Overall survival of elderly patients with breast cancer is not related to breast-cancer specific survival: A single institution experience in Japan

Introduction

The elderly population is increasing worldwide. The life expectancy in Japan is the highest globally, and Japan has the most rapidly aging society in the world [1,2]. The population of people aged 65 years or older in Japan was anticipated to be 27.3% (34.6 million) in 2016 [3]. As the population continues to age, the number of elderly individuals with various diseases will increase. Among women, breast cancer is the most common cancer, and the number of elderly women with breast cancer will continue to increase as the society ages [4–7]. Especially Japan is currently facing with this aging society. The impact of medical expenses on the economy is enormous, which is also a big problem worldwide. However, optimal treatment for elderly breast cancer patients is not yet well-established. As the population ages, the risk of death due to other causes will also be higher and thus the rate of comorbidities affecting survival in breast cancer patients will also increase. Previous reports have shown that individuals aged over 70 years were undertreated, as not all of these patients received optimal therapy [4,8].

Generally, elderly breast cancer patients are defined as those aged 65 years and older. Patients over 70 years were selected in this study because they usually did not meet the criteria for various clinical trials due to complications or a history of other cancers. A comprehensive view of the patients’ comorbidities, organ functions, life expectancy, and life circumstances should be considered when strategizing breast cancer treatment, and the treatment plan should be discussed by a breast cancer board consisting of experts from various fields.

Here, we performed a retrospective cohort study for reviewing the treatment and prognoses of elderly breast cancer patients. Clinical and pathological disease characteristics, therapies received, and subsequent outcomes were compared between women aged 70–79 years, and ≥ 80 years.

Patients and methods

In this study, data were collected from the medical records of patients diagnosed with breast cancer at Shiga Medical Center of Adults between April 1989 and October 2016. Treatment strategies were recommended by physicians. However, for patients with serious comorbidities or life-threatening diseases, recommendations were made by a breast cancer board consisting of multiple experts, including breast surgeons, radiologists, oncologists, nurses from outpatient and inpatient wards, expert nurses in chemotherapy, pharmacologists, medical social workers, palliative therapists, clinical psychologists, and rehabilitation therapists. For patients with severe comorbidities, including other cancers, the treatment plan was discussed by the breast cancer board, considering their prognoses and the effectiveness of breast cancer therapy. Systemic therapy was performed when breast cancer was thought to affect prognosis. Treatment was omitted when obtaining cooperation with treatment was challenging due to dementia or when disadvantages, such as complications due to treatment, were predicted. All study participants provided informed consent, and the study design was approved by the appropriate ethics review board.

The patients were divided into two age groups, 70–79-years-old (70s) and ≥ 80-years-old (older group). A total of 273 operable cases were selected and classified into having received standard treatment or having been undertreated according to the National Comprehensive Cancer Network (NCCN) guidelines and the guidelines of the Japanese Breast Cancer Society (JBCS). The undertreated patient group consisted of those who received no surgery or only staging biopsy among patients with axillary lymph node metastasis, or had no therapeutic exposure. Low-dose chemotherapy or oral chemotherapy was included among the standard therapies, because oral chemotherapy for elderly patients is also recommended in the guidelines of the JBCS [9]. Low-dose chemotherapy was used mainly because of continuous bone marrow suppression. Regimens included 50–80% dose reduced epirubicine and cyclophosphamide (EC), or EC with 5-fluorouracil (FEC), adriamycine and cyclophosphamide with 5-fluorouracil (CAF), and docetaxel alone (DTX) or with cyclophosphamide (TC). Cyclophosphamide and methotrexate and 5-fluorouracil (CMF), tegafur/uracil (UFT), TS-1, doxifluridine (5’DFUR) and oral 5-fluorouracil were frequently used as oral chemotherapy. Indeed, most patients receiving chemotherapy before the 2000s were treated with oral anticancer drugs. Treatment differed, depending on the patients, as shown in Table 1; 273 operable cases were classified according to the therapy administered (Table 2). In Table 1, the data include patients who underwent surgery even for stage IV disease because they received palliative surgery in order to avoid continuous bleeding from the tumor ulcer. The operable patients shown in Table 2 are patients with non-stage IV resectable disease some of whom received preoperative therapy.

