 2003[Abstract/Free Full Text]

5. Femo M, Stal O, Baldertop B, et al: Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels: South Sweden Breast Cancer Group and South-East Sweden Breast Cancer Group. Breast Cancer Res Treat 59:69-76, 2000[CrossRef][Medline]

6. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998[CrossRef][Medline]

7. Rutqvist LE, Cedermark B, Pomander T, et al: The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer. J Clin Oncol 7:1474-1484, 1989[Abstract]

8. Dowsett M on behalf of the ATAC Trialists Group: Analysis of time to recurrence in the ATAC (arimidex, tamoxifen, alone or in combination) trial according to estrogen receptor and progesterone receptor status. Breast Cancer Res Treat 83:S7, 2003 (suppl 1; abstr 4)

9. Kastner P, Krust A, Turcotte B, et al: Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptors forms A and B. EMBO J 9:1603-1614, 1990[Medline]

10. Kraus WL, Katzenellenbogen BS: Regulation of progesterone receptor gene expression and growth in the rat uterus: Modulation of estrogen actions by progesterone and sex steroid hormone antagonists. Endocrinology 132:2371-2379, 1993[Abstract/Free Full Text]

11. Richer JK, Jacobsen BM, Manning NG, et al: Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 277:5209-5218, 2002[Abstract/Free Full Text]

12. Hoop TA, Weiss HI, Hilsenbeck SG, et al: Breast cancer patients with progesterone receptor PR-A-rich tumors have poorer disease-free survival rates. Clin Cancer Res 10:2751-2760, 2004[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Colozza, M. Articles by Piccart, M.J. Search for Related Content PubMed PubMed Citation Articles by Colozza, M. Articles by Piccart, M.J. Social Bookmarking                            What's this?