Introduction
Breast cancer is the most common cancer in women with increasing incidence. More than 50% of breast cancer cases are diagnosed in women at the age of 60 or older [
1]. However, there is a lack of evidence for specific treatment for elderly women with breast cancer [
2]. Furthermore, there is a substantial underrepresentation of patients aged 65 years or older in studies about cancer treatment. This has been particularly notable in breast cancer treatment trials [
3]. Indeed, elderly patients are often undertreated resulting in decreased survival [
4]. In order to overcome this problem, the International Society of Geriatric Oncology (SIOG) and the European Society of Breast Cancer Specialists (EUSOMA) developed recommendations for the management of elderly patients with breast cancer [
5].
Adjuvant treatment of early breast cancer is based on prognostic and predictive factors, which have been found to differ between older and young breast cancer patients. Elderly breast cancer patients more often exhibit tumors that are positive for hormone receptor (HR) expression but negative for over-expression of human epidermal growth factor receptor 2 (HER2) [
6]. Moreover, it has been presumed that tumor biology in elderly patients is different from younger patients [
7,
8]. Tumor biology increasingly affects treatment decisions for breast cancer patients [
9]. In 2000, Perou et al. revealed that histopathological parameters correlate with the respective genetic profile [
10]. In recent years, various gene expression profiling studies have enhanced our understanding of the heterogeneity and complexity of breast cancer [
11,
12]. In a previous study of our group, we showed that well-established histopathological parameters, i.e., estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 (4-IHC) could define the four common tumor biological subtypes Luminal A, Luminal B, HER2-like, and Basal-like in routine clinical work [
13]. Nevertheless, the distribution, treatment, and outcome of the tumor biological subtypes especially in elderly breast cancer patients are largely unknown.
The aim of the present study was to evaluate distribution and treatment of common tumor biological subtypes in elderly breast cancer patients based on comparison of two groups of patients with different access to medical care. Patients who are eligible for screening (50–69 years, ESG) and patients aged 70 years or older (not eligible for screening group, NESG) were compared and their local and systemic therapies in different subtypes as well as subtype-related overall survival (OS) were analyzed in a large cohort of a population-based clinical cancer registry.
Discussion
Decisions on treatment of breast cancer patients are based on national [
18] and international guidelines [
19]. However, these recommendations do not consider age-specific characteristics. There is a lack of evidence on the optimal management of elderly patients [
3]. Thus, due to increasing life expectancy, the treatment of elderly patients is an emerging clinical problem [
20].
A main cause for non-adherence to guideline recommendations may be the existence of co-morbidities of which elderly patients are more often affected than younger ones. Co-morbidities, especially cardiovascular diseases, may also be the cause of reduction of OS.
In the present study, we investigated the distribution of tumor biological subtypes in elderly patients both in the ESG (50–69 years) and the NESG (≥70 years) of breast cancer patients. Further, we studied local and systemic therapies in different subtypes as well as subtype-related OS by analyzing data of a large cohort of a clinical cancer registry. The distribution of the four common subtypes Luminal A, Luminal B, HER2-like, and Basal-like was quite comparable in the ESG versus the NESG. Luminal A tumors were found as often in the ESG (51.2%) as in the NESG (51.0%), whereas a slight increase of Luminal B tumors (25.8 vs. 23.2%) and a declining tendency of HER2-like (16.1 vs. 17.3%) and Basal-like tumors (7.1 vs. 8.3%) in the NESG was detected (Table
1). These results are in line with a study by Jenkins et al. who characterized the incidence of breast cancer patients by molecular subtypes and age using the PAM50 algorithm [
21]. In this study, the incidence of Luminal A and B tumors increased with age (
P < 0.01,
P < 0.001), whereas the percentage of basal-like tumors decreased (
P < 0.001) [
21].
Systemic therapies varied according to age. Patients in the ESG received CHT ± ET more often than patients in the NESG (Table
2). However, according to the SIOG guidelines, there is no evidence to support differential use of specific CHT or dose reductions in older patients compared with younger ones [
5]. As described in our study and in line with Cappellani et al., breast cancer in the elderly is not less aggressive compared to younger patients [
22]. In particular, prognostic and predictive factors are identical [
22]. A meta-analysis of the Early Breast Cancer Trialists´ Collaborative group (EBCTCG) with 15 years of follow-up on more than 100,000 women enrolled in breast cancer clinical trials evaluated adjuvant ET and CHT in detail [
23]. They documented statistically significant benefits of adjuvant CHT to reduce breast cancer recurrence and mortality in women aged 50–69 years [
23].
