Originally published as JCO Early Release 10.1200/JCO.2007.12.2747 on September 17 2007

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Biologic and Clinical Characteristics of Breast Cancer With Single Hormone Receptor–Positive Phenotype

Emad A. Rakha, Maysa E. El-Sayed, Andrew R. Green, E. Claire Paish, Desmond G. Powe, Julia Gee, Robert I. Nicholson, Andrew H.S. Lee, John F.R. Robertson, Ian O. Ellis

From the Department of Histopathology and Surgery, School of Molecular Medical Sciences, Nottingham University Hospitals National Health Service Trust and University of Nottingham, Nottingham, and Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom

Address reprint requests to Emad Rakha, MD, PhD, Molecular Medical Sciences, University of Nottingham, Department of Histopathology, Nottingham City Hospital National Health Service Trust, Hucknall Road, Nottingham, NG5 1PB, United Kingdom; e-mail: emadrakha{at}yahoo.com

	ABSTRACT

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Purpose Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PgR) status. It is usually easier to decide treatment strategies in cases of double-positive/-negative phenotypes than in single-positive tumors.

Patients and Methods We have examined a large and well-characterized series of primary invasive breast carcinoma (1,944 cases) with long-term clinical follow-up and hormone therapy data. Patients were stratified according to ER and PgR expression and the study was focused on the single-positive groups (ER–/PgR+ and ER+/PgR–), to assess their main features and evaluate any prognostic and predictive difference between them and compare them with the double-positive/-negative tumors.

Results ER+/PgR–tumors were found more frequently in elderly, postmenopausal women. The majority were grade 2 ductal/no specific type carcinomas. There was no difference between the two groups with regard to lymph node stage. Survival analyses showed no difference between the two groups in terms of disease-free interval and overall survival. However, when compared with the double-negative phenotype, ER+/PgR–showed an association with better outcome but no such survival advantage was detected in case of ER–/PgR+ tumors. In the group of patients with ER+ tumors who received adjuvant hormonal therapy, absence of PgR (ER+/PgR–) was an independent predictor of development of recurrence and shorter survival and, hence, poorer response to hormonal therapy.

Conclusion ER+/PgR–and ER–/PgR+ tumors are biologically and clinically distinct groups of breast cancer that may require different treatment strategies with ER–/PgR+ exhibiting more aggressive behavioral characteristics.

	INTRODUCTION

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Steroid hormone receptors (HRs) have been shown to be prognostic and, more importantly, a predictive marker for endocrine therapy in the clinical management of breast cancer. Therefore, it is critical to evaluate HR status when considering endocrine therapy. However, the contribution of each receptor, or their combinations, remains controversial. The nuclear receptor for estrogen functions as a transcription factor controlling estrogen-regulated genes. Progesterone receptor (PgR) is a ligand-activated nuclear transcription factor that mediates progesterone action. Its presence in breast tumors is used to predict functional estrogen receptor (ER) and, therefore, the likelihood of response to endocrine therapies and disease prognosis.¹ Some authors reported that lack of PgR expression in ER+ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to tamoxifen resistance,² and others have demonstrated that PgR is a stronger predictor of response to hormonal treatment than ER.^3-7

HR-negative tumors are more likely to be of higher grade and associated with a higher recurrence rate, decreased overall survival, and unresponsiveness to antiestrogens.^8-10 However, some types of invasive carcinoma that are typically HR negative such as adenoid cystic carcinoma and secretory carcinoma have an excellent prognosis with minimal regional recurrence.^11,12 Medullary carcinomas are also typically HR negative and have better prognosis.^13,14 All of these features point toward the heterogeneous nature of an HR-negative subgroup of invasive breast cancers and may indicate the presence of more aggressive subgroups that could benefit from a more aggressive therapeutic approach.

