Abstract
Background
There are racial disparities in breast cancer mortality. Our purpose was to determine whether racial/ethnic differences in use and discontinuation of AET differed by hormone receptor status and whether discontinuation was associated with mortality.
Methods
We conducted a retrospective cohort study with SEER/Medicare dataset of women age ≥65 years diagnosed with stage I-III breast cancer in Medicare Part-D from 2007-2009, stratified by hormone receptor status. We performed multivariable logistic regressions to assess racial differences for the odds of AET initiation and Cox proportional hazard models to determine the risk of discontinuation and mortality.
Results
Of 14,902 women, 64.5% initiated AET <12 months of diagnosis. Among those with hormone receptor–positive cancer, 74.8% initiated AET compared with 5.6% of women with negative and 54.0% with unknown-receptor status. Blacks were less likely to initiate (OR: 0.76, 95% CI: 0.66–0.88) compared to whites. However, those with hormone-receptor positive disease were less likely to discontinue (HR: 0.89, 95% CI: 0.80–0.98). Women who initiated with aromatase inhibitors had increased risk of discontinuation compared with women who initiated tamoxifen (1.12, 1.05–1.20). Discontinuation within 12 months was associated with higher risk of all-cause (1.75, 1.74–2.00) and cancer-specific mortality (2.76, 1.74–4.38) after controlling for race/ethnicity.
Conclusions
There are racial/ethnic differences in AET use and discontinuation. Discontinuing treatment was associated with higher risk of all-cause and cancer-specific mortality regardless of hormone receptor status.
Impact
This study underscores the need to study factors that influence discontinuation and the survival benefits of receiving AET for hormone receptor–negative breast cancer.
Keywords: AET, race/ethnicity, discontinuation, mortality, Medicare
INTRODUCTION
Blacks and Hispanics have increased risk of breast cancer death than non-Hispanic whites.(1–4) These racial/ethnic mortality disparities have been attributed to differences in cancer prognostic,(2, 3, 5, 6) sociodemographic factors,(4) and the initiation and timing of treatment.(2, 4) One way to significantly reduce breast cancer mortality is to improve adherence to effective, recommended treatment.(7) Adhering to guidelines for adjuvant endocrine therapy (AET) is associated with improved disease-free survival for women with early-stage breast cancer,(8–12) however, adherence rates for recommended treatment remain low. It is estimated that between 55–75% of breast cancer patients received recommended AET medication in a one-year period.(13) Discontinuation of AET is associated with the number of other medications prescribed for comorbidities,(14) demographic characteristics such as age, (15, 16) and the side-effects (13, 17–21). Previous studies have examined higher discontinuation for minorities which compared white women (15, 22).
The National Comprehensive Cancer Network (NCCN) recommends that postmenopausal women with early-stage hormone receptor–positive breast cancer receive an aromatase inhibitor (AI) for 5 years, or tamoxifen for 2–3 years followed by an AI to complete 5 years, or tamoxifen alone for 5 years, if AIs are contraindicated.(23) The guidelines suggest that postmenopausal women can begin with tamoxifen or AIs and understanding whether discontinuation is associated with each drug during the first 12 months of treatment post-diagnosis may provide additional evidence to physicians and patients when deciding one drug over another.”
Nearly two-thirds of breast cancer cases in the U.S. are hormone receptor–positive (estrogen or progesterone receptor), and are eligible for AET.(23–25) While recommendations from both the NCCN and the American Society of Clinical Oncology (ASCO) recommend AET for women with stage I–III cancer, none of the organizations recommended AET for women with hormone receptor–negative disease.(23, 26) However, women with hormone receptor–negative breast cancer may still receive AET for the following reasons. First, determining hormone receptor–positive status using immunohistochemistry was initially defined as having ≥10% positive tumor cells.(27) However, subsequent studies have identified improved disease-free survival for patients with ≥1% positive tumor cells(28) and even >0%.(29) Second, classification of hormone receptor status differed among institutions. Although SEER defined hormone receptor–positive status as having ≥1% positive tumor cells,(30) other institutions or providers may consider those patients with any percentage of positive tumor cells (>0%) to be eligible for AET.(27, 28) Third, studies have recently shown that even those with hormone receptor–negative breast cancer may experience lower risk of disease-free survival from receiving tamoxifen.(31, 32) Therefore, we aimed to examine the patterns of initiation, discontinuation, and mortality associated with AET in these populations. To the best of our knowledge, this would be the first study to examine these research questions in a large, nationwide cohort of elderly women with breast cancer since Medicare Part-D was implemented in 2006 and oral AET was covered under that plan.
Furthermore, what remains unclear is whether there are racial/ethnic differences in initiation and discontinuation by hormone receptor status, and whether discontinuing AET is associated with all-cause mortality. We hypothesized that AET discontinuation would be associated with a higher risk of death, regardless of hormone receptor status, and after controlling for AET discontinuation, there would be no significant differences in the risk of mortality among Hispanics, Blacks and non-Hispanic whites.
METHODS
Data source
This study utilized the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) and Medicare–linked database for cases in 2007–2009 with Medicare Part-D claims up to December 2010.(33, 34) Briefly, available SEER information includes patient demographics, primary tumor site, tumor morphology, stage at diagnosis, first course of treatment, and vital statistics. Medicare data contain detailed diagnoses, procedures, and billing information for inpatient, outpatient, and pharmacy claims.
Study design and population
This was a retrospective cohort study of women ≥65 years with stage I-III breast cancer who were enrolled in Medicare for ≥12 months before and after the date they filled their first AET prescription (either tamoxifen or AI). Women were excluded if they were not enrolled in Medicare Part-D, did not have both Parts A and B, or were enrolled with a HMO from the year of diagnosis to the last follow-up. We stratified the analysis into three cohorts to reflect NCCN recommendations. NCCN strongly recommends AET for women with stage I–III, hormone-receptor positive breast cancer (Group 1) but does not recommend for hormone receptor-negative (Group 2) or unknown status for stage I–III (Group 3).(23)
Independent Variables
We identified women who belonged to four racial/ethnic groups: non-Hispanic white, non-Hispanic Black/African American, Hispanic, and Asian which were described elsewhere.30
Women with breast cancer were categorized in the SEER registry as hormone receptor–positive, –negative, or -unknown based on tumor specimen values.(30) If, at a minimum, one tumor specimen assay was noted to be positive for estrogen or progesterone receptors, then the patient was considered to have hormone receptor–positive disease.(30) The SEER, as of 2010, considered hormone receptor–positive breast cancer if ≥1% cells stained positive.(30)
Demographic information included age (median 75) and marital status. Socioeconomic status information obtained from the 2000 U.S. Census included tertiles of the percentage of residents living below the federal poverty level (FPL) at the census tract level (<5.4%, 5.4–11.8%, and ≥11.8%) and whether they lived in a metropolitan region.(4, 34) Tumor characteristics included AJCC tumor stage, size, grade, and lymph node status. Radiation therapy and surgery were identified from SEER data or through procedure codes in Medicare claims made <6 months of diagnosis, and chemotherapy use was identified only from Medicare claims <6 months of diagnosis using the methods described elsewhere.(4) Comorbidity scores were then generated and described in detail elsewhere.(35–37) We calculated average 30-day out-of-pocket payments for AET medication.(38, 39)
Dependent variables
Initiation of AET (tamoxifen or AI) was considered a single prescription based on the drug name up to 1 year after the date of diagnosis.(40) AIs were defined as anastrozole, exemestane, or letrozole. We created a binary variable (yes or no) for initiation if a women filled a prescription for any AET medication and an indicator for the type of AET (AI or Tamoxifen) at initiation. A woman could only initiate AET therapy with AI or Tamoxifen based on the first prescription following cancer diagnosis. We categorized patients as having discontinued therapy (yes or no) if they initiated therapy, and the calculated drug supply based on the last prescription date plus any surplus from a prior prescription indicated a minimum of 120-day supply gap with no AET medication on hand. All patients for the discontinuation measure were followed from their initial prescription date until the end of the study period (December 31, 2010). We censored other patients at the end of the study period or until they went >2 consecutive months without Medicare Part-D coverage or died. The median and mean length of follow-up from initiation to discontinuation was 523 days and 580 days, respectively (range 5~1,460 days). All-cause mortality and breast cancer-specific mortality were defined separately as dead (of any causes or breast cancer-specific) or alive at the last follow-up of vital statistics (December 31, 2011) to be censored. The median and mean length of follow-up from diagnosis to death was 1,205 days and 1,214 days, respectively (range 320~1,845 days).
