Advertisement

Characterizing Clinicopathologic Features of Estrogen Receptor-Positive/Progesterone Receptor-Negative Breast Cancers

  • Fei Fei
    Affiliations
    Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249

    Present address: Department of Pathology and Laboratory Medicine, Stanford University School of Medicine, Stanford, CA 94305
    Search for articles by this author
  • Gene P. Siegal
    Affiliations
    Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249
    Search for articles by this author
  • Shi Wei
    Correspondence
    Address for correspondence: Shi Wei, Departmentof of Pathology & Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Mailstop 4049, Kansas City, KS 66160.
    Affiliations
    Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249

    Present address: Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine, Kansas City, Kansas, 66160
    Search for articles by this author

      Abstract

      Background

      While most estrogen receptor-positive (ER+) breast cancers express progesterone receptor (PR), a small subset of tumors exhibits an ER+/PR- phenotype despite the fact that PR is an ER-dependent gene product. Previous studies have shown that these tumors are generally associated with a worse clinical outcome when compared to the ER+/PR+ breast cancers, indicating that they are clinically and probably genetically different entities.

      Methods

      We characterized the clinicopathologic features of ER+/PR- tumors from the Surveillance, Epidemiology and End Results (SEER) database and the authors’ institutional cohort.

      Results

      ER+/PR- tumors, constituting 12% of all breast cancers in both cohorts, less frequently occurred in Caucasians, were more likely to be of a higher histologic grade and presented with a higher stage when compared to ER+/PR+ tumors. Conversely, ER+/PR- neoplasms were more frequently seen in Caucasians, less likely to be of a higher histologic grade and less frequently presented with an advanced clinical stage when compared to ER-/PR- tumors. Further, the ER+/PR- tumors were associated with a disease-specific survival intermediate to that between ER+/PR+ and ER-/PR- tumors. An ER H-score of ≥270 was associated with a significantly superior relapse-free survival in the ER+/PR- tumors, suggesting that a near-maximal ER expression is needed to compensate for the altered ER signaling in these tumors. Pathologic stage and HER2 status were independent prognostic factors in the ER+/PR- tumors. These findings may provide additional insights in directing clinical decision making for individualized systemic therapy in the pursuit of precision medicine.

      Keywords

      Introduction

      Breast cancer is the most common cancer in women globally, with over 2 million cases diagnosed annually, and is also the most frequent cause of cancer deaths in most regions of the world.
      • Ferlay J.
      • Colombet M.
      • Soerjomataram I.
      • et al.
      Cancer statistics for the year 2020: An overview.
      In the United States, breast cancer accounts for 31% of all female cancers, with a continued slowly increased incidence rate up by 0.5% annually, and an estimated 287,850 new cases and 43,250 deaths in 2022, respectively.
      • Siegel R.L.
      • Miller K.D.
      • Fuchs H.E.
      • Jemal A.
      Cancer statistics, 2022. CA.
      Estrogen receptor (ER) signaling is essential for normal mammary gland development, and drives the majority of breast cancers as approximately 78% of invasive breast cancers are ER+, and this rate is projected to increase 0.75% per year.
      • Anderson W.F.
      • Katki H.A.
      • Rosenberg P.S.
      Incidence of breast cancer in the United States: current and future trends.
      The independent predictive and prognostic values of ER have been well established as ER-targeted endocrine therapies have significantly improved the clinical outcomes in patients with these cancers, and the therapeutic effects are correlated with the expression levels of the ER protein in tumor cells.
      • Burstein H.J.
      • Temin S.
      • Anderson H.
      • et al.
      Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.
      • Bouchard-Fortier A.
      • Provencher L.
      • Blanchette C.
      • Diorio C.
      Prognostic and predictive value of low estrogen receptor expression in breast cancer.
      • Early Breast Cancer Trialists' Collaborative G.
      • Davies C.
      • Godwin J.
      • et al.
      Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
      Progesterone receptor (PR) is an ER-dependent gene product, thus is theoretically a surrogate marker for a functional ER pathway.
      • Horwitz K.B.
      • McGuire W.L.
      Predicting response to endocrine therapy in human breast cancer: a hypothesis.
      However, ER+ breast cancers are not always PR+, and 10-15% of tumors reportedly exhibit an ER+/PR- phenotype.
      • Dauphine C.
      • Moazzez A.
      • Neal J.C.
      • Chlebowski R.T.
      • Ozao-Choy J.
      Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
      ,
      • Lv M.
      • Mao Y.
      • Song Y.
      • et al.
      Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
      There have been controversies on its independent predictive and prognostic values. Some studies have demonstrated that PR is independently associated with disease-free and overall survivals in the adjuvant setting and in patients with ER+ metastatic disease,
      • Bardou V.J.
      • Arpino G.
      • Elledge R.M.
      • Osborne C.K.
      • Clark G.M.
      Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.
      • Liu S.
      • Chia S.K.
      • Mehl E.
      • et al.
      Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients.
      • MacGrogan G.
      • de Mascarel I.
      • Sierankowski G.
      • et al.
      Time for reappraisal of progesterone-receptor testing in breast cancer management.
      while others have argued that PR is not a strong factor for predicting endocrine response nor for survival outcome, thus adding neither diagnostic information nor having a therapeutic impact.
      • Olivotto I.A.
      • Truong P.T.
      • Speers C.H.
      • et al.
      Time to stop progesterone receptor testing in breast cancer management.
      • Viale G.
      • Regan M.M.
      • Maiorano E.
      • et al.
      Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98.
      • Mackey J.R.
      Can quantifying hormone receptor levels guide the choice of adjuvant endocrine therapy for breast cancer?.
      Given that the ER+/PR- phenotype suggests a blockade of the functional ER signaling, it is not surprising that these tumors show a more aggressive biological behavior than that of ER+/PR+ breast cancers.
      • Dauphine C.
      • Moazzez A.
      • Neal J.C.
      • Chlebowski R.T.
      • Ozao-Choy J.
      Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
      • Lv M.
      • Mao Y.
      • Song Y.
      • et al.
      Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
      • Bardou V.J.
      • Arpino G.
      • Elledge R.M.
      • Osborne C.K.
      • Clark G.M.
      Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.
      ,
      • Arpino G.
      • Weiss H.
      • Lee A.V.
      • et al.
      Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.
      Thus, tumors with the two different phenotypes are clinically and probably genetically different entities.
      While the clinical practice decisions in endocrine therapy are primarily based on the ER status of the tumors, different strategies may be required for patients with ER+/PR- breast cancer to ensure optimal treatment and maximum benefits, as endocrine therapies have been shown to be less effective for tumors with this phenotype when compared to the ER+/PR+ tumors.
      • Dauphine C.
      • Moazzez A.
      • Neal J.C.
      • Chlebowski R.T.
      • Ozao-Choy J.
      Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
      • Lv M.
      • Mao Y.
      • Song Y.
      • et al.
      Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
      • Bardou V.J.
      • Arpino G.
      • Elledge R.M.
      • Osborne C.K.
      • Clark G.M.
      Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.
      ,
      • Li Y.
      • Yang D.
      • Yin X.
      • et al.
      Clinicopathological Characteristics and Breast Cancer-Specific Survival of Patients With Single Hormone Receptor-Positive Breast Cancer.
      ,
      • Bae S.Y.
      • Kim S.
      • Lee J.H.
      • et al.
      Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer.
      Nonetheless, while the clinical significance of evaluating PR expression remains controversial, it is generally accepted that PR status may further stratify ER-positive tumors into different prognostic categories, although the thresholds of PR for this purpose have not been well studied.
      In this study, we sought to further characterize the clinicopathologic features and prognostic outcomes of ER+/PR- breast cancers using the Surveillance, Epidemiology, and End Results (SEER) database and the authors’ institutional cohort. Further, the levels of ER expression in ER+/PR- tumors on the survival outcome was also studied.

