Get 20M+ Full-Text Papers For Less Than $1.50/day. Subscribe now for You or Your Team.

Learn More →

Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients

Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast... Background Breast cancer patients with tumors that are diagnosis, ranging from 1.2- to 1.5-fold differences for ER+/PR- estrogen receptor (ER)-positive and/or progesterone receptor cases, 1.5- to 2.1-fold differences for ER-/PR+ cases, and 2.1- (PR)-positive have lower risks of mortality after their diagnosis to 2.6-fold differences for ER-/PR- cases. Greater differences compared to women with ER- and/or PR-negative disease. were observed in analyses stratified by grade; among women However, few studies have evaluated variations in the risks of with low-grade lesions, ER-/PR- patients had a 2.6-fold (95% breast cancer-specific mortality across ER/PR status by either confidence interval [CI] 1.7 to 3.9) to 3.1-fold (95% CI 2.8 to demographic or clinical characteristics. 3.4) increased risk of mortality compared to ER+/PR+ patients, but among women with high-grade lesions, they had a 2.1-fold Methods Using data from 11 population-based cancer (95% CI 1.9 to 2.2) to 2.3-fold (95% CI 1.8 to 2.8) increased registries that participate in the SEER (Surveillance, risk. Epidemiology, and End Results) program, 155,175 women at least 30 years old with a primary diagnosis of invasive breast carcinoma from 1990 to 2001 were included in the study. Associations between joint hormone receptor status and breast Conclusion Compared to women with ER+/PR+ tumors, cancer mortality risk within categories of diagnosis age, women with ER+/PR-, ER-/PR+, or ER-/PR- tumors diagnosis year, race/ethnicity, histologic tumor type, stage, experienced higher risks of mortality, which were largely grade, size, and axillary lymph node status were evaluated using independent of the various demographic and clinical tumor the Cox proportional hazards model. characteristics assessed in this study. The higher relative mortality risks identified among ER-/PR- patients with small or Results Compared to ER+/PR+ cases, elevations in risk of low-grade tumors raise the question of whether there may be a mortality were observed across all subcategories of age at beneficial role for adjuvant chemotherapy in this population. tus by either demographic or clinical characteristics. The goal of this study was to determine whether the greater relative risk Introduction of breast cancer mortality observed among women with hor- Breast cancer patients with tumors that are estrogen receptor mone receptor-negative tumors was similar for those with dif- (ER)-positive and/or progesterone receptor (PR)-positive have ferent demographic characteristics, such as race/ethnicity, lower risks of mortality after their diagnosis compared to age of cancer diagnosis, and year of cancer diagnosis, and for women with ER- and/or PR-negative disease [1-6]. Clinical tri- those with different tumor characteristics, such as stage, als have also shown that the survival advantage for women grade, tumor size, and histology, using data from Surveillance, with hormone receptor-positive tumors is enhanced by treat- Epidemiology, and End Results (SEER), the population-based ment with adjuvant hormonal and/or chemotherapeutic regi- tumor registry program of the National Cancer Institute (NCI). mens [7-9]. However, few studies have evaluated variations in Such an assessment may further elucidate the relationships the risks of breast cancer-specific mortality across ER/PR sta- AJCC = American Joint Committee on Cancer; CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; NCHS = National Center for Health Statistics; NCI = National Cancer Institute; NDI = National Death Index; PR = progesterone receptor; SEER = Surveillance, Epidemiology, and End Results. Page 1 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. between various prognostic indicators in breast cancer and analysis was 31 December 2001. Because we were inter- provide knowledge regarding the prognostic utility of ER/PR ested primarily in cause-specific mortality, our outcome of status by demographic and clinical tumor characteristics. interest was death due to breast cancer as indicated by cause- of-death International Classification of Diseases codes. Women who died of causes other than breast cancer were Materials and methods Patient selection censored at their date of death. The cohort for this study was assembled using data from the NCI's SEER program in the United States [10]. Since the early Statistical analysis 1970s, the SEER program has collected incidence and sur- The statistical software program Stata for Macintosh version vival data from population-based cancer registries spanning 9.1 (StataCorp LP, College Station, TX, USA) was used to five states and four metropolitan areas: Connecticut, Hawaii, perform all analyses. Women with ER+/PR+ tumors served as Iowa, New Mexico, Utah, San Francisco-Oakland (CA), Detroit the referent category in all analyses because this was the larg- (MI), Seattle (Puget Sound) (WA), and Atlanta (GA). In 1992, est ER/PR subgroup. Associations between joint ER/PR two population-based registries were added: San Jose- receptor status and breast cancer mortality risk within catego- Monterey (CA) and Los Angeles (CA). SEER began collecting ries of diagnosis age (<50, 50 to 64, ≥65 years), diagnosis data on ER and PR status in 1990 for breast cancer cases. year (3-year intervals: 1990 to 1992, 1993 to 1995, 1996 to Therefore, only data from 1 January 1990 through 31 Decem- 1998, and 1999 to 2001), race/ethnicity (non-Hispanic white, ber 2001 were included in this analysis. African-American, Native American, Asian/Pacific Islander, Hispanic white), histologic tumor type (ductal, lobular, ductal/ We identified 209,276 women at least 30 years old with a pri- lobular, inflammatory, mucinous, tubular, comedo, medullary, mary diagnosis of invasive carcinoma of the breast as poten- papillary), AJCC stage grouping (I, II, III, IV), SEER grade (I, tially eligible subjects for this study. Women under the age of well differentiated; II, moderately differentiated; III, poorly dif- 30 years were excluded because the occurrence of breast ferentiated; IV, undifferentiated), size (0 to 1.9, 2 to 5, >5 cm), cancer among this age group is rare. Also excluded were and axillary lymph node status (binary – yes/no or 0, 1 to 3, 4 1,873 women whose breast carcinomas were diagnosed only to 10, >11 positive) were estimated using the Cox propor- by autopsy or death certificate or whose diagnostic confirma- tional hazards model. Unknown factors or those with missing tion of breast cancer was unknown. Because our primary anal- data were excluded from all model estimates. We used likeli- ysis focused on associations between joint ER/PR status and hood ratio testing to evaluate whether variations in mortality breast cancer-specific mortality, we excluded 50,291 women risks by these categories were statistically significant. Hazard missing tumor marker data for ER and/or PR (24% of the total ratios (HRs) and their associated 95% confidence intervals potentially eligible subjects). After the noted exclusions, (CIs) were calculated as estimates of relative risks of mortality 155,175 subjects were included in the study. [11,12]. Based on log-log survival curves, proportional haz- ards assumption in these data was validated for all categories Women were categorized into four groups according to their of ER/PR status except for ER-PR+. This is likely a conse- joint ER/PR status: ER+/PR+, ER+/PR-, ER-/PR+, and ER-/ quence of ER-/PR+ being the rarest ER/PR subtype, and for PR-. The SEER registries provide information on age of diag- this subgroup, a gross violation of the proportional hazards nosis, year of diagnosis, and race/ethnicity. Data on other clin- assumption was not observed. In our analyses, we evaluated ical characteristics, such as tumor histology, grade, stage age of diagnosis, year of diagnosis, SEER registry site (strati- (American Joint Committee on Cancer [AJCC] classification fied variable), race/ethnicity, histologic type, tumor size, stage, system), and size, were also available. Additionally, SEER col- grade, and lymph node status as potential confounders in mul- lects data regarding the first course of cancer-directed surgi- tivariate Cox regression modeling. We also evaluated the pos- cal and radiation treatment interventions. However, SEER sible influence of initial cancer treatments (surgery/radiation – does not make data on adjuvant chemotherapy or hormonal yes/no) given that treatment recommendations are based on therapy publicly available. SEER does not collect information tumor characteristics and that therapeutic interventions are on other relevant factors such as reproductive history, anthro- associated with survival. We assessed whether associations pometrics, medical history, family history of cancer, or cancer between ER/PR status and demographic/clinical characteris- screening history. tics were different for varying levels of a factor by fitting inter- action models. For each model, dummy variables were created Outcome measures and each represented the combination of an ER/PR category Each SEER registry routinely updates vital status and follow- and the characteristic assessed, with ER+PR+ and the follow- up information for all patients with cancer. Survival time is cal- ing characteristics as referent categories: age less than 50 culated in months by using the subject's date of breast cancer years, year of diagnosis 1990 to 1992, non-Hispanic white, diagnosis and one of the following: (a) date of death, (b) date tumor grade 1, tumor stage 1, tumor size less than 2 cm, last known to be alive, or (c) the most recent follow-up cutoff negative lymph nodes, and ductal tumor histology. Each full date. The follow-up cutoff date for the SEER data used in our model with the cross-categorized variables was compared to Page 2 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 the reduced model (main effects only) by likelihood ratio test- reduction was greater among women with ER+ disease than ing to assess statistical significance. We also estimated ER- disease. In general, the magnitudes of the HRs associated trends in HRs for each ER/PR profile and the following: (a) age with each ER/PR profile were comparable across race/ethnic- at diagnosis, per 5 years (30 to <35 years referent), (b) diag- ity classifications (p for interaction = 0.77). nosis year, per year (1990 referent), (c) tumor stage (stage 1 referent), (d) tumor size (0 to <1 cm [referent], 1 to <2, 3 to Elevations in breast cancer mortality risks were observed <4, 4 to <5, 5 to <10, ≥10), (e) axillary nodal positivity (0 [ref- among women with ER+/PR-, ER-/PR+, and ER-/PR- tumors erent], 1 to 3, 4 to 10, ≥11), and (f) tumor grade (grade 1 ref- relative to women with ER+/PR+ tumors across the majority of erent). These variables were treated as continuous variables clinical characteristics examined (Table 2). The magnitudes of for trend estimates. All statistical tests were two-sided, and p these relative risks did not vary appreciably by