Previous studies have shown survival advantages among women with hormone receptor-positive tumors relative to women with hormone receptor-negative tumors [6
]. A recent study by Grann and coworkers [17
] that also used data collected from the SEER program reported that joint ER/PR status was an independent predictor of outcome in a large cohort of women with breast carcinoma. Our study expands on this study, further evaluating the association between ER/PR status and breast cancer-specific mortality within subgroups of women defined by personal characteristics (including race/ethnicity, age at cancer diagnosis, and year of cancer diagnosis) and tumor characteristics (including histology, stage, grade, size, and axillary lymph node metastases). In general, we observed that the higher relative risks of mortality associated with having an ER+/PR-, an ER-/PR+, or an ER-/PR- tumor relative to an ER+/PR+ tumor were consistently present across almost all tumor characteristics. Even among women with poor prognoses, such as those with stage IV disease, multiple positive lymph nodes, or tumors of high grade, differences in the relative risk of mortality by ER/PR status were observed. We also estimated mortality trends by ER/PR status within the study population. Within each ER/PR profile, we document an increase in the relative risk of breast cancer mortality for each 5-year increase in age and for each incremental increase in tumor stage, size, grade, or axillary lymph node metastases. These findings are in agreement with the known correlation between increased breast cancer mortality risk and increasing tumor stage, size, grade, or regional lymph node metastases [18
]. We observed a decreased mortality trend each year over the study period of 1990 to 2001 which was greatest in magnitude among women with ER+ tumors. This trend may be related to improvements in breast cancer treatments and/or early detection methods resulting in improved patient outcomes.
We did observe some variations in the association between ER/PR status and risk of breast cancer mortality by tumor size, grade, and histology. Relative to ER+/PR+ patients, and within subcategories of tumor size and grade, the highest observed relative mortality risks were among ER-/PR- patients whose tumors were small (0 to 1.9 cm) or of low grade (grade 1 and 2). These elevated risks are likely related to adjuvant treatment standards given that hormonal therapy generally is recommended for women with ER+/PR+ disease, regardless of tumor size. Conversely, adjuvant chemotherapy is not routinely recommended for ER-/PR- patients whose tumors are small and have favorable features (that is, negative lymph nodes, highly differentiated) [20
]. Our data also showed that ER-/PR+ patients whose tumors were more than 5 cm in size or of high grade had particularly elevated relative mortality risks (HRs = 2.2 and 2.1, respectively) that were higher than those with ER+/PR- tumors of similar size and grade (HRs = 1.3 and 1.4, respectively), suggesting that ER negativity may have a greater influence on mortality risk than PR negativity among women with these tumor types. Compared to women with ER+/PR+ tumors, those with ER-/PR- tumors had increased risks of mortality across almost all histologic classifications, suggesting that combined ER/PR negativity has implications for relative mortality risk, regardless of tumor histology. The one noted exception was that ER/PR status did not appear to be related to the relative risk of mortality among women with medullary carcinomas. Medullary carcinomas are rare, and although they are typically high-grade, they tend to have well-defined, distinct borders. Their prognosis is more favorable than that of other invasive breast carcinomas, such as ductal carcinoma [21
Researchers who examined the risk of invasive breast carcinoma diagnosis among women of different races reported that certain ethnicities have elevated risks of presenting with ER-/PR- tumors. African-Americans, Asians, Native Americans, and Hispanic whites were found to have greater risks of presenting with ER-/PR- breast tumors compared to non-Hispanic whites [22
]. Although it has been shown that women of certain racial/ethnic groups have increased risks of developing hormone receptor-negative tumors, our results show little or no difference in mortality risks within ethnic classes for each ER/PR profile. For example, African-American women whose tumors were ER-/PR+ or ER-/PR- were found to have relative risks of breast cancer mortality similar to non-Hispanic whites with ER-/PR+ or ER-/PR- tumors, respectively.
There are potential study limitations using SEER data. First, ER/PR status, tumor histology, and tumor grade were not assessed centrally since the data recorded by SEER are derived from review of clinical pathology reports. Most importantly, assays and techniques used for ER/PR testing likely varied both across and within laboratories over the course of this study. For example, cutoff points may have been dissimilar in differentiating hormone receptor positivity. High cutoff values may result in tumors being misclassified as ER- [26
]. However, assay techniques for ER and PR have improved since their inception nearly 30 years ago and receptor status can be appropriately determined with relative ease [27
]. In the period to which this study was restricted (1990 to 2001), pathology laboratories in general routinely performed ER/PR testing of breast cancer. Also reassuring is the fact that the proportions of the four joint tumor ER/PR receptor profiles in our study population were comparable to those reported in other studies [13
The exclusion of subjects with no recorded ER/PR data is a second potential limitation of this study. The absence of recorded hormone receptor data has been reported to be associated with age and year of diagnosis, tumor stage, grade, histology, and SEER registries [17
], and thus the lack of ER/PR data on these cases could bias our results. However, the number of SEER records missing ER/PR data has declined over time and the decline has been shown to be consistent across all age categories [29
]. The proportion of records containing ER/PR data for this cohort increased over time, ranging from 67.5% in 1990 to 73% in the years 1994 to 1995 and 80.7% in 2001, results that are consistent with prior reports [17
Survivorship for SEER registries is tracked through state vital records and the National Death Index (NDI) established by the National Center for Health Statistics (NCHS). Cause-of-death data in relation to death certificate completion or coding are subject to misclassification. However, US death certificates are checked at several levels for completeness before transmission to the NCHS. The NDI is reported to have the highest sensitivity of all major US mortality databases [30
]. In addition, a study that evaluated the accuracy of the cause-of-death code found small discrepancy rates (ranging from 4% to 7%) between NDI Plus codes, final study codes, and NCHS nosologists' original codes [31
The SEER program does not collect data regarding mammography screening program participation within the designated state and metropolitan tumor registries. Mammography screening programs have been shown to improve patient outcomes [32
]. The decreased mortality trend we observed each year over the study period, particularly among women with ER+ tumors, may be due in part to screening programs.
A final limitation of this study is that SEER registries do not provide data on the receipt of adjuvant or hormonal therapies following primary surgical and/or radiotherapy interventions. Treating hormone receptor-positive tumors with hormonal therapies has been shown to be a contributing factor in better survival among women with breast cancer [9
]. A large proportion of the survival advantage experienced by ER+/PR+ patients compared to ER-/PR- patients may be due to the use of hormonal therapy. Our data indicate that in 1990 to 1992, when the use of hormonal therapy had just begun, ER-/PR- patients had a 1.7-fold greater relative risk of mortality; however, by 1999 to 2001, when hormonal therapy was widely integrated into clinical practice and guidelines for its use were well established, women with ER-/PR- tumors had a 4.9-fold greater relative risk of mortality. In future years, the advent of better chemotherapy treatments for the ER- patient population may result in improved disease-free survival and overall survival. Recent studies have reported that the large survival differences among ER+ patients treated with hormonal therapy versus ER- patients treated with chemotherapy have dwindled and that ER- patients are now deriving a greater benefit from improved chemotherapy regimens with risk reductions as high as 49% [33