Abstract
Objectives
This study aimed to investigate the impact of adjuvant chemotherapy (ACT) on survival outcomes in older women with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC).
Design
A retrospective cohort study using data from the Surveillance, Epidemiology, and End Results database, which contains publicly available information from US cancer registries.
Setting and participants
The study included 45 762 older patients with BC aged over 65 years diagnosed between 2010 and 2015.
Methods
Patients were divided into two groups based on age: 65–79 years and ≥80 years. Propensity score matching (PSM) was employed to balance clinicopathological characteristics between patients who received ACT and those who did not. Data analysis used the χ2 test and Kaplan-Meier method, with a subgroup analysis conducted to identify potential beneficiaries of ACT.
Outcome measures
Overall survival (OS) and cancer-specific survival (CSS).
Results
Due to clinicopathological characteristic imbalances between patients with BC aged 65–79 years and those aged ≥80 years, PSM was used to categorise the population into two groups for analysis: the 65–79 years age group (n=38 128) and the ≥80 years age group (n=7634). Among patients aged 65–79 years, Kaplan-Meier analysis post-PSM indicated that ACT was effective in improving OS (p<0.05, HR=0.80, 95% CI 0.73 to 0.88), particularly in those with advanced disease stages, but did not show a significant benefit in CSS (p=0.09, HR=1.13, 95% CI 0.98 to 1.31). Conversely, for patients aged ≥80 years, ACT did not demonstrate any improvement in OS (p=0.79, HR=1.04, 95% CI 0.79 to 1.36) or CSS (p=0.09, HR=1.46, 95% CI 0.69 to 2.26) after matching. Subgroup analysis also revealed no positive impact on OS and CSS.
Conclusions
Patients with HR+/HER2− BC ≥80 years of age may be considered exempt from ACT because no benefits were found in terms of OS and CSS.
Keywords: breast cancer, adjuvant chemotherapy, older women, SEER, propensity score-matched
STRENGTHS AND LIMITATIONS OF THIS STUDY.
This is a systematic analysis that used a large sample from the Surveillance, Epidemiology, and End Results (SEER) database.
This study eliminated the effects of relevant factors in the group receiving ACT and the group not receiving ACT by use of propensity score matching.
The impact of comorbidities, endocrine therapy and ACT regimens on survival could not be assessed due to limitations of the SEER database.
The effect of selection bias could not be excluded entirely due to limitations of retrospective studies.
Introduction
Along with the increase in population ageing, the incidence of breast cancer (BC) in older women is also increasing worldwide annually.1 There is currently no uniform definition of older patients with BC, female patients aged 65 years or older are generally considered older women. Approximately half of patients with BC are diagnosed at age 65 or older,2 3 and patients aged ≥80 comprise a large percentage of this population. About one in four patients diagnosed with BC at over 65 years are 80 years of age or older, accounting for 10.6% of all patients with BC. Those diagnosed at ≥80 years have the highest mortality rate.4 5 In addition, the proportion of new BC among women aged over 70 years is expected to increase from 24% in 2011 to 35% in 2030,6 promoting the need to optimise cancer treatment recommendations for older adults.
Compared with younger patients, older patients are more likely to be hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−), a subtype with a better prognosis.7 8 Some studies have demonstrated that BC in patients in older cohorts is less aggressive, with smaller tumour sizes and less or no lymph node involvement.9–11 However, these patients carry a more significant burden of comorbidities and geriatric syndromes, such as cardiovascular and cerebrovascular diseases, functional cognitive impairment, malnutrition, polypharmacy and psychological distress.12 13 The treatment of older patients with BC has always been controversial for several reasons. First, most clinical trials excluded elderly patients, and treatment strategies for elderly patients were often derived from an extended application of the evidence for treatment in the general age group. Second, the treatment strategy in older women is significantly inferior to that of younger patients due to older patients’ higher rate of incompliance, toxic drug adverse effects and poorer health conditions.14 Third, chronological age does not always coincide with biological age,15 requiring clinical treatment decision-makers to assess patients more carefully and comprehensively.16
Patients with HR+/HER2− BC account for 70% of all BC cases.17 Standard treatment varies depending on the risk of recurrence, and includes combinations of surgery, radiotherapy, adjuvant/neoadjuvant chemotherapy and endocrine therapy.11 18 Previous studies have confirmed that endocrine therapy and surgery are associated with better overall survival in elderly patients with HR+ BC.17 19–21 However, whether adjuvant chemotherapy (ACT) is beneficial in elderly patients, especially HR+/HER2− patients ≥80 years old, has rarely been studied. Recently updated American Society of Clinical Oncology (ASCO) practice guidelines recommend the use of multigene assays in HR+/HER2− early BC adjuvant decision-making, of which the 21-gene test (Oncotype DX) is the most widely used.22 Although Oncotype DX is considered the genomic test of choice worldwide, the high cost and the remaining areas of uncertainty make the widespread use of this tool challenging.23 This paper attempts to find a more straightforward way to measure the benefits of ACT in older patients with HR+/HER2− BC by determining whether this cohort should receive ACT by age alone.
