Increased Mortality Risk among Early Stage Hormone Receptor Positive Breast Cancer Patients Who Did Not Receive Adjuvant or Neoadjuvant Therapy

Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) is the most common biologic subtype of breast cancer. Although adjuvant therapy has demonstrated a survival benefit in clinical trials, its use is poorly understood in the real-world among elderly breast cancer patients since age is a barrier to receiving adjuvant therapy. An examination of treatment patterns and outcomes associated with receipt of adjuvant/neoadjuvant therapy among elderly HR + HER2-breast cancer patients was undertaken. Methods: There were 18,470 HR + HER2-breast cancer patients from the linked SEER-Medicare database. Patients were diagnosed with stage I-III disease between 1/1/2007-12/31/2011, ≥66 years, enrolled in Medicare Parts A, B and D, and underwent breast cancer surgery after diagnosis. Time-varying Cox proportional hazards regression assessed overall survival. Results: There were 13,670 (74%) patients treated with adjuvant/neoadjuvant therapy and 4800 (26%) untreated. Compared to treated patients, untreated patients were older, had earlier stage, lower grade, smaller tumors, poorer performance, higher comorbidity score, and less use of a 21-gene recurrence score (RS) assay (p < 0.0001). In the survival model, increasing age, stage, tumor size, tumor grade, comorbidity score and poor performance were significantly associated with higher mortality risks, while use of an RS assay was associated with lower risks. The Cox model showed a 48% higher risk of death in untreated compared to treated patients. In a subset of 8967 patients with stage I disease, tumor size < 2.0 cm and grade 1/2; untreated patients had a 22% higher risk of death compared to treated patients. Conclusions: Older patients with favorable clinical characteristics (earlier stage, smaller tumor, lower grade) are less likely to be treated and have a How to cite this paper: Satram-Hoang, S., Stein, A., Cortazar, P., Momin, F. and Reyes, C. (2019) Increased Mortality Risk among Early Stage Hormone Receptor Positive Breast Cancer Patients Who Did Not Receive Adjuvant or Neoadjuvant Therapy. Journal of Cancer Therapy, 10, 1-20. https://doi.org/10.4236/jct.2018.101001 Received: December 6, 2018 Accepted: January 1, 2019 Published: January 4, 2019 Copyright © 2019 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access S. Satram-Hoang et al. DOI: 10.4236/jct.2018.101001 2 Journal of Cancer Therapy higher risk of death compared to adjuvant/neoadjuvant treated patients. An unmet need among older breast cancer patients persists.


Introduction
Breast cancer is the most common invasive cancer in women and the second leading cause of death from cancer among women in the United States [1].
One-percent of breast cancer occurs in men [2] [3].Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) is the most common biologic subtype of breast cancer occurring in post-menopausal women and men [3], and accounts for about 73% of incident cases [4].About 50% of women diagnosed with breast cancer are over the age of 65 [5].Breast cancer mortality has declined over the past few decades because of advances in awareness, earlier detection, and adjuvant treatments [6] [7].
In general, patients with early-stage breast cancer undergo primary breast cancer surgery with or without radiation therapy.The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant endocrine therapy for postmenopausal women with HR+ breast cancer for a five-year period following diagnosis [8].The decision to add chemotherapy to adjuvant endocrine therapy is individualized based on patient factors such as age, tumor size, tumor grade, lymph node involvement, and the results of prognostic multigene assays like the 21-gene Recurrence Score (RS) assay [9] [10] [11].Recent updates in the American Joint Committee on Cancer Criteria (AJCC) for breast cancer staging manual (8 th edition) have incorporated biomarkers and prognostic panel data to guide clinical decision-making.
The benefit of adjuvant therapy is poorly understood among older patients with breast cancer since age is a barrier to receiving adjuvant therapy and older patients are underrepresented in clinical trials [12] [13].Observational studies have demonstrated that breast cancer mortality increases with age [14] and older age and comorbidities are associated with less aggressive treatment in non-metastatic breast cancer [13] [15].We aimed to contribute to the existing evidence by examining adjuvant therapy patterns and survival outcomes among HR+HER2-, stage I-III patients with breast cancer using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database.