The significance of breast carcinomas (BCs) with a single HR-positive phenotype (ER+/PgR–or ER–/PgR+) is still poorly understood. Clinical data regarding metastatic and adjuvant treatment responsiveness suggest that tamoxifen is less effective in ER+/PR–tumors than in double-positive (ER+/PR+) tumors,^7,15,16 with only approximately 40% of the single-positive phenotype responding to hormonal manipulation.^17,18 Although some authors questioned the value of assessing PgR status in breast cancer,¹⁹ others have provided evidence for the importance of PgR assessment in breast cancer.^20,21 A recent clinical trial demonstrated that ER+/PR–and ER+/PR+ tumors respond similarly to an aromatase inhibitor that decreases systemic and/or local tissue estrogen levels.²² In addition, a study of 22 ER–/PgR+ breast tumors suggested that these tumors might have biologic characteristics somewhere in between ER+/PgR+ and ER+/PgR–.²³

In this study, we have examined a large and well-characterized series of breast cancer patients with long-term follow-up with immunophenotyping data for a wide range of proteins of known relevance in breast cancer to (1) identify and characterize those tumors with single-positive phenotype (ER+/PgR–and ER–/PgR+) and determine whether any inherent biologic differences exist between them and (2) observe their clinical behavior and study their relation to double-positive and double-negative tumors. Therefore, we can identify tumors that may require a more aggressive treatment strategy.

	PATIENTS AND METHODS

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This study investigated a consecutive series of 1,944 cases of primary operable invasive BC obtained from Nottingham Tenovus Primary Breast Carcinoma Series from patients presenting between 1986 and 1998. This is a well-characterized series of patients under the age of 70 years presenting with primary BC with a long-term follow-up that has been treated in a uniform way and previously used to study a wide range of biomarkers.^24-26 Patients' clinical history and tumor characteristics were assessed in a uniform fashion and maintained on a prospective basis. The median follow-up time of the whole series was 108 months (range, 1 to 233 months). Recurrence occurred in 335 cases (18.8%; 184 cases, 16.4%, were in the lymph node [LN]-negative and 150, 23%, in the LN-positive group) and distant metastases (DM) in 203 cases (11.4%), and 176 patients (9.9%) died from breast cancer during the period of follow-up (75 patients, 6.7%, were LN negative and 100 patients, 15.4%, were LN positive).

Patients' treatment was based on Nottingham Prognostic Index score derived from grade, size, and LN stage. Premenopausal patients in the moderate and poor prognostic groups were offered chemotherapy, and those ER+/node+ patients were offered hormone therapy (HT) and chemotherapy. Postmenopausal patients in the moderate and poor prognostic groups were offered tamoxifen if they were ER+; if ER–, they were given the option of chemotherapy if fit. Assessment of PgR was not carried out routinely and was not used in clinical decision making.²⁷ HT was administered to 503 patients (37%) and chemotherapy to 253 patients (18%). Ninety-eight percent of patients who received chemotherapy were treated with CMF (cyclophosphamide, methotrexate, fluorouracil), and the remaining (2%) were received an anthracycline-based regime (Tables A1 and A2, online only).

Breast cancer tissue microarrays (TMAs) were prepared as previously described.^28,29 TMA sections were immunohistochemically stained with a panel of antibodies using the standard streptavidin-biotin complex method as previously described (Table A3, online only).^24,25,30 Positive and negative controls for each marker were used according to the supplier's data sheet. Two cores were evaluated from each tumor and only staining of the invasive malignant cells was considered. Immunohistochemical scoring was performed in a blinded fashion. Assessment of staining was based on a semiquantitative approach. A modified histochemical score (H-score) was used.³¹ Negative expression of ER and PgR was defined as complete absence of staining of the malignant cells (< 1%).³²

