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IN REPLY

Breast Center, Baylor College of Medicine and the Methodist Hospital, Houston, TX

Neven et al highlight their recent studies on the relationship between progesterone receptor (PR) and HER-2 status in breast cancer. It is gratifying to note that they also found increased HER-2 positivity in estrogen receptor (ER) -positive/PR-negative tumors (11.5%) compared with ER-positive/PR-positive tumors (5.4%). A recent study using fluorescent in situ hybridization (FISH) measurement of HER-2 amplification, showed a similar 2.75-fold increase,¹ which is very similar to several other reports.²

Neven et al also point out their observation that the association between PR and HER-2 is only found in women older than 45 years. This is an attractive hypothesis, as it incorporates some of the interesting biology of these tumors, and may explain the antiestrogen sensitivity of HER-2 amplified tumors in young women. It is possible that in premenopausal women high estrogen levels drive ER to predominantly regulate classic ER-regulated genes. In contrast, in postmenopausal women, low estrogen levels may allow an increasing affect of growth factor signaling on ER action, resulting in a different set of ER-regulated genes being expressed. However, there are some important considerations to take into account before accepting this hypothesis.

First, and most importantly, Huang et al³ found that following stratification for age ( 45 or > 45), the association between HER-2 and PR was only found in women older than 45 years (odd ratio [OR], 2.58; 95% CI, 1.49 to 4.47; P = .001). As only 23% (n = 17) of HER-2–positive tumors were in women 45, it is possible (and probable) that the lack of association in the younger women simply reflects the fact that there were very few HER-2–positive tumors (n = 17 of which two were PR-negative and 15 were PR-positive). Similarly, the author's analysis of PR and HER-2 according to stratifications of age (every 5 years from < 45 to > 70) also contained numbers of HER-2–positive tumors that were so small that determining a subsequent association with PR status may have revealed statistically spurious results rather than true biologic differences.

Despite the hazards inherent in performing multiple subgroup analyses, we reanalyzed our data set according to PR, HER-2, and age. As presented in Table 1, we also found that after stratifying for age ( 45 or > 45), there was a significant association between PR and HER-2 in older women (P < .001), but not in younger women (P = .22). However, similar to Huang et al there was only a small fraction of HER-2–positive (n = 53) tumors in the young women. Furthermore, the difference in the percentage of tumors that were PR-positive/HER-2–positive and PR-negative/HER-2–positive was identical (7%) between women 45 and older than 45. Indeed, a test for homogeneity of ORs between younger women versus older women was not significant (P = .76), suggesting that the lack of statistical difference in women 45 is probably due to the small number of samples. Therefore, we conclude that multiple stratifications and subset analysis by Huang et al and in our data set maybe producing spurious significant interactions. Similarly, we were unable to determine if there is an interaction between PR, HER-2, age, and response to tamoxifen due to the even smaller subsets of patients, thus any possible interactions must be assessed in larger datasets.

Finally, the authors show that PR is a predictor of lymph node invasion (OR, 0.547; 95% CI, 0.300 to 0.997; P = .049), but only in younger women (< 50 years). Our data set contains 6,035 ER-positive tumors from women younger than 45 years of age (13-fold more tumors than Neven et al), yet we failed to find any association between PR and lymph node invasion, even following stratification according to age ( 45, P = .57; > 45, P = .08). Therefore, we believe that the result of Neven et al may again reflect the play of chance resulting from stratification and diminishing sample size.

In summary, multiple studies now point to the fact that HER-2 levels are decreased in ER-positive/PR-negative tumors compared with ER-positive/PR-positive tumors. We have previously set forth numerous hypotheses and arguments for both the etiology of this observation, and also the resulting biology, particularly the ability of increased growth factor signaling to cause antiestrogen resistance in ER-positive/PR-negative tumors. In respect to the study of Huang et al, at present we cannot conclude that there is a differential effect of PR status on HER-2 positivity between young women and older women. To definitively test this question, larger data sets of HER-2–positive tumors from young women are required.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Prati R, Apple SK, He J, et al: Histopathologic characteristics predicting HER-2/neu amplification in breast cancer. Breast J 11:433-439, 2005[CrossRef][Medline]

2. Kim HJ, Cui X, Hilsenbeck SG, et al: Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor-positive breast cancer. Clin Cancer Res 12:1013s-1018s, 2006[Abstract/Free Full Text]

3. Huang HJ, Neven P, Drijkoningen M, et al: Association between HER-2/neu and the progesterone receptor in oestrogen-dependent breast cancer is age related. Breast Cancer Res Treat 91:81-87, 2005[CrossRef][Medline]

4. Balsari A, Casalini P, Tagliabue E, et al: Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle. Am J Pathol 155:1543-1547, 1999[Abstract/Free Full Text]

5. Pujol P, Daures JP, Thezenas S, et al: Changing estrogen and progesterone receptor patterns in breast carcinoma during the menstrual cycle and menopause. Cancer 83:698-705, 1998[CrossRef][Medline]

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Related Correspondence

• Progesterone Receptor in Estrogen Receptor–Positive Breast Cancer: The Association Between HER-2 and Lymph Node Involvement Is Age Related
  Patrick Neven, Nathalie Pochet, Maria Drijkoningen, Frederic Amant, Frank De Smet, Robert Paridaens, Marie-Rose Christiaens, and Ignace Vergote
  JCO 2006 24: 2595 [Full Text]

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