Affiliations of authors: Breast Center, Baylor College of Medicine and The Methodist Hospital, Houston, TX (GA, HW, AVL, RS, CKO, RME); Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universita di Napoli Federico II, Naples, Italy (SDP)
Correspondence to: Richard M. Elledge, MD, Breast Care Center, 6550 Fannin St., Ste. 701, Houston, TX 77030 (e-mail: relledge{at}breastcenter.tmc.edu).
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ABSTRACT |
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INTRODUCTION |
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Clinical data have confirmed in both the metastatic and adjuvant treatment settings that tamoxifen is less efficacious in ER+/PR tumors than in ER+/PR+ tumors (713). Data from the large ATAC adjuvant trial, a worldwide trial comparing the efficacy of tamoxifen with that of the aromatase inhibitor anastrazole, showed overall that patients with ER+/PR+ tumors had a lower recurrence rate than those with ER+/PR tumors (7.6% versus 14.8%) (14). This difference in overall recurrence was due largely to the lower efficacy of tamoxifen in the subgroup of patients with ER+/PR tumors; there was little difference in the recurrence rate of PR+ versus PR tumors in patients who were treated with anastrozole. The observation that patients with ER+/PR tumors respond nearly as well to anastrozole as those with ER+/PR+ tumors suggests that the ER signaling pathway is functional in many ER+/PR tumors and that these tumors are still dependent on estrogen for growth, despite having somewhat lower ER levels. Thus, the etiology of the ER+/PR phenotype, either de novo or acquired, cannot be attributed entirely to the nonfunctional ER hypothesis. Furthermore, ER activity has been observed in freshly prepared breast lysates of ER+/PR tumors (15).
Several clinical reports have suggested that high growth factor signaling may be associated with decreased PR levels in breast cancer (6,1619). Indeed, a recent study showed that growth factors that activate the PI3KAktmTOR pathway can decrease PR transcription (2022). Increased HER-1 or HER-2 activity may also lead to tamoxifen resistance in some patients, and this result has also been shown using several experimental preclinical models (2326). The cumulative data raise the possibility that PR loss is a surrogate marker for excessive growth factor receptor activation, which translates into reduced tamoxifen benefit.
The aim of this study was to determine whether ER+/PR+ and ER+/PR breast tumors represent distinct biologic and clinical entities and to investigate whether PR loss is associated with higher HER-1 (epidermal growth factor receptor [EGFR]) and HER-2 content in human breast cancer. Finally, we investigated whether PR expression is associated with the clinical outcome of patients treated with tamoxifen adjuvant therapy. Because of the limited sample size in some of the tamoxifen-treated HER-1, HER-2, and hormone receptordefined subsets, this is a hypothesis-generating analysis.
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SUBJECTS AND METHODS |
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The Breast Center at Baylor College of Medicine maintains databases of breast cancer patients whose biopsy or mastectomy specimens were sent to two central laboratories for steroid receptor assays. The reference laboratories were located at the University of Texas Health Science Center at San Antonio and at Nichols Institute in San Juan Capistrano, California, and they used identical assays and cooperated at regular intervals in quality control procedures. The patients were diagnosed and treated at more than 370 academic and community institutions throughout the United States. Follow-up information was obtained from tumor registries, by direct review of medical records performed by data managers, or by data collection forms completed by the office staff of the referring physicians. These databases contain information on receptor status and outcomes of 54 865 patients who were diagnosed between 1970 and 1998 with early breast cancer (stage IIIIA, as defined by American Joint Committee on Cancer staging classification) (27). The patient information contained in this report was obtained from two data repositories maintained by the Breast Center at Baylor College of Medicine. Each repository has been reviewed by institutional review boards at the University of Texas Health Science Center at San Antonio and at Baylor College of Medicine. Both institutional review boards determined that a waiver of written informed consent was appropriate for each of these repositories. No patient identifiers were provided to the authors.
