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Does Estrogen Receptor–Negative/Progesterone Receptor–Positive Breast Carcinoma Exist?

Department of Radiotherapy; Multidisciplinary Breast Centre, UZ-Katholieke Universiteit Leuven, Leuven, Belgium

Philippe Moerman

Department of Pathology; Multidisciplinary Breast Centre, UZ-Katholieke Universiteit Leuven, Leuven, Belgium

Nathalie Pochet

ESAT-SCD, Katholieke Universiteit Leuven, Leuven, Belgium

Wouter Hendrickx

Multidisciplinary Breast Centre, UZ-Katholieke Universiteit Leuven, Leuven, Belgium

Hans Wildiers, Robert Paridaens

Multidisciplinary Breast Centre; Department of Medical Oncology, UZ-Katholieke Universiteit Leuven, Leuven, Belgium

Ann Smeets, Marie-Rose Christiaens

Multidisciplinary Breast Centre; Department of Surgery, UZ- Katholieke Universiteit Leuven, Leuven, Belgium

Ignace Vergote

Department of Gynaecological Oncology, UZ-Katholieke Universiteit Leuven, Leuven, Belgium

Karin Leunen, Frederic Amant, Patrick Neven

Multidisciplinary Breast Centre; Department of Gynaecological Oncology, UZ- Katholieke Universiteit Leuven, Leuven, Belgium

To the Editor:

It was with great interest that we have read the article by Rakha et al.¹ The authors presented data on clinicopathological characteristics of single hormone receptor-positive breast cancers, demonstrating that estrogen receptor (ER)–positive/progesterone reception (PR)–positive and ER-positive/PR-negative tumors are distinct breast cancer phenotypes when compared with double-positive or double-negative–breast cancers. Single hormone receptor positive breast cancers appear in different age groups, they are more often high grade and HER-2 positive, and patient outcome is worse when compared with ER-positive/PR-positive tumors.

We recently presented and published a similar study regarding the clinicopathological findings of the single hormone receptor-positive breast cancer phenotype.²-⁴ Focusing on the ER-negative/PR-positive breast cancer phenotype, we did find that 1.5% of our primary operated cases presented as such. The statistical analysis showed similar results to these of Rahka et al suggesting that single hormone receptor positive tumors have worse clinicopathological features than double positive or double negative controls. When compared with the ER-negative/PR-negative group, ER-negative/PR-positive lesions were less likely grade 3, but more likely larger, lymph node-positive, lobular type and HER-2 positive with an earlier age and premenopausal state at diagnosis.³ When compared with the ER-positive/PR-positive lesions, ER-negative/PR-positive lesions were also more often larger, HER-2 positive, higher grade, and also with an earlier presentation at diagnosis (data presented in table).⁴

Results showed that 20 out of 32 cases initially considered ER-negative as a result of the then applied threshold cutoff, were in fact ER-positive/PR-positive when ‘any’ immunohistochemical (IHC) staining was considered as a positive result. In the other 12 so-called ER-negative/PR-positive cases, technical failure was the main reason for this result. When staining was repeated with the above mentioned techniques, five were considered false-positive for PR, and seven were considered false-negative for ER.

As a result of our reanalysis, we could not confirm the presence of ER-negative/PR-positive breast tumors in the period between January 2000 and February 2005 at the Leuven University Hospital when any positive IHC staining is reported as such. These results are similar to those reported by Nadji et al. They evaluated almost 6,000 breast cancers for ER expression by IHC analysis and found that all PR-positive cases were also ER-positive, reporting any positive staining result as positive.⁵ In contrast, Rahka et al did report 3.4% of breast cancer cases as ER-negative/PR-positive.¹

We do believe that the reason for low or negative IHC staining of ER in some PR-positive cases using less sensitive IHC techniques might be related to variables such as younger age, higher tumor grade, and HER-2–positive status. All such factors are well known to be associated with lower levels of ER expression as assessed by quantitative analysis of ER using real-time polymerase chain reaction.^8,9

We would like to stress that IHC staining of hormone receptors appears to be a qualitative rather than a quantitative technique. IHC analysis indicates if hormone receptors are present, but does not correctly quantify the amount of ER protein in breast cancer cell nuclei.^4,5 Regarding this fact, we should consider whether it is simply the presence of hormone receptors, or more specifically the level in which hormone receptors are expressed, that is important in clinical outcome and decision making. Clear standards and guidelines for IHC staining procedures and delineated cutoff values should be found in order to be able to compare results from different research groups.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Rakha EA, El-Sayed ME, Green AR, et al: Biologic and clinical characteristics of breast cancer with single hormone receptor-positive phenotype. J Clin Oncol 25:4772-4778, 2007[Abstract/Free Full Text]

2. Huang HJ, Neven P, Drijkoningen M, et al: Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1,362 women with primary operable breast cancer. J Clin Pathol 58:611-616, 2005[Abstract/Free Full Text]

3. Huang HJ, Neven P, Drijkoningen M, et al: The progesterone receptor has a prognostic value in oestrogen receptor negative breast cancers. Eur J Cancer 2004 2:103-104 (suppl 2; abstr 170)

4. De Maeyer L, Neven P, Drijkoningen R, et al: The estrogen receptor has a prognostic value in progesterone receptor-positive breast cancer. Int J Gynecol Cancer 16:589-598, 2006 (suppl 2)[CrossRef]

5. Nadji M, Gomez-Fernandez C, Ganjei-Azar P, et al: Immunohistochemistry of estrogen and progesterone receptors reconsidered: Experience with 5,993 breast cancers. Am J Clin Pathol 123:21-27, 2005[CrossRef][Medline]

6. Collins LC, Botero ML, Schnitt SJ: Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer. Am J Clin Pathol 123:16-20, 2005[CrossRef][Medline]

7. Schnitt SJ: Estrogen receptor testing of breast cancer in current clinical practice: What's the question? J Clin Oncol 24:1797-1799, 2006[Free Full Text]

8. Konecny G, Pauletti G, Pegram M, et al: Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 95:142-153, 2003[Abstract/Free Full Text]

9. Iwao K, Miyoshi Y, Egawa C, et al: Quantitative analysis of estrogen receptor-alpha and -beta messenger RNA expression in breast carcinoma by real-time polymerase chain reaction. Cancer 89:1732-1738, 2000[CrossRef][Medline]

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				A Rhodes and B Jasani The oestrogen receptor-negative/progesterone receptor-positive breast tumour: a biological entity or a technical artefact? J. Clin. Pathol., January 1, 2009; 62(1): 95 - 96. [Full Text] [PDF]

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