In this study, we compared the clinical and pathological characteristics, treatments and long-term outcomes of patients with HR+/HER2− BC aged 65–79 years and those aged ≥80 years using the Surveillance, Epidemiology, and End Results (SEER) database, and investigated the impact of ACT on overall survival (OS) and cancer-specific survival (CSS) in both age cohorts of older women. This study aimed to evaluate the potential benefits of ACT to patients with BC aged ≥80 years.
Methods
Data source
This retrospective study analysed the SEER 17 Registry maintained by the National Cancer Institute (NCI; 2000–2019; data set submitted in November 2021; www.seer.cancer.gov)24.The SEER*Stat software (V.8.4.0) was used to extract clinicopathological and survival information from the database. The NCI (USA) provided permission to access the research data file in the SEER Registry (reference number 15031, November 2021).
Study cohort
Since the database only included HER2-related data after 2010 and to ensure a specific follow-up time, female patients diagnosed with HR+/HER2− primary invasive ductal BC (histological codes 8500, 8521, 8522 and 8523 of International Classification of Disease for Oncology third edition, ICD-O-3) between 2010 and 2015 were enrolled. All patients underwent surgery and received postoperative systemic therapy. Exclusion criteria included (1) male patients; (2) age <65 at diagnosis; (3) T0, Tx and Nx stage; (4) patients with distant metastases (M1 stage); and (5) missing data. According to age at diagnosis, patients were divided into two groups: 38 128 patients in the 65–79 years age group and 7634 patients in the older age group (≥80 years).
Exposures and covariates
The primary study endpoints were OS and CSS. Other covariates included race (white/black/others), tumour grade (I–II/III–IV), T stage (T1–T4), N stage (N0–N3), marital status (absence or presence of a marital partner at diagnosis of BC, indicated by ‘No’ or ‘Yes’, respectively), radiotherapy (‘No/Unknown’ or ‘Yes’), chemotherapy (‘No’ or ‘Yes’) and surgery (breast-conserving surgery, mastectomy, modified radical mastectomy). Staging was classified according to the American Joint Committee on Cancer Tumor Node Metastasis (TNM) Sixth Edition.
Outcomes
OS was calculated from the date of diagnosis to the date of death from any cause. CSS was measured from the date of diagnosis to the date of direct or indirect death from BC. The SEER database shows the survival status as ‘Vital Status’.
Statistical analysis
The baseline characteristics of elderly patients with BC aged 65–79 years and ≥80 years with HR+/HER2− were compared using χ2 or Fisher’s exact test. We then further studied the two cohorts separately. Each cohort was subdivided into two groups based on whether the patient received ACT, that is, the group receiving ACT and the group not receiving ACT. To reduce possible confounding factors, we used a 1:1 propensity score matching (PSM) to balance important clinicopathological characteristics between the group receiving and not receiving ACT, with a calliper value of 0.0001 for the 65–79 years age group and 0.001 for the ≥80 years age group. Variables in the PSM analysis included age, race, marital status, grade, T stage, N stage, radiotherapy and surgery. The Kaplan-Meier method was used to calculate the OS and CSS curves for patients who received ACT and those who did not receive ACT before and after PSM. The log-rank test was performed to determine statistical significance. After PSM, the Cox proportional hazards regression model was used to explore subgroups that might benefit from ACT. Subgroups were analysed according to age, race, marital status, grade, T stage, N stage, radiotherapy and surgery. In cases where the HR and 95% CI were between 0 and 1, a smaller HR meant the patient benefited more from ACT. In cases where the HR and 95% CI were more significant than 1, a larger HR meant the patient did not benefit more from ACT. HR and 95% CI were calculated and a two-sided p value <0.05 was considered statistically significant. Statistical analyses were performed using R software (V.4.2.2).
Patient and public involvement
None.