Statistical analysis was performed using SPSS 13.0 statistical software (SPSS Inc, Chicago, IL). We examined the association between the single-positive phenotype and other clinicopathologic variables using ² test, ² test for trend, and Fisher's exact test as appropriate. The association with survival was analyzed initially by Kaplan-Meier plot and log-rank test, and also with Cox regression to adjust for other prognostic indicators. A P value less than .05 was considered significant. Overall survival (OS) was defined as the interval between the operation and death resulting from breast cancer, death being scored as an event, and patients who died as a result of other causes or were still alive were excluded at the time of last follow-up. Disease-free interval (DFI) was also calculated from the date of first operation, with first recurrences, local, regional, or distant, being scored as an event, and with exclusion of other patients at the time of last follow-up or death. Cutoff values for the different biomarkers included in this study were chosen before statistical analysis. Standard cutoffs were used for established prognostic factors and were the same as for previously published patient series (Table A3).^26,30

	RESULTS

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In the current study, 71% of tumors were positive for ER and 59% positive for PgR. Of the informative cases, 272 (15.6%) were ER+/PgR–, 60 cases (3.4%) showed an ER–/PgR+ phenotype, 963 (55.3%) showed double-positive phenotype, and 448 (25.7%) were negative for both ER and PgR. These figures were highly correlated with those obtained by the clinical testing at the time of diagnosis (P < .0001). In ER+/PgR–group, ER percentage ranged from 10% to 100% (median, 88%) and mean H-score was 147, whereas in ER–/PgR+, PgR percentage ranged from 7% to 100% (median, 67.6%) and mean of H-score was 123. Tables A4 and A5 (online only) show the distribution of ER and PgR scores in the whole series.

In ER+/PgR–disease, the majority of tumors (54%) were ductal carcinoma of no special type (duct/NST), and classical lobular carcinoma (ILC) type was found in 10.7%. One hundred three cases (45.4%) received HT, and only 15 cases received adjuvant chemotherapy. In ER–/PgR+ disease, duct/NST comprised the majority of tumors (62%) and only one case of ILC was identified. HT was administered to only 6 patients, whereas 18 patients received chemotherapy (Tables A1 and A2).

Relationship of the Two Single Receptor–Positive Groups to Other Prognostic Factors
The majority of patients in the ER+/PgR–group were older (median age, 58 years) than the ER–/PgR+ group (median age, 48 years; P < .001). Grade 3 tumors were more common in ER–/PgR+, whereas grade 2 tumors were more frequent in ER+/PgR–(P = .02). There was an association between ER–/PgR+ and positive expression of p53 (P = .006), basal cytokeratin (CK5/6 and/or CK14) expression (basal-like phenotype; P = .004), reduced expression of E-cadherin (P = .003), and negative expression of androgen (AR; P < .001) and c-erbB3 (² = 5.9, P = .01). There was no difference between the ER–/PgR+ and ER+/PgR+ phenotypes with regard to LN stage, site of DM, breast cancer survival, or expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2), FHIT protein, c-erbB4, p21 and BRCA1 (Table 1).

Compared with the double-negative phenotype (ER–/PgR–), the ER+/PgR–and ER–/PgR+ groups showed a more favorable prognosis with lower grade, lower mitotic counts, absence of definite vascular invasion (VI), negative expression of EGFR, p53, P-cadherin, basal CKs, neuroendocrine markers, positive MUC-1 and nuclear BRCA1 expression (P < .01). Furthermore, the ER+/PgR–group differed from the ER–/PgR+ in showing an association with variables of good prognosis (eg, smaller size, absence of recurrence and DM, positive expression of AR and FHIT protein, and negative c-erbB3 expression) compared with the double-negative tumors.

The effect of ER and PgR status was also assessed according to whether adjuvant HT was administered. However, these results should be interpreted as observational studies only because the decision to offer adjuvant HT was based on NPI score and ER status. In patients who did not receive HT, no difference was noticed between ER+/PgR–and ER–/PgR+ with respect to development of recurrence or DM. Only six patients with ER–/PgR+ tumors received HT, and therefore this group was not considered for analysis. Multivariate analysis of ER+ tumors including both groups (ER+/PgR+ and ER+/PgR–), LN stage, histologic grade, tumor size, VI, and patient age, showed that ER+/PgR–(absence of PgR in the ER+ tumors) was an independent predictor of development of recurrence and shorter survival. Moreover, in the LN-negative subgroup of these cases, absence of PgR (ER+/PgR–) was the only predictor of recurrence and shorter survival, whereas tumor size, grade, presence of VI, or patient age were not significant (Table 2).