stage; also, for values of 0.05 or less were considered significant. each increase in tumor stage level, two-fold or greater increases in mortality risks were observed within each ER/PR profile (p for trend < 0.0001) (Table 3). Tumor size, lymph Results Within the identified cohort of 155,175 women with known node status, histology, and grade appeared to modify the rela- joint ER/PR receptor status, 98,463 cases had ER+/PR+ tionship between ER/PR status and relative risk of mortality. tumors (63%). Of the remaining women, 19,886 cases had For tumor size and grade, the mortality risks associated with ER+/PR- tumors (13%), 4,896 cases had ER-/PR+ tumors ER-/PR+ tumors were particularly high among women whose (3%), and 31,930 cases had ER-/PR- tumors (21%). Older tumors were either more than 5 cm in size or of high grade. The women were more likely to be diagnosed with ER+/PR+ mortality risks associated with ER-/PR- tumors, relative to tumors, whereas more than one third of women 30 to 39 years ER+/PR+ tumors, were particularly high among women old presented with ER-/PR- tumors (Table 1). The proportion whose tumors were less than 2 cm in size or of low grade of tumors that were ER+/PR+ increased over the study period, (Table 2). In addition, the HRs increased with increasing tumor whereas the proportions of tumors that were ER+/PR- and size, number of axillary lymph node metastases, and disease ER-/PR- held fairly constant, and the proportion of tumors that grade within each ER/PR profile (p for trend < 0.0001, all pro- were ER-/PR+ declined. In general, for the other characteris- files) (Table 3). The magnitude of the associated relative mor- tics shown in Table 1, ER+/PR+ and ER+/PR- tumors were tality risk depended on ER/PR status. For example, women similar to each other and ER-/PR+ and ER-/PR- tumors were with ER-/PR- tumors had a 24% increase in the relative risk of similar to each other. Specifically, compared to women with breast cancer mortality with each increase in tumor grade ER+PR+ and ER+/PR- tumors, those diagnosed with ER-/ level, whereas women with ER+/PR+ tumors had a 62% ele- PR+ and ER-/PR- tumors were somewhat more likely to be vated mortality risk with each increase in tumor grade level. younger and African-American, to have larger tumors, more With respect to histology, compared to women with ER+/PR+ advanced disease stage, and higher tumor grade, and to tumors, women with ER+/PR- tumors had elevated risks of present with axillary lymph node metastases. In addition, mortality if their tumor was ductal or lobular, women with ER-/ women with ER-/PR+ and ER-/PR- tumors were somewhat PR+ tumors had elevated risks of mortality if their tumor was less likely to have lobular, ductal/lobular, mucinous, or tubular ductal or inflammatory, and women with ER-/PR- tumors had carcinomas and were somewhat more likely to have inflamma- elevated risks of mortality across all histologies, except for tory, comedo, or medullary carcinomas. medullary carcinoma. Due to the sparse number of subjects in each hormonal category and limited or no recorded deaths, The risks of breast cancer-specific mortality were elevated data were not shown for mucinous, papillary, and tubular among women with ER+/PR-, ER-/PR+, and ER-/PR- tumors carcinomas. relative to women with ER+/PR+ tumors across all subcatego- ries of age at cancer diagnosis (Table 2). Age was an effect Discussion modifier of the relationship between ER/PR status and relative Previous studies have shown survival advantages among risk of breast cancer mortality (p = 0.03). Specifically, HRs for women with hormone receptor-positive tumors relative to ER-/PR+ and ER-/PR- disease were particularly high among women with hormone receptor-negative tumors [6,9,13-16]. A women 65 years of age and older. For each 5-year increase in recent study by Grann and coworkers [17] that also used data age, a 5% to 7% elevation in mortality risk was observed within collected from the SEER program reported that joint ER/PR each ER/PR profile (p for trend < 0.0001, all profiles) (Table status was an independent predictor of outcome in a large 3). Among the population of women with ER-/PR- tumors rel- cohort of women with breast carcinoma. Our study expands ative to women with ER+/PR+ tumors, a higher relative mor- on this study, further evaluating the association between ER/ tality risk was associated with a tumor diagnosed in the most PR status and breast cancer-specific mortality within sub- recent years versus a tumor diagnosed in the early 1990s (p groups of women defined by personal characteristics (includ- for interaction < 0.0001). However, decreases in HRs ranging ing race/ethnicity, age at cancer diagnosis, and year of cancer from 4% to 8% per year were observed with increasing calen- diagnosis) and tumor characteristics (including histology, dar year within each ER/PR profile and the magnitude of this stage, grade, size, and axillary lymph node metastases). In gen- Page 3 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. Table 1 Selected characteristics among breast cancer cases by hormone receptor status: SEER program, 1990–2001 ER+PR+ ER+PR- ER-PR+ ER-PR- (n = 98,463) (n = 19,886) (n = 4,896) (n = 31,930) Characteristics n Column % Row % n Column % Row % n Column % Row % n Column % Row % Age at diagnosis, years 30–39 4,903 5.0 49.5 885 4.5 8.9 569 11.6 5.7 3,558 11.1 35.9 40–49 18,575 18.9 60.9 2,490 12.5 8.2 1,508 30.8 4.9 7,929 24.8 26.0 50–59 21,807 22.1 61.4 4,464 22.5 12.5 1,161 23.7 3.3 8,094 25.4 22.8 60–69 22,019 22.4 65.9 4,752 23.9 14.2 801 16.4 2.4 5,856 18.3 17.5 70–79 20,667 21.0 68.2 4,662 23.4 15.4 584 11.9 1.9 4,401 13.8 14.5 ≥80 10,492 10.6 67.7 2,633 13.2 17.0 273 5.6 1.8 2,092 6.6 13.5 Diagnosis year 1990–1992 16,500 16.8 61.6 3,751 18.9 14.0 1,111 22.7 4.1 5,435 17.0 20.3 1993–1995 22,087 22.4 61.7 4,514 22.7 12.6 1,485 30.3 4.1 7,728 24.2 21.6 1996–1998 27,734 28.2 64.2 5,239 26.3 12.1 1,367 27.9 3.2 8,884 27.8 20.5 1999–2001 32,142 32.6 65.2 6,382 32.1 12.9 933 19.1 1.9 9,883 31.0 20.0 SEER registry Atlanta, GA 5,696 5.8 59.4 1,171 5.9 12.2 381 7.8 4 2,344 7.3 24.4 Connecticut 11,093 11.3 61.4 2,448 12.3 13.6 602 12.3 3.3 3,914 12.3 21.7 Detroit, MI 10,559 10.7 60.4 2,314 11.6 13.2 539 11 3.1 4,063 12.7 23.3 Hawaii 4,149 4.2 67.0 703 3.5 11.3 273 5.6 4.4 1,072 3.4 17.3 Iowa 10,238 10.4 65.2 1,914 9.6 12.2 530 10.8 3.4 3,017 9.4 19.2 Los Angeles, CA 15,586 15.8 61.4 3,399 17.1 13.4 919 18.8 3.6 5,491 17.2 21.6 New Mexico 4,066 4.1 61.8 885 4.5 13.5 193 3.9 2.9 1,435 4.5 21.8 San Francisco-Oakland, CA 13,063 13.3 63.9 2,750 13.8 13.5 652 13.3 3.2 3,957 12.4 19.4 San Jose, CA 5,474 5.5 65.3 1,134 5.7 13.5 228 4.7 2.7 1,548 4.9 18.5 Seattle, WA 14,241 14.5 68 2,517 12.7 12.0 423 8.6 2.0 3,770 11.8 18.0 Utah 4,298 4.4 66.9 651 3.3 10.1 156 3.2 2.5 1,319 4.1 20.5 Race Non-Hispanic white 78,805 81.7 65.4 15,716 80.5 13.0 3,515 73.5 2.9 22,532 72.1 18.7 African-American 5,724 5.9 48.0 1,488 7.6 12.5 504 10.5 4.2 4,206 13.5 35.3 Native American 284 0.3 55.0 57 0.3 11.0 23 0.5 4.5 152 0.5 29.5 Asian/Pacific Islander 6,065 6.3 65.1 1,061 5.4 11.4 382 8.0 4.1 1,805 5.8 19.4 Hispanic white 5,585 5.8 57.8 1,203 6.2 12.4 359 7.5 3.7 2,524 8.1 26.1 Other/Unknown 2,000 - - 361 - - 113 - - 711 - - Tumor histology Ductal 71,199 72.3 62.7 13,981 70.3 12.3 3,641 74.4 3.2 24,722 77.4 21.8 Lobular 8,980 9.1 73.6 2,160 10.9 17.7 283 5.8 2.3 784 2.5 6.4 Page 4 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 Table 1 (Continued) Selected characteristics among breast cancer cases by hormone receptor status: SEER program, 1990–2001 Ductal/Lobular 7,576 7.7 76.7 1,341 6.7 13.6 233 4.8 2.4 722 2.3 7.3 Inflammatory 543 0.5 37.8 191 1.0 13.3 90 1.8 6.3 611 1.9 42.6 Mucinous 2,927 3.0 80.9 486 2.4 13.5 41 0.8 1.1 164 0.5 4.5 Tubular 1,696 1.7 79 327 1.6 15.2 44 0.9 2.1 79 0.3 3.7 Comedo 1,159 1.2 43.6 318 1.6 12.0 179 3.6 6.7 1,003 3.1 37.7 Medullary 266 0.3 14.7 148 0.8 8.2 97 2.0 5.4 1,292 4.0 71.7 Papillary 582 0.6 79.0 58 0.3 7.9 10 0.2 1.3 87 0.3 11.8 Other 3,535 3.6 49.4 876 4.4 12.2 278 5.7 3.9 2,466 7.7 34.5 Tumor stage I 50,172 52.4 69.2 9,232 48 12.7 1,999 42.7 2.8 11,114 36.2 15.3 II 37,335 39.0 60.3 7,606 39.5 12.3 2,068 44.2 3.3 14,878 48.4 24.1 III 5,332 5.5 51.3 1,471 7.6 14.1 385 8.2 3.7 3,210 10.4 30.9 IV 2,943 3.1 52.1 936 4.9 16.6 230 4.9 4.1 1,536 5.0 27.2 Unstaged 2,681 - - 641 - - 214 - - 1,192 - - Tumor grade 1 18,012 21.8 81.1 2,885 17.5 13.0 405 9.9 1.8 914 3.3 4.1 2 40,642 49.3 74.2 7,133 43.4 13.0 1,324 32.5 2.4 5,682 20.6 10.4 3 22,082 26.8 44.4 6,027 36.6 12.1 2,174 53.3 4.4 19,412 70.4 39.1 4 1,774 2.1 45.0 413 2.5 10.5 173 4.3 4.4 1,579 5.7 40.1 Unknown 15,953 - 3,428 - 820 - 4,343 - Tumor size (cm) 0–1.9 56,547 59.9 69.2 10,302 54.6 12.6 2,271 49.5 2.8 12,576 41.8 15.4 2–5 32,977 34.9 58.7 7,135 37.8 12.7 1,891 41.3 3.4 14,147 47.1 25.2 >5 4,949 5.2 48.8 1,432 7.6 14.1 422 9.2 4.2 3,330 11.1 32.9 Unknown 3,990 - - 1,017 - - 312 - - 1,877 - - Axillary lymph node status Negative 54,948 65.3 64.8 10,428 63.0 12.3 2,622 61.0 3.1 16,749 60.3 19.8 Positive 29,234 34.7 60.9 6,110 37.0 12.7 1,675 39.0 3.5 11,015 39.7 22.9 Unknown 14,281 - - 3,348 - - 599 - - 4,166 - - Surgical treatment Performed 96,387 98.0 63.7 19,216 96.7 12.7 4,764 97.4 3.2 30,847 96.8 20.4 Not performed 2,012 2.0 52.7 648 3.3 17.0 126 2.6 3.3 1,032 3.2 27 Unknown 64 - - 22 - - 6 -- 51 -- Radiation therapy Treated 46,859 48.5 65.5 8,694 44.5 12.1 2,048 42.9 2.9 13,922 44.8 19.5 None 49,776 51.5 61.9 10,836 55.5 13.4 2,725 57.1 3.4 17,131 55.2 21.3 Unknown 1,828 - - 356 - - 123 - - 877 - - ER, estrogen receptor; PR, progesterone receptor; SEER, Surveillance, Epidemiology, and End Results. Page 5 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. Table 2 Breast cancer mortality risk by hormone receptor status among women of different diagnosis age, race/ethnicity, diagnosis year, tumor stage, grade, histology, and axillary lymph node positivity ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- (n = 98,463) (n = 19,886) (n = 4,896) (n = 31,930) Characteristics No. at No. HR No. at No. HR 95% CI No. at No. HR 95% CI No. at No. HR 95% CI p value for risk deaths risk deaths risk deaths risk deaths interaction b c c c All cases 98,463 7,319 1.0 19,886 2,434 1.4 1.3–1.5 4,896 848 1.8 1.6–1.9 31,930 6,300 2.3 2.2–2.4 Age at diagnosis, years c c c <50 16,962 1,042 1.0 2,387 245 1.2 1.1–1.4 1,430 209 1.6 1.4–1.9 8,056 1,323 2.1 1.9–2.3 c c c 50–64 23,467 1,104 1.0 4,745 416 1.5 1.3–1.7 1,072 124 1.5 1.2–1.8 7,651 1,214 2.3 2.1–2.5 c c c ≥65 25,078 1,496 1.0 5,563 540 1.5 1.3–1.7 718 119 2.1 1.8–2.6 5,536 1,020 2.6 2.4–2.8 0.03 Diagnosis year c c c 1990–1992 8,298 1,285 1.0 1,889 419 1.3 1.2–1.5 597 146 1.6 1.3–1.9 2,850 831 1.7 1.5–1.9 c c c 1993–1995 13,665 1,348 1.0 2,688 428 1.5 1.3–1.7 944 160 1.5 1.2–1.8 4,859 1,234 2.2 2.0–2.4 c c c 1996–1998 19,350 837 1.0 3,493 282 1.5 1.3–1.7 971 121 2.1 1.7–2.6 6,181 1,059 2.8 2.5–3.1 c c c 1999–2001 24,194 172 1.0 4,625 69 1.6 1.2–2.1 708 25 3.6 2.3–5.1 7,353 433 4.9 4.1–6.0 <0.001 Race/Ethnicity c c c Non- 53,397 2,831 1.0 10,187 916 1.5 1.3–1.6 2,396 313 1.8 1.6–2.0 15,371 2,462 2.3 2.2–2.5 Hispanic white c c c African- 3,536 348 1.0 907 125 1.2 1.0–1.5 293 60 