Statistical analysis
Differences in the distribution of sociodemographic and tumor characteristics were first examined across racial/ethnic groups and then by AET initiation. Multivariable logistic regression models were performed to assess the association of race/ethnicity and AET initiation, controlling for tumor prognostic, sociodemographic, and clinical treatment factors. We performed Cox proportional hazard regressions to estimate the association between race/ethnicity and AET discontinuation and to determine the risk of all-cause and cancer-specific mortality in association with AET discontinuation. For this model, we included AET discontinuation within 12 months since every patient in the cohort were alive and had at least 12 consecutive months of continuous enrollment in Part-D after their first AET prescription. All analyses were stratified by hormone receptor status and controlled for prognostic and treatment factors.
RESULTS
We identified 14,902 Medicare patients with stage I-III breast cancer enrolled in Part-D (Table 1). Greater than four-fifths (81.8%) had hormone receptor–positive breast cancer and the remaining were hormone receptor–negative (13.3%) or unknown status (6.0%). The cohort consisted predominately of non-Hispanic whites (81.1%), followed by non-Hispanic Blacks (7.2%), Hispanics (6.1%), and Asian (4.8%). A larger proportion of Blacks (71.2%) and Hispanics (60.8%) compared with non-Hispanic whites (29.6%) lived in areas where >11.8% lived below the FPL. A greater proportion of non-Hispanic whites (83.0%) than Blacks (71.9%) and Hispanics (77.6%) were diagnosed with hormone receptor–positive breast cancer. A larger proportion of Blacks and Hispanics, compared with non-Hispanic whites had stage III breast cancer (15.5% and 15.3% versus 9.3%).
Table 1.
Characteristics of women with diagnosed breast cancer by race/ethnicity, 2007–2009
| Non-Hispanic White N (%) | Non-Hispanic Black N (%) | Hispanic N (%) | Asian N (%) | |
|---|---|---|---|---|
| Total | 12,178 (81.1) | 1,085 (7.2) | 923 (6.1) | 716 (4.8) |
| Age (years) | ||||
| 65–69 | 3,206 (26.3) | 292 (26.9) | 295 (32.1) | 199 (27.8) |
| 70–74 | 2,805 (23.0) | 273 (25.2) | 228 (24.7) | 172 (24.0) |
| 75–79 | 2,520 (20.7) | 224 (20.7) | 183 (19.8) | 172 (24.0) |
| ≥80 | 3,647 (30.0) | 296 (27.3) | 217 (23.5) | 173 (24.2) |
| Marital status | ||||
| Married | 5,023 (41.3) | 185 (17.1) | 314 (24.0) | 254 (49.4) |
| Unmarried | 6,722 (55.2) | 848 (78.2) | 575 (62.3) | 348 (48.6) |
| Unknown | 433 (3.6) | 52 (4.8) | 34 (3.7) | 14 (2.0) |
| SES (% living below FPL) | ||||
| 1st tertile (<5.4) | 4,322 (35.5) | 109 (10.1) | 146 (15.8) | 215 (30.0) |
| 2nd tertile (5.4–11.8) | 4,251 (34.9) | 203 (18.7) | 216 (23.4) | 253 (35.3) |
| 3rd tertile (>11.8) | 3,605 (29.6) | 773 (71.2) | 561 (60.8) | 248 (34.6) |
| SEER Registry Region | ||||
| Northeast | 2,554 (21.0) | 229 (21.1) | 151 (16.4) | 50 (7.0) |
| South | 3,168 (26.0) | 528 (48.7) | <4% | <3% |
| Midwest | 1,580 (13.0) | 109 (10.1) | <2% | <2% |
| West | 4,876 (40.0) | 219 (20.2) | 726 (78.7) | 635 (88.7) |
| Metropolitan area (yes) | 9,625 (79.0) | 917 (84.5) | 845 (91.6) | 685 (95.7) |
| Comorbidity scores | ||||
| 0 | 6,992 (57.4) | 411 (37.9) | 448 (48.5) | 360 (50.3) |
| 1 | 3,082 (25.3) | 299 (27.6) | 266 (28.8) | 235 (32.8) |
| 2 | 1204 (9.9) | 168 (15.5) | 110 (11.9) | 75 (10.5) |
| 3+ | 900 (7.4) | 207 (19.1) | 99 (10.7) | 46 (6.4) |
| Year of diagnosis | ||||
| 2007 | 3,956 (32.5) | 363 (33.5) | 295 (32.0) | 230 (32.1) |
| 2008 | 4,043 (33.2) | 354 (32.6) | 310 (33.6) | 237 (33.1) |
| 2009 | 4,176 (34.3) | 368 (33.9) | 318 (34.5) | 249 (34.8) |
| Tumor size (cm) | ||||
| <2.0 | 7,519 (61.7) | 483 (44.5) | 466 (50.5) | 410 (57.3) |
| ≥2.0 | 4,623 (38.0) | <56% | <49% | <43% |
| Unknown | 36 (0.3) | <2% | <2% | <2% |
| Number of positive nodes | ||||
| 0 | 7,906 (64.9) | 565 (52.1) | 547 (59.3) | 460 (64.3) |
| ≥1 | 2,768 (22.7) | 331 (30.5) | 270 (29.3) | 183 (25.6) |
| Unknown | 1,504 (12.4) | 189 (17.4) | 106 (11.5) | 73 (10.2) |
| Tumor grade | ||||
| Well differentiated | 3,178 (26.1) | 168 (15.5) | 186 (20.2) | 173 (24.2) |
| Moderately differentiated | 5,445 (44.7) | 428 (39.5) | 402 (43.6) | 305 (42.6) |
| Poorly differentiated | 2,956 (24.3) | 413 (38.1) | 282 (30.6) | 206 (28.8) |
| Unknown | 599 (4.9) | 76 (7.0) | 53 (5.7) | 32 (4.5) |
| Surgery treatment | ||||
| None | 294 (2.4) | 73 (6.7) | 32 (3.5) | 16 (2.2) |
| BCS | 7,216 (59.3) | 512 (47.2) | 505 (54.7) | 368 (51.4) |
| Mastectomy | 4,668 (38.3) | 500 (46.1) | 386 (41.8) | 332 (46.4) |
| Chemotherapy (yes) | 2,849 (23.4) | 332 (30.6) | 310 (33.6) | 204 (28.5) |
| Radiation therapy (yes) | 6,864 (56.4) | 515 (47.5) | 537 (58.2) | 380 (53.1) |
| Hormone receptor status | ||||
| ER+ or PR+ | 10,111 (83.0) | 780 (71.9) | 716 (77.6) | 577 (80.6) |
| ER− and PR− | 1,507 (12.4) | 234 (21.6) | 144 (15.6) | 101 (14.1) |
| Unknown | 560 (4.6) | 71 (6.5) | 63 (6.83) | 38 (5.3) |
| AJCC Stage | ||||
| I | 7,038 (57.8) | 454 (41.8) | 445 (48.2) | 386 (53.9) |
| II | 4,010 (32.9) | 463 (42.7) | 337 (36.5) | 248 (34.6) |
| III | 1,130 (9.3) | 168 (15.5) | 141 (15.3) | 82 (11.5) |
BCS, breast conservation therapy; ER, estrogen receptor; PR, progesterone receptor.
*Actual percentages were not reported to avoid N<11 reporting, as required by the data user agreement.