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Relation among four different estrogen-receptor (ER)/progesterone-receptor (PgR) combination subgroups and overall survival in the whole series (log-rank = 76.1; P < .001) showing that both ER+/PgR–and ER–/PgR+ subgroups are located in the middle between double positive (best outcome) and double negative (worst outcome; Kaplan-Meier method and log-rank test).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Relation among four different estrogen-receptor (ER)/progesterone-receptor (PgR) combination subgroups and disease-free interval in the whole series (log-rank = 76.1; P < .001). It shows that ER+/PgR–subgroup is located in the middle between double positive (best outcome) and double negative (worst outcome), whereas ER–/PgR+ subgroup overlap with the double-negative subgroup.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Association between different estrogen-receptor (ER) and progesterone-receptor (PgR) subgroups with (A) overall survival and (B) disease-free interval in the group received hormonal therapy (tamoxifen).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Currently, routine clinical management of breast cancer relies on traditional prognostic factors, in addition to ER, PgR, and HER-2 status.^33,34 Evaluation of these biomarkers is most valuable in predicting response to targeted therapy for these proteins. For example, it has been reported that 75% to 85% of tumors with double-positive phenotype respond to hormonal manipulation, whereas less than 10% of those with double-negative phenotype respond.^17,18,35

HR-negative breast cancers are a heterogeneous group of breast cancers that are generally thought to be aggressive with poor prognosis and have reduced treatment strategies compared with tumors expressing HR. However, some tumors express one HR (ER or PgR; single HR positive), which can result in difficulties in deciding an appropriate treatment strategy. Most previous studies have shown that these single HR tumors (both ER+/PgR–and ER–/PgR+) are clinically and biologically distinct groups of breast cancer that differ from the more common double-positive tumors (ER+/PgR+).^{2,21,23,36-40} However, to our knowledge, a comprehensive evaluation of the biologic characteristics of both ER–/PgR+ and ER+/PgR–groups of breast cancer in relation to each other and to the double-negative (ER–/PgR–) tumors is lacking.

Despite the importance of establishing HR status of tumors and the widespread use of immunohistochemistry (IHC) for their assessment, standardization has not been achieved, and a wide variety of scoring systems have been used.^41-46 Moreover, universally accepted cutoff points for IHC positivity are still a matter of debate.^46-48 Some authors regard any demonstrable staining (> 0%) as a positive result,^46,49 whereas some use 10%,⁵⁰ or at least 20% nuclei staining as positive results.^30,46 In a previous study to evaluate HR status for predicting response to endocrine therapy, Yamashita et al³² reported that patients with even very low ( 1%) ER+ or PgR+ cells had better survival after relapse, and recommended using a low cutoff. Therefore, in the current study, we used the percentage of positive malignant cells, and the cutoff points for negative expression were less than 1%, which was virtually equal to absence of positive nuclear staining.

We have investigated in detail the biologic features of these two single-positive groups and their associations with other prognostic variables, patient outcome, and response to HT. In our series, ER+/PgR–and ER–/PgR+ tumors constituted 15.6% and 3.4% of the case series, respectively. These figures are consistent with the previously published series using ER and PgR IHC.^15,21,51 ER+/PgR–were seen more frequently in older, postmenopausal women with moderately differentiated tumors that were frequently positive for AR receptor. In contrast, the majority of ER–/PgR+ tumors occurred in younger premenopausal women with poorly differentiated tumors and were rarely of classical lobular type. These tumors were more frequently associated with biomarkers of poor prognosis such as positive p53 and basal cytokeratins and reduced E-cadherin expression. When both ER+/PgR–and ER–/PgR+ groups were compared with the double-negative (ER–/PgR–) tumors, only the ER+/PgR–phenotype showed positive association with most of the good prognostic variables and patient outcome in our series. These results suggest that ER+/PgR–and ER–/PgR+ are biologically and clinically distinct groups of breast cancer and that ER–/PgR+ group is a more aggressive phenotype than ER+/PgR–tumors.