      Materials and Methods

      This study was performed after the approval of the institutional review board of the University of Alabama at Birmingham. A search to identify breast cancer patients was conducted in the SEER database which retrospectively collects data from population-based cancer registries covering approximately 34.6% of the US population. SEER program statistical analysis software packages were used to identify the patients. The patients were included in the study when meeting the following criteria: female older than 18 years age and diagnosed with invasive breast cancer between 2010 and 2015. A search of the tumor registry at the authors’ institution was also performed to identify female patients diagnosed with invasive breast cancer between 1998 and 2018. The patients’ demographic information (age at diagnosis and race), the pathologic characteristics of the primary tumor (histologic type and grade, TNM status, ER, PR and HER2 status), and survival outcomes were collected from both cohorts. All patients included in the authors’ cohort received standard of care treatment at the time of diagnosis. The median follow-up time was 53 months and 1881 days (63 months) for the SEER and authors’ cohorts, respectively.
      Of the 627 ER+/PR- breast cancers identified in the authors’ cohort, 140 had HER2 amplification and/or overexpression, and 67 patients received HER2-targeted therapy at the authors’ institution. Most patients who did not receive HER2-directed therapy were diagnosed early in the study period (prior to 2010).
      Hormonal receptor (ER and PR) and HER2 overexpression or gene amplification status were assessed by following the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) Guideline Recommendations as previously described.
      • Fei F.
      • Siegal G.P.
      • Wei S.
      Characterization of estrogen receptor-low-positive breast cancer.
      While the cutoff value for ER and PR positivity at the authors’ institution was 10% prior to the 2010 ASCO/CAP Guideline Recommendations and revised to 1% thereafter, the cases with an 1-10% ER and PR expression prior to 2010 were re-reviewed and regarded as ER+ and/or PR+ in the analyses in order to maintain the same cutoff values in the study period. In addition, semiquantitative analysis of ER expression in ER+PR- tumors was performed using an H-score as calculated by multiplying the intensity (0, 1+, 2+, and 3+) by the percentage of tumor cell nuclei stained, giving a range of 0 to 300, as previously described.
      • Shen T.
      • Brandwein-Gensler M.
      • Hameed O.
      • Siegal G.P.
      • Wei S.
      Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.
      The categorical data were evaluated by Chi-square testing, while continuous data were analyzed by an independent t-test. Distant recurrence-free survival (RFS; from the date of diagnosis to the date of distant recurrence) and disease-specific survival (DSS; from the date of diagnosis to the date of death from the disease) were determined by Kaplan-Meier analysis. Patients who survived or were lost to follow-up were considered as censored data in the analyses. The Cox proportional hazards regression model was utilized to identify significant factors for survival. A P value of less than .05 was considered statistically significant. All data were analyzed using IBM SPSS Statistics (Version 26) predictive analytics software.

      Results

      Clinicopathologic characteristics of breast cancers stratified by ER and PR status