A retrospective study by the Cancer and Leukemia Group B (CALGB) noticed that older and younger women had similar reductions in breast cancer mortality from regimens containing more CHT [
24]. Likewise, Muss et al. demonstrated that in women aged 65 years or older, standard adjuvant poly-chemotherapy is superior to a single-agent CHT (capecitabine) in patients with early-stage breast cancer [
25].
Especially in patients with Luminal B tumors, the missing ET ± CHT led to worse outcomes both in the ESG and in the NESG (See appendix Tables
7 and
8). In line with results from Kruiff et al., this might be explained by the fact that these tumors may benefit more from CHT than other subtypes due to their high proliferative characteristics [
6]. However, the problem of identifying older patients who will benefit from adjuvant CHT and to weigh potential survival advantages versus serious side effects has not been solved [
26].
In contrast to CHT, patients in the NESG received more often ET only (Table
2) with 69.0% (
n = 455) of Luminal A patients compared to 63.0% (
n = 700) in the ESG. With respect to Luminal B patients, these differences were even more distinct. 40.7% (
n = 205) of patients in the ESG received ET in comparison with 63.7% (
n = 212) of patients in the NESG. Likewise, a study analyzing data from the Netherlands Cancer Registry demonstrated that the percentage of patients who received ET only increased with age for all stages [
27].
For HER2-like positive patients, the application of trastuzumab in combination with CHT represents the gold standard in the adjuvant setting [
28,
29]. Also, in elderly patients with HER2-positive breast cancer the use of trastuzumab should be considered as standard of care [
30], even though careful management regarding mainly cardiovascular side effects is essential [
31,
32]. A subgroup analysis from the herceptin adjuvant study (HERA) showed an effect of trastuzumab independent of age [
33]. In line with the findings of Grumpelt et al., we observed that the use of trastuzumab was insufficient both in the ESG and the NESG [
34].
Withholding basal-like patients, CHT resulted in exceeding low OS rates in both subgroups. Patients with basal-like breast cancer in the ESG receiving CHT had a 7-year OS rate of 85.5% in contrast to those patients receiving no adjuvant therapy with a 7-year OS rate of 66.9% (See appendix Table
7). Analogous to this, 7-year OS rate in the NESG deteriorated to 48.5 versus 77.0% in patients with Basal-like tumors without CHT (See appendix Table
8). Two retrospective studies of the Surveillance, Epidemiology and End Results (SEER) database revealed that adjuvant CHT improves OS in geriatric patients aged older than 65 years with ER-negative tumors [
35,
36]. In an observational study of 1711 women aged ≥66 years with ER-negative breast cancer, multivariate regression analysis showed that CHT led to a 15% reduction in risk of death from any cause, in comparison with patients without CHT (HR = 0.83, 95% CI 0.74–0.92) [
35]. Our results are consistent with these findings.
With respect to local therapies, breast conserving therapy (BCT) is the standard of care for operable breast cancer plus whole-breast radiotherapy (WBRT) [
19]. Nevertheless, patients in the NESG received less surgery and less WBRT than patients in the ESG. This observation corresponds with a Dutch population-based study selecting 2336 female breast cancer patients ≥60 years versus ≥80 years between 2001 and 2006. The proportion of patients undergoing surgery decreased with increasing age: 99% for patients aged 60–69 years, 98% for patients aged 70–79 years, and 83% for patients ≥80 years old [
37]. Patients in the ESG mostly received BCT (78.9%), whereas patients in the NESG received BCT only in 52.9%, but mastectomy in 41.9% (Table
3). A study by Rocco et al. [
38] who analyzed treatment and outcomes of 449 women aged ≥65 years compared to 1049 younger patients showed higher rates of mastectomy in older patients. 72% (
n = 324) of patients older than 65 years got mastectomy compared to 28% (
n = 125) with BCT [
38].
Omission of WBRT after BCT in elderly breast cancer patients remains a controversial issue, particularly because most randomized trials analyzing WBRT excluded patients older than 70 years. Radiotherapy after primary surgery was performed less frequently in the oldest age group in a study by Weggelaar et al. [
37] agreeing with our results and with previous studies reporting less loco-regional surgery and frequent omission of radiotherapy in elderly patients [
34,
36,
39‐
41].