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Tumor Variants by Hormone Receptor Expression in White Patients With Node-Negative Breast Cancer From the Surveillance, Epidemiology, and End Results Database

From the Division of Cancer Prevention, Office of Special Population Research, and Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Address reprint requests to William F. Anderson, MD, MPH, National Cancer Institute Division of Cancer Prevention, Room EPN 211L, MSC-7322, 6130 Executive Blvd, Bethesda, MD 20892-7161; email wanderso@ mail.nih.gov.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Hormone receptor expression (presence-positive or absence-negative) may reflect different stages of one disease or different breast cancer types. Determining whether hormone receptor expression represents one or more breast cancer phenotypes would have important paradigmatic and practical implications.

METHODS: Breast cancer records were obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. The study included 19,541 non-Hispanic white women with node-negative breast cancer. Standard tumor cell characteristics and breast cancer-specific survival were analyzed by independent estrogen receptor (ER+ and ER-), independent progesterone receptor (PR+ and PR-), and joint ERPR expression (ER+PR+, ER+PR-, ER-PR+, and ER-PR-).

RESULTS: Age frequency density plots by hormone receptor expression showed two overlapping breast cancer populations with early-onset and/or late-onset etiologies. Independent ER+ and PR+ phenotype were associated with smaller tumor sizes, better grade, and better cancer-specific survival than ER- and PR- breast cancer types. Joint ERPR phenotype exhibited biologic gradients for tumor size, grade, and cancer-specific survival, which ranked from good to worse for ER+PR+ to ER+PR- to ER-PR+ to ER-PR-.

CONCLUSION: Variations of standard tumor cell characteristics and breast cancer–specific survival by hormone receptor expression in white patients with node-negative breast cancer suggested two breast cancer phenotypes with overlapping etiologies and distinct clinical features.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
CONVENTIONAL WISDOM views breast cancer as a multistep process with a spectrum of proclivities (or stages); that is, one disease along a linear biologic pathway from early to late tumor stages.^1-5 Albeit the etiologic mechanisms of breast carcinogenesis are not fully understood, decades of research suggest an important role for the reproductive hormones (especially estrogen) and their nuclear receptors.^6-10 Presumably, the carcinogenic insult initiates genomic alterations in estrogen-sensitive breast epithelium (estrogen receptor–positive, or ER+), and this insult is promoted by estrogen. ER+ tumor cells then drift to estrogen insensitive (ER-) tumor cells.¹¹ In this model, ER+ to ER- phenotypic drift is a product of clonal evolution and expansion, reflecting different tumor stages rather than different breast cancer types.¹²

However, ER expression may be a stable phenotype.¹³ Sequential ER assays generally do not show ER+ to ER- phenotypic drift from primary to metastatic breast carcinoma.¹⁴ Additionally, if tumor cells did drift from ER+ to ER-, it is counterintuitive for ER+ breast cancer to increase with patient aging.^15,16 Taken to its logical conclusion, the spectrum model predicts that younger (not older) women should have ER+ disease. Absent ER+ to ER- phenotypic drift would suggest that variations in hormone receptor expression represent different breast cancer types rather than different tumor stages.^17-20 Establishing whether hormone receptor expression represents one or more breast cancer types (or variants) has important paradigmatic and practical implications.^5,21-26

To investigate putative breast cancer variants, we examined patient age at diagnosis, tumor size, histologic grade, and breast cancer survival by independent ER, independent progesterone receptor (PR), and joint ERPR phenotype. Results suggested that hormone receptor phenotype reflects two types of breast cancer with early-onset and/or late-onset variants.

	METHODS

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Breast cancer records were obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Cancer Incidence Public-Use CD-ROM, 1973 through 1996, August 1998 submission. The original breast.txt raw data file was imported from the Public-Use CD-ROM to SAS for Windows (Version 6.12, SAS Institute, Cary, NC), S-Plus 2000 for Windows (Statistical Sciences, Seattle, WA), and Statistica for Windows ’99 edition (Version 5.5A, StatSoft, Tulsa, OK). Collected from nine population-based cancer registries, the SEER database includes 2.3 million cancer cases from representative American subsets comprising 9.5% of the United States population.²⁷ SEER did not gather hormone receptor data before 1990. This analysis was restricted to white women with node-negative breast cancer who were accrued during the years of hormone receptor collection.

From 1990 through 1996, there were 132,159 breast cancer records in the Public-Use CD-ROM. This breast cancer cohort was sequentially filtered for the following: (1) female sex (n = 131,306); (2) infiltrating ductal carcinoma not otherwise specified (histopathologic code 8500; n = 79,768); (3) one or first primary breast cancer only (n = 68,801); (4) microscopic confirmation (n = 68,775); (5) American Joint Committee on Cancer tumor sizes T1-T3²⁸ corresponding to SEER extent of disease codes 10 through 30 (n = 63,309); (6) axillary lymph node–negative breast cancer cases (n = 40,491); (7) tumor size 5.0 centimeters (n = 37,871); (8) records with complete information for histologic grade (n = 29,671), ER expression (presence-positive or absence-negative; n = 24,445), and PR expression (presence-positive or absence-negative; n = 23,483); (9) non-Hispanic white race (n = 19,541).