Data Source
The SEER-Medicare database has been described previously [16]

Study Population
See Figure 1 for the schematic of the inclusion/exclusion process.Patients with a first primary breast cancer diagnosis were identified using SEER cancer site variables labeled "breast" by International Classification of Diseases for Oncology, 3 rd edition (ICD-O-3) codes, C50.0-C50.9.We included patients with AJCC stage I, II, or III invasive breast cancer from SEER.Patients, ≥66 years with a first primary breast cancer diagnosed between January 1, 2001 and December 31, 2011 were then linked to their Medicare claims for the years 2000 through 2013.Patients needed to be enrolled in Medicare Parts A and B for a full 12 months prior to diagnosis date and were excluded if breast cancer was diagnosed at the time of death or autopsy, and if enrolled in a health maintenance organization (HMO) any time within the 12 months prior to diagnosis as HMO claims are not available in the dataset.
In July 2006, Medicare coverage was expanded to include prescription drugs under Medicare Part D. We had to further restrict our sample to patients diagnosed between 2007-2011 and enrolled in Part D for at least 1 month in the year after diagnosis date in order to capture patients eligible for adjuvant endocrine therapy.Patients also underwent breast cancer surgery (lumpectomy and mastectomy) within 6 months after diagnosis.Those who received oral or infused neoadjuvant/adjuvant systemic therapy from diagnosis up to 6 months after breast cancer surgery were part of the "treated" group while those who did not were classified as "untreated".The final analytic cohort included 18,470 patients with HR + HER2-breast cancer.

Survival Outcomes
The mean and median follow-up time for the overall cohort was 48.Adjusting for demographic and clinical characteristics in Table 3, untreated patients exhibited a 48% higher risk of death compared to treated patients.Increasing age, male gender, being widowed, poor performance, increasing stage, increasing tumor size, increasing tumor grade, and increasing comorbidity score were significantly associated with higher mortality risks.Receipt of genomic testing was associated with a 45% reduction in mortality risk.Prior radiotherapy was associated with a 41% reduction in mortality risk, and black African ancestry was associated with a 16% reduction in mortality risk compared to whites, after adjusting for all other variables in the model.In a subset of 8967 patients with stage I disease, tumor size < 2.0 cm and tumor grade 1 or grade 2; untreated patients had a 22% higher risk of death compared to treated patients.In the subset of treated patients, those receiving sequential chemotherapy plus hormonal therapy exhibited a 26% (HR = 1.26; 95% CI: 1.01 -1.58) higher risk of death compared to hormonal therapy alone, and there was no mortality risk difference with chemotherapy-only (HR = 1.10; 95% CI: 0.94 -1.30) compared to hormonal therapy, after adjusting for demographic and clinical characteristics (data not shown).