Prognostic Factors
ER levels were measured by the dextran-coated charcoal method, as previously described (28). From 1970 to 1984, [3H]estradiol was used as the labeled ligand. During the same period, PR levels were measured by sucrose density gradient (29). In 1985, the standard multipoint dextran-coated charcoal assay was modified to incorporate [125I]estradiol and [3H]R5020 in a single assay, allowing the simultaneous determination of both ER and PR. Samples containing at least 3 fmol/mg protein were considered ER positive, and those containing at least 5 fmol/mg protein were considered PR positive, based on prior clinical studies (7,10,30). DNA ploidy and S-phase fraction were evaluated by flow cytometry and the histograms were analyzed by Modfit (Verify Software House, Topsham, ME) using single-cut debris stripping (31). Cutpoints were determined by calibrating S-phase fraction with clinical outcome in a group of more than 28 800 patients with breast cancer (low, <6%; intermediate, 6%10%; high >10%) (31). HER-2 status was determined by western blot analysis, using a rabbit polyclonal antibody directed against the C terminus of the HER-2 protein (32). The cutoff value between low (negative) and high (positive) HER-2 expression was set at 1 U/µg protein based on prior studies in which protein level above this cutpoint was associated with several poor prognostic factors and a worse disease-free and overall survival (32,33). HER-1 levels were measured by radioligand binding assay using a fixed concentration of radiolabeled EGF and various concentrations of unlabeled EGF. Levels of at least 10 fmol/mg were considered positive. This method for assessing HER-1 expression and cutoff value is similar to that used in previously published studies (34,35).
Statistical Methods
Descriptive statistics are reported as frequencies or as medians. The clinical and biologic characteristics of women with ER+/PR+ and ER+/PR tumors were compared using contingency tables, chi-square tests, and Fisher exact tests. ER and PR levels were compared between ER+/PR+ and ER+/PR tumors and by HER-1 and HER-2 positivity status using nonparametric Wilcoxon rank-sum tests.
Disease-free survival (DFS) was calculated from the date of the diagnostic biopsy, with first recurrences, local or distant, being scored as an event, and with censoring of other patients at the time of last follow-up or death. Overall survival (OS) was defined as the interval between the diagnostic biopsy and death from any cause, death being scored as an event. Patients who were still alive at the time of last follow-up were censored then. DFS and OS curves were estimated using the KaplanMeier product limit method and were compared by the log-rank test. A univariate Cox regression model was used to determine the association of HER-1 and HER-2 status with DFS and OS in tamoxifen-treated ER+/PR+ and ER+/PR patients. The assumption of proportionality of HER-1 and HER-2 on DFS and OS was verified by performing hypothesis tests of HER-1 and HER-2 status as time-dependant variables in the Cox model. Hazard ratios (HRs) are presented with their 95% confidence intervals (CIs). The simultaneous association of these growth factor receptors along with clinical and biological characteristics was assessed in a multivariable Cox regression model. The potential interaction between ER/PR status and HER-1 and HER-2 status was also tested in this multivariable model, which included the following variables and cutpoints were determined based on previous studies or conventional definitions: tumor size (2 cm versus >2 cm), axillary nodes (0, 13,
4), age (<50 years versus
50 years), ploidy (diploid versus aneuploid), S-phase fraction (low 0%<6%, intermediate 6%10%, high >10%), HER-1 (negative <10, positive
10 fmol/mg), HER-2 (negative <1 U/µg, positive
1 U/µg), and ER and PR status (ER+/PR+ versus ER+/PR). All analyses were performed using SAS 9.1 (SAS, Cary, NC). All statistical tests were two-sided, and comparisons made in which P<.05 were deemed statistically significant. Comparisons of the two growth factor receptors, HER-1 and HER-2, were performed in the overall population and by ER and PR subgroups (ER+/PR+ and ER+/PR); therefore, P values of .05 should be interpreted with caution. Median follow-up of all patients was 72 months (range = 0120 months) at the time of last follow-up in 2002. Patients are no longer being actively followed up.
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RESULTS |
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The clinical and biologic tumor characteristics are summarized in Table 1. Overall, in women more than 50 years of age, ER+/PR tumors were found more frequently than ER+/PR+ tumors (82% versus 77% respectively; P<.001). However, ER+/PR tumors were larger (greater than 2 cm in diameter) than ER+/PR+ tumors (51% versus 45%, respectively; P<.001). In addition, 19% of patients whose tumors were ER+/PR had four or more axillary nodes involved with tumor compared with 16% of patients with ER+/PR+ tumors (P<.001).
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ER+/PR tumors displayed features of a more aggressive biologic phenotype than ER+/PR+ tumors (Table 1). For example, as has been previously shown in other studies (10), the median level of ER in ER+/PR tumors was approximately half that in ER+/PR+ tumors (median = 47 fmol/mg, range = 32211, versus median = 103 fmol/mg, range = 33290, respectively; P<.001). Furthermore, ER+/PR tumors were more likely to be aneuploid than ER+/PR+ tumors (54% versus 48%, respectively; P<.001). In addition, ER+/PR tumors had higher proliferation rates than ER+/PR+ tumors, as evidenced by their higher S-phase fraction (33% for ER+/PR versus 19% for ER+/PR+; P<.001). Only 45% of ER+/PR tumors had low S-phase fractions, compared with 63% of the ER+/PR+ tumors.