      There are a total of 36279 patients from the SEER database meeting the inclusion criteria and thus were included in the study for further analyses. Most of the patients were Caucasians (28431; 78.4%), followed by African Americans (4375; 12.1%) and others. The ER+/PR+, ER+/PR-, ER-/PR+ and ER-PR- cases were 26006 (71.68%), 4172 (11.5%), 347 (0.96%) and 5754 (15.86%), respectively (Table 1). Approximately 14% of ER+ tumors (4127/30178) had an ER+/PR- phenotype, an incidence rate similar to that observed in the National Cancer Database.
      • Dauphine C.
      • Moazzez A.
      • Neal J.C.
      • Chlebowski R.T.
      • Ozao-Choy J.
      Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
      The ER-/PR+ tumors were not further analyzed given their low incidence rate and beyond the scope of the study.
      Table 1Clinicopathologic features of the patients from the SEER cohort.
      Clinicopathologic factorPhenotype (N)P value
      ER+/PR+ (26006)ER+/PR- (4172)ER-/PR+ (347)ER-/PR- (5754)ER+/PR- vs. ER+/PR+ER+/PR- vs. ER-/PR-
      Age (median) (range)
      61 (18-85+)62 (20-85+)57 (20-85+)58 (22-85+)< 0.0001< 0.0001
      Race
       Caucasian2089331952594084< 0.0001< 0.0001
       African American2659588481080
       Other226536037556
       Unknown18929334
      Histologic type
       Ductal19572322931252830.798< 0.0001
       Lobular344857910122
       Ductal & lobular24622408113
       Other52412717236
      Histologic grade
       I630758210114< 0.0001< 0.0001
       II135311722771202
       III616818682604438
      HER2 status
       Positive311611751282121< 0.0001< 0.0001
       Negative2289029972193633
      Mean tumor size (mm) (range)
      58.7 (1-999)83.4 (1-999)136.6 (1-999)121.7 (1-999)< 0.0001< 0.0001
      Pathologic nodal stage
       N01531121951592708< 0.0001< 0.0001
       N1720712351231870
       N2210140132591
       N3138734133585
      Clinical stage
       I159811408811517< 0.0001< 0.0001
       II553811961051402
       III253210781071817
       IV195549054864
      When compared to ER+/PR+ breast cancers, the patients with ER+/PR- tumors were significantly older and less frequently Caucasians (80.3% vs. 76.6%). Further, the ER+PR- tumors were more likely to be HER2-positive (28.2% vs 12.0%), of higher histologic grades (Grades II & III 86.0% vs. 75.7%), and to present with a higher pathologic tumor stage (mean size 83.4 vs. 58.7 mm) and nodal stage (N1/2/3 47.4% vs. 41.1%). Thus, it is not surprising that ER+PR- tumors more frequently presented with advanced clinical stages (stage II/III/IV 66.3% vs. 38.5%).
      We next compared ER+/PR- and ER-PR- tumors. To that end, the patients with ER+/PR- tumors were significantly older and more frequently Caucasians (76.6% vs. 71.0%). The ER-PR- tumors were more likely to be HER2-positive (36.9% vs. 28.2%), of higher histologic grades (Grades II and III 98.0% vs. 86.0%), and to present with a higher pathologic tumor stage (mean size 121.7 mm vs. 83.4 mm) and nodal stage (N1/2/3 52.9% vs. 47.4%). Again, these tumors were more likely to present with advanced clinical stages (Stage II/III/IV 71.0% vs. 66.3%).
      The clinicopathologic features of the 5309 patients from the authors’ institutional cohort are summarized in Table 2, of which the ER+/PR+, ER+/PR-, ER-/PR+ and ER-/PR- tumors were 3582 (67.47%), 627 (11.81%), 144 (2.71%) and 956 (18%), respectively. Approximately 15% of ER+ tumors (627/4209) had an ER+/PR- phenotype. Interestingly, the proportions of ER-/PR+ and ER-/PR- tumors in our cohort were significantly higher than those of the SEER database (both P < 0.0001), likely reflecting the racial and ethnic differences in the Southern United States.
      • Shen T.
      • Brandwein-Gensler M.
      • Hameed O.
      • Siegal G.P.
      • Wei S.
      Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.
      Table 2Clinicopathologic features of the patients from the authors’ cohort.
      Clinicopathologic factorPhenotype (N)P value
      ER+/PR+ (3582)ER+/PR- (627)ER-/PR+ (144)ER-/PR- (956)ER+/PR- vs. ER+/PR+ER+/PR- vs. ER-/PR-
      Age (median) (range)
      58 (18-99)58 (20-98)54.5 (24-93)54 (22-95)0.743< 0.0001
      Race
       Caucasian286645886620< 0.0001< 0.0001
       African American66915856324
       Other4111211
       Unknown6001
      Histologic type
       Ductal26024661218560.921< 0.0001
       Lobular385681580
       Ductal & lobular56579716
       Other301414
      Histologic grade
       I919101313< 0.0001< 0.0001
       II183929031167
       III799230110776
       Unknown25600
      HER2 status
       Positive43314138243< 0.0001< 0.0001
       Negative3083465103701
       Equivocal561637
       Unknown10505
      Mean tumor size (mm) (range)
      22 (1-170)24.4 (1-275)34.5 (3-150)30.5 (1-205)0.002< 0.0001
      Pathologic nodal stage
       N0232036979551< 0.0001< 0.0001
       N181214943228
       N218954762
       N3100221044
       Unknown16133571
      Clinical stage
       I250824143293< 0.0001< 0.0001
       II71723350317
       III15910540232
       IV1894811111
       Unknown9003
      Analyses of the patients in this latter cohort revealed largely similar observations. When compared to ER+PR+ tumors, the patients with ER+/PR- tumors were less frequently Caucasians (82.8% vs. 73.0%), while no significant difference for median age between the two groups was identified. Once again, the ER+PR- tumors were more likely to be HER2-positive (22.5% vs. 12.1%), of higher histologic grades (Grades II & III 82.9% vs. 73.6%), and to present with a higher pathologic tumor stage (mean size 24.4 mm vs. 20 mm) and nodal stage (N1/2/3 35.9% vs. 30.7%). Accordingly, these tumors were more likely to present wih advanced clinical stages (Stage II/III/IV 61.6% vs. 30.0%, P < 0.0001). Comparing to those with ER-/PR- tumors, the patients with ER+PR- carcinomas were significantly older at the time of presentation and more frequently Caucasians (73.0% vs. 64.9%). Once again, The ER-PR- tumors were more likely to be HER2-positive (25.4% vs. 22.5%), of higher histologic grades (Grade II/III 98.6% vs. 82.9%), and to present with a higher pathologic tumor stage (mean size 30.5 mm vs. 24.4 mm) but of similar nodal stage (N1/2/3 34.9% vs. 35.9%, P = 0.9), and thus expectedly more advanced clinical stages (Stage II/III/IV 69.4% vs. 61.6%).