Results
Clinicopathological characteristics
The baseline clinical characteristics of older patients with HR+/HER2− BC who had undergone surgery are shown in table 1. There were 45 762 eligible patients in this study, including patients aged 65–79 years (n=38 128) and patients aged ≥80 years (n=7634). Compared with the 65–79 years age group, at initial diagnosis, the ≥80 years age group had higher tumour histological grade (III/IV: 17.1% vs 19.1%, p<0.05), later T stage (T3: 1.87% vs 2.92%; T4: 0.60% vs 2.16%, p<0.05) and N stage (N2: 3.23% vs 3.89%; N3: 1.44% vs 1.70%, p<0.05), a relatively low proportion with marital partners (54.1% vs 32.3%, p<0.05), and a lower ratio receiving radiotherapy (63.2% vs 40.3%, p<0.05) and chemotherapy (20.7% vs 3.76%, p<0.05). They all differed statistically, confirming significant differences in the clinicopathological characteristics of patients with HR+/HER2− BC aged 65–79 and ≥80 years.
Table 1.
Comparison of the clinical characteristics of patients with HR+/HER2− breast cancer between the 65–79 years age group and the ≥80 years age group
| Characteristics | 65–79 years | ≥80 years | P value |
| Patients, n | 38 128 | 7634 | |
| Race, n (%) | <0.001 | ||
| White | 32 285 (84.7) | 6667 (87.3) | |
| Black | 2696 (7.1) | 487 (6.4) | |
| Other/unknown | 3147 (8.3) | 480 (6.3) | |
| Marital status, n (%) | <0.001 | ||
| No | 16 502 (43.3) | 5044 (66.1) | |
| Yes | 21 626 (56.7) | 2590 (33.9) | |
| Grade, n (%) | <0.001 | ||
| I/II | 31 596 (82.9) | 6175 (80.9) | |
| III/IV | 6532 (17.1) | 1459 (19.1) | |
| T stage, n (%) | <0.001 | ||
| T1 | 28 806 (75.6) | 4978 (65.2) | |
| T2 | 8380 (22.0) | 2268 (29.7) | |
| T3 | 713 (1.9) | 223 (2.9) | |
| T4 | 229 (0.6) | 165 (2.2) | |
| N stage, n (%) | 0.007 | ||
| N0 | 29 525 (77.4) | 5832 (76.4) | |
| N1 | 6820 (17.9) | 1375 (18.0) | |
| N2 | 1233 (3.2) | 297 (3.9) | |
| N3 | 550 (1.4) | 130 (1.7) | |
| Radiotherapy, n (%) | <0.001 | ||
| No/unknown | 14 028 (36.8) | 4561 (59.7) | |
| Yes | 24 100 (63.2) | 3073 (40.3) | |
| ACT, n (%) | <0.001 | ||
| No | 30 218 (79.3) | 7347 (96.2) | |
| Yes | 7910 (20.7) | 287 (3.8) | |
| Surgery, n (%) | <0.001 | ||
| BCS | 26 355 (69.1) | 5114 (67.0) | |
| MAST | 7938 (20.8) | 1571 (20.6) | |
| MRM | 3835 (10.1) | 949 (12.4) |
ACT, adjuvant chemotherapy; BCS, breast conservative surgery; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MAST, mastectomy; MRM, modified radical mastectomy; N stage, lymph node stage; T stage, tumour stage.
Survival outcomes before and after PSM
The variables before and after matching are shown in table 2 for patients with BC aged 65–79 years and in table 3 for patients with BC aged ≥80 years. There were 5543 patients with BC in the ACT and non-ACT groups in the matched cohort of patients aged 65–79 years and 232 patients with BC in the ACT and non-ACT groups in the matched cohort of patients aged ≥80 years. After PSM, the p values of the statistical tests for each variable in the groups receiving and not receiving ACT were close to ‘1’, suggesting that PSM minimised the bias caused by other variables.
Table 2.
