Abstract
Purpose.
Estrogen receptor (ER)+/progesterone receptor (PR)- or ER−/PR+ breast cancer prognosis has not been well-described outside of clinical trials. We evaluated the relationship between ER/PR (ER+/PR−, ER−/PR+, ER+/PR+, ER−/PR−) subgroups and breast cancer-specific mortality within a general community setting in the US.
Methods.
A Retrospective cohort of 11,737 women diagnosed with breast cancer between 1990–2016 within US integrated healthcare systems (median follow-up=7 years; 1,104 breast cancer-specific deaths) were included in this analysis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusting for site, demographic and clinicopathological characteristics, and treatment (surgery/radiotherapy, chemotherapy, endocrine therapy).
Results.
Breast cancer-specific mortality was higher for those with ER+/PR− (n=1,233) compared with ER+/PR+ tumors (n=8,439) before (HR=1.43; 95%CI=1.17–1.75) and after treatment adjustment (HR=1.58; 95%CI=1.27–1.97). ER+/PR− breast cancer-specific mortality remained higher than ER+/PR+ tumors when stratified by treatment received. Breast cancer-specific mortality was similar in ER−/PR+ (n=161) compared with ER+/PR+ tumors.
Conclusions.
Our findings suggest that ER+/PR− tumors may have worse breast cancer-specific mortality than ER+/PR+ tumors in a community setting.
Keywords: Breast neoplasm, estrogen receptor, progestogen receptor, mortality, tamoxifen aromatase inhibitors, radiotherapy, chemotherapy
Introduction
Estrogen receptor (ER) and progesterone receptor (PR) status are well-established prognostic factors for breast cancer (1). About 65% of breast cancers are ER+/PR+ whereas <10% are defined as ER+/PR− or ER−/PR+ (2). There has been some controversy as to whether ER+/PR− or ER−/PR+ are biological plausible subgroups or the result of misclassification (3, 4). A recent study using US Surveillance, Epidemiology and End Results (SEER) registry data reported women with ER+/PR− or ER−/PR+ breast cancer had higher breast cancer-specific mortality compared with ER+/PR+ breast cancer, but lower breast cancer-specific mortality than ER−/PR− disease (2). Although these findings were consistent with prior observational studies (5, 6), clinical trials have found that PR status does not influence breast cancer outcomes among those treated with endocrine therapy (7–9). One limitation of the SEER study (2) was the likely under-ascertainment of treatment (10). We therefore evaluated breast cancer-specific mortality across ER/PR subgroups within a large cohort of breast cancer patients with comprehensive treatment records collected within two US integrated healthcare delivery systems.
Methods
We identified 13,184 women, aged 18–84 years, diagnosed with a first invasive or in situ primary unilateral breast cancer at Kaiser Permanente (KP) Colorado (n=5,286, 1994–2014) or KP Washington (n=7,898, 1990–2016). Eligible women had surgery and survived without developing any second cancer within 12 months of initial breast cancer diagnosis. Women with unknown or borderline ER/PR status were excluded (n=1,447), resulting in an analytic population of 11,737. Follow-up time started 12-months after diagnosis and continued until the earliest of date of death, exit from healthcare plan, or end of follow-up. Data on cancer diagnoses, tumor characteristics, and initial treatment (surgery, radiotherapy, chemotherapy, endocrine therapy) were obtained from electronic medical record databases and local tumor registries (KP Colorado) or SEER (KP Washington). Electronic pharmacy data was used for initial chemotherapy and endocrine therapy. Date and underlying cause of death were ascertained via tumor and state death registries, and National Death Index linkage. International Classification of Diseases (ICD) codes were used to identify breast cancer deaths (ICD-9: 174,175; ICD-10: C50). This study was approved by the NIH Institutional Review Board (IRB) and the KP Colorado and Washington IRBs.
Cumulative incidence of breast cancer-specific mortality was estimated by ER/PR subgroups after accounting for competing events (11). Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for breast cancer-specific mortality by ER/PR subgroups. Multivariable models adjusted for race, study site, clinicopathological factors, body mass index (BMI), and treatment (see Table 1 footnotes). Analyses stratified separately by endocrine therapy, initial chemotherapy, or initial radiotherapy (among women with breast conserving surgery) were conducted and restricted to ER+/PR+ and ER+/PR− subgroups due to small numbers for other subgroups. Proportional hazard assumptions were tested based on Schoenfeld’s residuals slope (12). We conducted a post hoc analysis to evaluate secular changes in treatment following the St. Gallen Expert Panel’s clinicopathological surrogate definitions of luminal breast cancer subtypes in 2013 (13). Analyses were conducted using R software (version 4.0.5). All statistical tests were two-sided; P-values <0.05 were considered statistically significant.