1.7 1.3–2.2 2,734 615 2.2 1.9–2.6 American Native 196 19 1.0 34 11 1.5 0.5–3.8 12 1 1.7 0.1–16.4 102 25 3.4 1.5–7.3 American c c c Asian/Pacific 4,497 189 1.0 748 63 1.8 1.3–2.4 267 34 1.6 1.1–2.4 1,273 166 2.3 1.8–2.8 Islander c c c Hispanic 3,881 255 1.0 819 83 1.3 1.0–1.7 252 44 1.9 1.3–2.6 1,763 289 2.3 1.9–2.8 0.77 white Tumor stage c c c I 33,821 487 1.0 6,038 146 1.4 1.2–1.7 1,369 51 1.6 1.2–2.1 7,704 391 2.3 2.0–2.7 c c c II 27,363 2,110 1.0 5,472 674 1.4 1.3–1.6 1,529 248 1.6 1.4–1.9 11,051 2,069 2.3 2.2–2.5 c c c III 3,410 659 1.0 922 252 1.3 1.2–1.6 245 104 2.1 1.7–2.6 1,940 763 2.3 2.0–2.6 Page 6 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 Table 2 (Continued) Breast cancer mortality risk by hormone receptor status among women of different diagnosis age, race/ethnicity, diagnosis year, tumor stage, grade, histology, and axillary lymph node positivity c c c IV 672 302 1.0 192 102 1.3 1.0–1.6 59 42 1.9 1.3–2.7 357 245 2.3 1.9–2.8 0.45 Tumor size (cm) c c c 0–1.9 39,418 865 1.0 6,957 243 1.4 1.2–1.6 1,607 91 1.5 1.2–1.9 8,799 715 2.6 2.3–2.9 c c c 2–5 22,579 2,081 1.0 4,781 708 1.5 1.3–1.6 1,331 253 1.8 1.5–2.0 10,214 2,019 2.2 2.1–2.4 c c c >5 2,718 526 1.0 761 206 1.3 1.1–1.6 217 89 2.2 1.7–2.7 1,730 636 2.2 1.9–2.5 <0.001 Axillary lymph node status c c c Negative 42,451 942 1.0 7,924 324 1.6 1.4–1.8 1,898 114 2.0 1.6–2.4 12,541 1,006 2.8 2.6–3.1 c c c 1–3 14,953 1,021 1.0 2,828 324 1.5 1.3–1.7 790 133 1.8 1.5–2.1 4,857 977 2.5 2.3–2.7 c c c 4–10 5,313 861 1.0 1,133 277 1.4 1.2–1.6 332 108 1.7 1.3–2.1 2,268 793 2.4 2.2–2.7 c c c ≥11 2,549 734 1.0 739 249 1.2 1.0–1.4 182 90 1.7 1.3–2.1 1,386 692 2.2 1.9–2.4 0.08 Tumor histology c c c Ductal 52,178 2,919 1.0 9,978 994 1.5 1.4–1.6 2,711 390 1.8 1.6–2.0 18,542 3,040 2.3 2.2–2.5 c c Lobular 3,975 186 1.0 938 64 1.4 1.0–1.9 123 3 0.4 0.1–1.4 325 47 1.9 1.4–2.7 Ductal/ 5,472 254 1.0 929 59 1.3 0.9–1.7 148 13 1.1 0.6–2.0 511 83 2.7 2.1–3.5 Lobular c c Inflammatory 241 52 1.0 77 22 1.4 0.8–2.3 39 19 3.4 1.9–6.1 258 123 3.5 2.4–5.0 Comedo 652 91 1.0 187 19 0.6 0.4–1.1 91 16 1.2 0.7–2.1 556 109 1.6 1.2–2.1 Medullary 120 14 1.0 73 6 0.7 0.2–2.2 48 4 0.9 0.2–3.0 716 54 0.7 0.4–1.4 <0.001 Tumor grade c c 1 13,854 156 1.0 2,141 40 1.6 1.1–2.3 310 6 1.0 0.4–2.5 661 32 2.6 1.7–3.9 c c c 2 32,661 1,349 1.0 5,555 374 1.5 1.3–2.1 1,074 95 1.7 1.3–2.1 4,312 575 3.1 2.8–3.4 c c c 3 17,352 1,873 1.0 4,613 710 1.3 1.2–1.5 1,694 319 1.7 1.5–1.9 14,967 2,635 2.1 1.9–2.2 c c c 4 1,399 180 1.0 315 50 1.4 1.0–2.0 124 25 2.1 1.4–3.3 1,112 226 2.3 1.8–2.8 <0.001 a b The reference ER/PR profile for all analyses was ER+/PR+. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation c d treatment, and lymph node status (positive/negative). p < 0.05. HRs adjusted for year at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). HRs adjusted for age at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). HRs adjusted for age and year at diagnosis, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). Race unknown, n = 3,185. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status (categorical), and surgical and radiation treatment. Stage unknown, n = 4,728. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status (categorical), and surgical and radiation treatment. Size unknown, n = 7,196. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, grade, and surgical and radiation treatment. Nodal status unknown, n = 22,394. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor grade, stage, lymph node status (categorical), and surgical and radiation treatment. Other/unknown histology, n = 7,155. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, lymph node status (categorical), and surgical and radiation treatment. Grade unknown, n = 24,544. CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; PR, progesterone receptor; SEER, Surveillance, Epidemiology, and End Results. Page 7 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. Table 3 Trends in hazard ratios for breast cancer mortality associated with hormone receptor status and different demographic and clinical characteristics ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- Characteristics HR 95% CI HR 95% CI HR 95% CI HR 95% CI Age at diagnosis, per 5 years 1.05 1.04–1.06 1.07 1.04–1.09 1.07 1.03–1.10 1.06 1.05–1.07 Diagnosis year, per year 0.93 0.92–0.94 0.92 0.90–0.94 0.95 0.91–0.98 0.96 0.95–0.97 Tumor stage 2.33 2.20–2.46 2.29 2.09–2.51 2.55 2.19–2.96 2.06 1.94–2.18 Tumor size (cm) 1.27 1.24–1.30 1.29 1.24–1.34 1.33 1.25–1.41 1.22 1.20–1.25 Axillary lymph node status 1.71 1.65–1.78 1.55 1.46–1.66 1.61 1.44–1.80 1.64 1.58–1.70 Tumor grade 1.62 1.55–1.70 1.49 1.36–1.63 1.72 1.46–2.03 1.24 1.16–1.32 Five-year categories. Reference = 30 to <35 years. HRs adjusted for year at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). Reference = 1990. HRs adjusted for age at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). Reference = stage 1. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status, and surgical and radiation treatment. Stage unknown, n = 4,728. Categories = 0 to <1, 1 to <2, 2 to <3, 3 to <4, 4 to <5, 5 to <10, ≥10 cm. Reference = 0 to <1 cm. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status, and surgical and radiation treatment. Size unknown, n = 7,196. Categories = 0, 1 to 3, 4 to 10, ≥11. Reference = 0. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, grade, and surgical and radiation treatment. Nodal status unknown, n = 22,394. Reference = grade 1. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, lymph node status, and surgical and radiation treatment. Grade unknown, n = 24,544. CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; PR, progesterone receptor; SEER, Surveillance, Epidemiology, and End Results. eral, we observed that the higher relative risks of mortality recommended for ER-/PR- patients whose tumors are small associated with having an ER+/PR-, an ER-/PR+, or an ER-/ and have favorable features (that is, negative lymph nodes, PR- tumor relative to an ER+/PR+ tumor were consistently highly differentiated) [20]. Our data also showed that ER-/ present across almost all tumor characteristics. Even among PR+ patients whose tumors were more than 5 cm in size or of women with poor prognoses, such as those with stage IV dis- high grade had particularly elevated relative mortality risks ease, multiple positive lymph nodes, or tumors of high grade, (HRs = 2.2 and 2.1, respectively) that were higher than those differences in the relative risk of mortality by ER/PR status with ER+/PR- tumors of similar size and grade (HRs = 1.3 and were observed. We also estimated mortality trends by ER/PR 1.4, respectively), suggesting that ER negativity may have a status within the study population. Within each ER/PR profile, greater influence on mortality risk than PR negativity among we document an increase in the relative risk of breast cancer women with these tumor types. Compared to women with mortality for each 5-year increase in age and for each incre- ER+/PR+ tumors, those with ER-/PR- tumors had increased mental increase in tumor stage, size, grade, or axillary lymph risks of mortality across almost all histologic classifications, node metastases. These findings are in agreement with the suggesting that combined ER/PR negativity has implications known correlation between increased breast cancer mortality for relative mortality risk, regardless of tumor histology. The risk and increasing tumor stage, size, grade, or regional lymph one noted exception was that ER/PR status did not appear to node metastases [18,19]. We observed a decreased mortality be related to the relative risk of mortality among women with trend each year over the study period of 1990 to 2001 which medullary carcinomas. Medullary carcinomas are rare, and was greatest in magnitude among women with ER+ tumors. although they are typically high-grade, they tend to have well- This trend may be related to improvements in breast cancer defined, distinct borders. Their prognosis is more favorable treatments and/or early detection methods resulting in than that of other invasive breast carcinomas, such as ductal improved patient outcomes. carcinoma [21]. We did observe some variations in the association between Researchers who examined the risk of invasive breast carci- ER/PR status and risk of breast cancer mortality by tumor size, noma diagnosis among women of different races reported that grade, and histology. Relative to ER+/PR+ patients, and within certain ethnicities have elevated risks of presenting with ER-/ subcategories of tumor size and grade, the highest observed PR- tumors. African-Americans, Asians, Native Americans, and relative mortality risks were among ER-/PR- patients whose Hispanic whites were found to have greater risks of presenting tumors were small (0 to 1.9 cm) or of low grade (grade 1 and with ER-/PR- breast tumors compared to non-Hispanic whites 2). These elevated risks are likely related to adjuvant treatment [22-25]. Although it has been shown that women of certain standards given that hormonal therapy generally is recom- racial/ethnic groups have increased risks of developing hor- mended for women with ER+/PR+ disease, regardless of mone receptor-negative tumors, our results show little or no tumor size. Conversely, adjuvant chemotherapy is not routinely difference in mortality risks within ethnic classes for each ER/ Page 8 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 PR profile. For example, African-American women whose comes [32]. The decreased mortality trend we observed each tumors were ER-/PR+ or ER-/PR- were found to have relative year over the study period, particularly among women with risks of breast cancer mortality similar to non-Hispanic whites ER+ tumors, may be due in part to screening programs. with ER-/PR+ or ER-/PR- tumors, respectively. A final limitation of this study is that SEER registries do not There are potential study limitations using SEER data. First, provide data on the receipt of adjuvant or hormonal therapies ER/PR status, tumor histology, and tumor grade were not following primary surgical and/or radiotherapy interventions. assessed centrally since the data recorded by SEER are Treating hormone receptor-positive tumors with hormonal derived from review of clinical pathology reports. Most impor- therapies has been shown to be a contributing factor in better tantly, assays and techniques used for ER/PR testing likely var- survival among women with breast cancer [9]. A large propor- ied both across and within laboratories over the course of this tion of the survival advantage experienced by ER+/PR+ study. For example, cutoff points may have been dissimilar in patients compared to ER-/PR- patients may be due to the use differentiating hormone receptor positivity. High cutoff values of hormonal therapy. Our data indicate that in 1990 to 1992, may result in tumors being misclassified as ER- [26]. However, when the use of hormonal therapy had just begun, ER-/PR- assay techniques for ER and PR have improved since their patients had a 1.7-fold greater relative risk of mortality; inception nearly 30 years ago and receptor status can be however, by 1999 to 2001, when