Clinicopathological features of patients aged 65–79 years with or without ACT before and after PSM
| Variables | Before PSM | P value | After PSM | P value | ||
| Without ACT | With ACT | Without ACT | With ACT | |||
| n=30 218 | n=7910 | n=5433 | n=5433 | |||
| Age, n (%) | <0.001 | 1 | ||||
| 65–69 | 12 417 (41.1) | 4551 (57.5) | 2853 (52.5) | 2853 (52.5) | ||
| 70–79 | 17 801 (58.9) | 3359 (42.5) | 2580 (47.5) | 2580 (47.5) | ||
| Race, n (%) | <0.001 | 0.999 | ||||
| White | 25 721 (85.1) | 6564 (83.0) | 4646 (85.5) | 4646 (85.5) | ||
| Black | 1954 (6.5) | 742 (9.4) | 404 (7.4) | 405 (7.5) | ||
| Other/unknown | 2543 (8.4) | 604 (7.6) | 383 (7.1) | 382 (7.0) | ||
| Marital status, n (%) | 1 | 1 | ||||
| No | 13 078 (43.3) | 3424 (43.3) | 2339 (43.1) | 2338 (43.0) | ||
| Yes | 17 140 (56.7) | 4486 (56.7) | 3094 (56.9) | 3095 (57.0) | ||
| Grade, n (%) | <0.001 | 0.968 | ||||
| I/II | 26 865 (88.9) | 4731 (59.8) | 3563 (65.6) | 3566 (65.6) | ||
| III/IV | 3353 (11.1) | 3179 (40.2) | 1870 (34.4) | 1867 (34.4) | ||
| T stage, n (%) | <0.001 | 0.984 | ||||
| T1 | 24 913 (82.4) | 3893 (49.2) | 3134 (57.7) | 3135 (57.7) | ||
| T2 | 4915 (16.3) | 3465 (43.8) | 2121 (39.0) | 2122 (39.1) | ||
| T3 | 291 (1.0) | 422 (5.3) | 148 (2.7) | 149 (2.7) | ||
| T4 | 99 (0.3) | 130 (1.6) | 30 (0.6) | 27 (0.5) | ||
| N stage, n (%) | <0.001 | 0.969 | ||||
| N0 | 26 222 (86.8) | 3303 (41.8) | 3013 (55.5) | 3013 (55.5) | ||
| N1 | 3679 (12.2) | 3141 (39.7) | 2162 (39.8) | 2162 (39.8) | ||
| N2 | 231 (0.8) | 1002 (12.7) | 193 (3.6) | 188 (3.5) | ||
| N3 | 86 (0.3) | 464 (5.9) | 65 (1.2) | 70 (1.3) | ||
| Radiotherapy, n (%) | <0.001 | 1 | ||||
| No/unknown | 10 745 (35.6) | 3283 (41.5) | 2256 (41.5) | 2256 (41.5) | ||
| Yes | 19 473 (64.4) | 4627 (58.5) | 3177 (58.5) | 3177 (58.5) | ||
| Surgery, n (%) | <0.001 | 1 | ||||
| BCS | 22 134 (73.2) | 4221 (53.4) | 3211 (59.1) | 3210 (59.1) | ||
| MAST | 6057 (20.0) | 1881 (23.8) | 1400 (25.8) | 1400 (25.8) | ||
| MRM | 2027 (6.7) | 1808 (22.9) | 822 (15.1) | 823 (15.1) | ||
ACT, adjuvant chemotherapy; BCS, breast conservative surgery; MAST, mastectomy; MRM, modified radical mastectomy; PSM, propensity score matching; N stage, lymph node stage; T stage, tumour stage.
Table 3.
Clinicopathological features of patients aged ≥80 years with or without ACT before and after PSM
| Before PSM | P value | After PSM | P value | |||
| Without ACT | With ACT | Without ACT | With ACT | |||
| n=7347 | n=287 | n=232 | n=232 | |||
| Age, n (%) | <0.001 | 1 | ||||
| 80–84 | 4719 (64.2) | 237 (82.6) | 189 (81.5) | 189 (81.5) | ||
| 85+ | 2628 (35.8) | 50 (17.4) | 43 (18.5) | 43 (18.5) | ||
| Race, n (%) | 0.002 | 1 | ||||
| White | 6425 (87.5) | 242 (84.3) | 208 (89.7) | 208 (89.7) | ||
| Black | 455 (6.2) | 32 (11.1) | 18 (7.8) | 18 (7.8) | ||
| Other/unknown | 467 (6.4) | 13 (4.5) | 6 (2.6) | 6 (2.6) | ||
| Marital status, n (%) | 0.007 | 1 | ||||
| No | 4876 (66.4) | 168 (58.5) | 138 (59.5) | 138 (59.5) | ||
| Yes | 2471 (33.6) | 119 (41.5) | 94 (40.5) | 94 (40.5) | ||
| Grade, n (%) | <0.001 | 1 | ||||
| I/II | 6023 (82.0) | 152 (53.0) | 134 (57.8) | 134 (57.8) | ||
| III/IV | 1324 (18.0) | 135 (47.0) | 98 (42.2) | 98 (42.2) | ||
| T stage, n (%) | <0.001 | 1 | ||||
| T1 | 4856 (66.1) | 122 (42.5) | 109 (47.0) | 109 (47.0) | ||
| T2 | 2145 (29.2) | 123 (42.9) | 100 (43.1) | 100 (43.1) | ||
| T3 | 199 (2.7) | 24 (8.4) | 14 (6.0) | 14 (6.0) | ||
| T4 | 147 (2.0) | 18 (6.3) | 9 (3.9) | 9 (3.9) | ||
| N stage, n (%) | <0.001 | 1 | ||||
| N0 | 5725 (77.9) | 107 (37.3) | 101 (43.5) | 101 (43.5) | ||
| N1 | 1274 (17.3) | 101 (35.2) | 84 (36.2) | 84 (36.2) | ||
| N2 | 240 (3.3) | 57 (19.9) | 39 (16.8) | 39 (16.8) | ||
| N3 | 108 (1.5) | 22 (7.7) | 8 (3.5) | 8 (3.5) | ||
| Radiotherapy, n (%) | <0.001 | 1 | ||||
| No/unknown | 4421 (60.2) | 140 (48.8) | 113 (48.7) | 113 (48.7) | ||
| Yes | 2926 (39.8) | 147 (51.2) | 119 (51.3) | 119 (51.3) | ||