      Clinical outcomes stratified by ER/PR profiles

      We next turned to analyze the clinical outcomes of the patients stratified by ER/PR profiles of their tumors. To that end, a significantly inferior DSS was seen in patients with ER+/PR- tumors when compared to those with ER+/PR+ tumors [hazard ratio (HR) 2.732, 95% confidence interval (CI) (2.471 - 3.022), P<0.0001] in the SEER cohort. Further, the former was associated with a significantly prolonged DSS when compared to those with ER-/PR- tumors [HR 0.6331, 95% CI (0.5845 - 0.6857), P<0.0001], in keeping with the previous studies.
      • Dauphine C.
      • Moazzez A.
      • Neal J.C.
      • Chlebowski R.T.
      • Ozao-Choy J.
      Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
      • Lv M.
      • Mao Y.
      • Song Y.
      • et al.
      Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
      • Bardou V.J.
      • Arpino G.
      • Elledge R.M.
      • Osborne C.K.
      • Clark G.M.
      Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.
      ,
      • Li Y.
      • Yang D.
      • Yin X.
      • et al.
      Clinicopathological Characteristics and Breast Cancer-Specific Survival of Patients With Single Hormone Receptor-Positive Breast Cancer.
      ,
      • Bae S.Y.
      • Kim S.
      • Lee J.H.
      • et al.
      Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer.
      ,
      • Shen T.
      • Brandwein-Gensler M.
      • Hameed O.
      • Siegal G.P.
      • Wei S.
      Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.
      Similar observations were obtained in the authors’ institutional cohort [ER+/PR- vs. ER+/PR+: HR 2.917, 95% CI (2.077 - 4.098), P<0.0001; ER+/PR- vs. ER-/PR-: HR 0.4311, 95% CI (0.3411 - 0.5447), P<0.0001] (Figure 1).
      Figure 1
      Figure 1Disease-specific survival of breast cancers stratified by ER and PR status in the SEER database (A) and the authors’ cohort (B).

      Factors associated with survival outcomes for ER+/PR- breast cancers

      Univariate and multivariate analyses were performed to identify significant prognostic factors for DSS in the subset of patients with ER+/PR- tumors. To that end, an older age, being African American, high histologic grade, a negative HER2 status, higher pathologic tumor and nodal stages were independently associated with a worse DSS in the SEER cohort (Table 3). Similar observations were obtained in the authors’ institutional cohort, except for the age and race of the patients, probably attributed to their relatively smaller sample size. Interestingly, a positive HER2 status was a worse prognosticator in the univariate analysis but not an independent factor after controlling for other variables in this cohort (Table 4).
      Table 3Univariate and multivariate analyses for disease specific survival in the patients with ER+/PR- breast cancer from the SEER cohort.
      Clinicopathologic factorUnivariate analysisMultivariate analysis
      HR (95% CI)P valueHR (95% CI)P value
      Age (> 60 vs ≤ 60)1.129 (0.986 - 1.293)0.0791.445(1.255 - 1.664)< 0.0001
      Race (African American vs. Caucasian)1.467 (1.231 - 1.748)< 0.00011.282 (1.073 - 1.5320.006
      Histologic type (lobular vs. ductal)0.881 (0.717 - 1.082)0.2280.926 (0.743 - 1.155)0.496
      Histologic grade (III vs. I/II)2.141 (1.863 - 2.461)< 0.00011.664 (1.430 - 1.935)< 0.0001
      Tumor size (2.0-5.0 cm vs. ≤ 2.0 cm)2.660 (2.191 - 3.229)< 0.00012.014 (1.649 - 2.460)< 0.0001
      Tumor size (>5.0 cm vs. ≤ 2.0 cm)7.068 (5.871 - 8.510)< 0.00014.704 (3.860 - 5.733)< 0.0001
      HER2 (positive vs. negative)0.934 (0.801 - 1.088)0.3810.764 (0.653 - 0.894)0.001
      Lymph node status (positive vs. negative)3.497 (3.001 - 4.074)< 0.00011.445 (1.255 - 1.664)< 0.0001
      Abbreviations: HR, hazard ratio; CI, confidence interval
      Table 4Univariate and multivariate analyses for disease specific survival in the patients with ER+/PR- breast cancer from the authors’ cohort.
      Clinicopathologic factorUnivariate analysisMultivariate analysis
      HR (95% CI)P valueHR (95% CI)P value
      Age (> 60 vs ≤ 60)0.389 (0.171 - 0.885)0.0240.515 (0.222 - 1.192)0.121
      Race (African American vs. Caucasian)0.942 (0.445 - 1.993)0.8750.567 (0.260 - 1.241)0.156
      Histologic type (lobular vs. ductal)0.694 (0.213 - 2.257)0.5431.153 (0.311 - 4.271)0.831
      Histologic grade (III vs. I/II)3.221 (1.655 - 6.270)0.0012.538 (1.200 - 5.368)0.015
      Tumor size (2.0-5.0 cm vs. ≤ 2.0 cm)3.755 (1.830 - 7.705)< 0.00012.647 (1.262 - 5.551)0.010
      Tumor size (>5.0 cm vs. ≤ 2.0 cm)4.197 (1.457 - 12.084)0.0083.111 (1.041 - 9.297)0.042
      HER2 (positive vs. negative)2.004 (1.051 - 3.821)0.0351.322 (0.663 - 2.636)0.427
      Lymph node status (positive vs. negative)5.141 (2.504 - 10.556)< 0.00013.995 (1.930 - 8.267)< 0.0001
      Abbreviations: HR, hazard ratio; CI, confidence interval
      Given that the effects of ER-targeted therapies are correlated with the ER levels in the tumor cells of ER+ breast cancers,

      Burstein H.J., Temin S., Anderson H., et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. 2014;32:2255.