Chi-square tests were used to analyze differences in characteristics, including the distribution of tumor characteristics between the two age groups (age at diagnosis 70–79 years, or ≥80 years). Overall survival (OS) was defined as the period from the date of diagnosis to the last date of follow-up or death due to any cause. Disease-free survival (DFS) was defined as the period from the date of diagnosis to the occurrence of any event, such as progression, relapse, recurrence, or death. Breast cancer-specific survival (BCSS) was determined based on breast cancer-specific death only. Kaplan–Meier estimates were performed to calculate OS, DFS, and BCSS. Differences in survival were analyzed using the log-rank test, and a p -value less than 0.05 was considered significant. A multivariable Cox proportional hazard regression model was used to assess the impact of the prognostic variable on OS, DFS, and BCSS. To estimate effects, hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Data were analyzed using Stat Mate V for Win & Mac Hybrid software (ATMS, Tokyo, Japan).

Results

From April 1989 to October 2016, 1617 patients were diagnosed breast cancer. Among them, 286 patients (17.7%) were over 70 years of age. The median age at diagnosis of breast cancer in this patient subgroup was 76 years (range: 70–94 years). The Ki-67-labeling index was higher in the older group (6.6% versus 17.1%, p = 0.006). Axillary surgery, radiation therapy, endocrine therapy, and chemotherapy were performed less frequently in the older age group (p < 0.001, p < 0.001, p = 0.021, p = 0.038, respectively) (Table Table 1). Forty-two patients (14.7%) had overlapping cancers, either before or after the onset of breast cancer. Twenty-four patients (8.4%) had synchronous or metachronous bilateral breast cancers.

Fifteen patients (5.2%) died due to other cancers, and 14 patients (4.9%) died due to breast cancer. Thirteen patients (4.5%) died of chronic diseases associated with aging, such as chronic heart failure or aspiration pneumonia, and 4 (1.4%) due to acute events, such as acute myocardial infarction or pulmonary embolism. Another 9 patients (3.2%) died of a liver abscess, aspiration suffocation, upper gastrointestinal bleeding not associated with malignancy, or other reasons. In total, 55 patients (19.2%) died during observation.

Figure 1 shows the Kaplan–Meier curves by DFS, OS, and BCSS, according to age group. During a median follow-up period of 59 months, OS differed between the two age groups (p < 0.001); however, there were no significant differences in DFS and BCSS according to age group (p = 0.388, p = 0.172, respectively). However, the older patients tended to be undertreated (Table 1, Table 2).

The results of the multivariate analyses related to DFS, OS, and BCSS are shown in Table 3. Comorbidities that required medication, including other cancer therapy, as well as higher Ki-67 levels, were identified as dependent risk factors for OS (hazard ratio [HR]: 2.58, 95% confidence interval [CI]: 1.34–4.95; p = 0.004; HR: 2.14, 95% CI: 1.24–3.72, p = 0.007; HR: 2.70, 95% CI: 1.17–6.21, p = 0.020, respectively). However, they were found to be independent risk factors for DFS and BCSS.

Discussion

In Japan, the percentage of breast cancer patients aged 70 years or older were 18.4, 20.9, and 26.5% in 2004, 2009, and 2014, respectively [10], and is expected to continue this increasing trend in future. The percentage of elderly people among employed workers in Japan is 11.4%, the highest among the major developed countries [2,3]; thus, despite their age, these individuals can contribute to society by extending survival time. The mean life expectancy of Japanese women was 86.8 years in 2014, and the expected survival times for 70- and 75-year-old women were 19.8 and 15.6 years, respectively. This value is increasing every year [3]. The mortality rate of breast cancer among the over-70-years patients is rising and the establishment of a treatment strategy for elderly patients is an urgent task [1]. Elderly people have lower physiological reserves in their organ systems and an individualizing approach for each patient is therefore essential for geriatrics.

In JBCS Clinical Practice Guidelines, chemotherapy can be considered when elderly breast cancer patients are expected to live for more than 5 years [9]. According to this guideline, even in octogenarians, not only endocrine therapy, but also chemotherapy remains an option. Previous studies have shown the effectiveness of adjuvant chemotherapy and radiotherapy in improving survival for older women with early-stage breast cancer [4,5,8,11]. Undertreatment typically leads to a worse clinical outcome in elderly breast cancer patients. Generally, elderly breast cancer patients tended to be undertreated as compared to younger patients [12,13]. A comprehensive geriatric assessment (CGA) is used as an analytical tool when physicians plan treatment for elderly breast cancer patients [12,14,15]. Treatment plans were recommended based on this assessment for elderly patients.