| Surgery, n (%) | <0.001 | 1 | ||||
| BCS | 4985 (67.9) | 129 (44.9) | 121 (52.2) | 121 (52.2) | ||
| MAST | 1507 (20.5) | 64 (22.3) | 48 (20.7) | 48 (20.7) | ||
| MRM | 855 (11.6) | 94 (32.8) | 63 (27.2) | 63 (27.2) | ||
ACT, adjuvant chemotherapy; BCS, breast conservative surgery; MAST, mastectomy; MRM, modified radical mastectomy; PSM, propensity score matching; N stage, lymph node stage; T stage, tumour stage.
Interestingly, before matching, the results of the Kaplan-Meier survival curves showed that ACT did not improve OS and CSS in both groups and decreased patient survival time (figure 1A–D). After matching, ACT was effective in improving OS (p<0.001; figure 2A) but not CSS (p=0.092; figure 2B) in patients in the 65–79 years age group. For patients in the ≥80 years age group, ACT treatment had no noticeable effect on OS (p=0.79; figure 2C) and CSS (p=0.091; figure 2D).
Figure 1.
Overall survival (A) and cancer-specific survival (B) in the group of patients with breast cancer aged 65–79 years, and overall survival (C) and cancer-specific survival (D) in the group of patients with breast cancer aged ≥80 years, before matching.
Figure 2.
Overall survival (A) and cancer-specific survival (B) in the group of patients with breast cancer aged 65–79 years, and overall survival (C) and cancer-specific survival (D) in the group of patients with breast cancer aged ≥80 years, after matching.
In the subgroup survival analysis, ACT improved the OS in all age and histological grade subgroups in the 65–79 years age group. Also, for more advanced T stages (T2–T4) and N stages (N1–N3), ACT was effective in improving OS (online supplemental figure 1). Similarly, ACT improved CSS in T3, T4, N2 and N3 patients (online supplemental figure 2). However, the subgroup analysis for patients with BC aged ≥80 showed that ACT did not improve prognosis in terms of OS or CSS in each subgroup (online supplemental figures 3 and 4).
bmjopen-2023-078782supp001.pdf (1.2MB, pdf)
Discussion
With population ageing, the number of Americans aged 65 and older is expected to reach 88.5 million by 2050. Many older women with HR+/HER2− BC are diagnosed with stage II–III disease.25 There is no consensus definition for elderly patients; however, in the context of clinical trials, female patients older than 65 years old are usually considered older women.26 This group is less likely to receive guideline-concordant treatment, including chemotherapy, partly due to their reduced tolerance to treatment.27–30 Comorbidities and geriatric syndromes such as cardiovascular and cerebrovascular diseases, functional cognitive impairment, malnutrition polypharmacy, psychological distress and diabetes have been shown to lower the ability of patients to tolerate chemotherapy.31–35 Older patients with BC have a higher risk of adverse events such as electrolyte imbalances, acute kidney injury, and cardiotoxicity and haematotoxicity than younger patients.36 Also, BC treatment in older women often relies on extrapolated evidence from younger populations.37 The above reasons lead to treatment of older patients with BC not being standardised and to few clinical trials being conducted specifically for this group, increasing their risk of recurrence. In addition, Oncotype DX is considered the genomic assay of choice worldwide and its primary purpose is to assess the risk of early HR+/ HER2− BC local and distant recurrence so that patients could be exempted from receiving ACT. However, it has the disadvantages of high price and uncertainty.23 Using data from a large sample based on the SEER database, this study concluded that further age stratification was necessary for older women with HR+/HER2− BC over 65 years of age. According to our age classification, ACT improved the prognosis of patients aged 65–79. In contrast, ACT did not provide survival benefit and was even harmful to those aged ≥80 years.