hormonal therapy was appropriately determined with relative ease [27,28]. In the widely integrated into clinical practice and guidelines for its period to which this study was restricted (1990 to 2001), use were well established, women with ER-/PR- tumors had a pathology laboratories in general routinely performed ER/PR 4.9-fold greater relative risk of mortality. In future years, the testing of breast cancer. Also reassuring is the fact that the advent of better chemotherapy treatments for the ER- patient proportions of the four joint tumor ER/PR receptor profiles in population may result in improved disease-free survival and our study population were comparable to those reported in overall survival. Recent studies have reported that the large other studies [13,14]. survival differences among ER+ patients treated with hormo- nal therapy versus ER- patients treated with chemotherapy The exclusion of subjects with no recorded ER/PR data is a have dwindled and that ER- patients are now deriving a greater second potential limitation of this study. The absence of benefit from improved chemotherapy regimens with risk reduc- recorded hormone receptor data has been reported to be tions as high as 49% [33,34]. associated with age and year of diagnosis, tumor stage, grade, histology, and SEER registries [17,29], and thus the lack of Conclusion ER/PR data on these cases could bias our results. However, Overall, our findings suggest that the higher risks of mortality the number of SEER records missing ER/PR data has in women with ER+/PR-, ER-/PR+, and ER-/PR- tumors, com- declined over time and the decline has been shown to be con- pared to women with ER+/PR+ tumors, are largely independ- sistent across all age categories [29]. The proportion of ent of the various demographic and clinical tumor records containing ER/PR data for this cohort increased over characteristics assessed in this study. This indicates that the time, ranging from 67.5% in 1990 to 73% in the years 1994 prognostic utility of ER/PR status is for the most part inde- to 1995 and 80.7% in 2001, results that are consistent with pendent of these other factors. However, the strength of the prior reports [17]. associations we assessed did vary within subcategories of certain factors. The higher relative mortality risks we identified Survivorship for SEER registries is tracked through state vital among ER-/PR- patients with small or low-grade tumors raise records and the National Death Index (NDI) established by the the question of whether there may be a beneficial role for adju- National Center for Health Statistics (NCHS). Cause-of-death vant chemotherapy in this population. The lack of data on adju- data in relation to death certificate completion or coding are vant chemotherapies from SEER limits our ability to make this subject to misclassification. However, US death certificates determination. Other underlying biological factors may are checked at several levels for completeness before trans- account for the observed variations in tumor hormone receptor mission to the NCHS. The NDI is reported to have the highest status and mortality risk, requiring additional research to be sensitivity of all major US mortality databases [30]. In addition, conducted. a study that evaluated the accuracy of the cause-of-death code found small discrepancy rates (ranging from 4% to 7%) Competing interests between NDI Plus codes, final study codes, and NCHS nosol- The authors declare that they have no competing interests. ogists' original codes [31]. Authors' contributions The SEER program does not collect data regarding mammog- LD drafted the study design proposal, extracted and prepared raphy screening program participation within the designated the SEER data for statistical analysis, performed the statistical state and metropolitan tumor registries. Mammography analysis, and drafted the manuscript. MR participated in the screening programs have been shown to improve patient out- study design and coordination and made substantial contribu- Page 9 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. based cohort of patients with breast carcinoma. Cancer 2005, tions to manuscript revisions. CL conceived of the study, par- 103:2241-2251. ticipated in the study design and coordination, and made 18. Donegan WL: Prognostic factors. Stage and receptor status in substantial contributions to manuscript revisions. All authors breast cancer. Cancer 1992, 70(6 Suppl):1755-1764. 19. Cianfrocca M, Goldstein LJ: Prognostic and predictive factors in read and approved the final manuscript. early-stage breast cancer. Oncologist 2004, 9:606-616. 20. National Cancer Comprehensive Network (NCCN) Clinical Practice Guidelines in Oncology, Breast Cancer, V.I.2007 References [http://www.nccn.org/professionals/physician_gls/default.asp] 1. Fisher B, Redmond C, Fisher ER, Caplan R: Relative worth of 21. Li CI, Uribe DJ, Daling JR: Clinical characteristics of different estrogen or progesterone receptor and pathologic character- histologic types of breast cancer. Br J Cancer 2005, istics of differentiation as indicators of prognosis in node neg- 93:1046-1052. ative breast cancer patients: findings from National Surgical 22. Gapstur SM, Dupuis J, Gann P, Collila S, Winchester DP: Hor- Adjuvant Breast and Bowel Project Protocol B-06. J Clin Oncol mone receptor status of breast tumors in black, Hispanic, and 1988, 6:1076-1087. non-Hispanic white women. An analysis of 13,239 cases. Can- 2. Parl FF, Schmidt BP, Dupont WD, Wagner RK: Prognostic signif- cer 1996, 77:1465-1471. icance of estrogen receptor status in breast cancer in relation 23. Li CI, Malone KE, Daling JR: Differences in breast cancer hor- to tumor stage, axillary node metastasis, and histopathologic mone receptor status and histology by race and ethnicity grading. Cancer 1984, 54:2237-2242. among women 50 years of age and older. Cancer Epidemiol 3. Crowe JP Jr, Gordon NH, Hubay CA, Shenk RR, Zollinger RM, Biomarkers Prev 2002, 11:601-607. Brumberg DJ, McGuire WL, Shuck JM: Estrogen receptor deter- 24. Pegoraro RJ, Karnan V, Nirmul D, Joubert SM: Estrogen and pro- mination and long term survival of patients with carcinoma of gesterone receptors in breast cancer among women of differ- the breast. Surg Gynecol Obstet 1991, 173:273-278. ent racial groups. Cancer Res 1986, 46(4 Pt 2):2117-2120. 4. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava 25. Elledge RM, Clark GM, Chamness GC, Osborne CK: Tumor bio- E, Syrjanen K: Hormone receptors as prognostic factors in logic factors and breast cancer prognosis among white, His- female breast cancer. Ann Med 1991, 23:643-648. panic, and black women in the United States. J Natl Cancer 5. Lethaby AE, Mason BH, Harvey VJ, Holdaway IM: Survival of Inst 1994, 86:705-712. women with node negative breast cancer in the Auckland 26. Osborne CK: Steroid hormone receptors in breast cancer region. N Z Med J 1996, 109:330-333. management. Breast Cancer Res Treat 1998, 51:227-238. 6. Anderson WF, Chu KC, Chatterjee N, Brawley O, Brinton LA: 27. Allred DC, Bustamante MA, Daniel CO, Gaskill HV, Cruz AB Jr: Tumor variants by hormone receptor expression in white Immunocytochemical analysis of estrogen receptors in human patients with node-negative breast cancer from the surveil- breast carcinomas. Evaluation of 130 cases and review of the lance, epidemiology, and end results database. J Clin Oncol literature regarding concordance with biochemical assay and 2001, 19:18-27. clinical relevance. Arch Surg 1990, 125:107-113. 7. Smith RE, Good BC: Chemoprevention of breast cancer and 28. Harvey JM, Clark GM, Osborne CK, Allred DC: Estrogen receptor the trials of the National Surgical Adjuvant Breast and Bowel status by immunohistochemistry is superior to the ligand- Project and others. Endocr Relat Cancer 2003, 10:347-357. binding assay for predicting response to adjuvant endocrine 8. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, therapy in breast cancer. J Clin Oncol 1999, 17:1474-1481. Senn HJ: Meeting highlights: updated international expert con- 29. Li CI, Daling JR, Malone KE: Incidence of invasive breast cancer sensus on the primary therapy of early breast cancer. J Clin by hormone receptor status from 1992 to 1998. J Clin Oncol Oncol 2003, 21:3357-3365. 2003, 21:28-34. 9. Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, 30. Cowper DC, Kubal JD, Maynard C, Hynes DM: A primer and com- Wolmark N: Treatment of lymph-node-negative, oestrogen- parative review of major US mortality databases. Ann receptor-positive breast cancer: long-term findings from Epidemiol 2002, 12:462-468. National Surgical Adjuvant Breast and Bowel Project ran- 31. Sathiakumar N, Delzell E, Abdalla O: Using the National Death domised clinical trials. Lancet 2004, 364:858-868. Index to obtain underlying cause of death codes. J Occup 10. Surveillance, Epidemiology, and End Results (SEER) Program Environ Med 1998, 40:808-813. Public-Use Data (1973–2001), National Cancer Institute, Divi- 32. IARC Handbooks of Cancer Prevention. Breast Cancer sion of Cancer Control and Population Sciences, Surveillance Screening Volume 7. Lyon, France: IARC Press; 2002. Research Program, Cancer Statistics Branch, released April 33. International Breast Cancer Study Group: Endocrine responsive- based on the November 2003 submission [http:// ness and tailoring adjuvant therapy for postmenopausal www.seer.cancer.gov] lymph node-negative breast cancer: a randomized trial. J Natl 11. Cox DR: Regression models and life tables (with discussion). Cancer Inst 2002, 94:1054-1065. J R Stat Soc Ser B 1972, 34:187-220. 34. Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, 12. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, et al.: Time Data 2nd edition. New York: John Wiley & Sons; 2002. Estrogen-receptor status and outcomes of modern chemo- 13. Pichon MF, Broet P, Magdelenat H, Delarue JC, Spyratos F, Bas- therapy for patients with node-positive breast cancer. JAMA uyau JP, Saez S, Rallet A, Courriere P, Millon R, et al.: Prognostic 2006, 295:1658-1667. value of steroid receptors after long-term follow-up of 2257 operable breast cancers. Br J Cancer 1996, 73:1545-1551. 14. Bernoux A, de Cremoux P, Laine-Bidron C, Martin EC, Asselain B, Magdelenat H: Estrogen receptor negative and progesterone receptor positive primary breast cancer: pathological charac- teristics and clinical outcome. Institut Curie Breast Cancer Study Group. Breast Cancer Res Treat 1998, 49:219-225. 15. Costa SD, Lange S, Klinga K, Merkle E, Kaufmann M: Factors influencing the prognostic role of oestrogen and progesterone receptor levels in breast cancer – results of the analysis of 670 patients with 11 years of follow-up. Eur J Cancer 2002, 38:1329-1334. 16. Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM: Pro- gesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003, 21:1973-1979. 17. Grann VR, Troxel AB, Zojwalla NJ, Jacobson JS, Hershman D, Neu- gut AI: Hormone receptor status and survival in a population- Page 10 of 10 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Breast Cancer Research Springer Journals

Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients

Loading next page...