A total of 64.5% initiated AET regardless of hormone receptor status (Table 2). Among hormone receptor–positive breast cancer patients, 74.8% initiated therapy. Notably, more women with hormone receptor–positive breast cancer initiated therapy with AIs (61.8%) than with tamoxifen (12.9%). Among hormone receptor–negative and unknown status breast cancer patients, 5.6% and 54.0% initiated AET, respectively. Among hormone receptor–positive and hormone receptor-unknown patients, a greater proportion of Hispanics initiated AET than any other racial/ethnic group (79.2% and 63.5%, respectively). A smaller proportion of women over the age of 80 and those with 3 or more comorbidities initiated AET compared to younger women or those with fewer comorbidities regardless of hormone receptor status. Women in areas where ≥11.8% of the population lived below the FPL initiated AET regardless of hormone receptor status.
Table 2.
Patients initiating adjuvant endocrine therapy among all women diagnosed with breast cancer by therapy type, 2007–2009
| Patients (%) receiving AET by type (any, tamoxifen, or aromatase inhibitors) | ||||
|---|---|---|---|---|
|
| ||||
| AJCC Tumor stage I–III | ||||
|
| ||||
| Total cohort | ER+ or PR+ | ER− and PR− | ER/PR unknown | |
|
| ||||
| n=14,902 | n=12,184 | n=1,986 | n=732 | |
| Initiation of any AET | ||||
|
| ||||
| Total Cohort | 64.5 | 74.8 | 5.6 | 54.0 |
| Race/Ethnicity | ||||
| Non-Hispanic White | 65.0 | 74.4 | 5.3 | 54.5 |
| Non-Hispanic Black | 57.2 | 73.1 | 6.4 | 50.7 |
| Hispanic | 67.0 | 79.2 | 7.6 | 63.5 |
| Asian | 65.4 | 77.5 | 5.9 | 39.5 |
| Age (years) | ||||
| 65–69 | 69.5 | 81.1 | 6.0 | 61.2 |
| 70–74 | 69.7 | 81.1 | 6.2 | 57.6 |
| 75–79 | 65.1 | 74.5 | 5.9 | 58.7 |
| ≥80 | 55.4 | 64.0 | 4.6 | 45.2 |
| SES (% living below FPL) | ||||
| 1st tertile (<5.4) | 64.9 | 75.1 | 3.8 | 49.7 |
| 2nd tertile (5.4–11.8) | 64.5 | 73.7 | 6.0 | 55.9 |
| 3rd tertile (>11.8) | 64.1 | 75.6 | 6.9 | 54.8 |
| Comorbidity scores | ||||
| 0 | 66.5 | 76.4 | 5.8 | 59.6 |
| 1 | 63.6 | 74.5 | 4.5 | 48.5 |
| 2 | 61.3 | 70.6 | 6.1 | 53.1 |
| 3+ | 58.6 | 69.7 | 7.3 | 45.4 |
|
| ||||
| Initiation of tamoxifen | ||||
|
| ||||
| Total Cohort | 17.6 | 12.9 | 2.1 | 10.7 |
| Race/Ethnicity | ||||
| Non-Hispanic White | 12.0 | 13.6 | 2.1 | 10.9 |
| Non-Hispanic Black | 8.0 | 9.5 | <5% | <16% |
| Hispanic | 8.6 | 9.8 | <8% | <17% |
| Asian | 9.5 | 10.8 | <11% | <29% |
| Age (years) | ||||
| 65–69 | 10.4 | 11.8 | 2.8 | 8.8 |
| 70–74 | 11.2 | 12.8 | <3% | <13% |
| 75–79 | 11.3 | 12.9 | <3% | <9% |
| ≥80 | 12.5 | 14.2 | 2.0 | 11.9 |
| SES (% living below FPL) | ||||
| 1st tertile (<5.4) | 9.6 | 11.0 | <2% | <9% |
| 2nd tertile (5.4–11.8) | 11.8 | 13.5 | <3% | <8% |
| 3rd tertile (>11.8) | 12.6 | 14.4 | 2.7 | 13.0 |
| Comorbidity scores | ||||
| 0 | 12.1 | 13.6 | 2.4 | 13.2 |
| 1 | 11.0 | 12.7 | <3% | <10% |
| 2 | 10.2 | 11.5 | <6% | <12% |
| 3+ | 9.7 | 11.5 | <6% | <13% |
|
| ||||
| Initiation of aromatase inhibitors | ||||
|
| ||||
| Total Cohort | 53.2 | 61.8 | 3.5 | 43.4 |
| Race/Ethnicity | ||||
| Non-Hispanic White | 53.0 | 60.9 | 3.3 | 43.6 |
| Non-Hispanic Black | 49.2 | 63.6 | <5% | <40% |
| Hispanic | 58.4 | 69.4 | <8% | <56% |
| Asian | 55.9 | 66.7 | <11% | <29% |
| Age (years) | ||||
| 65–69 | 59.1 | 69.3 | 3.2 | 52.4 |
| 70–74 | 58.5 | 68.3 | 4.6 | 45.0 |
| 75–79 | 53.8 | 61.6 | 4.1 | 50.4 |
| ≥80 | 42.9 | 49.8 | 2.6 | 33.2 |
| SES (% living below FPL) | ||||
| 1st tertile (<5.4) | 55.3 | 64.1 | 2.7 | 41.3 |
| 2nd tertile (5.4–11.8) | 52.6 | 60.2 | 3.6 | 47.9 |
| 3rd tertile (>11.8) | 51.7 | 61.2 | 4.2 | 41.8 |
| Comorbidity scores | ||||
| 0 | 54.4 | 62.9 | 3.4 | 46.4 |
| 1 | 52.7 | 61.8 | 3.2 | 39.2 |
| 2 | 51.1 | 59.1 | <6% | <44% |
| 3+ | 48.9 | 58.3 | <6% | <41% |
AET, adjuvant endocrine therapy; ER, estrogen receptor; PR, progesterone receptor.
Blacks had lower odds of AET initiation within 12 months of diagnosis compared to non-Hispanic whites (OR: 0.76, 95% CI 0.66–0.88) after controlling for all demographic, treatment, and prognostic factors (Table 3). Older women (over 80 years) compared to younger women (65–69) had lower odds of AET initiation among hormone receptor-positive patients (0.69, 0.61–0.79). Also women with more comorbidities, compared to none, had lower odds of AET initiation. Women who lived in areas where ≥11.8% of the population lived below the FPL had higher odds of initiating AET than those who lived in areas where <5.4% were below the FPL (1.16, 1.05–1.28). Initiation of tamoxifen was less likely among non-Hispanic blacks compared to whites (0.70, 0.55–0.89) and less likely among women with 3 or more comorbidities compared to 0 (0.79, 0.64–0.97),whereas Hispanics had higher odds of aromatase inhibitor initiation compared to whites with hormone receptor-positive breast cancer (1.30, 1.09–1.55). Older women (age ≥80) were also less likely to initiation AET with aromatase inhibitors compared to younger women (age 70–74) (0.51, 0.45–0.56).
Table 3.