Table 1.
Risk of breast cancer cancer-specific mortality for hormone receptor subgroups in Kaiser Permanente Colorado and Kaiser Permanente Washington (N=11,737)
| Hormone receptor subgroups | No. of women at risk | No. of breast cancer deaths | Unadjusted | Multivariable-adjusteda | Multivariable-adjusted + treatment receiptb |
|---|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | HR (95% CI) | |||
| ER+/PR+ | 8,439 | 610 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| ER+/PR− | 1,233 | 144 | 1.62 (1.35 to 1.94) | 1.43 (1.17 to 1.75) | 1.58 (1.27 to 1.97) |
| ER−/PR+ | 161 | 25 | 2.06 (1.38 to 3.07) | 1.39 (0.94 to 2.13) | 1.08 (0.65 to 1.79) |
| ER−/PR− | 1,904 | 325 | 2.53 (2.21 to 2.89) | 1.59 (1.35 to 1.88) | 1.47 (1.12 to 1.92) |
Abbreviations: HR, hazard ratio; ER, estrogen receptor; PR, progesterone receptor
Adjusted for race (white, Black or other/unknown), BMI (<25, 25–30, ≥30, missing), and study site (KP Colorado, KP Washington) and stratified the baseline hazard by age at diagnosis (5-year groups: <30, 30–35; 35–40; 40–45; 45–50; 50–55; 55–60; 60–65; 65–70; 70–75; 75–80; ≥80), grade (well differentiated, moderately differentiated, poorly differentiated, undifferentiated, unknown), stage (0, I, II, III/IV), and histology (ductal, lobular, mixed, other).
Adjusted for race (white, Black or other/unknown), study site (KP Colorado, KP Washington), initial surgery combined with radiotherapy (breast conserving surgery alone, breast conserving surgery including unilateral mastectomy and radiotherapy, and bilateral mastectomy), BMI (<25, 25–30, ≥30, missing), and the baseline hazard was stratified by age at diagnosis (5-year groups: <30, 30–35; 35–40; 40–45; 45–50; 50–55; 55–60; 60–65; 65–70; 70–75; 75–80; ≥80), grade (well differentiated, moderately differentiated, poorly differentiated, undifferentiated, unknown), stage (0, I, II, III/IV), histology (ductal, lobular, mixed, other), ever receiving chemotherapy (yes, no) and ever taking adjuvant endocrine therapy (yes, no; women were considered users of adjuvant endocrine therapy if they had accumulated at least 90 days of therapy during any one treatment course)
Results
Most women were ER+/PR+ (71.9%), 10.5% were ER+/PR−, 1.4% were ER−/PR+, and 16.2% were ER−/PR− (eTable 1 in the Supplement). Compared with ER+/PR+ tumors, ER+/PR− patients were older and diagnosed with higher grade and stage. Clinical characteristics were similar for ER−/PR+ and ER−/PR− patients. Although receipt of endocrine therapy was comparable in ER+/PR− and ER+/PR+ patients (72.9% vs. 74.2%), it was substantially lower for ER−/PR+ patients (42.9%). Endocrine therapy duration was similar between ER+/PR− and ER+/PR+ patients (median: 2.2 vs. 2.3 years).