 
/lp/springer-journals/hormone-receptor-status-tumor-characteristics-and-prognosis-a-Rr3EWiHwcE

References (37)

Publisher
Springer Journals
Copyright
Copyright © 2007 by Dunnwald et al.; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Oncology; Surgical Oncology
eISSN
1465-542X
DOI
10.1186/bcr1639
pmid
17239243
Publisher site
See Article on Publisher Site

Abstract

Background Breast cancer patients with tumors that are diagnosis, ranging from 1.2- to 1.5-fold differences for ER+/PR- estrogen receptor (ER)-positive and/or progesterone receptor cases, 1.5- to 2.1-fold differences for ER-/PR+ cases, and 2.1- (PR)-positive have lower risks of mortality after their diagnosis to 2.6-fold differences for ER-/PR- cases. Greater differences compared to women with ER- and/or PR-negative disease. were observed in analyses stratified by grade; among women However, few studies have evaluated variations in the risks of with low-grade lesions, ER-/PR- patients had a 2.6-fold (95% breast cancer-specific mortality across ER/PR status by either confidence interval [CI] 1.7 to 3.9) to 3.1-fold (95% CI 2.8 to demographic or clinical characteristics. 3.4) increased risk of mortality compared to ER+/PR+ patients, but among women with high-grade lesions, they had a 2.1-fold Methods Using data from 11 population-based cancer (95% CI 1.9 to 2.2) to 2.3-fold (95% CI 1.8 to 2.8) increased registries that participate in the SEER (Surveillance, risk. Epidemiology, and End Results) program, 155,175 women at least 30 years old with a primary diagnosis of invasive breast carcinoma from 1990 to 2001 were included in the study. Associations between joint hormone receptor status and breast Conclusion Compared to women with ER+/PR+ tumors, cancer mortality risk within categories of diagnosis age, women with ER+/PR-, ER-/PR+, or ER-/PR- tumors diagnosis year, race/ethnicity, histologic tumor type, stage, experienced higher risks of mortality, which were largely grade, size, and axillary lymph node status were evaluated using independent of the various demographic and clinical tumor the Cox proportional hazards model. characteristics assessed in this study. The higher relative mortality risks identified among ER-/PR- patients with small or Results Compared to ER+/PR+ cases, elevations in risk of low-grade tumors raise the question of whether there may be a mortality were observed across all subcategories of age at beneficial role for adjuvant chemotherapy in this population. tus by either demographic or clinical characteristics. The goal of this study was to determine whether the greater relative risk Introduction of breast cancer mortality observed among women with hor- Breast cancer patients with tumors that are estrogen receptor mone receptor-negative tumors was similar for those with dif- (ER)-positive and/or progesterone receptor (PR)-positive have ferent demographic characteristics, such as race/ethnicity, lower risks of mortality after their diagnosis compared to age of cancer diagnosis, and year of cancer diagnosis, and for women with ER- and/or PR-negative disease [1-6]. Clinical tri- those with different tumor characteristics, such as stage, als have also shown that the survival advantage for women grade, tumor size, and histology, using data from Surveillance, with hormone receptor-positive tumors is enhanced by treat- Epidemiology, and End Results (SEER), the population-based ment with adjuvant hormonal and/or chemotherapeutic regi- tumor registry program of the National Cancer Institute (NCI). mens [7-9]. However, few studies have evaluated variations in Such an assessment may further elucidate the relationships the risks of breast cancer-specific mortality across ER/PR sta- AJCC = American Joint Committee on Cancer; CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; NCHS = National Center for Health Statistics; NCI = National Cancer Institute; NDI = National Death Index; PR = progesterone receptor; SEER = Surveillance, Epidemiology, and End Results. Page 1 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. between various prognostic indicators in breast cancer and analysis was 31 December 2001. Because we were inter- provide knowledge regarding the prognostic utility of ER/PR ested primarily in cause-specific mortality, our outcome of status by demographic and clinical tumor characteristics. interest was death due to breast cancer as indicated by cause- of-death International Classification of Diseases codes. Women who died of causes other than breast cancer were Materials and methods Patient selection censored at their date of death. The cohort for this study was assembled using data from the NCI's SEER program in the United States [10]. Since the early Statistical analysis 1970s, the SEER program has collected incidence and sur- The statistical software program Stata for Macintosh version vival data from population-based cancer registries spanning 9.1 (StataCorp LP, College Station, TX, USA) was used to five states and four metropolitan areas: Connecticut, Hawaii, perform all analyses. Women with ER+/PR+ tumors served as Iowa, New Mexico, Utah, San Francisco-Oakland (CA), Detroit the referent category in all analyses because this was the larg- (MI), Seattle (Puget Sound) (WA), and Atlanta (GA). In 1992, est ER/PR subgroup. Associations between joint ER/PR two population-based registries were added: San Jose- receptor status and breast cancer mortality risk within catego- Monterey (CA) and Los Angeles (CA). SEER began collecting ries of diagnosis age (<50, 50 to 64, ≥65 years), diagnosis data on ER and PR status in 1990 for breast cancer cases. year (3-year intervals: 1990 to 1992, 1993 to 1995, 1996 to Therefore, only data from 1 January 1990 through 31 Decem- 1998, and 1999 to 2001), race/ethnicity (non-Hispanic white, ber 2001 were included in this analysis. African-American, Native American, Asian/Pacific Islander, Hispanic white), histologic tumor type (ductal, lobular, ductal/ We identified 209,276 women at least 30 years old with a pri- lobular, inflammatory, mucinous, tubular, comedo, medullary, mary diagnosis of invasive carcinoma of the breast as poten- papillary), AJCC stage grouping (I, II, III, IV), SEER grade (I, tially eligible subjects for this study. Women under the age of well differentiated; II, moderately differentiated; III, poorly dif- 30 years were excluded because the occurrence of breast ferentiated; IV, undifferentiated), size (0 to 1.9, 2 to 5, >5 cm), cancer among this age group is rare. Also excluded were and axillary lymph node status (binary – yes/no or 0, 1 to 3, 4 1,873 women whose breast carcinomas were diagnosed only to 10, >11 positive) were estimated using the Cox propor- by autopsy or death certificate or whose diagnostic confirma- tional hazards model. Unknown factors or those with missing tion of breast cancer was unknown. Because our primary anal- data were excluded from all model estimates. We used likeli- ysis focused on associations between joint ER/PR status and hood ratio testing to evaluate whether variations in mortality breast cancer-specific mortality, we excluded 50,291 women risks by these categories were statistically significant. Hazard missing tumor marker data for ER and/or PR (24% of the total ratios (HRs) and their associated 95% confidence intervals potentially eligible subjects). After the noted exclusions, (CIs) were calculated as estimates of relative risks of mortality 155,175 subjects were included in the study. [11,12]. Based on log-log survival curves, proportional haz- ards assumption in these data was validated for all categories Women were categorized into four groups according to their of ER/PR status except for ER-PR+. This is likely a conse- joint ER/PR status: ER+/PR+, ER+/PR-, ER-/PR+, and ER-/ quence of ER-/PR+ being the rarest ER/PR subtype, and for PR-. The SEER registries provide information on age of diag- this subgroup, a gross violation of the proportional hazards nosis, year of diagnosis, and race/ethnicity. Data on other clin- assumption was not observed. In our analyses, we evaluated ical characteristics, such as tumor histology, grade, stage age of diagnosis, year of diagnosis, SEER registry site (strati- (American Joint Committee on Cancer [AJCC] classification fied variable), race/ethnicity, histologic type, tumor size, stage, system), and size, were also available. Additionally, SEER col- grade, and lymph node status as potential confounders in mul- lects data regarding the first course of cancer-directed surgi- tivariate Cox regression modeling. We also evaluated the pos- cal and radiation treatment interventions. However, SEER sible influence of initial cancer treatments (surgery/radiation – does not make data on adjuvant chemotherapy or hormonal yes/no) given that treatment recommendations are based on therapy publicly available. SEER does not collect information tumor characteristics and that therapeutic interventions are on other relevant factors such as reproductive history, anthro- associated with survival. We assessed whether associations pometrics, medical history, family history of cancer, or cancer between ER/PR status and demographic/clinical characteris- screening history. tics were different for varying levels of a factor by fitting inter- action models. For each model, dummy variables were created Outcome measures and each represented the combination of an ER/PR category Each SEER registry routinely updates vital status and follow- and the characteristic assessed, with ER+PR+ and the follow- up information for all patients with cancer. Survival time is cal- ing characteristics as referent categories: age less than 50 culated in months by using the subject's date of breast cancer years, year of diagnosis 1990 to 1992, non-Hispanic white, diagnosis and one of the following: (a) date of death, (b) date tumor grade 1, tumor stage 1, tumor size less than 2 cm, last known to be alive, or (c) the most recent follow-up cutoff negative lymph nodes, and ductal tumor histology. Each full date. The follow-up cutoff date for the SEER data used in our model with the cross-categorized variables was compared to Page 2 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 the reduced model (main effects only) by likelihood ratio test- reduction was greater among women with ER+ disease than ing to assess statistical significance. We also estimated ER- disease. In general, the magnitudes of the HRs associated trends in HRs for each ER/PR profile and the following: (a) age with each ER/PR profile were comparable across race/ethnic- at diagnosis, per 5 years (30 to <35 years referent), (b) diag- ity classifications (p for interaction = 0.77). nosis year, per year (1990 referent), (c) tumor stage (stage 1 referent), (d) tumor size (0 to <1 cm [referent], 1 to <2, 3 to Elevations in breast cancer mortality risks were observed <4, 4 to <5, 5 to <10, ≥10), (e) axillary nodal positivity (0 [ref- among women with ER+/PR-, ER-/PR+, and ER-/PR- tumors erent], 1 to 3, 4 to 10, ≥11), and (f) tumor grade (grade 1 ref- relative to women with ER+/PR+ tumors across the majority of erent). These variables were treated as continuous variables clinical characteristics examined (Table 2). The magnitudes of for trend estimates. All statistical tests were two-sided, and