Multivariable logistic regression for the adjusted odds of adjuvant endocrine therapy initiation among women diagnosed with breast cancer, 2007–2009 (n=14,902).
| AORa (95% confidence intervals) of AET initiation | ||||
|---|---|---|---|---|
|
| ||||
| AJCC Tumor stage I–III | ||||
|
| ||||
| Total cohort | ER+ or PR+ | ER−/PR− | ER/PR unknown | |
| Initiation of any AET | ||||
|
| ||||
| Race/Ethnicity | ||||
| Non-Hispanic white | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
| Non-Hispanic Black | 0.76 (0.66–0.88) | 0.84 (0.70–1.00) | 1.08 (0.57–2.04) | 0.96 (0.53–1.73) |
| Hispanic | 1.16 (1.00–1.36) | 1.20 (0.99–1.46) | 1.32 (0.64–2.71) | 1.47 (0.78–2.77) |
| Asian | 1.13 (0.95–1.34) | 1.25 (1.01–1.54) | 1.15 (0.46–2.84) | 0.69 (0.33–1.47) |
| Age (years) | ||||
| 65–69 | 1 | 1 | 1 | 1 |
| 70–74 | 0.95 (0.86–1.06) | 1.00 (0.88–1.14) | 0.96 (0.57–1.63) | 0.81 (0.49–1.32) |
| 75–79 | 0.73 (0.66–0.81) | 0.69 (0.61–0.79) | 0.86 (0.48–1.53) | 0.90 (0.54–1.49) |
| ≥80 | 0.50 (0.45–0.56) | 0.47 (0.41–0.53) | 0.57 (0.31–1.06) | 0.65 (0.40–1.04) |
| SES (% living below FPL) | ||||
| 1st tertile (<5.4) | 1 | 1 | 1 | 1 |
| 2nd tertile (5.4–11.8) | 1.06 (0.96–1.16) | 1.02 (0.92–1.13) | 1.67 (0.96–2.89) | 1.13 (0.69–1.84) |
| 3rd tertile (>11.8) | 1.16 (1.05–1.28) | 1.17 (1.04–1.32) | 1.78 (1.00–3.15) | 1.16 (0.70–1.92) |
| Comorbidity scores | ||||
| 0 | 1 | 1 | 1 | 1 |
| 1 | 0.95 (0.87–1.03) | 0.95 (0.86–1.05) | 0.75 (0.45–1.23) | 0.67 (0.46–0.99) |
| 2 | 0.86 (0.76–0.97) | 0.81 (0.71–0.94) | 1.00 (0.52–1.94) | 0.74 (0.44–1.23) |
| 3+ | 0.83 (0.73–0.95) | 0.82 (0.70–0.96) | 1.10 (0.57–2.13) | 0.79 (0.46–1.37) |
|
| ||||
| Initiation of tamoxifen | ||||
|
| ||||
| Race/Ethnicity | ||||
| Non-Hispanic White | 1 | 1 | 1 | 1 |
| Non-Hispanic Black | 0.70 (0.55–0.89) | 0.70 (0.54–0.90) | 1.05 (0.36–3.01) | 1.05 (0.43–2.57) |
| Hispanic | 0.80 (0.62–1.02) | 0.78 (0.60–1.01) | 1.32 (0.41–4.22) | 0.68 (0.24–1.95) |
| Asian | 0.87 (0.67–1.13) | 0.84 (0.63–1.10) | 1.31 (0.29–6.01) | 0.90 (0.28–2.94) |
| Age (years) | ||||
| 65–69 | 1 | 1 | 1 | 1 |
| 70–74 | 1.05 (0.91–1.22) | 1.07 (0.63–1.10) | 0.64 (0.26–1.56) | 1.81 (0.84–3.90) |
| 75–79 | 1.03 (0.88–1.20) | 1.07 (0.91–1.25) | 0.64 (0.25–1.67) | 0.92 (0.40–2.15) |
| ≥80 | 1.09 (0.94–1.27) | 1.13 (0.96–1.32) | 0.64 (0.25–1.65) | 1.37 (0.64–2.92) |
| SES (% living below FPL) | ||||
| 1st tertile (<5.4) | 1 | 1 | 1 | 1 |
| 2nd tertile (5.4–11.8) | 1.12 (0.98–1.28) | 1.10 (0.96–1.27) | 2.19 (0.85–5.64) | 0.69 (0.92–1.61) |
| 3rd tertile (>11.8) | 1.30 (1.12–1.50) | 1.27 (1.09–1.48) | 2.00 (0.75–5.37) | 1.20 (0.53–2.75) |
| Comorbidity scores | ||||
| 0 | 1 | 1 | 1 | 1 |
| 1 | 0.90 (0.80–1.02) | 0.93 (0.82–1.05) | 0.56 (0.24–1.32) | 0.65 (0.35–1.21) |
| 2 | 0.81 (0.68–0.98) | 0.81 (0.67–0.98) | 0.91 (0.31–2.71) | 0.55 (0.25–1.24) |
| 3+ | 0.79 (0.64–0.97) | 0.81 (0.65–1.01) | 1.14 (0.40–3.22) | 0.28 (0.09–0.86) |
|
| ||||
| Initiate aromatase inhibitors | ||||
|
| ||||
| Race/Ethnicity | ||||
| Non-Hispanic white | 1 | 1 | 1 | 1 |
| Non-Hispanic Black | 0.89 (0.78–1.02) | 1.02 (0.87–1.21) | 1.15 (0.52–2.51) | 0.93 (0.52–1.68) |
| Hispanic | 1.25 (1.08–1.45) | 1.30 (1.09–1.55) | 1.22 (0.49–3.05) | 1.63 (0.88–3.03) |
| Asian | 1.18 (1.00–1.39) | 1.30 (1.08–1.57) | 1.03 (0.34–3.17) | 0.69 (0.31–1.52) |
| Age (years) | ||||
| 65–69 | 1 | 1 | 1 | 1 |
| 70–74 | 0.94 (0.85–1.03) | 0.97 (0.86–1.08) | 1.18 (0.61–2.30) | 0.64 (0.40–1.04) |
| 75–79 | 0.75 (0.68–0.83) | 0.73 (0.65–0.82) | 1.03 (0.49–2.14) | 0.93 (0.57–1.52) |
| ≥80 | 0.51 (0.46–0.56) | 0.50 (0.45–0.56) | 0.56 (0.25–1.26) | 0.56 (0.35–0.90) |
| SES (% living below FPL) | ||||
| 1st tertile (<5.4) | 1 | 1 | 1 | 1 |
| 2nd tertile (5.4–11.8) | 1.00 (0.92–1.09) | 0.96 (0.88–1.06) | 1.46 (0.74–2.88) | 1.28 (0.78–2.09) |
| 3rd tertile (>11.8) | 1.02 (0.93-1.13) | 1.01 (0.92–1.13) | 1.68 (0.83–3.93) | 1.07 (0.64–1.76) |
| Comorbidity scores | ||||
| 0 | 1 | 1 | 1 | 1 |
| 1 | 0.99 (0.92-1.08) | 1.00 (0.91–1.09) | 0.88 (0.48–1.63) | 0.82 (0.55–1.21) |
| 2 | 0.95 (0.85–1.07) | 0.93 (0.82–1.06) | 1.11 (0.49–2.51) | 0.97 (0.58–1.61) |
| 3+ | 0.93 (0.82–1.06) | 0.99 (0.90–1.08) | 1.06 (0.47–2.42) | 1.25 (0.72–2.18) |
AOR, adjusted odds ratio; AET, adjuvant endocrine therapy; ER, estrogen receptor; PR, progesterone receptor.
AOR controlled for marital status, metropolitan area, tumor size, node status, tumor grade, tumor stage, surgical treatment, and chemotherapy and radiation treatment.
A total of 80.6% of women discontinued therapy during the study period. Among women with hormone receptor–positive breast cancer who initiated AET, non-Hispanic Blacks had a lower risk of AET discontinuation than did non-Hispanic whites (HR: 0.89, 95% CI: 0.80–0.98) during the study period after controlling for all other factors (Table 4). The risk of discontinuing AET was greater for women with hormone receptor-positive cancer who initiated therapy with AIs than with tamoxifen (1.12, 1.05–1.20).
Table 4.