      ,

      Davies C., Godwin J., Gray R., et al. Early Breast Cancer Trialists’ Collaborative G. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. 2011;378:771-784.

      we next explored if the level of ER expression was prognostically significant in the subset of tumors with an ER+PR- phenotype. Logistic regression and survival analyses for RFS and DSS were performed in the authors’ institutional cohort using consecutive cutoffs of ER H-scores with increment by 10. To that end, an ER H-score of 270 yielded an optimal cutoff with a significant difference for RFS [HR1.737, 95% CI (1.083 - 2.787), P=0.0221] and a marginal significance for DSS [HR 1.701, 95% CI (0.9586 - 3.017), P=0.0694] (Figure 2). Interestingly, the patients with a tumor showing an ER H-score < 270 were significantly younger. These tumors were more frequently HER2-positive (24.3% vs. 14.3%; P=0.015), of higher histologic grades (Grade II/III 85% vs. 73.5%; P<0.0001), presented with both higher pathologic tumor and nodal stages (P=0.008 and 0.002, respectively), and thus were at more advanced clinical stages (Stage II/III/IV 62.3% vs. 40.7%; P=0.001), as illustrated in Table 5.
      Figure 2
      Figure 2Relapse-free survival (A) and disease-specific survival (B) of ER+/PR- breast cancers stratified by ER H-score.
      Table 5Clinicopathologic features of ER+PR- breast cancers stratified by ER H-score.
      Clinicopathologic factorER H-score (N)P value
      ER < 270 (300)ER ≥ 270 (230)
      Age (median) (range)
      57.4 (20 - 98)62.0 (28-96)< 0.0001
      Race
       Caucasian2071730.325
       African American7954
       Other143
      Histologic type
       Ductal2281650.152
       Lobular6563
       Other72
      Histologic grade
       I3458< 0.0001
       II128122
       III12747
       Unknown113
      HER2 status
       Positive73330.015
       Negative200173
       Equivocal67
       Unknown2117
      Mean tumor size (mm) (range)
      26.5 (0.4 - 275)21.1 (1 - 100)0.008
      Pathologic nodal stage
       N01741600.002
       N17637
       N22415
       N3412
       Unknown226
      Clinical stage
       I1051190.001
       II12976
       III3427
       IV247
       Unknown81
      We further included the ER H-score in the survival analyses to ascertain if the level of ER expression is of prognostic significance in ER+/PR- tumors. To that end, the level of ER expression was only significantly correlated with RFS, but not DSS, whereas patient age, histologic grade, HER2 status, and pathologic tumor and nodal stages were associated with both RFS and DSS by univariate analyses (Table 6). In multivariate analysis, tumor size and nodal status were independently correlated with both RFS and DSS, while the significance of HER2 status was only seen in DSS (Table 7).
      Table 6Univariate analysis for survival outcomes in the patients with ER+/PR- breast cancer.
      Clinicopathologic factorRelapse-free survivalDisease-specific survival
      HR (95% CI)P valueHR (95% CI)P value
      ER H-score (≥ 270 vs. < 270)0.562 (0.341 - 0.926)0.0240.592 (0.322 - 1.086)0.090
      Age (> 60 vs ≤ 60)0.598 (0.363 - 0.985)0.0440.419 (0.212 - 0.827)0.012
      Race (African American vs. Caucasian)0.789 (0.469 - 1.327)0.3710.606 (0.326 - 1.126)0.113
      Histologic type (lobular vs. ductal)1.007 (0.574 - 1.765)0.9810.745 (0.347 - 1.602)0.451
      Histologic grade (III vs. I/II)2.298 (1.412 - 3.742)0.0012.744 (1.512 - 4.980)0.001
      Tumor size (2.0-5.0 cm vs. ≤ 2.0 cm)2.217 (1.161 - 4.234)0.0162.765 (1.283 - 5.961)0.009
      Tumor size (>5.0 cm vs. ≤ 2.0 cm)5.781 (2.806 -11.911)< 0.00015.443 (2.188 - 13.538)< 0.0001
      HER2 (positive vs. negative)1.679 (1.002 - 2.813)0.0492.808 (1.546 - 5.101)0.001
      Lymph node status (positive vs. negative)7.168 (3.744 - 13.724)< 0.00014.628 (2.255 - 9.500)< 0.0001
      Abbreviations: HR, hazard ratio; CI, confidence interval
      Table 7Multivariant analysis for survival outcomes in the patients with ER+/PR- breast cancer.
      Clinicopathologic factorRelapse-free survivalDisease-specific survival
      HR (95% CI)P valueHR (95% CI)P value
      ER H-score (≥ 270 vs. < 270)1.013 (0.580 - 1.769)0.9631.290 (0.660 - 2.523)0.456
      Age (> 60 vs ≤ 60)0.754 (0.437 - 1.298)0.3080.583 (0.278 - 1.225)0.154
      Race (African American vs. Caucasian)1.325 (0.754 - 2.329)0.3280.926 (0.481 - 1.781)0.818
      Histologic type (lobular vs. ductal)1.098 (0.590 - 2.044)0.7670.984 (0.418 - 2.319)0.971
      Histologic grade (III vs. I/II)1.679 (0.957 - 2.943)0.0711.772 (0.919 - 3.417)0.088
      Tumor size (2.0-5.0 cm vs. ≤ 2.0 cm)1.582 (0.803 - 3.116)0.1852.032 (0.899 - 4.594)0.088
      Tumor size (>5.0 cm vs. ≤ 2.0 cm)2.886 (1.299 -6.412)0.0093.233 (1.154 - 9.054)0.026
      HER2 (positive vs. negative)1.203 (0.701 - 2.066)0.5032.056 (1.109 - 3.812)0.022
      Lymph node status (positive vs. negative)5.778 (2.951 - 11.311)< 0.00013.392 (1.587 - 7.249)0.002
      Abbreviations: HR, hazard ratio; CI, confidence interval