When we stratified our cases according to HT, we did not find significant differences between the ER+/PgR–and ER–/PgR+ groups regarding response to this adjuvant treatment in the grade-, size-, and LN-matched cases. However, this finding could be explained by the following: (1) both groups possibly have similar response to HT or (2) the small number of cases in the ER–/PgR+ group that received hormonal treatment (n = 6) may not reflect the actual response of these tumors to this adjuvant therapy, and hence limits the value of this analysis. Although we were not able to demonstrate whether there is any difference between both groups with respect to adjuvant HT, when we compared ER+/PgR–tumors to the double-positive group, we found an association between ER+/PgR–and development of recurrence and shorter survival. These results showed that negative PgR expression in the ER+ tumors was an independent predictor of poorer outcome and hence emphasizes the role of PgR as a predictor of response to adjuvant tamoxifen therapy, particularly in the LN-negative subgroup.

Our results are consistent with previous studies of breast cancer that showed that ER+/PgR–tumors were more frequent in older patients^2,52 and associated with smaller size, lower grades, and better disease-free survival^23,40 but not with recurrence rate, metastases, or overall survival.²³ Keshgegian et al³⁷ have shown that ER–/PgR+ is associated with high recurrence rate similar to the recurrence rate of ER–/PgR–tumors. Our findings contrast with other studies that reported no significant association between ER–/PgR+ tumors and younger age,³⁸ or found no difference between ER+/PgR–and ER–/PgR+ in relation to protein expression features.²³ However, most of these previous studies examined smaller numbers of cases in each category,^4,23 or compared these tumors with ER+/PgR+ tumors alone.²

In conclusion, we have identified biologic and outcome differences between ER–/PgR+ and ER+/PgR–tumors, inferring that these be regarded as biologically and clinically distinct groups of breast cancer. The differences observed suggest that consideration be given to exploring the behavioral characteristics of these tumors with respect to treatment response in more detail. Although the response of both groups to HT was similar in our series, we believe that the limited number of adjuvant-treated patients in our series may underestimate the actual response of these tumors to HT. Further confirmatory studies in a more appropriate or clinical trial setting are recommended. We believe that assessment of PgR can provide important prognostic information and prediction of response to adjuvant HT in ER+ tumors.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Emad A. Rakha, Andrew H.S. Lee, Ian O. Ellis

Administrative support: Andrew R. Green, Emma Claire Paish, Desmond R. Powe, Julia Gee, John F.R. Robertson, Ian O. Ellis

Provision of study materials or patients: Emma Claire Paish, Desmond R. Powe, Julia Gee, John F.R. Robertson, Ian O. Ellis

Collection and assembly of data: Andrew R. Green, Ian O. Ellis

Data analysis and interpretation: Emad A. Rakha, Maysa E. El-Sayed, Julia Gee, Robert I. Nicholoson, Ian O. Ellis

Manuscript writing: Emad A. Rakha, Maysa E. El-Sayed, Andrew R. Green, Emma Claire Paish, Desmond R. Powe, Robert I. Nicholoson, Andrew H.S. Lee, John F.R. Robertson, Ian O. Ellis

	Appendix

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	NOTES

 
published online ahead of print at www.jco.org on September 17, 2007.

This research was approved by Nottingham Research Ethics Committee 2 under the title of "Development of a Molecular Genetic Classification of Breast Cancer."

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 24, 2007; accepted July 30, 2007.

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