Multivariable hazards ratio of time to discontinuation during study period among breast cancer patients who initiated adjuvant endocrine therapy, 2007–2009.
| HRa (95% confidence intervals) of discontinuation of AET | |||||
|---|---|---|---|---|---|
|
| |||||
| AJCC Tumor stage I–III | |||||
|
| |||||
| Discontinued AET (%) | Total cohort (n=9,618) | ER+ or PR+ (n=9,110) | ER−/PR− (n=112) | ER/PR unknown (n=396) | |
| Total Cohort | 80.6 | ||||
| Type of AET at initiation | |||||
| Tamoxifen | 80.8 | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
| Aromatase Inhibitor | 80.6 | 1.12 (1.05–1.20) | 1.12 (1.05–1.20) | 1.66 (0.91–3.04) | 1.23 (0.87–1.73) |
| AET OOP cost for 30-day supply | |||||
| $0–2.35 | 78.7 | 1 | 1 | 1 | 1 |
| $2.36–6.99 | 81.8 | 1.45 (1.34–1.56) | 1.06 (0.98–1.15) | 1.19 (0.55–2.58) | 0.99 (0.69–1.42) |
| $7.00–34.99 | 85.6 | 1.53 (1.41–1.65) | 1.43 (1.32–1.54) | 3.69 (1.69–8.00) | 1.40 (0.93–2.11) |
| $35.00–93.50 | 81.5 | 0.95 (0.87–1.03) | 1.53 (1.41–1.66) | 0.86 (0.33–2.21) | 1.38 (0.86–2.07) |
| >$93.50 | 75.9 | 1.12 (1.05–1.20) | 0.94 (0.87–1.02) | 0.91 (0.37–2.25) | 0.88 (0.56–1.40) |
| Race/Ethnicity | |||||
| Non-Hispanic white | 80.8 | 1 | 1 | 1 | 1 |
| Non-Hispanic Black | 76.7 | 0.91 (0.83–1.01) | 0.89 (0.80–0.98) | 0.72 (0.30–1.72) | 1.43 (0.91–2.23) |
| Hispanic | 82.7 | 1.01 (0.92–1.12) | 1.02 (0.92–1.13) | 1.10 (0.45–2.72) | 0.93 (0.59–1.46) |
| Asian | 80.6 | 0.83 (0.74–0.92) | 0.83 (0.72–0.93) | 0.29 (0.08–1.02) | 0.97 (0.52–1.81) |
| Age (years) | |||||
| 65–69 | 81.6 | 1 | 1 | 1 | 1 |
| 70–74 | 82.5 | 1.03 (0.97–1.10) | 1.04 (0.97–1.10) | 0.94 (0.45–1.96) | 1.08 (0.76–1.55) |
| 75–79 | 81.4 | 1.02 (0.96–1.09) | 1.03 (0.96–1.10) | 1.86 (0.83–4.15) | 0.85 (0.59–1.22) |
| ≥80 | 76.9 | 1.04 (0.97–1.12) | 1.04 (0.97–1.12) | 1.70 (0.70–4.13) | 1.18 (0.81–1.71) |
| SES (% living below FPL) | |||||
| 1st tertile (<5.4) | 79.9 | 1 | 1 | 1 | 1 |
| 2nd tertile (5.4–11.8) | 81.9 | 1.01 (0.96–1.07) | 1.02 (0.96–1.08) | 0.91 (0.45–1.82) | 0.74 (0.50–1.09) |
| 3rd tertile (>11.8) | 80.1 | 1.02 (0.96–1.09) | 1.02 (0.96–1.10) | 1.83 (0.82–4.08) | 0.79 (0.53–1.18) |
| Comorbidity scores | 81.3 | ||||
| 0 | 81.3 | 1 | 1 | 1 | 1 |
| 1 | 81.5 | 1.04 (0.99–1.10) | 1.05 (1.00–1.11) | 0.66 (0.35–1.27) | 0.86 (0.63–1.17) |
| 2 | 78.9 | 1.07 (0.99–1.61) | 1.08 (1.00–1.18) | 0.93 (0.41–2.12) | 0.99 (0.68–1.45) |
| 3+ | 74.9 | 1.07 (0.97–1.17) | 1.05 (0.95–1.15) | 1.22 (0.51–2.93) | 1.29 (0.78–2.13) |
HR, hazards ratio; AET, adjuvant endocrine therapy; ER, estrogen receptor; PR, progesterone receptor; OOP, out-of-pocket cost.
HR controlled for marital status, metropolitan area, tumor size, node status, tumor grade, tumor stage, surgical treatment, and chemotherapy and radiation treatment.
AET discontinuation within 12-months of initiation was associated with a significantly higher risk of all-cause mortality among women with hormone receptor-positive (HR: 1.70, 1.48–1.95) and negative (11.65, 2.33–58.39) breast cancer, but not among those with unknown hormone receptor status (Table 5). Discontinuation of AET within 12 months of diagnosis was also associated with a 2.7-fold increased risk of breast cancer-specific mortality compared to those who did not discontinue therapy (2.76, 1.74–4.38) after controlling for all other factors. Women from areas where ≥11.8% live below the FPL had an increased risk of all-cause death than women in areas with <5.4% living below the FPL (1.25, 1.05–1.47). In the age-adjusted analysis, blacks had a 92% increased risk of death compared to non-Hispanic whites (1.92, 1.59–2.30). No significant differences in the risk of death were observed between Blacks and Hispanics compared with non-Hispanic whites after controlling for discontinuation, poverty status, and all other treatment and prognostic factors.
Table 5.
Multivariable hazards ratio of all-cause and breast cancer-specific mortality among patients diagnosed with breast cancer who initiated AET, 2007–2009
| HRa (95% confidence intervals) of all-cause mortality | ||||
|---|---|---|---|---|
|
| ||||
| AJCC Tumor stage I-III | ||||
|
| ||||
| Total cohort (n=9,618) | ER+ or PR+ (n=9,110) | ER− / PR− (n=112) | ER/PR unknown (n=396) | |
| All-cause mortality | ||||
| Number of deaths | 1,142 | 1,044 | 22 | 76 |
| AET Type at initiation | ||||
| Tamoxifen | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
| Aromatase inhibitor | 0.97 (0.83–1.14) | 1.03 (0.87–1.21) | 0.38 (0.09–1.62) | 0.48 (0.27–0.86) |
| Discontinuation within 12 months | ||||
| No | 1 | 1 | 1 | 1 |
| Yes | 1.76 (1.54–2.00) | 1.70 (1.48–1.95) | 11.65 (2.33–58.39) | 1.69 (0.94–3.04) |
| Race/Ethnicity | ||||
| Non-Hispanic white | 1 | 1 | 1 | 1 |
| Non-Hispanic Black | 1.05 (0.86–1.29) | 1.07 (0.86–1.32) | 3.65 (0.65–20.56) | 0.88 (0.39–1.96) |
| Hispanic | 0.84 (0.64–1.09) | 0.82 (0.62–1.09) | 8.24 (0.56–120.16) | 1.12 (0.47–2.71) |
| Asian | 0.51 (0.34–0.75) | 0.53 (0.35–0.79) | 0.72 (0.01–82.80) | – |
| Age (years) | ||||
| 65–69 | 1 | 1 | 1 | 1 |
| 70–74 | 1.19 (0.96–1.48) | 1.18 (0.94–1.48) | 2.04 (0.19–21.86) | 0.68 (0.25–1.87) |
| 75–79 | 1.51 (1.22–1.86) | 1.53 (1.23–1.89) | 0.79 (0.06–9.88) | 1.32 (0.52–3.38) |
| ≥80 | 2.55 (2.09–3.10) | 2.49 (2.03–3.05) | 8.19 (0.81–82.7) | 3.15 (1.33–7.45) |
| SES (% living below poverty) | ||||
| 1st tertile (<5.4) | 1 | 1 | 1 | 1 |
| 2nd tertile (5.4–11.8) | 1.09 (0.92–1.27) | 1.11 (0.94–1.31) | 2.14 (0.21–21.57) | 0.85 (0.35–2.07) |
| 3rd tertile (>11.8) | 1.25 (1.05–1.47) | 1.24 (1.04–1.48) | 1.63 (0.12–22.26) | 1.19 (0.52–2.72) |
| Comorbidity scores | ||||
| 0 | 1 | 1 | 1 | 1 |
| 1 | 1.45 (1.23–1.67) | 1.44 (1.23–1.68) | 1.59 (0.23–11.16) | 1.25 (0.60–2.64) |
| 2 | 2.39 (2.01–2.83) | 2.33 (1.94–2.79) | 0.49 (0.01–46.43) | 4.43 (2.19–8.63) |
| 3+ | 3.21 (2.72–3.79) | 3.06 (2.56–3.65) | 2.34 (0.37–14.80) | 6.49 (3.28–12.83) |
| Breast cancer-specific mortality | ||||
| Number of breast cancer deaths | 83 | 75 | † | † |
| AET Type at initiation | ||||
| Tamoxifen | 1 | 1 | ||
| Aromatase inhibitor | 1.02 (0.56–1.88) | 1.36 (0.66–2.78) | ||
| Discontinuation within 12 months | ||||
| No | 1 | 1 | ||
| Yes | 2.76 (1.74–4.38) | 2.95 (1.82–4.76) | ||
| Race/Ethnicity | ||||
| Non-Hispanic white | 1 | 1 | ||
| Non-Hispanic Black | 0.66 (0.29–1.53) | 0.67 (0.27–1.68) | ||
| Hispanic | 0.97 (0.40–2.36) | 1.03 (0.42–2.51) | ||
| Asian | 0.55 (0.13–2.34) | 0.60 (0.14–2.58) | ||
| Age (years) | ||||
| 65–69 | 1 | 1 | ||
| 70–74 | 0.97 (0.44–2.16) | 0.90 (0.40–2.03) | ||
| 75–79 | 0.88 (0.38–2.04) | 0.85 (0.36–2.00) | ||
| ≥80 | 2.85 (1.39–5.81) | 2.70 (1.30–5.63) | ||
| SES (% living below poverty) | ||||
| 1st tertile (<5.4) | 1 | 1 | ||
| 2nd tertile (5.4–11.8) | 1.76 (0.96–3.21) | 1.94 (1.05–3.58) | ||
| 3rd tertile (>11.8) | 1.63 (0.85–3.12) | 1.59 (0.80–3.16) | ||