Study variables included standard tumor cell characteristics, patient age at diagnosis, tumor size, histologic grade, and hormone receptor expression. All study variables were stratified by independent ER, independent PR, and joint ERPR expression. Tumor size and age were analyzed as continuous and categoric variables. Age less than 50 years versus 50+ years was a surrogate measure for menopausal status. Tumor size was divided into two groups: more than 2.0 centimeters versus 2.0 centimeters, corresponding to American Joint Committee on Cancer stage IIA versus stage I. Histopathologic grading and differentiation were defined according to the International Classification of Diseases for Oncology (ed 2): grade 1, well differentiated; grade 2, moderately differentiated; grade 3, poorly differentiated; and grade 4, undifferentiated.²⁹ Because grade 1 and grade 4 comprised less than 20% of the breast cancer records, we collapsed histologic grade into two categories, with grades 1 and 2 being considered a good prognostic group and grades 3 and 4 a poor category. SEER has no standard definition or centralized laboratory to determine hormone receptor expression. Depending on the assay used, each SEER site codes ER and PR expression as presence-positive or absence-negative.

Student’s t test for independent samples and one-way analysis of variance were used to detect differences in mean ages at diagnosis between groups defined by hormone receptor expression.³⁰ Continuous 1-year age frequency distributions were generated with density plots, which were constructed with a smoothing method of the corresponding age-at-diagnosis frequency histogram.³¹ Using the density function in S-Plus 2000,³² the density plot used a filter width of 10. The vertical axis for each density plot represented smoothed estimates of the proportion (or density) of patients who developed breast cancer at the corresponding age at diagnosis on the horizontal axis. Kolmogorov-Smirnov statistics tested statistically significant differences between age frequency distributions.³³ Kolmogorov-Smirnov statistics define the maximum difference in the cumulative proportions of two nonparametric distributions. Univariate and multivariate associations between hormone receptor expression and study variables were estimated with odds ratios and P values. Logistic regression was used to derive adjusted odds.³⁴ All P values were two-sided. P values .05 were considered statistically significant.

Outcome measures included overall survival and breast cancer–specific survival. SEER’s vital status code established whether the patient was alive or dead. Cause of death was categorized as either breast cancer–specific or non–breast cancer death. Overall survival was defined as the interval between date of breast cancer diagnosis and date of death from any cause. Breast cancer–specific survival was measured from the date of diagnosis to the date of breast cancer–specific death. The Kaplan-Meier product-limit method estimated overall and breast cancer–specific survivals from 1990 to 1995.³⁵ Stratified log-rank test compared time to overall and cancer-specific survivals between groups by independent and/or joint hormone receptor expression.³⁶

	RESULTS

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Descriptive statistics by independent ER and independent PR phenotypes yielded similar results (Tables 1 and 2, respectively). ER- compared with ER+ and PR- compared with PR+ were both associated with younger age at diagnosis, surrogate premenopausal status, larger tumor diameter, and poor histologic grade. Age frequency density plots showed bimodal distribution with early-onset mode (or peak frequency) and/or late-onset mode (or peak frequency; Fig 1). The vertical axis of each density plot represented smoothed estimates of the proportion of patients who had breast cancer at the corresponding age at diagnosis on the horizontal axis. Early-onset peak frequency approximated the premenopausal age of 40 to 50 years, whereas late-onset peak frequency occurred close to the postmenopausal age of 70 years. The postmenopausal peak predominated in ER+, PR+, and PR- phenotypes, whereas the premenopausal peak was dominant with ER- breast cancer.

View larger version (18K): [in this window] [in a new window]   Fig 1. Age frequency density plot by independent ER and PR phenotype.

View larger version (19K): [in this window] [in a new window]   Fig 2. Age frequency density plot by joint ERPR phenotype.

Tumor size and histologic grade showed a type of dose response (or biologic gradient) with joint hormone receptor expression, which were ranked from good to worse for ER+PR+ to ER+PR- to ER-PR+ to ER-PR- (Tables 3 and 4). Age at diagnosis and surrogate menopausal status showed no biologic gradient by ERPR phenotype. With multivariate modeling, all relationships remained statistically significant except for tumor size in the ER-PR+ group (P = .314) (Table 4).