Discussion
We evaluated the predictors of neoadjuvant/adjuvant therapy receipt and survival among Medicare beneficiaries diagnosed with HR + HER2-breast cancer and found that older patients with more favorable disease characteristics (earlier stage, smaller tumor size, lower tumor grade) were less likely to receive neoadjuvant/adjuvant therapy and had a higher risk of death compared to neoadjuvant/adjuvant treated patients, controlling for other competing causes of mortal-ity such as age, co-morbidity burden, and poor performance.Our multivariate survival model also demonstrated that after adjusting for tumor characteristics and neoadjuvant/adjuvant treatment, increasing co-morbidity score was associated with increasing mortality risk, similar to a recent study [22].The logistic regression model demonstrated that increasing age was associated with lower likelihood of therapy independent of performance status, co-morbidities and tumor characteristics, suggesting that physicians may be under-treating otherwise healthy older patients.Older patients represent a heterogeneous population in terms of fitness, and chronological age alone should not contraindicate life-prolonging or curative treatment.Overall, only 16% of our study population had genomic testing and this was associated with a higher likelihood of receiving neoadjuvant/adjuvant therapy as well as a 45% reduction in mortality risk compared to patients who did not have the test.A recent meta-analysis of 15 studies that investigated the impact of RS assays on adjuvant treatment decisions, reported that the additional information provided by the test changed the recommendation for adjuvant treatment in 30% of cases with the majority being a de-escalation of chemoendocrine therapy to adjuvant endocrine therapy alone [29].In our study, we found that the rates of sequential therapy with chemotherapy followed by hormonal therapy decreased, while the use of hormonal therapy increased in association with the RS assay.Other trials showed that the benefit of adding chemotherapy to tamoxifen was mainly seen in patients with a high RS and no significant benefit from the addition of chemotherapy was noted in the low and intermediate RS risk groups [11] [30].However, given the nature of administrative claims data, we were unable to determine results of RS assays and RS score risk groups.In addition, RS assays are usually ordered for patients who are candidates for chemotherapy use.
It's possible that the higher mortality risk observed in the non-RS assay group was due to poorer fitness and tolerability concerns that also precluded them from chemotherapy use and RS assay testing.A recent sub analysis from the MINDACT study demonstrated that 24% of patients with node negative small tumors (<1 cm) who were identified as clinical low risk, but genomic high risk, derived a benefit from chemotherapy [31].While another study found that patients with indolent threshold (ultralow-risk) on the 70-gene assay genomic test have a significantly low risk of mortality after surgery without adjuvant systemic treatment [32].This adds further support that tumor biology is an important factor when considering adjuvant treatments.
Interestingly, our finding that patients of black African ancestry have lower mortality risk compared to white patients is discordant with prior research.
African American women have lower incidence of breast cancer but worse survival when compared to white women [33] [34] [35].Many have postulated that the survival disparity is related to access to healthcare, treatment differences or socioeconomic factors [36] [37] [38] and race alone is seen as an independent predictor of survival [39].However, a more recent SEER-Medicare analysis confirmed that after matching patients on treatment as well as demographics, comorbidities, and tumor characteristics at presentation, there was very little difference in survival between black and white women [40].
Receipt of treatment and survival varied by marital status, similar to patterns observed in prior oncology research [41] [42].In the current study unmarried status, especially widowhood were predictive of not receiving neoadjuvant/adjuvant treatment and was associated with a higher risk of mortality.Male in the oral hormonal therapy group, we required evidence of at least two prescriptions and no gaps of at least 120 days between prescriptions to increase the likelihood that patients are actually taking the medicine.
Fourth, the use of overall survival as an endpoint should be interpreted with caution.Although overall survival is the most reliable and available survival measure, it may not be specific enough to provide information on survival related to breast cancer treatment.Therefore, it's not clear if the higher survival we observed among treated patients is due to fewer deaths from other competing causes or fewer deaths from breast cancer treatment.Finally, the data presented here are limited to Medicare enrollees and patients enrolled in HMO represent a gap in the SEER-Medicare database.HMO enrollees tend to be younger and healthier than beneficiaries in fee-for-service plans resulting in a biased loss of information using the Medicare claims data [16].

Conclusion
Older patients with HR + HER2-resected breast cancer who have favorable disease characteristics (earlier stage, smaller tumor size and lower tumor grade) were less likely to receive adjuvant/neoadjuvant therapy with hormonal and/or chemotherapy.Untreated patients with favorable disease characteristics had a significantly higher risk of death compared to treated patients, after controlling for comorbidities, poor performance and other patient characteristics.Additional research is needed to determine why adjuvant/neoadjuvant therapies are omitted among the older "fit" breast cancer patient population.
. The SEER program, supported by the National Cancer Institute (NCI), collects data from diverse geographic tumor registries and is representative of about 26% of the U.S. population.The Medicare program is administered by the Centers for Medicare and Medicaid Services (CMS) and covers 97% of the U.S. population for patients aged 65 years and older.The SEER participants who were diagnosed with cancer at age 65 years or above are matched to their Medicare files through an agreement between the NCI and the CMS resulting in a 93% match rate.All Medicare beneficiaries receive Part A coverage (inpatient care, skilled nursing, home healthcare and hospice care) and approximately 95% of beneficiaries subscribe to Part B (outpatient and physician services) and this is combined with the clinical, demographic and cause of death information in SEER.The database linkage used in this study included cancer cases diagnosed until 2011 with their Medicare claims through 2013.Institutional review board (IRB) approval was waived by the New England IRB because the National Institutes of Health's Office of Human Subjects Research has determined that analyses using SEER-Medicare data are exempt from requiring further IRB review and approval.

Figure 2 .
Figure 2. Unadjusted Kaplan-Meier curve of overall survival by treatment status.