| Comorbidity scores | ||||
| 0 | 1 | 1 | ||
| 1 | 1.51 (0.87–2.61) | 1.53 (0.87–2.67) | ||
| 2 | 2.59 (1.38–4.85) | 2.32 (1.19–4.52) | ||
| 3+ | 1.76 (0.89–3.48) | 1.25 (0.57–2.74) | ||
HR, hazards ratio; AET, adjuvant endocrine therapy; ER, estrogen receptor; PR, progesterone receptor
HR controlled for marital status, metropolitan area, tumor size, node status, tumor grade, tumor stage, surgical treatment, and chemotherapy and radiation treatment.
We did not show any number of cases <11 for confidentiality reasons because it is required by the data use agreement of SEER-Medicare data.
DISCUSSION
In this retrospective cohort study of Medicare patients, a substantial proportion of women with hormone receptor–unknown breast cancer initiated AET, even though these patients were not expected to receive AET based on ASCO and NCCN clinical guidelines. Also, the odds of AET initiation and the risk of AET discontinuation differed by race/ethnicity and AET drug type, regardless of hormone-receptor status. Those who discontinued AET, regardless of hormone-receptor status positive or negative, had a significantly higher risk of all-cause mortality.
We previously reported AET initiation among older women with hormone receptor–positive, stage I–III breast cancer and found that 74.8% initiated therapy within 12 months.(40) Other studies have found initiation between 68–70%, but those women were younger and commercially insured (41, 42) and may have better initiation rates than our study population. We also found that Blacks, compared with non-Hispanic whites, had lower odds of initiating AET, but after stratifying by hormone receptor status there was no association. Previous studies showed that Hispanics (41, 43) and Blacks (43, 44) have lower odds of AET initiation compared with whites. These previous studies were conducted among different study populations and used AET initiation self-report, a younger cohort, or both.
We observed that racial/ethnic differences in discontinuation of AET. We have reported AET adherence for stage I–III, hormone receptor–positive breast cancer patients but did not find a significant difference among Hispanic and Black patients over non-Hispanic whites, after controlling for sociodemographic, prognostic and treatment factors.(45) What is even more interesting is that we found that the risk of AET discontinuation was greater for women who initiated therapy with the AIs than with tamoxifen among those with hormone receptor–positive breast cancer. This may be influenced by other factors, such as AI side effects, which we did not control for in this study.(10, 11, 46, 47) Similar to other studies, we did find that discontinuing AET was associated with medication cost,(12, 48) comorbidities,(49) and age.(49) Previous studies have examined lower adherence rates for non-whites, a finding that may contribute to the disparities in breast cancer mortality observed between minorities and whites.(15, 22, 50) However, after controlling for AET discontinuation, we did not observe racial/ethnic differences in the risk of all-cause mortality. We found that discontinuation of AET was independently associated with a higher risk of all-cause mortality, which is corroborated by Hershman et al,12 who studied a younger population but did not examine discontinuation among hormone receptor –negative or unknown cancer. However, they found that Hispanics had a lower risk of death than non-Hispanic whites.(12) We did not observe this association in older Medicare women with breast cancer.
No studies have examined AET initiation and discontinuation in women with hormone receptor–negative or unknown breast cancer. In our study, 5.6% of hormone receptor–negative and 54% of unknown status breast cancer patients initiated AET. While the sample size was limited among the hormone receptor-negative patients who initiated AET, still, women with hormone receptor–negative breast cancer who discontinued AET, had significantly increased risk of death. There are a few important points to consider when discussing the results of this finding. Previous studies based on medical claims data only for AET adherence or discontinuation included any women who filled a prescription for AET, and might have included women with hormone receptor–negative cancer because those data do not allow for differentiation of hormone-receptor status.(12, 22, 39) Women may be on AET despite having hormone receptor-negative breast cancer because they may have immunohistochemical assay >0% with positive tumor cells but were classified as negative based on a changing cut-point of >1%, which may vary based on institutional guidelines.(27, 28) Next, women with hormone receptor-negative breast cancer may be on AET for primary prevention of metachronous disease since it may reduce the risk of contralateral primary breast cancer (51, 52). Tamoxifen use can significantly improve 5-year disease-free survival in hormone receptor–positive breast cancer using immunohistochemical assay >0% cut-off.(29) Recently, a study found that the benefit of tamoxifen response in hormone receptor–negative breast cancer (using <1% tumor positive as cut-off) was mediated by androgen receptor expression.(31) Another study found that estrogen receptor–β1 status is a significant predictor of disease-free survival in estrogen receptor-α–negative breast cancers treated with tamoxifen.(32) Both of these receptor expressions (androgen receptor and estrogen receptor–β1) are not currently assessed in the SEER dataset but could explain our study results that AET discontinuation in hormone receptor–negative breast cancer is, at least partially, associated with increased mortality risk.
While previous studies of AET patterns and outcomes used only medical claims or pharmacy data without details on tumor characteristics,(39, 48, 53) we were able to examine initiation, discontinuation, and all-cause mortality by hormone receptor status, stage at diagnosis, and other prognostic factors because Medicare claims data were linked to the SEER registry database. Our measure of discontinuation was defined as patients with 120 consecutive days without AET coverage. Therefore, we observed a slightly lower rate of discontinuation than previous studies that used 45 or 90 days without coverage as a measure.(12, 22) Even with a conservative discontinuation measure, women who discontinued treatment within 12 months of initiation had a greater risk of death than those who did not, even after controlling for all other factors. Furthermore, because we had complete medical claims, pharmacy, and SEER registry data, this is one of the most comprehensive studies examining racial/ethnic differences in AET patterns and outcomes.