View larger version (23K): [in this window] [in a new window]   Fig 3. Breast cancer-specific survival by independent and joint hormone receptor expression.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Independent ER+ and independent PR+ expression were associated with older age at diagnosis, smaller tumor sizes, better histologic grade, and better breast cancer–specific survival than ER- and PR- disease. Age frequency density plots showed mixed breast cancer populations, with overlapping early-onset (premenopausal) and late-onset (postmenopausal) breast cancer types. ER+, PR+, and PR- had dominant postmenopausal peaks, whereas ER- had a dominant premenopausal peak (Fig 1). The trough between the bimodal peaks may represent the so-called Clemmesen’s hook, the characteristic midlife dip in age-specific breast cancer incidence that is attributed to the female climacteric.^39,40 Purportedly, Clemmesen’s hook occurs at the junction of declining premenopausal breast cancer incidence and increasing postmenopausal breast cancer incidence. The midlife drop approximated 58 years of age in this analysis.

It has been suggested that joint ERPR expression identifies breast cancer variants better than either independent ER or PR expression.^18,20,26 There may be general agreement concerning concordant joint profiles (ER+PR+ and ER-PR-), but the discordant pair (ER+PR- and ER-PR+) has been problematic. ER+PR+ represents hormone-responsive breast cancer, whereas ER-PR- reflects hormone-insensitive tumors.^18,41 In contrast, ER+PR- and/or ER-PR+ have been characterized as dubious discordant subsets,¹⁸ mutant pairs,^42,43 laboratory artifacts,⁴⁴ and imaginary.⁴⁵ However, in this analysis, the discordant joint ERPR phenotypes had distinct age frequency density plots and prognostic factor profiles.

The purest postmenopausal age frequency distribution was in the ER+PR- group, whereas the purest premenopausal pattern had ER-PR+ expression (Fig 2). for ER+PR- expression, the mean age at diagnosis was 65.1 years, with a single peak frequency distribution of 70 years, similar to the age of greatest risk for sporadic breast cancer.^27,46 For ER-PR+ expression, peak age frequency distribution was between 40 and 50 years of age. Consequently, the oldest patients had a joint ER+PR- profile, whereas the youngest women were in the ER-PR+ group, consistent with the association of increased ER concentrations with aging and increased PR concentrations with premenopausal status.^16,17,47-49 Greater premenopausal levels of endogenous estrogens presumably induce PR expression. Therefore, because increasing ER level is associated with increasing age and increasing PR level is associated with premenopausal status, it makes sense for ER+PR- to include the oldest women while ER-PR+ contains the youngest patients. Intermediate mean ages and age frequency distribution patterns are in the concordant groups, with ER+PR+ women being older than are ER-PR- women.

There is thus a complicated relationship between age at diagnosis and menopausal status, which is reflected by joint ERPR phenotypes. Menopausal status was a surrogate measure in this analysis, but the Iowa Women’s Health Study collected reproductive history as well as other epidemiologic risk factors from a self-reported questionnaire.²⁶ Sporadic breast cancer was highly associated with ER+PR-, whereas family history of breast cancer had its strongest association with ER-PR+ profile. Similarly, a case-control analysis in Japan reported that family history was not associated with ER+PR- expression.⁵⁰ Loman et al⁵¹ also suggested that familial tumors with high levels of PR might compose a distinct subgroup of hereditary breast carcinomas that are not related to BRCA1 and/or BRCA2. All three studies are consistent with our observation for the oldest and youngest patients to be in the ER+PR- and ER-PR+ groups, given that sporadic and familial breast cancers tend to occur in older and younger women, respectively.^27,52,53 The Iowa Women’s Health Study described joint ER+PR- expression as true sporadic breast cancers. The ER-PR+ profile could be a familial equivalent. Future etiologic studies should possibly focus on discordant ERPR phenotypes for analyzing sporadic and familial breast cancer.

Tumor size, grade, and breast cancer survival demonstrated biologic gradients, whereas age at diagnosis and menopausal status showed no biologic gradients by joint ERPR expression. Tumor size (> 2.0 v 2.0 cm) and grade (poor v good) increased, whereas cancer-specific survival decreased from ER+PR+, ER+PR-, ER-PR+, and ER-PR-. The absence of a biologic gradient for age at diagnosis and/or menopausal status was due to the fact that the oldest and youngest patients were associated with the discordant joint phenotypes (Table 3), which had intermediate cancer-specific survivals (Fig 3).