In the entire patient population of older women, most of the elderly patients had lower tumour histological grade, earlier tumour stage and negative lymph node involvement. These findings are consistent with previous studies10 38 and may explain why, of all age groups, the highest percentage of patients with BC who underwent breast-conserving surgery is in older patients.39 We demonstrated significant differences in clinical characteristics and treatment patterns between female patients aged 65–79 years and ≥80 years with primary invasive ductal BC. In the two subgroups, the ≥80 years age group manifested more aggressive and advanced tumour stage, with larger tumour size and more advanced lymph node staging, than the 65–79 years age group, which may explain the concept that mortality increases with age.11
A retrospective study from Japan including 12 727 older patients with BC aged >75 years found lower chemotherapy use in older women with stage II/III BC. Still, chemotherapy improved OS in luminal and HER2-positive patients.40 It should be noted that the proportion of HR+/HER2− patients in their study was small, accounting for only 9.2%, and the sample size was much smaller than in our study, indicating that our findings are more reliable. A recently published retrospective study that included 1703 elderly patients with BC over 65 years of age found that ACT improved OS in older patients, particularly those with larger tumour diameters and positive lymph nodes.41 The study included a higher percentage of HR+/HER2− patients, at 70%. However, its sample size was much smaller than our study. Our study also showed that ACT improved survival in patients aged 65–79 years and was more pronounced in patients with more advanced staging, consistent with their study. However, our analysis of patients aged ≥80 years did not find a survival advantage for ACT, which was complementary to their results because the sample size of their study’s ≥80 years of age population was much smaller than ours.
In a study that included 592 patients with BC over 70 years with complications and lymph node-positive disease, those who received ACT had better survival rates than those who did not (HR=0.67, 95% CI 0.48 to 0.98).42 Another multicentre prospective observational study of 3456 patients with BC aged ≥70 years showed that chemotherapy reduced the risk of metastasis but did not significantly improve OS and CSS. Chemotherapy improved OS and CSS only in patients with HR− BC.43 In a study designed to assess the impact of chemotherapy on patients over 70 years of age, it was shown that older women with BC who are in good health may tolerate chemotherapy as well as younger patients. Still, the number of patients meeting the criteria was too small.44 Overall, most of the studies on the choice of chemotherapy for older women with BC had small sample sizes. Most of these studies did not further stratify by age because older patients became less tolerant of chemotherapy with age. In contrast, our study took advantage of a large sample size and subdivided older women over 65 into two groups: the 65–79 years age group and the ≥80 years age group. In the 65–79 years age group, we reached conclusions consistent with most previous studies. However, in the ≥80 years age group, our study concluded that ACT did not improve long-term survival, including OS and CSS.
Based on our findings and on previous studies,17 45 endocrine therapy could be an alternative treatment. Several classes of endocrine therapies have been developed, including selective oestrogen receptor modulators, selective oestrogen receptor downregulators, aromatase inhibitors, luteinising hormone-releasing hormone agonists, high-dose oestrogens and primarily targeted therapies.46 47 Several clinical studies have shown that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors or histone deacetylase (HDAC) inhibitors combined with conventional endocrine therapy had comparable efficacy to chemotherapy in patients with advanced BC, with low adverse drug reactions.48–50 If patients with BC cannot tolerate chemotherapy, CDK4/6 or HDAC inhibitors combined with conventional endocrine therapy might be a good option. Of course, clinical safety and survival benefits require rigorous clinical trials.
Equally important, deciding on treatment strategies based solely on chronological age increases the risk of overtreatment or undertreatment in older patients.51 Chronological age, based on date of birth, is the traditional criterion for assessing ageing, and the degree of ageing can vary widely between individuals,52 making chronological age not the best indicator for assessing the degree of ageing in humans. Biological age is often used as an alternative to chronological age to assess ageing.53 Based on tens of thousands of genetic samples from human tissues, Steve Horvath found the pattern of DNA methylation in the ageing process and developed a tool for measuring physiological age—epigenetic clock—with an accuracy of 98%.54 The value of physiological age should be fully considered in practical treatment decisions.15 Geriatric assessment (GA) helps estimate life expectancy better and contributes to therapeutic decision-making in geriatric oncology. GA usually includes several dimensions, such as physical performance, risk of falls, functional status, multiple comorbidities, polypharmacy status, depressive symptoms, cognitive ability, psychosocial distress, nutritional status and socioeconomic support.55 The European Society of Breast Cancer Specialists and the International Society of Geriatric Oncology recommend that GA be used in the management of all elderly patients with BC.56 Our study further demonstrates the importance of performing GA for older patients with BC to make sound decisions when considering cancer treatment to maximise benefit and minimise harm to each patient.