p these relative risks did not vary appreciably by stage; also, for values of 0.05 or less were considered significant. each increase in tumor stage level, two-fold or greater increases in mortality risks were observed within each ER/PR profile (p for trend < 0.0001) (Table 3). Tumor size, lymph Results Within the identified cohort of 155,175 women with known node status, histology, and grade appeared to modify the rela- joint ER/PR receptor status, 98,463 cases had ER+/PR+ tionship between ER/PR status and relative risk of mortality. tumors (63%). Of the remaining women, 19,886 cases had For tumor size and grade, the mortality risks associated with ER+/PR- tumors (13%), 4,896 cases had ER-/PR+ tumors ER-/PR+ tumors were particularly high among women whose (3%), and 31,930 cases had ER-/PR- tumors (21%). Older tumors were either more than 5 cm in size or of high grade. The women were more likely to be diagnosed with ER+/PR+ mortality risks associated with ER-/PR- tumors, relative to tumors, whereas more than one third of women 30 to 39 years ER+/PR+ tumors, were particularly high among women old presented with ER-/PR- tumors (Table 1). The proportion whose tumors were less than 2 cm in size or of low grade of tumors that were ER+/PR+ increased over the study period, (Table 2). In addition, the HRs increased with increasing tumor whereas the proportions of tumors that were ER+/PR- and size, number of axillary lymph node metastases, and disease ER-/PR- held fairly constant, and the proportion of tumors that grade within each ER/PR profile (p for trend < 0.0001, all pro- were ER-/PR+ declined. In general, for the other characteris- files) (Table 3). The magnitude of the associated relative mor- tics shown in Table 1, ER+/PR+ and ER+/PR- tumors were tality risk depended on ER/PR status. For example, women similar to each other and ER-/PR+ and ER-/PR- tumors were with ER-/PR- tumors had a 24% increase in the relative risk of similar to each other. Specifically, compared to women with breast cancer mortality with each increase in tumor grade ER+PR+ and ER+/PR- tumors, those diagnosed with ER-/ level, whereas women with ER+/PR+ tumors had a 62% ele- PR+ and ER-/PR- tumors were somewhat more likely to be vated mortality risk with each increase in tumor grade level. younger and African-American, to have larger tumors, more With respect to histology, compared to women with ER+/PR+ advanced disease stage, and higher tumor grade, and to tumors, women with ER+/PR- tumors had elevated risks of present with axillary lymph node metastases. In addition, mortality if their tumor was ductal or lobular, women with ER-/ women with ER-/PR+ and ER-/PR- tumors were somewhat PR+ tumors had elevated risks of mortality if their tumor was less likely to have lobular, ductal/lobular, mucinous, or tubular ductal or inflammatory, and women with ER-/PR- tumors had carcinomas and were somewhat more likely to have inflamma- elevated risks of mortality across all histologies, except for tory, comedo, or medullary carcinomas. medullary carcinoma. Due to the sparse number of subjects in each hormonal category and limited or no recorded deaths, The risks of breast cancer-specific mortality were elevated data were not shown for mucinous, papillary, and tubular among women with ER+/PR-, ER-/PR+, and ER-/PR- tumors carcinomas. relative to women with ER+/PR+ tumors across all subcatego- ries of age at cancer diagnosis (Table 2). Age was an effect Discussion modifier of the relationship between ER/PR status and relative Previous studies have shown survival advantages among risk of breast cancer mortality (p = 0.03). Specifically, HRs for women with hormone receptor-positive tumors relative to ER-/PR+ and ER-/PR- disease were particularly high among women with hormone receptor-negative tumors [6,9,13-16]. A women 65 years of age and older. For each 5-year increase in recent study by Grann and coworkers [17] that also used data age, a 5% to 7% elevation in mortality risk was observed within collected from the SEER program reported that joint ER/PR each ER/PR profile (p for trend < 0.0001, all profiles) (Table status was an independent predictor of outcome in a large 3). Among the population of women with ER-/PR- tumors rel- cohort of women with breast carcinoma. Our study expands ative to women with ER+/PR+ tumors, a higher relative mor- on this study, further evaluating the association between ER/ tality risk was associated with a tumor diagnosed in the most PR status and breast cancer-specific mortality within sub- recent years versus a tumor diagnosed in the early 1990s (p groups of women defined by personal characteristics (includ- for interaction < 0.0001). However, decreases in HRs ranging ing race/ethnicity, age at cancer diagnosis, and year of cancer from 4% to 8% per year were observed with increasing calen- diagnosis) and tumor characteristics (including histology, dar year within each ER/PR profile and the magnitude of this stage, grade, size, and axillary lymph node metastases). In gen- Page 3 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. Table 1 Selected characteristics among breast cancer cases by hormone receptor status: SEER program, 1990–2001 ER+PR+ ER+PR- ER-PR+ ER-PR- (n = 98,463) (n = 19,886) (n = 4,896) (n = 31,930) Characteristics n Column % Row % n Column % Row % n Column % Row % n Column % Row % Age at diagnosis, years 30–39 4,903 5.0 49.5 885 4.5 8.9 569 11.6 5.7 3,558 11.1 35.9 40–49 18,575 18.9 60.9 2,490 12.5 8.2 1,508 30.8 4.9 7,929 24.8 26.0 50–59 21,807 22.1 61.4 4,464 22.5 12.5 1,161 23.7 3.3 8,094 25.4 22.8 60–69 22,019 22.4 65.9 4,752 23.9 14.2 801 16.4 2.4 5,856 18.3 17.5 70–79 20,667 21.0 68.2 4,662 23.4 15.4 584 11.9 1.9 4,401 13.8 14.5 ≥80 10,492 10.6 67.7 2,633 13.2 17.0 273 5.6 1.8 2,092 6.6 13.5 Diagnosis year 1990–1992 16,500 16.8 61.6 3,751 18.9 14.0 1,111 22.7 4.1 5,435 17.0 20.3 1993–1995 22,087 22.4 61.7 4,514 22.7 12.6 1,485 30.3 4.1 7,728 24.2 21.6 1996–1998 27,734 28.2 64.2 5,239 26.3 12.1 1,367 27.9 3.2 8,884 27.8 20.5 1999–2001 32,142 32.6 65.2 6,382 32.1 12.9 933 19.1 1.9 9,883 31.0 20.0 SEER registry Atlanta, GA 5,696 5.8 59.4 1,171 5.9 12.2 381 7.8 4 2,344 7.3 24.4 Connecticut 11,093 11.3 61.4 2,448 12.3 13.6 602 12.3 3.3 3,914 12.3 21.7 Detroit, MI 10,559 10.7 60.4 2,314 11.6 13.2 539 11 3.1 4,063 12.7 23.3 Hawaii 4,149 4.2 67.0 703 3.5 11.3 273 5.6 4.4 1,072 3.4 17.3 Iowa 10,238 10.4 65.2 1,914 9.6 12.2 530 10.8 3.4 3,017 9.4 19.2 Los Angeles, CA 15,586 15.8 61.4 3,399 17.1 13.4 919 18.8 3.6 5,491 17.2 21.6 New Mexico 4,066 4.1 61.8 885 4.5 13.5 193 3.9 2.9 1,435 4.5 21.8 San Francisco-Oakland, CA 13,063 13.3 63.9 2,750 13.8 13.5 652 13.3 3.2 3,957 12.4 19.4 San Jose, CA 5,474 5.5 65.3 1,134 5.7 13.5 228 4.7 2.7 1,548 4.9 18.5 Seattle, WA 14,241 14.5 68 2,517 12.7 12.0 423 8.6 2.0 3,770 11.8 18.0 Utah 4,298 4.4 66.9 651 3.3 10.1 156 3.2 2.5 1,319 4.1 20.5 Race Non-Hispanic white 78,805 81.7 65.4 15,716 80.5 13.0 3,515 73.5 2.9 22,532 72.1 18.7 African-American 5,724 5.9 48.0 1,488 7.6 12.5 504 10.5 4.2 4,206 13.5 35.3 Native American 284 0.3 55.0 57 0.3 11.0 23 0.5 4.5 152 0.5 29.5 Asian/Pacific Islander 6,065 6.3 65.1 1,061 5.4 11.4 382 8.0 4.1 1,805 5.8 19.4 Hispanic white 5,585 5.8 57.8 1,203 6.2 12.4 359 7.5 3.7 2,524 8.1 26.1 Other/Unknown 2,000 - - 361 - - 113 - - 711 - - Tumor histology Ductal 71,199 72.3 62.7 13,981 70.3 12.3 3,641 74.4 3.2 24,722 77.4 21.8 Lobular 8,980 9.1 73.6 2,160 10.9 17.7 283 5.8 2.3 784 2.5 6.4 Page 4 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 Table 1 (Continued) Selected characteristics among breast cancer cases by hormone receptor status: SEER program, 1990–2001 Ductal/Lobular 7,576 7.7 76.7 1,341 6.7 13.6 233 4.8 2.4 722 2.3 7.3 Inflammatory 543 0.5 37.8 191 1.0 13.3 90 1.8 6.3 611 1.9 42.6 Mucinous 2,927 3.0 80.9 486 2.4 13.5 41 0.8 1.1 164 0.5 4.5 Tubular 1,696 1.7 79 327 1.6 15.2 44 0.9 2.1 79 0.3 3.7 Comedo 1,159 1.2 43.6 318 1.6 12.0 179 3.6 6.7 1,003 3.1 37.7 Medullary 266 0.3 14.7 148 0.8 8.2 97 2.0 5.4 1,292 4.0 71.7 Papillary 582 0.6 79.0 58 0.3 7.9 10 0.2 1.3 87 0.3 11.8 Other 3,535 3.6 49.4 876 4.4 12.2 278 5.7 3.9 2,466 7.7 34.5 Tumor stage I 50,172 52.4 69.2 9,232 48 12.7 1,999 42.7 2.8 11,114 36.2 15.3 II 37,335 39.0 60.3 7,606 39.5 12.3 2,068 44.2 3.3 14,878 48.4 24.1 III 5,332 5.5 51.3 1,471 7.6 14.1 385 8.2 3.7 3,210 10.4 30.9 IV 2,943 3.1 52.1 936 4.9 16.6 230 4.9 4.1 1,536 5.0 27.2 Unstaged 2,681 - - 641 - - 214 - - 1,192 - - Tumor grade 1 18,012 21.8 81.1 2,885 17.5 13.0 405 9.9 1.8 914 3.3 4.1 2 40,642 49.3 74.2 7,133 43.4 13.0 1,324 32.5 2.4 5,682 20.6 10.4 3 22,082 26.8 44.4 6,027 36.6 12.1 2,174 53.3 4.4 19,412 70.4 39.1 4 1,774 2.1 45.0 413 2.5 10.5 173 4.3 4.4 1,579 5.7 40.1 Unknown 15,953 - 3,428 - 820 - 4,343 - Tumor size (cm) 0–1.9 56,547 59.9 69.2 10,302 54.6 12.6 2,271 49.5 2.8 12,576 41.8 15.4 2–5 32,977 34.9 58.7 7,135 37.8 12.7 1,891 41.3 3.4 14,147 47.1 25.2 >5 4,949 5.2 48.8 1,432 7.6 14.1 422 9.2 4.2 3,330 11.1 32.9 Unknown 3,990 - - 1,017 - - 312 - - 1,877 - - Axillary lymph node status Negative 54,948 65.3 64.8 10,428 63.0 12.3 2,622 61.0 3.1 16,749 60.3 19.8 Positive 29,234 34.7 60.9 6,110 37.0 12.7 1,675 39.0 3.5 11,015 39.7 22.9 Unknown 14,281 - - 3,348 - - 599 - - 4,166 - - Surgical treatment Performed 96,387 98.0 63.7 19,216 96.7 12.7 4,764 97.4 3.2 30,847 96.8 20.4 Not performed 2,012 2.0 52.7 648 3.3 17.0 126 2.6 3.3 1,032 3.2 27 Unknown 64 - - 22 - - 6 -- 51 -- Radiation therapy Treated 46,859 48.5 65.5 8,694 44.5 12.1 2,048 42.9 2.9 13,922 44.8 19.5 None 49,776 51.5 61.9 10,836 55.5 13.4 2,725 57.1 3.4 17,131 55.2 21.3 Unknown 1,828 - - 356 - - 123 - - 877 - - ER, estrogen receptor; PR, progesterone receptor; SEER, Surveillance, Epidemiology, and End Results. Page 5 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. Table 2 Breast cancer mortality risk by hormone receptor status among women of different diagnosis age, race/ethnicity, diagnosis year, tumor stage, grade, histology, and axillary lymph node positivity ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- (n = 98,463) (n = 19,886) (n = 4,896) (n = 31,930) Characteristics No. at No. HR No. at No. HR 95% CI No. at No. HR 95% CI No. at No. HR 95% CI p value for risk deaths risk deaths risk deaths risk deaths interaction b c c c All cases 98,463 7,319 1.0 19,886 2,434 1.4 1.3–1.5 4,896 848 1.8 1.6–1.9 31,930 6,300 2.3 2.2–2.4 Age at diagnosis, years c c c <50 16,962 1,042 1.0 2,387 245 1.2 1.1–1.4 1,430 209 1.6 1.4–1.9 8,056 1,323 2.1 1.9–2.3 c c c 50–64 23,467 1,104 1.0 4,745 416 1.5 1.3–1.7 1,072 124 1.5 1.2–1.8 7,651 1,214 2.3 2.1–2.5 c c c ≥65 25,078 1,496 1.0 5,563 540 1.5 1.3–1.7 718 119 2.1 1.8–2.6 5,536 1,020 2.6 2.4–2.8 0.03 Diagnosis year c c c 1990–1992 8,298 1,285 1.0 1,889 419 1.3 1.2–1.5 597 146 1.6 1.3–1.9 2,850 831 1.7 1.5–1.9 c c c 1993–1995 13,665 1,348 1.0 2,688 428 1.5 1.3–1.7 944 160 1.5 1.2–1.8 4,859 1,234 2.2 2.0–2.4 c c c 1996–1998 19,350 837 1.0 3,493 282 1.5 1.3–1.7 971 121 2.1 1.7–2.6 6,181 1,059 2.8 2.5–3.1 c c c 1999–2001 24,194 172 1.0 4,625 69 1.6 1.2–2.1 708 25 3.6 2.3–5.1 7,353 433 4.9 4.1–6.0 <0.001 Race/Ethnicity c c c Non- 53,397 2,831 1.0 10,187 916 1.5 1.3–1.6 2,396 313 1.8 1.6–2.0 15,371 2,462 2.3 2.2–2.5 Hispanic white c c c African- 3,536 348 1.0 907 125 1.2 1.0–1.5 293 60 1.7 1.3–2.2 2,734 615 2.2 1.9–2.6 