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Treatment Patterns and Clinical Outcomes in Elderly Patients with Breast Cancer

Treatment Patterns and Clinical Outcomes in Elderly Patients with Breast Cancer Kyu Min Kang, M.D.*, Eun-Kyu Kim, M.D., Ph.D.*, Hyunju Kim, M.D., Jee Hyun Kim, M.D., Ph.D., Se Hyun Kim, M.D., Koung Jin Suh, M.D., In Ah Kim, M.D., Ph.D., Sumin Chae, M.D., Sung-Won Kim, M.D., Ph.D., Eunyoung Kang, M.D., Ph.D. Department of Surgery, Department of Internal Medicine, Department of Radiation Oncology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam; Department of Surgery, Kyung Hee University School of Medicine, Kyung Hee University Medical Center, Seoul; Department of Surgery, Daerim St. Mary’s Hospital, Seoul, Korea


INTRODUCTION
The World Health Organization criteria categorize individuals aged 65 years and older as 'elderly' [1]. According to the Korea Statistical Office, elderly people will account for 28.7% of the Korean population by 2035 [2]. Moreover, the life expectancy of Korean women born in 2030 is projected to be 86.7 years, which is the longest in the world [3].
As the average life expectancy increases, the proportion of elderly patients with breast cancer is also projected to rise. Despite the expected increase in elderly breast cancer patients, there is insufficient evidence regarding the most suitable treatment for these women.
It is difficult to determine suitable therapeutic plans in these patients because aging is a complex and heterogeneous process in which chronological age does not always reflect the physiological state. A variety of factors should be considered when treating geriatric patients, including comorbidities, life expectancy, cognitive ability, performance status, concurrent medication, and socioeconomic support [4,5]. Elderly breast cancer patients tend to be undertreated for the reasons mentioned above and the survival rate of elderly patients who are undertreated is lower than that of those who receive adjuvant systemic therapy [6][7][8][9]. Moreover, the prognostic factors associated with older patients with breast cancer may include not only age but also comorbidities. Elderly breast cancer patients with multiple comorbidities have high rates of mortality and complications associated with adjuvant therapy [10][11][12][13][14].
Therefore, it is necessary to understand how elderly patients with breast cancer are treated and to improve the quality of current care.
This study investigated the patterns of treatment and prognostic fac-

Patients and data collection
We retrospectively reviewed the data of 560 patients over 65 years of age who underwent surgery for breast cancer at the Seoul National Data on the type of surgery in the breast and axilla; comorbidities; histologic type; histologic grade (HG); stage; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression; adjuvant therapy (chemotherapy, radiotherapy, hormone therapy, and targeted therapy); and disease status at the last follow-up visit were collected from electronic medical records (EMRs). Data on survival status were collected in conjunction with the Ministry of the Interior and Safety. Our study classified comor-bidities into four categories (0, 1, 2, and ≥ 3) using the Charlson comorbidity index (CCI), which is composed of 19 disease groups assigning scores of 1, 2, 3, and 6 to each of a patient's comorbid conditions [15]. Histologic type was divided into favorable (tubular carcinoma and mucinous carcinoma) and usual (invasive ductal carcinoma, invasive lobular carcinoma, metaplastic carcinoma, and mixed ductal & lobular carcinoma) types. The staging system was based on the American Joint Committee on Cancer 7th edition [16]. Breast cancer subtypes were classified as luminal type A, luminal type B, HER2-enriched, and triple-negative breast cancer (TNBC) on based on ER, PR, HER2, and Ki-67 expression, as suggested by the 2013 St. Gallen Consensus [17]. Samples were defined as hormone receptor-positive when at least 1% of cells were positive by immunohistochemistry. The Ki-67 index was divided into high (≥14%) and low (<14%) expression. The adjuvant chemotherapy regimens administered included doxorubicin and cyclophosphamide (AC); AC plus docetaxel; epirubicin and cyclophosphamide; cyclophosphamide, methotrexate, and fluorouracil (CMF); fluorouracil, doxorubicin, and cyclophosphamide; and cyclophosphamide, epirubicin, and fluorouracil.