Breast Cancer Diagnosis N=439,806 First primary Breast Cancer between 2001-2011 N=364,485 ≥ 66 years at diagnosis N=211,837 No diagnosis by death certificate N=208,425 Medicare Parts A and B ≥ 12 months prior to diagnosis N=195,159 No HMO coverage in the 12 months prior to diagnosis N=140,185 No oral/infused therapy prior to diagnosis N=137,813 HR+HER2-Subtype N=93,928 Early Stage I-III N=76,194 Diagnosed January 1, 2007-December 31, 2011 N=34,521 Enrolled in Part D for at least 1 month within 12 months after diagnosis N=19,768 Breast cancer surgery within 6 months of diagnosis N=18,470 Oral/infused therapy after diagnosis up to 6 months after breast cancer surgery N=13,670 Journal
[20]ancer Therapy Estrogen receptor (ER) and progesterone receptor (PR) status have been collected by SEER since 1990 and ER and PR results were combined and analyzed jointly as HR status.The year 2010 is the most recent year for which HER2 was available in the dataset.Therefore, we used the presence of Medicare claims for HER2 targeted therapies, i.e., trastuzumab (Herceptin®, Roche) and lapatinib (Tykerb, GSK) as a proxy for HER2 positive status and absence of these claims implied HER2 negative status.A case was defined as HR+HER2-if ER and/or PR were positive and HER2 were negative.Medicare began covering multigene RS assays in February 2006.A modified algorithm from Dinan et al.[20]was used to identify claims for RS assays using Healthcare Common Procedural Coding System (HCPCS) code 84,999 (unlisted chemistry procedure) and provider ID corresponding to Genomic Health within the time period of 2 months before diagnosis to 12 months after diagnosis.
Patients who had breast cancer surgery (lumpectomy and mastectomy) were identified by searching Medicare claims for ICD-9 procedure codes and Current Procedural Terminology (CPT) procedure codes from initial diagnosis date of first primary breast cancer up until 6 months after diagnosis.ICD-9 and CPT procedure codes for radiation therapy within 12 months after diagnosis date were also captured in Medicare claims.We identified Medicare claims associated with oral hormonal therapy and intravenous chemotherapy from breast cancer diagnosis up to 6 months after breast cancer surgery.The Medicare claims data contain information on each agent administered and date administered, but do not indicate whether the agent is being used in the neoadjuvant, adjuvant, or later-line setting or whether it's part of a sequential or combination regimen.Thus, we developed an algorithm to separate claims into regimen lines.All agents administered preoperatively from diagnosis date were considered to be part of a single neoadjuvant regimen line.Patients were considered to have received adjuvant therapy if administered between breast cancer surgery date and up to 6 months after.Chemotherapy followed by hormonal therapy without a 120-day gap in therapy was considered sequential adjuvant therapy.If a gap in therapy of at least 120 days occurs, then this would indicate the end of adjuvant therapy to avoid capturing treatment for metastatic or recurrent disease.
Journal of Cancer Therapy gery to date of death.Death date was captured through 2013 using Medicare enrollment files.If the Medicare date of death was missing, then the SEER date of death was used.Patients were censored at the end of the follow-up period (December 31, 2013) or until Medicare claims were no longer available.Crude ).A p-value of <0.05 was considered statistically significant.Multivariable logistic regression modeling examined the effect of demographic and clinical factors on the odds of receiving neoadjuvant/adjuvant therapy.All cause overall survival (OS) was measured from date of breast cancer sur-

Table 1
. 62.8% had small tumor size of <2.0 cm compared to treated patients.Untreated patients were also less likely to have received radiotherapy, had poorer performance, a higher comorbidity burden, and were less likely to have genomic testing for risk of recurrence (p < 0.0001).

Table 1 .
Baseline demographic and clinical characteristics by treatment status.
a Cells with counts of less than 11 are combined in compliance with the National Cancer Institute data use agreement for small cell sizes.

Table 2 .
Logistic regression model of factors associated with the odds of not receiving neoadjuvant/adjuvant treatment.
a Model also includes geographic region, education, income, year of diagnosis, and histology.

Table 3 .
[28]-varying Cox model of overall mortality risk in the total population and the stage/size/grade subpopulation.Prior studies show that patients over the age of 80 are only half as likely as younger patients to have a discussion about tamoxifen with their physicians due to physician concerns about side effects and treatment adherence[27][28].
[26]erence and risk for local recurrence[24][25].Although adjuvant systemic therapy has clear benefits in patients with HR+ early breast cancer[26], the treatment rate in our older aged cohort was low.