HER-1 and HER-2 Status in ER+/PR+ and ER+/PR Tumors
HER-1 and HER-2 was performed on only a portion of patients because testing for these molecular markers was not the routine standard of care for all patients when this database was gathered. ER+/PR tumors were three times more likely than ER+/PR+ tumors to express HER-1 (25% versus 8%, respectively; P<.001), and the levels of HER-1 in ER+/PR tumors (median = 40 fmol/mg protein, range = 1011 084) were nearly twice those in ER+/PR+ tumors (median = 24 fmol/mg of protein, range = 104071; P = .02) (Table 2). ER+/PR tumors were also statistically significantly more likely to overexpress HER-2 (21% for ER+/PR versus 14% for ER+/PR+; P<.001) (Table 2).
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Clinical Outcome of Tamoxifen-Treated Women With ER+/PR+ and ER+/PR Tumors According to HER-1 and HER-2 levels
In this database, 11 399 patients (8421 with ER+/PR+ breast cancer and 2978 with ER+/PR breast cancer) were treated with tamoxifen as the only systemic therapy (Supplementary Table 3 available at http://jncicancerspectrum.oxfordjournals.org/jnci/content/vol97/issue17). Among all 11 399 patients, information on HER-1 status was available for 465. Patients with HER-1positive tumors had a higher likelihood of recurrence than patients with HER-1negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05) (Fig. 2, A); no statistically significant difference was observed for OS (data not shown). Information on HER-2 status was available for a total of 392 of the 11 399 women (with ER+ tumors treated with adjuvant tamoxifen). As with patients with HER-1expressing tumors, patients with HER-2overexpressing tumors had a higher recurrence risk than patients with HER-2nonoverexpressing tumors (HR = 2.3, 95% CI = 1.24 to 4.3; P = .006) (Fig. 2, B). HER-2positive patients also had a higher chance of death from any cause than HER-2negative patients (HR = 1.6, 95% CI = 1.0, 2.75; P = .05).
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We next determined whether quantitative ER levels in the HER-1 or HER-2positive groups alone were associated with outcome in tamoxifen-treated patients (Table 4). Overall, in both ER+/PR+ and in ER+/PR tumors, those with HER-1 expression had statistically significantly lower ER levels than those negative for HER-1. This difference was particularly evident in the ER+/PR cohort, with HER-1negative tumors having an eightfold higher median ER level (median = 91 fmol, range = 31092) than HER-1positive tumors (median = 11 fmol, range = 3168; P<.001). However, further analysis of this association controlling for continuous levels of ER in a Cox model in the ER+/PR subgroup of patients still showed statistically significant worse DFS and OS in women with HER-1positive tumors than in those with HER-1negative tumors (data not shown), suggesting that the lower ER level in the HER-1positive, ER+/PR tumors does not fully explain the worse outcome in these patients. In contrast, there was no statistically significant difference in the ER level among the HER-2overexpressing versus HER-2nonoverexpressing tumors in the ER+/PR+ patient subset. However, in patients with ER+/PR tumors, the median ER level was five times lower in the HER-2overexpressing tumors (median = 18 fmol, range = 41092) than in the HER-2nonoverexpressing tumors (median = 94 fmol, range = 3777; P = .004). As with HER-1, after controlling for continuous levels of ER, HER-2 overexpression, compared with HER-2 nonoverexpression, remained statistically significantly associated with worse DFS (P = .03) and OS (P = .04) in ER+/PR tumors.
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DISCUSSION |
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Several recent clinical reports also indicate that high growth factor receptor activity may be associated with reduced PR levels in breast cancer (6,1618,37,38). Recent laboratory studies suggest a molecular basis for this observation. Growth factors in the insulin-like growth factor (IGF) and epidermal growth factor (EGF) families that activate the P13KAktmTor pathway can cause reduced expression of PR at the transcriptional level. This transcriptional suppression may be mediated by an AP-1 site in the PR gene promoter that blocks transcription (22,39). Transcription factors in the AP-1 family are activated by several external cellular stimuli including stress, cytokines, and growth factor receptor signaling. These molecular data, in concert with our clinical findings, raise the possibility that loss of PR in some tumors is due to increased growth factor receptor activity rather than to a nonfunctional ER signaling pathway.