American Native 196 19 1.0 34 11 1.5 0.5–3.8 12 1 1.7 0.1–16.4 102 25 3.4 1.5–7.3 American c c c Asian/Pacific 4,497 189 1.0 748 63 1.8 1.3–2.4 267 34 1.6 1.1–2.4 1,273 166 2.3 1.8–2.8 Islander c c c Hispanic 3,881 255 1.0 819 83 1.3 1.0–1.7 252 44 1.9 1.3–2.6 1,763 289 2.3 1.9–2.8 0.77 white Tumor stage c c c I 33,821 487 1.0 6,038 146 1.4 1.2–1.7 1,369 51 1.6 1.2–2.1 7,704 391 2.3 2.0–2.7 c c c II 27,363 2,110 1.0 5,472 674 1.4 1.3–1.6 1,529 248 1.6 1.4–1.9 11,051 2,069 2.3 2.2–2.5 c c c III 3,410 659 1.0 922 252 1.3 1.2–1.6 245 104 2.1 1.7–2.6 1,940 763 2.3 2.0–2.6 Page 6 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 Table 2 (Continued) Breast cancer mortality risk by hormone receptor status among women of different diagnosis age, race/ethnicity, diagnosis year, tumor stage, grade, histology, and axillary lymph node positivity c c c IV 672 302 1.0 192 102 1.3 1.0–1.6 59 42 1.9 1.3–2.7 357 245 2.3 1.9–2.8 0.45 Tumor size (cm) c c c 0–1.9 39,418 865 1.0 6,957 243 1.4 1.2–1.6 1,607 91 1.5 1.2–1.9 8,799 715 2.6 2.3–2.9 c c c 2–5 22,579 2,081 1.0 4,781 708 1.5 1.3–1.6 1,331 253 1.8 1.5–2.0 10,214 2,019 2.2 2.1–2.4 c c c >5 2,718 526 1.0 761 206 1.3 1.1–1.6 217 89 2.2 1.7–2.7 1,730 636 2.2 1.9–2.5 <0.001 Axillary lymph node status c c c Negative 42,451 942 1.0 7,924 324 1.6 1.4–1.8 1,898 114 2.0 1.6–2.4 12,541 1,006 2.8 2.6–3.1 c c c 1–3 14,953 1,021 1.0 2,828 324 1.5 1.3–1.7 790 133 1.8 1.5–2.1 4,857 977 2.5 2.3–2.7 c c c 4–10 5,313 861 1.0 1,133 277 1.4 1.2–1.6 332 108 1.7 1.3–2.1 2,268 793 2.4 2.2–2.7 c c c ≥11 2,549 734 1.0 739 249 1.2 1.0–1.4 182 90 1.7 1.3–2.1 1,386 692 2.2 1.9–2.4 0.08 Tumor histology c c c Ductal 52,178 2,919 1.0 9,978 994 1.5 1.4–1.6 2,711 390 1.8 1.6–2.0 18,542 3,040 2.3 2.2–2.5 c c Lobular 3,975 186 1.0 938 64 1.4 1.0–1.9 123 3 0.4 0.1–1.4 325 47 1.9 1.4–2.7 Ductal/ 5,472 254 1.0 929 59 1.3 0.9–1.7 148 13 1.1 0.6–2.0 511 83 2.7 2.1–3.5 Lobular c c Inflammatory 241 52 1.0 77 22 1.4 0.8–2.3 39 19 3.4 1.9–6.1 258 123 3.5 2.4–5.0 Comedo 652 91 1.0 187 19 0.6 0.4–1.1 91 16 1.2 0.7–2.1 556 109 1.6 1.2–2.1 Medullary 120 14 1.0 73 6 0.7 0.2–2.2 48 4 0.9 0.2–3.0 716 54 0.7 0.4–1.4 <0.001 Tumor grade c c 1 13,854 156 1.0 2,141 40 1.6 1.1–2.3 310 6 1.0 0.4–2.5 661 32 2.6 1.7–3.9 c c c 2 32,661 1,349 1.0 5,555 374 1.5 1.3–2.1 1,074 95 1.7 1.3–2.1 4,312 575 3.1 2.8–3.4 c c c 3 17,352 1,873 1.0 4,613 710 1.3 1.2–1.5 1,694 319 1.7 1.5–1.9 14,967 2,635 2.1 1.9–2.2 c c c 4 1,399 180 1.0 315 50 1.4 1.0–2.0 124 25 2.1 1.4–3.3 1,112 226 2.3 1.8–2.8 <0.001 a b The reference ER/PR profile for all analyses was ER+/PR+. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation c d treatment, and lymph node status (positive/negative). p < 0.05. HRs adjusted for year at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). HRs adjusted for age at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). HRs adjusted for age and year at diagnosis, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). Race unknown, n = 3,185. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status (categorical), and surgical and radiation treatment. Stage unknown, n = 4,728. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status (categorical), and surgical and radiation treatment. Size unknown, n = 7,196. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, grade, and surgical and radiation treatment. Nodal status unknown, n = 22,394. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor grade, stage, lymph node status (categorical), and surgical and radiation treatment. Other/unknown histology, n = 7,155. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, lymph node status (categorical), and surgical and radiation treatment. Grade unknown, n = 24,544. CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; PR, progesterone receptor; SEER, Surveillance, Epidemiology, and End Results. Page 7 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. Table 3 Trends in hazard ratios for breast cancer mortality associated with hormone receptor status and different demographic and clinical characteristics ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- Characteristics HR 95% CI HR 95% CI HR 95% CI HR 95% CI Age at diagnosis, per 5 years 1.05 1.04–1.06 1.07 1.04–1.09 1.07 1.03–1.10 1.06 1.05–1.07 Diagnosis year, per year 0.93 0.92–0.94 0.92 0.90–0.94 0.95 0.91–0.98 0.96 0.95–0.97 Tumor stage 2.33 2.20–2.46 2.29 2.09–2.51 2.55 2.19–2.96 2.06 1.94–2.18 Tumor size (cm) 1.27 1.24–1.30 1.29 1.24–1.34 1.33 1.25–1.41 1.22 1.20–1.25 Axillary lymph node status 1.71 1.65–1.78 1.55 1.46–1.66 1.61 1.44–1.80 1.64 1.58–1.70 Tumor grade 1.62 1.55–1.70 1.49 1.36–1.63 1.72 1.46–2.03 1.24 1.16–1.32 Five-year categories. Reference = 30 to <35 years. HRs adjusted for year at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). Reference = 1990. HRs adjusted for age at diagnosis, race, SEER registry, tumor histology, grade, stage, surgical and radiation treatment, and lymph node status (positive/negative). Reference = stage 1. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status, and surgical and radiation treatment. Stage unknown, n = 4,728. Categories = 0 to <1, 1 to <2, 2 to <3, 3 to <4, 4 to <5, 5 to <10, ≥10 cm. Reference = 0 to <1 cm. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, grade, lymph node status, and surgical and radiation treatment. Size unknown, n = 7,196. Categories = 0, 1 to 3, 4 to 10, ≥11. Reference = 0. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, grade, and surgical and radiation treatment. Nodal status unknown, n = 22,394. Reference = grade 1. HRs adjusted for age and year at diagnosis, race, SEER registry, tumor histology, stage, lymph node status, and surgical and radiation treatment. Grade unknown, n = 24,544. CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; PR, progesterone receptor; SEER, Surveillance, Epidemiology, and End Results. eral, we observed that the higher relative risks of mortality recommended for ER-/PR- patients whose tumors are small associated with having an ER+/PR-, an ER-/PR+, or an ER-/ and have favorable features (that is, negative lymph nodes, PR- tumor relative to an ER+/PR+ tumor were consistently highly differentiated) [20]. Our data also showed that ER-/ present across almost all tumor characteristics. Even among PR+ patients whose tumors were more than 5 cm in size or of women with poor prognoses, such as those with stage IV dis- high grade had particularly elevated relative mortality risks ease, multiple positive lymph nodes, or tumors of high grade, (HRs = 2.2 and 2.1, respectively) that were higher than those differences in the relative risk of mortality by ER/PR status with ER+/PR- tumors of similar size and grade (HRs = 1.3 and were observed. We also estimated mortality trends by ER/PR 1.4, respectively), suggesting that ER negativity may have a status within the study population. Within each ER/PR profile, greater influence on mortality risk than PR negativity among we document an increase in the relative risk of breast cancer women with these tumor types. Compared to women with mortality for each 5-year increase in age and for each incre- ER+/PR+ tumors, those with ER-/PR- tumors had increased mental increase in tumor stage, size, grade, or axillary lymph risks of mortality across almost all histologic classifications, node metastases. These findings are in agreement with the suggesting that combined ER/PR negativity has implications known correlation between increased breast cancer mortality for relative mortality risk, regardless of tumor histology. The risk and increasing tumor stage, size, grade, or regional lymph one noted exception was that ER/PR status did not appear to node metastases [18,19]. We observed a decreased mortality be related to the relative risk of mortality among women with trend each year over the study period of 1990 to 2001 which medullary carcinomas. Medullary carcinomas are rare, and was greatest in magnitude among women with ER+ tumors. although they are typically high-grade, they tend to have well- This trend may be related to improvements in breast cancer defined, distinct borders. Their prognosis is more favorable treatments and/or early detection methods resulting in than that of other invasive breast carcinomas, such as ductal improved patient outcomes. carcinoma [21]. We did observe some variations in the association between Researchers who examined the risk of invasive breast carci- ER/PR status and risk of breast cancer mortality by tumor size, noma diagnosis among women of different races reported that grade, and histology. Relative to ER+/PR+ patients, and within certain ethnicities have elevated risks of presenting with ER-/ subcategories of tumor size and grade, the highest observed PR- tumors. African-Americans, Asians, Native Americans, and relative mortality risks were among ER-/PR- patients whose Hispanic whites were found to have greater risks of presenting tumors were small (0 to 1.9 cm) or of low grade (grade 1 and with ER-/PR- breast tumors compared to non-Hispanic whites 2). These elevated risks are likely related to adjuvant treatment [22-25]. Although it has been shown that women of certain standards given that hormonal therapy generally is recom- racial/ethnic groups have increased risks of developing hor- mended for women with ER+/PR+ disease, regardless of mone receptor-negative tumors, our results show little or no tumor size. Conversely, adjuvant chemotherapy is not routinely difference in mortality risks within ethnic classes for each ER/ Page 8 of 10 (page number not for citation purposes) Available online http://breast-cancer-research.com/content/9/1/R6 PR profile. For example, African-American women whose comes [32]. The decreased mortality trend we observed each tumors were ER-/PR+ or ER-/PR- were found to have relative year over the study period, particularly among women with risks of breast cancer mortality similar to non-Hispanic whites ER+ tumors, may be due in part to screening programs. with ER-/PR+ or ER-/PR- tumors, respectively. A final limitation of this study is that SEER registries do not There are potential study limitations using SEER data. First, provide data on the receipt of adjuvant or hormonal therapies ER/PR status, tumor histology, and tumor grade were not following primary surgical and/or radiotherapy interventions. assessed centrally since the data recorded by SEER are Treating hormone receptor-positive tumors with hormonal derived from review of clinical pathology reports. Most impor- therapies has been shown to be a contributing factor in better tantly, assays and techniques used for ER/PR testing likely var- survival among women with breast cancer [9]. A large propor- ied both across and within laboratories over the course of this tion of the survival advantage experienced by ER+/PR+ study. For example, cutoff points may have been dissimilar in patients compared to ER-/PR- patients may be due to the use differentiating hormone receptor positivity. High cutoff values of hormonal therapy. Our data indicate that in 1990 to 1992, may result in tumors being misclassified as ER- [26]. However, when the use of hormonal therapy had just begun, ER-/PR- assay techniques for ER and PR have improved since their patients had a 1.7-fold greater relative risk of mortality; inception nearly 