Our data confirmed that OS was worse in the older group, but BCSS did not differ between the older and younger groups, unlike that reported in previous studies [4–6]. The presence of characteristics such as older age and comorbidities are thought to be associated with worse patient prognosis than in the younger and generally healthier group. High Ki-67 is reported to be a prognostic factor in DFS and OS, particularly in luminal-like early-stage breast cancer [16–18]. However, multivariate Cox-regression analysis showed that these unfavorable characteristics affected OS, but not BCSS (Table 3). The Ki-67-labeling index was higher in the older age group (Table 1); this may be because ER and progesterone receptor expression tended to be negative in older patients. Some reports have shown that ER status is likely to be positive in the elderly [4,6], while other did not [8,16]. High Ki-67 expression levels were shown to have no effect on breast cancer prognosis (Table 3).

Chemotherapy is generally considered for high Ki-67 breast cancer patients. In our data, 14 patients (50.0%) of the 28 high Ki-67 patients were aged over 80 years. In the high Ki-67-expression group, 7 (50.0%) in 70s and 10 (71.4%) in older did not receive chemotherapy. Fourteen (50.0%) of these high Ki-67 were ER-negative (data not shown). Ki-67 was thus not correlated with prognosis. Furthermore, the majority of patients did not receive chemotherapy. Therefore, we spotted all age of triple negative (TNBC) patients to evaluate the therapeutic effect of chemotherapy on young people and elderly next. This is because TNBC usually requires only chemotherapy as systemic therapy. In the 153 cases with triple-negative breast cancer, OS of the over-70-years-old cases (n = 41) was similar to that of the under-70-years-old cases (n = 112) (Supplementary Figure 1). Nevertheless, the percentages of undertreated patients in the over-70 years and under-70 years were 66.7% and 21.6%, respectively. To elucidate the reason for this, it would be necessary to clarify how high Ki-67 cancer cells act in the living body in the elderly, how the host reacts, and how chemotherapy drugs are delivered and act on cancer cells.

Additionally, standard surgery and standard radiation therapy were identified as dependent factors for DFS. The patients who were initially undertreated have a higher recurrence risk, and might receive unnecessary treatment if they do experience recurrence. Thus, local control therapy should be properly recommended as the initial therapy, even if patients are elderly. The event hazard of DFS, OS, and BCSS tended to be better in patients who received standard therapy (Table 3). Table 2 and Supplementary Table 2 show that older age groups tend to be undertreated. However, DFS and OS were significantly affected by standard local control therapy, as shown in Table 3 and by standard therapy in TNBC patients, as shown in Supplementary Table 3. Tolerance of treatment did not depend only on the patient’s age, so we believe physicians should not omit therapy just because patients are elderly, but instead need to select the best treatment for them to live better and longer. We believe even oral chemotherapy or low-dose chemotherapy is better than no systemic therapy for an aggressive disease like TNBC. Supplementary Figure 2 shows the Kaplan Meier plot that compares survival between patients who received surgery before 2000 and after 2001. There was no significant difference. We believe this was because those who received surgery before 2000 also frequently underwent oral chemotherapy with UFT or 5’DFUR as adjuvant therapy.

Overall, physicians should recommend aggressive systemic therapy for elderly patients with comorbidities when the treatment benefits are considered greater than the disadvantages.

This study is limited in that elderly patients were not precisely followed-up, because geriatric care facilities or family doctors take care of them after their treatment is completed. Owing to this bias, it was difficult to assess outcomes. Moreover, cost-effectiveness was not analyzed in this study. Some reports also showed that irradiation after breast-conserving surgery was associated with cardiac toxicity [19,20]. Furthermore, health-related quality of life was not analyzed.

Elderly breast cancer patients aged ≥ 80 showed equivalent DFS and BCSS rates to those of patients aged 70–79 years, after adjustment for their therapy. The event hazard rate tended to be better in patients who received standard therapy. Physicians should not omit appropriate therapy for elderly patients when the benefits of treatment are considered greater than the disadvantages.

Supplementary material

The supplementary material is available in the electronic version of this article: https://dx-doi-org.web.bisu.edu.cn/10.3233/BD170280.

Conflict of interest statement

The authors have no conflicts of interest relevant to this article.