      Discussion

      In this study, we found that approximately 12% of breast cancers were ER+/PR-. This is in keeping with the 10-15% reported incidence range of this subtype in previous population-based studies.
      • Dauphine C.
      • Moazzez A.
      • Neal J.C.
      • Chlebowski R.T.
      • Ozao-Choy J.
      Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
      ,
      • Lv M.
      • Mao Y.
      • Song Y.
      • et al.
      Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
      Furthermore, up to 15% of ER+ tumors had an ER+/PR- phenotype.
      ER+/PR- breast cancers demonstrate different clinicopathologic features when compared to other subtypes. Reflecting the racial and ethnic differences, there were significantly more African American patients having an ER+/PR- tumor when compared to those with an ER+/PR+ tumor, while there were significantly more Caucasians with an ER+/PR- tumor than those with an ER-/PR- tumor in both cohorts. The patients with ER+/PR- tumors were significantly older than those with ER+/PR+ and ER-/PR- tumors in the SEER cohort, consistent with an analysis using an early (1990-2012) SEER database.
      • Lv M.
      • Mao Y.
      • Song Y.
      • et al.
      Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
      Similarly, a higher proportion of elderly patients (older than 70 years) were found to have ER+PR− tumors than the patients in the other age groups in a study using the National Cancer Database.
      • Dauphine C.
      • Moazzez A.
      • Neal J.C.
      • Chlebowski R.T.
      • Ozao-Choy J.
      Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
      Moreover, the significant association of younger age and the ER-/PR- subtype has been observed in most published cohorts.
      • Bauer K.R.
      • Brown M.
      • Cress R.D.
      • Parise C.A.
      • Caggiano V.
      Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry.
      • Keegan T.H.
      • DeRouen M.C.
      • Press D.J.
      • Kurian A.W.
      • Clarke C.A.
      Occurrence of breast cancer subtypes in adolescent and young adult women.
      • Kumar P.
      • Aggarwal R.
      An overview of triple-negative breast cancer.
      The discrepancies in the survival outcomes in the age and race between the SEER database and the authors’ cohort are of further interest. It is noteworthy that in the patients with an ER+/PR- tumor, the median age in the SEER database is significantly older than that of our cohort (62 vs. 58 years), and the proportion of African Americans is significantly higher in our database (25.6% vs.15.5%, P<0.0001). These findings are likely a reflection of larger African American patient population in the southern states from which our cohort derived. The relationship between age and racial disparity may also reflect the intrinsic nature of the tumor subtypes and thus is worth further investigation.
      • Keegan T.H.
      • DeRouen M.C.
      • Press D.J.
      • Kurian A.W.
      • Clarke C.A.
      Occurrence of breast cancer subtypes in adolescent and young adult women.
      ,
      • Parise C.A.
      • Caggiano V.
      Risk factors associated with the triple-negative breast cancer subtype within four race/ethnicities.
      When compared to the ER+/PR+ tumors, the ER+/PR- subtype was significantly associated with more frequent HER2 positivity and higher histologic grades, thus more likely to be of Luminal B intrinsic subtype. Of note, the frequency of Luminal B tumors in African American patients is reportedly higher when compared to that in Caucasians.
      • Carey L.A.
      • Perou C.M.
      • Livasy C.A.
      • et al.
      Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study.
      ,
      • Benefield H.C.
      • Reeder-Hayes K.E.
      • Nichols H.B.
      • et al.
      Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features.
      Reversed observations were found when comparing the ER+/PR- and ER-/PR- tumors in both cohorts, the latter of which are predominantly of HER2-enriched and basal-like subtypes. As these are largely reproducible findings in most large cohort studies, it is not surprising that the clinical outcomes of the ER+/PR- tumors are intermediate between the ER+/PR+ and ER-/PR- subtypes, even though the HER2 status was not available in early (prior to 2010) national databases. It is noteworthy that a recent Korean cohort study of 6980 patients demonstrated comparable prognostic outcomes between ER+/PR-/HER2- and ER-/PR-/HER2- (triple-negative) breast cancers.
      • Bae S.Y.
      • Kim S.
      • Lee J.H.
      • et al.
      Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer.
      This is in contrast to our recent cohort consisting of exclusively Caucasian and African American patients, in which ER+/PR-/HER2- tumors, even when limited to those of Grade III and ER-low (H-score ≤ 10), were associated with a significantly better RFS when compared to triple-negative breast cancers.
      • Fei F.
      • Siegal G.P.
      • Wei S.
      Characterization of estrogen receptor-low-positive breast cancer.
      Thus, similar large-scaled studies in patients with different genetic backgrounds may be needed to draw further conclusions.
      The biology of PR loss in breast cancer is of further interest given that PR is primarily regulated by ER at the transcriptional level. The predictive value of PR has long been attributed to its ER-dependent activity; therefore, the absence of PR has been thought to be a hallmark for a nonfunctional ER and thus resistance to endocrine therapy. However, previous studies have shown that ER+/PR- breast cancers may be specifically resistant to selective ER modulator (SERM) therapy (i.e., tamoxifen), but less resistant to aromatase inhibitors, agents blocking the synthesis of estrogen, thus conflicting with the nonfunctional ER theory.
      • Cui X.
      • Schiff R.
      • Arpino G.
      • Osborne C.K.
      • Lee A.V.
      Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy.
      Increased growth factor signaling (i.e., HER2 and other members of the epidermal growth factor receptor family) has been found to be associated both with the ER+/PR- phenotype and with SERM resistance functions.
      • Arpino G.
      • Weiss H.
      • Lee A.V.
      • et al.
      Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.
      ,
      • Tovey S.
      • Dunne B.
      • Witton C.J.
      • Forsyth A.
      • Cooke T.G.
      • Bartlett J.M.
      Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?.
      The significant association of HER2 overexpression/amplification with the ER+/PR- phenotype, when compared to ER+/PR+ tumors, was also found in the current study. It has been postulated that the enhanced cross talk between ER and growth factor signaling pathways may downregulate PR expression while activating other ER functions.
      • Arpino G.
      • Weiss H.
      • Lee A.V.
      • et al.
      Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.
      Moreover, differential sensitivity to endocrine agents has been linked to bypassing resistance pathways. An interesting finding in this regard is that tamoxifen and fulvestrant (a selective ER degrader) up-regulate ERα expression, while aromatase inhibitors induce ERβ expression, which may contribute to the superior antiestrogen effect of the latter.
      • Smollich M.
      • Götte M.
      • Fischgräbe J.
      • Radke I.
      • Kiesel L.
      • Wülfing P.
      Differential effects of aromatase inhibitors and antiestrogens on estrogen receptor expression in breast cancer cells.
      Nonetheless, ER+/PR- breast cancers may rely on more than one mechanism for its aggressiveness and resistance to endocrine therapies, thus further understanding the biology driving its oncogenic process is crucial for the development of better therapeutic strategies.
      We have performed further analyses to identify significant prognostic factors in the subset of patients with ER+/PR- tumors. In the previous analysis using the early (1990-2012) SEER database, similar observations were obtained on the significance of age and HER2 status, although the HER2 information was missing during most of the data collection period (prior to 2010).
      • Lv M.
      • Mao Y.
      • Song Y.
      • et al.
      Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
      While race/ethnicity and tumor grade were also significant prognostic factors in the early cohort, non-Caucasian/non-African American was used as the reference race, and Grade IV was used as reference grade which is nonstandard and not utilized in modern pathology practice.
      • Elston C.W.
      • Ellis I.O.
      Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up.
      ,
      • Rakha E.A.
      • Reis-Filho J.S.
      • Baehner F.
      • et al.
      Breast cancer prognostic classification in the molecular era: the role of histological grade.
      It has been well established that the prognostic outcomes of all ER+ breast cancers are significantly correlated with the expression levels of the ER protein in tumor cells.
      • Fei F.
      • Siegal G.P.
      • Wei S.
      Characterization of estrogen receptor-low-positive breast cancer.
      ,
      • Bartlett J.M.
      • Brookes C.L.
      • Robson T.
      • et al.
      Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial.
      • Morgan D.A.
      • Refalo N.A.
      • Cheung K.L.
      Strength of ER-positivity in relation to survival in ER-positive breast cancer treated by adjuvant tamoxifen as sole systemic therapy.
      • Ma H.
      • Lu Y.
      • Marchbanks P.A.
      • et al.
      Quantitative measures of estrogen receptor expression in relation to breast cancer-specific mortality risk among white women and black women.
      We thus sought to investigate if this remains true in the subset of ER+/PR- tumors, a study not previously conducted. To that end, an ER H-score of ≥270 was associated with a significantly superior RFS in the ER+/PR- tumors, suggesting that a near-maximal ER expression is needed to compensate for the altered ER signaling in these tumors. Molecular studies examining the crosstalk between ER and growth factor signaling as well as dissecting differentially expressed genes downstream of ER signaling in the two groups may provide further insight into the mechanisms of endocrine resistance in ER+/PR- breast cancers. Moreover, the cutoff changes for ER and PR from 10% to 1% in the study period and arbitrary thresholds for endocrine therapy used in practice for ER-low positive tumors might have an impact in the treatment decision-making and clinical outcomes in this small subset of patients.
      It is of further interest that HER2 positivity is a favorable factor for clinical outcome in the patients with ER+/PR- tumors in the SEER cohort, whereas it is a worse prognosticator in the authors’ cohort, although a statistical significance was not reached in the multivariant analysis. The patients in the SEER database included in this study were from 2010 to 2015 and thus more likely received HER2-targeted therapy for HER2+ diseases. These patients also had a relatively shorter follow up. This contrasts with our cohort derived from 1998-2018. Further, only a subset of patients with ER+/PR-/HER2+ breast cancer (67/140; 48%) in our cohort received HER2-targeted therapy at the authors’ institution. Thus, the fact that over 50% patients with HER2-positive disease did not receive HER2-targeted therapy likely biased the results toward unfavorable survival outcomes. Moreover, most of those who did not receive anti-HER2 therapy were diagnosed before 2010 and had a much longer follow up, thus likely represented the natural course of ER+/PR-/HER2+ disease without HER2-targeted therapy. A disadvantage of national databases is that detailed treatment information is not available.