Our study was limited, however, by the population, which only included women ≥65 years and enrolled in Medicare Part D. Therefore, results may not be generalizable to younger patients or those without comprehensive prescription drug coverage. Second, unmeasured confounding factors, such as psychosocial factors, related to the quality of care women receive (e.g., physician-patient communication) may influence their AET continuation but could not be captured in this study.(54) Third, calculating discontinuation using prescription claims assumes that patients take their medications as often as they refill prescriptions. However, pharmacy records are considered the most accurate and valid estimation of actual medication use in large populations over time.(55, 56) Fourth, 4.9% of the cohort had unknown and 13.4% had hormone receptor-negative status. Although we combined these groups in stratified analyses, those with unknown receptor status could be hormone-receptor positive and hence misclassified, leading to biased estimates. Also, as previously discussed, women were categorized as having hormone receptor–negative status (<1% positive immunohistochemistry) but may have actually had hormone receptor–positive disease according to the less-stringent definition used in other studies (>0% positive immunohistochemistry).
Conclusions
About three-fourths of patients with hormone receptor–positive breast cancer initiated AET, and over 50% of women with hormone receptor–unknown and more than 5% of those with hormone receptor-negative status received AET. AET discontinuation was associated with a significantly higher risk of all-cause mortality, regardless of hormone receptor status and tumor stage. Overall, our study underscores the importance of continuing AET for all breast cancer patients who initiate treatment. Future studies are needed to explore the survival benefits of receiving AET for hormone receptor–negative breast cancer in other populations and to study the factors that influence AET discontinuation.
Acknowledgments
We acknowledge the efforts of the National Cancer Institute; Center for Medicare and Medicaid Services; Information Management Services, Inc.; and the Surveillance, Epidemiology, and End Results Program tumor registries in the creation of this database. The interpretation and reporting of these data are the sole responsibilities of the authors.
Financial Support: A.J. Farias is a postdoctoral fellow supported by a University of Texas Health Science Center at Houston School of Public Health's Cancer Education and Career Development Program grant from the National Cancer Institute (R25-CA57712). This study was also supported, in part, by grants to X.L. Du from the Agency for Healthcare Research and Quality (R01-HS018956) and the Cancer Prevention and Research Institute of Texas (RP130051).
References
- 1.Ooi SL, Martinez ME, Li CI. Disparities in breast cancer characteristics and outcomes by race/ethnicity. Breast Cancer Res Treat. 2011;127:729–38. doi: 10.1007/s10549-010-1191-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Silber JH, Rosenbaum PR, Clark AS, Giantonio BJ, Ross RN, Teng Y, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013;310:389–97. doi: 10.1001/jama.2013.8272. [DOI] [PubMed] [Google Scholar]
- 3.Banegas MP, Li CI. Breast cancer characteristics and outcomes among Hispanic Black and Hispanic White women. Breast Cancer Res Treat. 2012;134:1297–304. doi: 10.1007/s10549-012-2142-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Du XL, Fang S, Meyer TE. Impact of treatment and socioeconomic status on racial disparities in survival among older women with breast cancer. Am J Clin Oncol. 2008;31:125–32. doi: 10.1097/COC.0b013e3181587890. [DOI] [PubMed] [Google Scholar]
- 5.O’Brien KM, Cole SR, Tse CK, Perou CM, Carey LA, Foulkes WD, et al. Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study. Clin Cancer Res. 2010;16:6100–10. doi: 10.1158/1078-0432.CCR-10-1533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–502. doi: 10.1001/jama.295.21.2492. [DOI] [PubMed] [Google Scholar]
- 7.De Geest S, Sabaté E. Adherence to long-term therapies: evidence for action. Eur J Cardiovasc Nurs. 2003;2:323. doi: 10.1016/S1474-5151(03)00091-4. [DOI] [PubMed] [Google Scholar]
- 8.Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–84. doi: 10.1016/S0140-6736(11)60993-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Haque R, Ahmed SA, Fisher A, Avila CC, Shi J, Guo A, et al. Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer. Cancer Med. 2012;1:318–27. doi: 10.1002/cam4.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005;365:60–2. doi: 10.1016/S0140-6736(04)17666-6. [DOI] [PubMed] [Google Scholar]
- 11.Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081–92. doi: 10.1056/NEJMoa040331. [DOI] [PubMed] [Google Scholar]
- 12.Hershman DL, Shao T, Kushi LH, Buono D, Tsai WY, Fehrenbacher L, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126:529–37. doi: 10.1007/s10549-010-1132-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Banning M. Adherence to adjuvant therapy in post-menopausal breast cancer patients: a review. Eur J Cancer Care (Engl) 2012;21:10–9. doi: 10.1111/j.1365-2354.2011.01295.x. [DOI] [PubMed] [Google Scholar]
- 14.Kimmick G, Anderson R, Camacho F, Bhosle M, Hwang W, Balkrishnan R. Adjuvant hormonal therapy use among insured, low-income women with breast cancer. J Clin Oncol. 2009;27:3445–51. doi: 10.1200/JCO.2008.19.2419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003;21:602–6. doi: 10.1200/JCO.2003.07.071. [DOI] [PubMed] [Google Scholar]
- 16.Fink AK, Gurwitz J, Rakowski W, Guadagnoli E, Silliman RA. Patient beliefs and tamoxifen discontinuance in older women with estrogen receptor–positive breast cancer. J Clin Oncol. 2004;22:3309–15. doi: 10.1200/JCO.2004.11.064. [DOI] [PubMed] [Google Scholar]
- 17.Adisa AO, Lawal OO, Adesunkanmi AR. Paradox of wellness and nonadherence among Nigerian women on breast cancer chemotherapy. J Cancer Res Ther. 2008;4:107–10. doi: 10.4103/0973-1482.42640. [DOI] [PubMed] [Google Scholar]
- 18.Winterhalder R, Hoesli P, Delmore G, Pederiva S, Bressoud A, Hermann F, et al. Self-reported compliance with capecitabine: findings from a prospective cohort analysis. Oncology. 2011;80:29–33. doi: 10.1159/000328317. [DOI] [PubMed] [Google Scholar]
- 19.Cella D, Fallowfield LJ. Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy. Breast Cancer Res Treat. 2008;107:167–80. doi: 10.1007/s10549-007-9548-1. [DOI] [PubMed] [Google Scholar]
- 20.Browall M, Ahlberg K, Karlsson P, Danielson E, Persson LO, Gaston-Johansson F. Health-related quality of life during adjuvant treatment for breast cancer among postmenopausal women. Eur J Oncol Nurs. 2008;12:180–9. doi: 10.1016/j.ejon.2008.01.005. [DOI] [PubMed] [Google Scholar]
- 21.Lorizio W, Wu AH, Beattie MS, Rugo H, Tchu S, Kerlikowske K, et al. Clinical and biomarker predictors of side effects from tamoxifen. Breast Cancer Res Treat. 2012;132:1107–18. doi: 10.1007/s10549-011-1893-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Hershman DL, Tsui J, Wright JD, Coromilas EJ, Tsai WY, Neugut AI. Household net worth, racial disparities, and hormonal therapy adherence among women with early-stage breast cancer. J Clin Oncol. 2015;33:1053–9. doi: 10.1200/JCO.2014.58.3062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Breast Cancer. 2014 [cited 2015 May]; Version 2.2015[: Available from: www.nccn.org.
- 24.American Cancer Society. Breast Cancer Facts & Figures 2013–2014. Atlanta, GA: American Cancer Society; 2013. [Google Scholar]
- 25.DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin. 2014;64:52–62. doi: 10.3322/caac.21203. [DOI] [PubMed] [Google Scholar]
- 26.Rugo HS, Rumble RB, Macrae E, Barton DL, Connolly HK, Dickler MN, et al. Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol. 2016;34:3069–103. doi: 10.1200/JCO.2016.67.1487. [DOI] [PubMed] [Google Scholar]
- 27.Regan MM, Viale G, Mastropasqua MG, Maiorano E, Golouh R, Carbone A, et al. Re-evaluating adjuvant breast cancer trials: assessing hormone receptor status by immunohistochemical versus extraction assays. J Natl Cancer Inst. 2006;98:1571–81. doi: 10.1093/jnci/djj415. [DOI] [PubMed] [Google Scholar]
- 28.Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 2010;6:195–7. doi: 10.1200/JOP.777003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Honma N, Horii R, Iwase T, Saji S, Younes M, Ito Y, et al. Proportion of estrogen or progesterone receptor expressing cells in breast cancers and response to endocrine therapy. Breast. 2014;23:754–62. doi: 10.1016/j.breast.2014.08.003. [DOI] [PubMed] [Google Scholar]
- 30.Surveillance Epidemiology and End Results Program. (Version 02.02).Site Specific Collaborate Stage Data Collection System. 2010 Available from: http://web2.facs.org/cstage202/breast/Breastschema.html.