Although our data need to be confirmed by other studies, the results suggest the hypothesis that PR levels are a surrogate for the level of activity in the signaling cascade generated by HER-1 and/or HER-2 activation. First, ER+/PR tumors that were also positive for HER-1 or that overexpressed HER-2 had higher proliferation rates (S-phase fraction). Second, tamoxifen-treated women whose tumors were ER+/PR, and either HER-1 positive or overexpressed HER-2, had statistically significantly worse outcome than patients in the same subgroup whose tumors had no HER-1 or low HER-2. In contrast, the effect of HER-1 expression and HER-2 overexpression was not statistically significant in the subset of patients with ER+/PR+ tumors. One possible explanation for the difference between ER+/PR+ and ER+/PR tumors in terms of associations of outcome with HER-1 and HER-2 is that HER-1 and HER-2 levels were statistically significantly higher in the ER+/PR tumors than in the ER+/PR+ tumors (Table 2), and several clinical studies suggest that such high levels of expression of HER-1 and HER-2 are associated with tamoxifen resistance (19,4043). Consequently, HER-1/HER-2 signaling may be more active in ER+PR tumors, resulting in a smaller impact in response to tamoxifen.
Another possibility that would explain the tamoxifen resistance is that ER levels are considerably lower in ER+ tumors that lack PR and also have abundant HER-1 or HER-2. Lower levels of ER are associated with less benefit from tamoxifen (44). In this study, ER levels were approximately 60%80% lower in HER-1positive and HER-2overexpressing tumors than in HER-1negative and HER-2nonoverexpressing tumors. However, multivariable analysis in this and other studies (19,42) that consider ER level as a continuous rather than dichotomous variable suggests that a low ER level is not the only factor explaining tamoxifen resistance in HER-1expressing and HER-2overexpressing tumors.
Laboratory studies provide a potential mechanism for the lower ER levels in HER-1positive and HER-2overexpressing tumors and suggest that cross-talk between ER and growth factor receptor signaling pathways in response to estrogen or tamoxifen can in part account for tamoxifen resistance. Tamoxifen, like estrogen, can directly activate the HER-1 and HER-2 tyrosine kinases and induce tumor growth when these membrane receptors are abundant (45). Estrogen deprivation therapy, in contrast, remains highly effective in such tumors, because, unlike tamoxifen, estrogen deprivation therapy does not result in activation of the growth factor receptor pathways.
This study has several potential limitations. First, it is a retrospective study, and therapy or lack of therapy was not determined on a randomized basis. Second, there were few patients in the tamoxifen-treated subgroups whose HER-1 and HER-2 status was known; however, it remains the largest study to our knowledge to address the issue of HER-1 and HER-2 expression in hormone receptor phenotypes and its potential relationship to tamoxifen efficacy. Third, although the study focused primarily on HER-1 and HER-2 receptors as possible contributors to tamoxifen resistance, additional downstream factors could also contribute, and such factors were not analyzed. Fourth, HER-2 overexpression was analyzed by western blotting, which is not currently a standard method for assessing the status of this molecule in clinical practice. It is however, a standardized, reproducible methodology. Fifth, for a substantial portion of the patients reported in this database, follow-up was not obtained from primary tumor registries. Recurrences are probably somewhat underreported because tumor registries do not always capture this information; however, underreporting of recurrences would have varied by hospital and not by PR or HER-1 or HER-2 status. Primarily because of the retrospective nature of this study and the other issues raised above, these findings are for hypothesis generation only and need to be confirmed in prospective, large, randomized trials or retrospective analysis of a prospective study.
In summary, our findings support the hypothesis that loss of PR in ER+ breast cancer is a surrogate marker for increased growth factor receptor tyrosine kinase activity that causes lower PR expression and tamoxifen resistance in some patients. The results raise the possibility that overexpression of only HER-1 and/or HER-2 affects tamoxifen response substantially only when PR is negative. If PR expression is maintained, perhaps signaling through the HER family pathways is low despite overexpression of the HER receptors themselves. Although response to trastuzumab has not been shown to vary by ER status, if the hypothesis that lack of PR expression is a reflection of active signaling in the HER family is correct, then the response to trastuzumab or other small-molecule HER-2 inhibitors might be different in the PR+ and PR subsets, an idea that could be explored in ongoing adjuvant clinical trials. Finally, if the link between PR negativity and high growth factor receptor signaling can be confirmed as a cause of tamoxifen resistance, then therapies targeting the growth factor pathways in combination with tamoxifen should be investigated in patients with ER+/PR tumors in future clinical trials.
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NOTES |
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Supported in part by NIH grants P01 CA30195 and P50 CA58183 (SPORE), Aventis Pharmaceuticals, and the Susan G. Komen Breast Cancer Foundation.
Funding to pay the Open Access publication charges for this article was provided by the National Cancer Institute, P50 CA 58183 (SPORE).
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Manuscript received January 19, 2005; revised June 28, 2005; accepted July 15, 2005.
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