      Conclusions

      In summary, we have characterized the clinicopathologic features and prognostic outcomes of ER+/PR- breast cancers using a population-based national database and our institutional cohort. While the results from the former have a greater statistical power given its sample size, the latter is superior in minimizing potential incomplete or inaccurate data more often in national tumor registries, available treatment information, and a longer clinical follow up. Nonetheless, analyses of the two cohorts resulted in similar observations for the clinicopathologic features and clinical outcomes for this subtype of breast cancer. The ER+/PR- tumors should be regarded clinically as distinct from ER+PR+ and ER-/PR- diseases. Furthermore, a near-maximal ER expression is needed to make up the altered ER signaling in the ER+/PR- tumors as indicated by the responsiveness to endocrine therapies. These findings may provide additional insights in directing clinical decision making for individualized systemic therapy in the pursuit of precision medicine.

      Clinical Practice Points

      • While most estrogen receptor-positive (ER+) breast cancers express progesterone receptor (PR), 12% of breast cancers have an ER+/PR- phenotype, despite the fact that PR is an ER-dependent gene product.
      • The prognosis of ER+/PR- tumors is intermediate to that between ER+/PR+ and ER-/PR- tumors from the Surveillance, Epidemiology and End Results (SEER) database and the authors’ institutional cohort.
      • A near-maximal ER expression (H-score of ≥270) is needed to compensate for the altered ER signaling in ER+/PR- tumors.
      • Pathologic stage and HER2 status were independent prognostic factors in the ER+/PR- tumors.
      • These findings may provide novel insights in directing clinical decision making for individualized systemic therapy in the pursuit of precision medicine.

      Disclosure

      The authors declare no conflict of interest.