30 years ago and receptor status can be however, by 1999 to 2001, when hormonal therapy was appropriately determined with relative ease [27,28]. In the widely integrated into clinical practice and guidelines for its period to which this study was restricted (1990 to 2001), use were well established, women with ER-/PR- tumors had a pathology laboratories in general routinely performed ER/PR 4.9-fold greater relative risk of mortality. In future years, the testing of breast cancer. Also reassuring is the fact that the advent of better chemotherapy treatments for the ER- patient proportions of the four joint tumor ER/PR receptor profiles in population may result in improved disease-free survival and our study population were comparable to those reported in overall survival. Recent studies have reported that the large other studies [13,14]. survival differences among ER+ patients treated with hormo- nal therapy versus ER- patients treated with chemotherapy The exclusion of subjects with no recorded ER/PR data is a have dwindled and that ER- patients are now deriving a greater second potential limitation of this study. The absence of benefit from improved chemotherapy regimens with risk reduc- recorded hormone receptor data has been reported to be tions as high as 49% [33,34]. associated with age and year of diagnosis, tumor stage, grade, histology, and SEER registries [17,29], and thus the lack of Conclusion ER/PR data on these cases could bias our results. However, Overall, our findings suggest that the higher risks of mortality the number of SEER records missing ER/PR data has in women with ER+/PR-, ER-/PR+, and ER-/PR- tumors, com- declined over time and the decline has been shown to be con- pared to women with ER+/PR+ tumors, are largely independ- sistent across all age categories [29]. The proportion of ent of the various demographic and clinical tumor records containing ER/PR data for this cohort increased over characteristics assessed in this study. This indicates that the time, ranging from 67.5% in 1990 to 73% in the years 1994 prognostic utility of ER/PR status is for the most part inde- to 1995 and 80.7% in 2001, results that are consistent with pendent of these other factors. However, the strength of the prior reports [17]. associations we assessed did vary within subcategories of certain factors. The higher relative mortality risks we identified Survivorship for SEER registries is tracked through state vital among ER-/PR- patients with small or low-grade tumors raise records and the National Death Index (NDI) established by the the question of whether there may be a beneficial role for adju- National Center for Health Statistics (NCHS). Cause-of-death vant chemotherapy in this population. The lack of data on adju- data in relation to death certificate completion or coding are vant chemotherapies from SEER limits our ability to make this subject to misclassification. However, US death certificates determination. Other underlying biological factors may are checked at several levels for completeness before trans- account for the observed variations in tumor hormone receptor mission to the NCHS. The NDI is reported to have the highest status and mortality risk, requiring additional research to be sensitivity of all major US mortality databases [30]. In addition, conducted. a study that evaluated the accuracy of the cause-of-death code found small discrepancy rates (ranging from 4% to 7%) Competing interests between NDI Plus codes, final study codes, and NCHS nosol- The authors declare that they have no competing interests. ogists' original codes [31]. Authors' contributions The SEER program does not collect data regarding mammog- LD drafted the study design proposal, extracted and prepared raphy screening program participation within the designated the SEER data for statistical analysis, performed the statistical state and metropolitan tumor registries. Mammography analysis, and drafted the manuscript. MR participated in the screening programs have been shown to improve patient out- study design and coordination and made substantial contribu- Page 9 of 10 (page number not for citation purposes) Breast Cancer Research Vol 9 No 1 Dunnwald et al. based cohort of patients with breast carcinoma. Cancer 2005, tions to manuscript revisions. CL conceived of the study, par- 103:2241-2251. ticipated in the study design and coordination, and made 18. Donegan WL: Prognostic factors. Stage and receptor status in substantial contributions to manuscript revisions. All authors breast cancer. Cancer 1992, 70(6 Suppl):1755-1764. 19. Cianfrocca M, Goldstein LJ: Prognostic and predictive factors in read and approved the final manuscript. early-stage breast cancer. Oncologist 2004, 9:606-616. 20. National Cancer Comprehensive Network (NCCN) Clinical Practice Guidelines in Oncology, Breast Cancer, V.I.2007 References [http://www.nccn.org/professionals/physician_gls/default.asp] 1. Fisher B, Redmond C, Fisher ER, Caplan R: Relative worth of 21. Li CI, Uribe DJ, Daling JR: Clinical characteristics of different estrogen or progesterone receptor and pathologic character- histologic types of breast cancer. Br J Cancer 2005, istics of differentiation as indicators of prognosis in node neg- 93:1046-1052. ative breast cancer patients: findings from National Surgical 22. Gapstur SM, Dupuis J, Gann P, Collila S, Winchester DP: Hor- Adjuvant Breast and Bowel Project Protocol B-06. J Clin Oncol mone receptor status of breast tumors in black, Hispanic, and 1988, 6:1076-1087. non-Hispanic white women. An analysis of 13,239 cases. Can- 2. Parl FF, Schmidt BP, Dupont WD, Wagner RK: Prognostic signif- cer 1996, 77:1465-1471. icance of estrogen receptor status in breast cancer in relation 23. Li CI, Malone KE, Daling JR: Differences in breast cancer hor- to tumor stage, axillary node metastasis, and histopathologic mone receptor status and histology by race and ethnicity grading. Cancer 1984, 54:2237-2242. among women 50 years of age and older. Cancer Epidemiol 3. Crowe JP Jr, Gordon NH, Hubay CA, Shenk RR, Zollinger RM, Biomarkers Prev 2002, 11:601-607. Brumberg DJ, McGuire WL, Shuck JM: Estrogen receptor deter- 24. Pegoraro RJ, Karnan V, Nirmul D, Joubert SM: Estrogen and pro- mination and long term survival of patients with carcinoma of gesterone receptors in breast cancer among women of differ- the breast. Surg Gynecol Obstet 1991, 173:273-278. ent racial groups. Cancer Res 1986, 46(4 Pt 2):2117-2120. 4. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava 25. Elledge RM, Clark GM, Chamness GC, Osborne CK: Tumor bio- E, Syrjanen K: Hormone receptors as prognostic factors in logic factors and breast cancer prognosis among white, His- female breast cancer. Ann Med 1991, 23:643-648. panic, and black women in the United States. J Natl Cancer 5. Lethaby AE, Mason BH, Harvey VJ, Holdaway IM: Survival of Inst 1994, 86:705-712. women with node negative breast cancer in the Auckland 26. Osborne CK: Steroid hormone receptors in breast cancer region. N Z Med J 1996, 109:330-333. management. Breast Cancer Res Treat 1998, 51:227-238. 6. Anderson WF, Chu KC, Chatterjee N, Brawley O, Brinton LA: 27. Allred DC, Bustamante MA, Daniel CO, Gaskill HV, Cruz AB Jr: Tumor variants by hormone receptor expression in white Immunocytochemical analysis of estrogen receptors in human patients with node-negative breast cancer from the surveil- breast carcinomas. Evaluation of 130 cases and review of the lance, epidemiology, and end results database. J Clin Oncol literature regarding concordance with biochemical assay and 2001, 19:18-27. clinical relevance. Arch Surg 1990, 125:107-113. 7. Smith RE, Good BC: Chemoprevention of breast cancer and 28. Harvey JM, Clark GM, Osborne CK, Allred DC: Estrogen receptor the trials of the National Surgical Adjuvant Breast and Bowel status by immunohistochemistry is superior to the ligand- Project and others. Endocr Relat Cancer 2003, 10:347-357. binding assay for predicting response to adjuvant endocrine 8. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, therapy in breast cancer. J Clin Oncol 1999, 17:1474-1481. Senn HJ: Meeting highlights: updated international expert con- 29. Li CI, Daling JR, Malone KE: Incidence of invasive breast cancer sensus on the primary therapy of early breast cancer. J Clin by hormone receptor status from 1992 to 1998. J Clin Oncol Oncol 2003, 21:3357-3365. 2003, 21:28-34. 9. Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, 30. Cowper DC, Kubal JD, Maynard C, Hynes DM: A primer and com- Wolmark N: Treatment of lymph-node-negative, oestrogen- parative review of major US mortality databases. Ann receptor-positive breast cancer: long-term findings from Epidemiol 2002, 12:462-468. National Surgical Adjuvant Breast and Bowel Project ran- 31. Sathiakumar N, Delzell E, Abdalla O: Using the National Death domised clinical trials. Lancet 2004, 364:858-868. Index to obtain underlying cause of death codes. J Occup 10. Surveillance, Epidemiology, and End Results (SEER) Program Environ Med 1998, 40:808-813. Public-Use Data (1973–2001), National Cancer Institute, Divi- 32. IARC Handbooks of Cancer Prevention. Breast Cancer sion of Cancer Control and Population Sciences, Surveillance Screening Volume 7. Lyon, France: IARC Press; 2002. Research Program, Cancer Statistics Branch, released April 33. International Breast Cancer Study Group: Endocrine responsive- based on the November 2003 submission [http:// ness and tailoring adjuvant therapy for postmenopausal www.seer.cancer.gov] lymph node-negative breast cancer: a randomized trial. J Natl 11. Cox DR: Regression models and life tables (with discussion). Cancer Inst 2002, 94:1054-1065. J R Stat Soc Ser B 1972, 34:187-220. 34. Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, 12. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, et al.: Time Data 2nd edition. New York: John Wiley & Sons; 2002. Estrogen-receptor status and outcomes of modern chemo- 13. Pichon MF, Broet P, Magdelenat H, Delarue JC, Spyratos F, Bas- therapy for patients with node-positive breast cancer. JAMA uyau JP, Saez S, Rallet A, Courriere P, Millon R, et al.: Prognostic 2006, 295:1658-1667. value of steroid receptors after long-term follow-up of 2257 operable breast cancers. Br J Cancer 1996, 73:1545-1551. 14. Bernoux A, de Cremoux P, Laine-Bidron C, Martin EC, Asselain B, Magdelenat H: Estrogen receptor negative and progesterone receptor positive primary breast cancer: pathological charac- teristics and clinical outcome. Institut Curie Breast Cancer Study Group. Breast Cancer Res Treat 1998, 49:219-225. 15. Costa SD, Lange S, Klinga K, Merkle E, Kaufmann M: Factors influencing the prognostic role of oestrogen and progesterone receptor levels in breast cancer – results of the analysis of 670 patients with 11 years of follow-up. Eur J Cancer 2002, 38:1329-1334. 16. Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM: Pro- gesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol 2003, 21:1973-1979. 17. Grann VR, Troxel AB, Zojwalla NJ, Jacobson JS, Hershman D, Neu- gut AI: Hormone receptor status and survival in a population- Page 10 of 10 (page number not for citation purposes)

Journal

Breast Cancer ResearchSpringer Journals

Published: Jan 19, 2007

There are no references for this article.