During a median follow-up of 6.7 years (range:1–28 years), 1,104 breast cancer deaths occurred. Breast cancer-specific mortality differed significantly by ER/PR subgroup (p<0.001; Figure 1). The 10-year cumulative mortality for breast cancer was lowest for ER+/PR+ women (8.6%, 95%CI: 7.8%-9.3%), followed by those with ER+/PR− (13.4%, 95%CI: 11.2%-15.8%), ER−/PR+ (18.2%, 95%CI: 11.7%-25.9%) and ER−/PR− disease (20.0%, 95%CI: 18.0%-22.1%). These differences persisted 20+ years post-diagnosis. In multivariable models, ER+/PR− patients had higher risk of breast cancer-specific death compared with ER+/PR+ patients before (HR=1.43, 95%CI: 1.17–1.75) and after treatment adjustment (HR=1.58, 95%CI:1.27–1.97) (Table 1). No significant association was observed for ER−/PR+ patients compared to ER+/PR+ patients. Breast cancer-specific mortality was also higher among ER−/PR− compared with ER+/PR+ patients. The risk of breast cancer-specific death for ER+/PR− patients compared with ER+/PR+ patients was not statistically different to the risk of breast cancer-specific death for ER−/PR− patients compared with ER+/PR+ patients in adjusted analysis, possibly due to limited statistical power. Elevated breast cancer-specific mortality remained for ER+/PR− and ER−/PR− breast cancer compared with ER+/PR+ breast cancer when stratifying by grade (not shown). Women with ER+/PR− tumors had higher breast cancer-specific mortality than ER+/PR+ patients irrespective of treatment received (eTable 2 in the Supplement). ER+/PR− patients were more likely to receive chemotherapy than ER+/PR+ patients after 2013 (p-value<0.001); no difference in endocrine therapy was observed (eTable 3 in the Supplement). We were unable to evaluate potential survival differences before and after 2013 due to limited sample size.
Figure 1.
Cumulative incidence of breast cancer-specific mortality by hormone receptor subgroups in Kaiser Permanente Colorado and Kaiser Permanente Washington (N=11,737)a
Abbreviations: ER, estrogen receptor; PR, progesterone receptor
a Cumulative incidence of breast cancer-specific mortality accounted for competing risks (non-breast cancer mortality) among 11,737 women who survived ≥1 years after being diagnosed with a first primary breast cancer with known ER/PR status at Kaiser Permanente Colorado (n=5,068 between 1994–2014) or Kaiser Permanente Washington (n=6,669 between 1990–2016). P-value was based on the Gray’s test.
Note: One patient diagnosed with ER+/PR+ had a breast cancer related death 25 years after her initial diagnosis and this event does not appear in the table above.
Discussion
Our findings extend previous studies on ER/PR subgroups (2, 4–6) and breast cancer-specific mortality by evaluating associations within two integrated healthcare settings with comprehensive treatment data. Consistent with prior studies, we found women with ER+/PR− tumors had more aggressive clinicopathological features, comparable treatment, and experienced significantly worse survival compared with ER+/PR+ patients (2, 5, 6). Adding to these studies, we examined the influence of treatment as a potential confounder or effect modifier of observed risk relationships. Our results, however, differ from adjuvant endocrine therapy trials, which found no difference in breast cancer-specific survival by PR status among patients who were largely diagnosed before the 2013 St. Gallen report (9, 14). Secular changes in defining ER/PR positivity (14) may have also contributed to misclassification of ER/PR subgroups in earlier data (6). As luminal A patients tend to have a better distant relapse-free survival than luminal B patients (15), future studies with complete data on HER2 status and Ki-67 are needed to facilitate more accurate approximation of intrinsic molecular subtypes. In addition, we cannot rule out the possible influence of other potential unmeasured confounders in our analysis.
In summary, we found that ER+/PR− patients had a statistically significant increased risk of breast cancer-specific mortality compared with ER+/PR+ patients, both before and after accounting for treatment. Further studies are needed to confirm our findings and, if so, highlight the importance of continued surveillance in breast cancer patients within real-world community settings to optimize treatment regimens according to ER/PR subgroups.
Supplementary Material
Funding
This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the US National Cancer Institute. Data collected at Kaiser Permanente Colorado was supported by contracts from the National Cancer Institute (HHSN 261201800469P, HHSN 261201700708P, HHSN 261201600711P) and a subcontract with RTI International (HHSN 26120090017C). Data collected at Kaiser Permanente Washington was supported by grants from NIH (1R01CA1205621 and P01CA154292) and contracts from NCI (HHSN 261201700564P, HHSN75N91019P00076, HHSN 5N91020P00327). Cancer incidence data used in this study was supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by Contract No. N01-CN-67009 and N01-PC-35142 from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington. Erin Bowles’s time was also supported by the National Cancer Institute (R50CA211115).
Abbreviations:
- ER
Estrogen receptor
- PR
Progesterone receptor
- KP
Kaiser Permanente
- SEER
Surveillance, Epidemiology and End Results
- HR
Hazard ratio
- CI
Confidence interval
Footnotes
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
The datasets generated or analyzed during the current study are not publicly available due to data privacy of patients. The authors will make the data available upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated or analyzed during the current study are not publicly available due to data privacy of patients. The authors will make the data available upon reasonable request.