We need to point out some limitations to this study. First, this was a regression study, and despite using statistical methods, such as PSM, selection bias and other problems could not be eliminated. Second, some patients were recorded as not receiving ACT in the SEER database; however, they may also have received chemotherapy during follow-up treatment which may not have been recorded. Also, data on endocrine therapy were not available in the database. Third, data on recurrence or metastasis during follow-up were also not available in the database. Fourth, the SEER database did not provide specific information on comorbidities other than cancer in older patients, the ACT regimen used, the dose received, the number of cycles given and the ACT complications. In this study, we defined receiving systemic therapy postoperatively and receiving ACT as chemotherapy. Future studies with large sample sizes and incorporating endocrine therapy conditions, comorbidities and adverse effects are needed to investigate the absolute clinical benefit of ACT in older women.
Conclusions
Our study suggests that older women with BC over 65 years of age should be further stratified according to age. Patients with HR+/HER2− BC aged ≥80 years may be considered exempt from receiving ACT, while ACT could be considered in patients with HR+/HER2− BC aged 65–79 years, especially in those with advanced tumour stage.
bmjopen-2023-078782supp002.pdf (89.7KB, pdf)
Supplementary Material
Footnotes
XM and SW contributed equally.
Contributors: Paper concept and design: YL, XM and SW. Review of the literature: YL, XM, SW, XZ, CheY and MC. Data analysis and interpretation: XM, NC, ChaY and KD. Manuscript editing and critical review: all authors. Approval of the final draft: all authors. YL approved the submission of the manuscript. YL has full responsibility for the overall content as the guarantor, had access to the data andcontrolled the decision to publish.
Funding: This study was supported by Project '100 Foreign Experts Plan of Hebei Province', China (no: 2022001).
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Data availability statement
Data are available in a public, open access repository.
Ethics statements
Patient consent for publication
Not required.
Ethics approval
The SEER database was used as the data source for this study. The SEER database has been approved by the NIH Ethics Program (Office of Ethics, NIH and the ethics programmes of the institutes and centres).
References
- 1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7–33. 10.3322/caac.21708 [DOI] [PubMed] [Google Scholar]
- 2. Derks MGM, Bastiaannet E, Kiderlen M, et al. Variation in treatment and survival of older patients with non-metastatic breast cancer in five European countries: a population-based cohort study from the EURECCA breast cancer group. Br J Cancer 2018;119:121–9. 10.1038/s41416-018-0090-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Lagacé F, Ghazawi FM, Le M, et al. Analysis of incidence, mortality trends, and geographic distribution of breast cancer patients in Canada. Breast Cancer Res Treat 2019;178:683–91. 10.1007/s10549-019-05418-2 [DOI] [PubMed] [Google Scholar]
- 4. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016;66:271–89. 10.3322/caac.21349 [DOI] [PubMed] [Google Scholar]
- 5. Bertolo A, Rosso C, Voutsadakis IA. Breast cancer in patients 80 years-old and older. Eur J Breast Health 2020;16:208–12. 10.5152/ejbh.2020.5659 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Rosenberg PS, Barker KA, Anderson WF. Estrogen receptor status and the future burden of invasive and in situ breast cancers in the United States. J Natl Cancer Inst 2015;107:djv159. 10.1093/jnci/djv159 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Eppenberger-Castori S, Moore DH, Thor AD, et al. Age-associated biomarker profiles of human breast cancer. Int J Biochem Cell Biol 2002;34:1318–30. 10.1016/s1357-2725(02)00052-3 [DOI] [PubMed] [Google Scholar]
- 8. Schonberg MA, Marcantonio ER, Li D, et al. Breast cancer among the oldest old: tumor characteristics, treatment choices, and survival. J Clin Oncol 2010;28:2038–45. 10.1200/JCO.2009.25.9796 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Sawaki M, Shimomura A, Shien T, et al. Management of breast cancer in older patients. Jpn J Clin Oncol 2022;52:682–9. 10.1093/jjco/hyac054 [DOI] [PubMed] [Google Scholar]
- 10. Syed BM, Green AR, Paish EC, et al. Biology of primary breast cancer in older women treated by surgery: with correlation with long-term clinical outcome and comparison with their younger counterparts. Br J Cancer 2013;108:1042–51. 10.1038/bjc.2012.601 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Desai P, Aggarwal A. Breast cancer in women over 65 years- a review of screening and treatment options. Clin Geriatr Med 2021;37:611–23. 10.1016/j.cger.2021.05.007 [DOI] [PubMed] [Google Scholar]