Statistical analysis
The patients were divided into early-aged (65-74 years, n =277) and late-aged (≥ 75 years, n = 85) groups. The differences between the early-aged and late-aged groups were analyzed using the Chi-square or Fisher's exact tests. Overall survival (OS) and distant metastasis-free survival (DMFS) were estimated using Kaplan-Meier analysis and log-rank tests were used to compare survival differences according to patient characteristics. Distant metastasis included recurrence in the contralateral breast, cervical lymph nodes (level I-V), contralateral lymph nodes (axillary, internal mammary, supraclavicular, and infraclavicular lymph nodes), bone, and visceral organs (lung, liver, and other organs) [18]

Patient characteristics
We analyzed 362 elderly patients with stage I-III breast cancer.
Their mean age was 71.1 years (range 65-88 years). We compared clinicopathological characteristics between the early-aged and lateaged groups ( Table 1). The surgery types for the breast and axilla, histologic type, HG, stage, subtype, and target therapy (trastuzumab) were similar between groups. The proportion of patients with CCI ≥ 3 was higher in the late-aged group than that in the early-aged group (37.6% vs. 16.6%, p < 0.001). Although no difference in stage distribution was observed between the two groups, significantly higher proportions of patients in the early-aged group received chemotherapy (45.5% vs. 12.9%, p < 0.001) and radiotherapy (63.9% vs. 43.5%, p < 0.001). Even when analyzed by stage, the proportion of patients who underwent chemotherapy was significantly higher in the early-aged group than that in the late-aged group for each stage (Table 2).

Clinical outcomes
The median follow-up period was 76.7 months (range 30-165 months). Distant metastasis was detected in 14 (5.1%) and eight (9.4%) patients in the early-aged and late-aged groups, respectively. The sites of distant metastasis were the lung (n =7), liver (n = 5), bone (n = 4), and contralateral breast (n =3) and three patients had multiple metastases. Twenty-four and 13 patients in the early-aged and late-aged groups died, respectively. EMR review revealed two patients with chemotherapy-related deaths (pancytopenia and cardiac toxicity, respectively), eight patients with deaths due to breast cancer progression, and 11 patients with deaths from other causes (two from brain infarction; two from gastric ulcer bleeding; and one each from gastric angiodys-

Factors associated with survival
The results of univariable and multivariable analyses to determine factors related to DMFS and OS are shown in Table 3. Multivariable analysis showed multiple comorbidities, high HG, and advanced stage to be independent prognostic factors for poor DMFS and OS. However, subtype and administration of adjuvant treatments, including che-

DISCUSSION
This study evaluated the treatment patterns and clinical outcomes of elderly patients with breast cancer. Patients in the late-aged group (≥ 75 years) had more comorbidities and were less likely to receive adjuvant chemotherapy and radiotherapy after breast cancer surgery. In multivariable analyses, higher comorbidities, HG, and stage were poor prognostic factors. The administration of adjuvant treatments did not affect prognosis in our elderly patients with breast cancer.
Several studies have reported that elderly breast cancer patients are less likely to receive adjuvant systemic therapy [19,20]. Hurria et al. [19] reported that only 5.2% of patients older than 75 years received adju- Garg et al. [26] assessed the relationship between CCI and chemotherapy toxicity in 65 elderly (≥ 70 years) patients and found increasing age, lower functional status, and high CCI to be associated with an increased discontinuation rate, dose reduction, and grade 3-4 toxicity.
Elderly patients with breast cancer are more likely to have ER-positive tumors that respond well to hormonal agents and are associated with a slightly better overall prognosis and reduced recurrence rate [27]. In the Early Breast Cancer Trialists' Collaborative Group analysis of patients with ER-positive breast cancer, 5 years of adjuvant endocrine therapy with tamoxifen reduced the annual recurrence rate at 15 years by 34% in women aged 50-59, 45% in women aged 60-69, and 51% in women older than 70 years. Among these patient groups, the annual death rate was also reduced by 24%, 35%, and 37%, respectively [28]. In another study, the effects of adjuvant endocrine therapy differed based on comorbidity. Land et al. [29] evaluated the breast cancer-specific survival (BCSS) by CCI score in elderly patients who re- Recent demographic changes suggest that the number of older patients with breast cancer will continue to increase; thus, clinicians need to be prepared to treat this patient population. Although it is rec-ommended that elderly breast cancer patients be as actively treated as young patients, the results of our study showed that adjuvant treatments were not associated with prognosis; furthermore, higher HG, stage, and CCI score were independently associated with poor prognosis in multivariate analysis. Therefore, treatment planning for elderly patients must consider various factors including not only important clinical features such as stage and subtype but also comorbidities, performance status, and life expectancy. Since, as a retrospective study in a single institution, this study has several limitations, it is difficult to conclude the effect of adjuvant therapy in elderly patients. Guidelines must be established for the treatment of breast cancer in elderly patients and the study of its therapeutic effects should be expanded.