This analysis has several potential sources of error that could effect internal and/or external validity. First, hormone receptor assays were not carried out in a centralized laboratory. However, ER and PR assays are now obtained on virtually every breast cancer patient and assay technology is becoming standardized.⁵⁴ Overall conclusions from a variety of different laboratories using different assays have usually been consistent.⁵⁵ It also seems highly unlikely that nine SEER sites would have differential hormone receptor misclassification across the four ERPR phenotypes. We derived some comfort from the fact that our joint ERPR distribution was very similar to other American studies; that is, ER+PR+, ER+PR-, ER-PR+, and ER-PR- are approximately 60%, 15% to 20%, less than 5%, and 15% to 20%, respectively.^18,26,41 In contrast, our hormone receptor distribution is strikingly different from a Japanese case-control study, which noted that ER+PR+, ER+PR-, ER-PR+, and ER-PR- were 39%, 25%, 5%, and 31%, respectively.^50,56 However, joint ERPR distribution by Japanese ethnicity in the SEER database is also different from the Japanese case-control study in Japan. There were 595 Japanese women with lymph node–negative breast cancer in the SEER 1973 through 1996 CD-ROM, and ERPR profiles were 69.6%, 12.1%, 5.2%, and 13.1% for ER+PR+, ER+PR-, ER-PR+, and ER-PR-, respectively. Japanese women in Japan and in America may have different breast cancers, or different ERPR phenotypes could have been due to selection bias, because joint receptor status was unknown in 60% of the Japanese cases in Japan.

Second, our results may not be generalizable to the global breast cancer population, because we examined a lymph node–negative subset from the SEER population-based database containing only non-Hispanic white women with infiltrating ductal carcinoma. We reasoned that early-stage breast cancer in a single ethnic group would reduce late-stage confounding of interrelated study variables such as race, delayed breast cancer detection, socioeconomic status, and so on.^57-65 A preliminary analysis has confirmed racial variation by joint ERPR phenotype especially for black versus white women, but this will be the subject of another report. A future report could also incorporate node-positive breast cancer patients.

A third concern relates to the fact that the SEER Public-Use CD-ROM does not include information pertaining to postoperative adjuvant treatment. Therefore, breast cancer outcome could not be adjusted for postoperative treatment. However, the observed biologic gradient (ER+PR+ to ER+PR- to ER-PR+ to ER-PR-) is not only biologically plausible but also consistent with previous studies. Wenger et al⁴⁴ reported in 1993 that S-phase fraction increased from ER+PR+, ER+PR-, ER-PR+, and ER-PR-. S-phase fraction is strongly correlated with poor breast cancer prognosis.⁶⁶ Early Breast Cancer Trialists’ Collaborative Group also observed relative improvements in early-stage breast cancer survival associated with adjuvant tamoxifen therapy, which were ranked from good to worse for ER+PR+ to ER+PR- to ER-PR+ to ER-PR-.⁶⁷ Additionally, hormone receptor status was first noted to be a predictor of cancer-specific survival more than 20 years ago, before routine adjuvant systemic treatment.^16,68 Hormone receptor status is also known to have prognostic value in node-negative patients who did not receive systemic treatment.^69,70

Fourth, the short median follow-up time of 31 months may not be adequate to detect long-term survival differences in node-negative breast cancer. However, ER studies with short-term follow-up (2 to 4 years) can yield valid conclusions concerning breast cancer etiology and early outcome effects, but late outcome results will require long-term follow-up.^16,71 Therefore, our early survival results must be verified with longer follow-up.

Notwithstanding these theoretical limitations, this is the largest node-negative population-based breast cancer analysis (n = 19,451) to ever simultaneously examine independent ER, independent PR, and joint ERPR expression. Our results provide potentially important etiologic clues, clinical insights, and caveats:

1. Although mean age at diagnosis is commonly used to describe breast cancer populations, population means assume normal frequency distributions. Our node-negative white breast cancer cohort had bimodal (not normal) age frequency distribution, and consequently, was also described with density plots. Notably, age frequency density plots by independent ER and PR expression suggested that there were two breast cancer types with overlapping early-onset and late-onset modes (or peak frequencies).
   
2. The concordant joint ERPR pair (ER+PR+ and ER-PR-) was characterized by a mixture of early-onset (premenopausal) and late-onset (postmenopausal) breast cancer populations. Postmenopausal breast cancer dominated the ER+PR+ phenotype, whereas premenopausal breast cancer was dominant in the ER-PR- phenotype. ER+PR+ and ER-PR- were associated with the best and worst cancer-specific survivals, respectively.
   
3. The discordant joint ERPR pair (ER+PR- and ER-PR+) had reciprocating unimodal late-onset and early-onset breast cancer variants, which possibly represented pure sporadic and familial breast cancer, respectively. ER+PR- and ER-PR+ had intermediate cancer survivals.
   
4. ER-PR+ expression seemed to be a true rather than imaginary phenotype or laboratory error.
   

In conclusion, variations of patient age at diagnosis, tumor size, grade, and cancer-specific survival by independent and joint hormone receptor expression posit two breast cancer variants with overlapping early or late-onset etiologies and distinct clinical features. The contemporary spectrum paradigm postulates that breast cancer is one disease along a continuous biologic pathway.^1-4 Our large-scale population-based observations suggest that breast cancer is two diseases rather than one.

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Submitted February 28, 2000; accepted July 18, 2000.

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