      References

        • Ferlay J.
        • Colombet M.
        • Soerjomataram I.
        • et al.
        Cancer statistics for the year 2020: An overview.
        Int J Cancer. 2021;
        • Siegel R.L.
        • Miller K.D.
        • Fuchs H.E.
        • Jemal A.
        Cancer statistics, 2022. CA.
        a cancer journal for clinicians. 2022; 72: 7-33
        • Anderson W.F.
        • Katki H.A.
        • Rosenberg P.S.
        Incidence of breast cancer in the United States: current and future trends.
        J Natl Cancer Inst. 2011; 103: 1397-1402
        • Burstein H.J.
        • Temin S.
        • Anderson H.
        • et al.
        Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.
        J Clin Oncol. 2014; 32: 2255-2269
        • Bouchard-Fortier A.
        • Provencher L.
        • Blanchette C.
        • Diorio C.
        Prognostic and predictive value of low estrogen receptor expression in breast cancer.
        Curr Oncol. 2017; 24: e106-e114
        • Early Breast Cancer Trialists' Collaborative G.
        • Davies C.
        • Godwin J.
        • et al.
        Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
        Lancet. 2011; 378: 771-784
        • Horwitz K.B.
        • McGuire W.L.
        Predicting response to endocrine therapy in human breast cancer: a hypothesis.
        Science. 1975; 189: 726-727
        • Dauphine C.
        • Moazzez A.
        • Neal J.C.
        • Chlebowski R.T.
        • Ozao-Choy J.
        Single Hormone Receptor-Positive Breast Cancers Have Distinct Characteristics and Survival.
        Annals of surgical oncology. 2020; 27: 4687-4694
        • Lv M.
        • Mao Y.
        • Song Y.
        • et al.
        Clinical Features and Survival of Single Hormone Receptor–Positive Breast Cancer: A Population-Based Study of 531,605 Patients.
        Clinical breast cancer. 2020; 20: e589-e599
        • Bardou V.J.
        • Arpino G.
        • Elledge R.M.
        • Osborne C.K.
        • Clark G.M.
        Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.
        Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003; 21: 1973-1979
        • Liu S.
        • Chia S.K.
        • Mehl E.
        • et al.
        Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients.
        Breast Cancer Res Treat. 2010; 119: 53-61
        • MacGrogan G.
        • de Mascarel I.
        • Sierankowski G.
        • et al.
        Time for reappraisal of progesterone-receptor testing in breast cancer management.
        J Clin Oncol. 2005; 23 (2870-2871; author reply 2871)
        • Olivotto I.A.
        • Truong P.T.
        • Speers C.H.
        • et al.
        Time to stop progesterone receptor testing in breast cancer management.
        J Clin Oncol. 2004; 22: 1769-1770
        • Viale G.
        • Regan M.M.
        • Maiorano E.
        • et al.
        Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98.
        J Clin Oncol. 2007; 25: 3846-3852
        • Mackey J.R.
        Can quantifying hormone receptor levels guide the choice of adjuvant endocrine therapy for breast cancer?.
        J Clin Oncol. 2011; 29: 1504-1506
        • Arpino G.
        • Weiss H.
        • Lee A.V.
        • et al.
        Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.
        Journal of the National Cancer Institute. 2005; 97: 1254-1261
        • Li Y.
        • Yang D.
        • Yin X.
        • et al.
        Clinicopathological Characteristics and Breast Cancer-Specific Survival of Patients With Single Hormone Receptor-Positive Breast Cancer.
        JAMA network open. 2020; 3e1918160
        • Bae S.Y.
        • Kim S.
        • Lee J.H.
        • et al.
        Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer.
        BMC cancer. 2015; 15: 138
        • Fei F.
        • Siegal G.P.
        • Wei S.
        Characterization of estrogen receptor-low-positive breast cancer.
        Breast Cancer Res Treat. 2021; 188: 225-235
        • Shen T.
        • Brandwein-Gensler M.
        • Hameed O.
        • Siegal G.P.
        • Wei S.
        Characterization of estrogen receptor-negative/progesterone receptor-positive breast cancer.
        Hum Pathol. 2015; 46: 1776-1784
      1. Burstein H.J., Temin S., Anderson H., et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. 2014;32:2255.

      2. Davies C., Godwin J., Gray R., et al. Early Breast Cancer Trialists’ Collaborative G. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. 2011;378:771-784.

        • Bauer K.R.
        • Brown M.
        • Cress R.D.
        • Parise C.A.
        • Caggiano V.
        Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry.
        Cancer. 2007; 109: 1721-1728
        • Keegan T.H.
        • DeRouen M.C.
        • Press D.J.
        • Kurian A.W.
        • Clarke C.A.
        Occurrence of breast cancer subtypes in adolescent and young adult women.
        Breast cancer research : BCR. 2012; 14: R55
        • Kumar P.
        • Aggarwal R.
        An overview of triple-negative breast cancer.
        Archives of gynecology and obstetrics. 2016; 293: 247-269
        • Parise C.A.
        • Caggiano V.
        Risk factors associated with the triple-negative breast cancer subtype within four race/ethnicities.
        Breast cancer research and treatment. 2017; 163: 151-158
        • Carey L.A.
        • Perou C.M.
        • Livasy C.A.
        • et al.
        Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study.
        JAMA. 2006; 295: 2492-2502
        • Benefield H.C.
        • Reeder-Hayes K.E.
        • Nichols H.B.
        • et al.
        Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features.
        JNCI Cancer Spectr. 2021; 5
        • Cui X.
        • Schiff R.
        • Arpino G.
        • Osborne C.K.
        • Lee A.V.
        Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy.
        J Clin Oncol. 2005; 23: 7721-7735
        • Tovey S.
        • Dunne B.
        • Witton C.J.
        • Forsyth A.
        • Cooke T.G.
        • Bartlett J.M.
        Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?.
        Clin Cancer Res. 2005; 11: 4835-4842
        • Smollich M.
        • Götte M.
        • Fischgräbe J.
        • Radke I.
        • Kiesel L.
        • Wülfing P.
        Differential effects of aromatase inhibitors and antiestrogens on estrogen receptor expression in breast cancer cells.
        Anticancer Res. 2009; 29: 2167-2171
        • Elston C.W.
        • Ellis I.O.
        Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up.
        Histopathology. 1991; 19: 403-410
        • Rakha E.A.
        • Reis-Filho J.S.
        • Baehner F.
        • et al.
        Breast cancer prognostic classification in the molecular era: the role of histological grade.
        Breast cancer research : BCR. 2010; 12: 207
        • Bartlett J.M.
        • Brookes C.L.
        • Robson T.
        • et al.
        Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial.
        J Clin Oncol. 2011; 29: 1531-1538
        • Morgan D.A.
        • Refalo N.A.
        • Cheung K.L.
        Strength of ER-positivity in relation to survival in ER-positive breast cancer treated by adjuvant tamoxifen as sole systemic therapy.
        Breast. 2011; 20: 215-219
        • Ma H.
        • Lu Y.
        • Marchbanks P.A.
        • et al.
        Quantitative measures of estrogen receptor expression in relation to breast cancer-specific mortality risk among white women and black women.
        Breast Cancer Res. 2013; 15: R90