- 31.Hilborn E, Gacic J, Fornander T, Nordenskjöld B, Stål O, Jansson A. Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-α-negative breast cancer. Br J Cancer. 2016;114:248–55. doi: 10.1038/bjc.2015.464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Honma N, Horii R, Iwase T, Saji S, Younes M, Takubo K, et al. Clinical importance of estrogen receptor-beta evaluation in breast cancer patients treated with adjuvant tamoxifen therapy. J Clin Oncol. 2008;26:3727–34. doi: 10.1200/JCO.2007.14.2968. [DOI] [PubMed] [Google Scholar]
- 33.Nattinger AB, McAuliffe TL, Schapira MM. Generalizability of the surveillance, epidemiology, and end results registry population: factors relevant to epidemiologic and health care research. J Clin Epidemiol. 1997;50:939–45. doi: 10.1016/s0895-4356(97)00099-1. [DOI] [PubMed] [Google Scholar]
- 34.Du XL, Fang S, Vernon SW, El-Serag H, Shih YT, Davila J, et al. Racial disparities and socioeconomic status in association with survival in a large population-based cohort of elderly patients with colon cancer. Cancer. 2007;110:660–9. doi: 10.1002/cncr.22826. [DOI] [PubMed] [Google Scholar]
- 35.Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83. doi: 10.1016/0021-9681(87)90171-8. [DOI] [PubMed] [Google Scholar]
- 36.Romano PS, Roos LL, Jollis JG. Adapting a clinical comorbidity index for use with ICD-9-CM administrative data: differing perspectives. J Clin Epidemiol. 1993;46:1075–9. doi: 10.1016/0895-4356(93)90103-8. discussion 81–90. [DOI] [PubMed] [Google Scholar]
- 37.Hu CY, Delclos GL, Chan W, Du XL. Assessing the initiation and completion of adjuvant chemotherapy in a large nationwide and population-based cohort of elderly patients with stage-III colon cancer. Med Oncol. 2011;28:1062–74. doi: 10.1007/s12032-010-9644-7. [DOI] [PubMed] [Google Scholar]
- 38.Farias AJ, Du XL. Association Between Out-Of-Pocket Costs, Race/Ethnicity, and Adjuvant Endocrine Therapy Adherence Among Medicare Patients With Breast Cancer. J Clin Oncol. 2017;35:86–95. doi: 10.1200/JCO.2016.68.2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Farias AJ, Hansen RN, Zeliadt SB, Ornelas IJ, Li CI, Thompson B. The Association Between Out-of-Pocket Costs and Adherence to Adjuvant Endocrine Therapy Among Newly Diagnosed Breast Cancer Patients. Am J Clin Oncol. 2016 doi: 10.1097/COC.0000000000000351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Farias AJ, Du XL. Ethnic differences in initiation and timing of adjuvant endocrine therapy among older women with hormone receptor-positive breast cancer enrolled in Medicare Part D. Med Oncol. 2016;33:19. doi: 10.1007/s12032-016-0732-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Livaudais JC, Hershman DL, Habel L, Kushi L, Gomez SL, Li CI, et al. Racial/ethnic differences in initiation of adjuvant hormonal therapy among women with hormone receptor-positive breast cancer. Breast Cancer Res Treat. 2012;131:607–17. doi: 10.1007/s10549-011-1762-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Yung RL, Hassett MJ, Chen K, Gesten FC, Roohan PJ, Boscoe FP, et al. Initiation of adjuvant hormone therapy by Medicaid insured women with nonmetastatic breast cancer. J Natl Cancer Inst. 2012;104:1102–5. doi: 10.1093/jnci/djs273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Freedman RA, Virgo KS, He Y, Pavluck AL, Winer EP, Ward EM, et al. The association of race/ethnicity, insurance status, and socioeconomic factors with breast cancer care. Cancer. 2011;117:180–9. doi: 10.1002/cncr.25542. [DOI] [PubMed] [Google Scholar]
- 44.Wang X, Du XL. Socio-demographic and geographic variations in the utilization of hormone therapy in older women with breast cancer after Medicare Part-D coverage. Med Oncol. 2015;32:599. doi: 10.1007/s12032-015-0599-6. [DOI] [PubMed] [Google Scholar]
- 45.Farias AJ, Du XL. The association between race/ethnicity, out-of-pocket costs for medication, and adherence to tamoxifen and aromatase inhibitors among women with breast cancer enrolled in Medicare Part D. Journal of Clinical Oncology. 2016 [Google Scholar]
- 46.Chlebowski RT, Geller ML. Adherence to endocrine therapy for breast cancer. Oncology. 2006;71:1–9. doi: 10.1159/000100444. [DOI] [PubMed] [Google Scholar]
- 47.Chlebowski RT, Kim J, Haque R. Adherence to endocrine therapy in breast cancer adjuvant and prevention settings. Cancer Prev Res (Phila) 2014;7:378–87. doi: 10.1158/1940-6207.CAPR-13-0389. [DOI] [PubMed] [Google Scholar]
- 48.Neugut AI, Subar M, Wilde ET, Stratton S, Brouse CH, Hillyer GC, et al. Association between prescription co-payment amount and compliance with adjuvant hormonal therapy in women with early-stage breast cancer. J Clin Oncol. 2011;29:2534–42. doi: 10.1200/JCO.2010.33.3179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.He W, Fang F, Varnum C, Eriksson M, Hall P, Czene K. Predictors of Discontinuation of Adjuvant Hormone Therapy in Patients With Breast Cancer. J Clin Oncol. 2015;33:2262–9. doi: 10.1200/JCO.2014.59.3673. [DOI] [PubMed] [Google Scholar]
- 50.Ursem CJ, Bosworth HB, Shelby RA, Hwang W, Anderson RT, Kimmick GG. Adherence to adjuvant endocrine therapy for breast cancer: importance in women with low income. J Womens Health (Larchmt) 2015;24:403–8. doi: 10.1089/jwh.2014.4982. [DOI] [PubMed] [Google Scholar]
- 51.Gierach GL, Curtis RE, Pfeiffer RM, Mullooly M, Ntowe EA, Hoover RN, et al. Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting. JAMA oncology. 2016 doi: 10.1001/jamaoncol.2016.3340. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N. Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. J Natl Cancer Inst. 1995;87:645–51. doi: 10.1093/jnci/87.9.645. [DOI] [PubMed] [Google Scholar]
- 53.Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010;28:4120–8. doi: 10.1200/JCO.2009.25.9655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Farias AJ, Ornelas IJ, Hohl SD, Zeliadt SB, Hansen RN, Li CI, et al. Exploring the role of physician communication about adjuvant endocrine therapy among breast cancer patients on active treatment: a qualitative analysis. Support Care Cancer. 2017;25:75–83. doi: 10.1007/s00520-016-3389-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Choo PW, Rand CS, Inui TS, Lee ML, Cain E, Cordeiro-Breault M, et al. Validation of patient reports, automated pharmacy records, and pill counts with electronic monitoring of adherence to antihypertensive therapy. Med Care. 1999;37:846–57. doi: 10.1097/00005650-199909000-00002. [DOI] [PubMed] [Google Scholar]
- 56.Steiner JF, Koepsell TD, Fihn SD, Inui TS. A general method of compliance assessment using centralized pharmacy records. Description and validation. Med Care. 1988;26:814–23. doi: 10.1097/00005650-198808000-00007. [DOI] [PubMed] [Google Scholar]