- 12. Chesney TR, Coburn N, Mahar AL, et al. All-cause and cancer-specific death of older adults following surgery for cancer. JAMA Surg 2021;156:e211425. 10.1001/jamasurg.2021.1425 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Satariano WA, Ragland DR. The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 1994;120:104–10. 10.7326/0003-4819-120-2-199401150-00002 [DOI] [PubMed] [Google Scholar]
- 14. Reinisch M, von Minckwitz G, Harbeck N, et al. Side effects of standard adjuvant and neoadjuvant chemotherapy regimens according to age groups in primary breast cancer. Breast Care (Basel) 2013;8:60–6. 10.1159/000346834 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. Lancet 2013;381:752–62. 10.1016/S0140-6736(12)62167-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Tejera D, Rana M, Basik M, et al. Population-based analysis of non-operative management and treatment patterns in older women with estrogen receptor-positive breast cancer. Breast Cancer Res Treat 2021;190:491–501. 10.1007/s10549-021-06393-3 [DOI] [PubMed] [Google Scholar]
- 17. Le Saux O, Lardy-Cleaud A, Frank S, et al. Assessment of the efficacy of successive endocrine therapies in hormone receptor-positive and HER2-negative metastatic breast cancer: a real-life multicentre national study. Eur J Cancer 2019;118:131–41. 10.1016/j.ejca.2019.06.014 [DOI] [PubMed] [Google Scholar]
- 18. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol 2020;38:3987–98. 10.1200/JCO.20.02514 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Xie W, Cao M, Zhong Z, et al. Survival outcomes for breast conserving surgery versus mastectomy among elderly women with breast cancer. Breast Cancer Res Treat 2022;196:67–74. 10.1007/s10549-022-06725-x [DOI] [PubMed] [Google Scholar]
- 20. Matar R, Sevilimedu V, Gemignani ML, et al. Impact of endocrine therapy adherence on outcomes in elderly women with early-stage breast cancer undergoing lumpectomy without radiotherapy. Ann Surg Oncol 2022;29:4753–60. 10.1245/s10434-022-11728-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Cortadellas T, Córdoba O, Gascón A, et al. Surgery improves survival in elderly with breast cancer. A study of 465 patients in a single institution. Eur J Surg Oncol 2015;41:635–40. 10.1016/j.ejso.2015.01.027 [DOI] [PubMed] [Google Scholar]
- 22. Andre F, Ismaila N, Allison KH, et al. Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO guideline update. J Clin Oncol 2022;40:1816–37. 10.1200/JCO.22.00069 [DOI] [PubMed] [Google Scholar]
- 23. Jacobs F, Gaudio M, Benvenuti C, et al. Controversies and opportunities in the clinical daily use of the 21-gene assay for prognostication and prediction of chemotherapy benefit in HR+/Her2- early breast cancer. Cancers (Basel) 2022;15:148. 10.3390/cancers15010148 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Data from: surveillance, epidemiology, and end results (SEER) program (www.seer.cancer.Gov) SEER*Stat database: incidence - SEER research plus data, 17 registries, Nov 2021 sub (2000–2019) - linked to County attributes - time dependent (1990–2019) income/Rurality,1969–2020 counties, National Cancer Institute, DCCPS, surveillance research program, released April 2022, based on the November 2021 submission; Available: https://seer.cancer.gov/
- 25. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and Her2 status. J Natl Cancer Inst 2014;106:dju055. 10.1093/jnci/dju055 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Torregrosa-Maicas MD, Del Barco-Berrón S, Cotes-Sanchís A, et al. Expert consensus to optimize the treatment of elderly patients with luminal metastatic breast cancer. Clin Transl Oncol 2022;24:1033–46. 10.1007/s12094-021-02766-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Owusu C, Lash TL, Silliman RA. Effect of undertreatment on the disparity in age-related breast cancer-specific survival among older women. Breast Cancer Res Treat 2007;102:227–36. 10.1007/s10549-006-9321-x [DOI] [PubMed] [Google Scholar]
- 28. Simes RJ, Coates AS. Patient preferences for adjuvant chemotherapy of early breast cancer: how much benefit is needed? JNCI Monographs 2001;2001:146–52. 10.1093/oxfordjournals.jncimonographs.a003453 [DOI] [PubMed] [Google Scholar]
- 29. Harder H, Ballinger R, Langridge C, et al. Adjuvant chemotherapy in elderly women with breast cancer: patients perspectives on information giving and decision making. Psychooncology 2013;22:2729–35. 10.1002/pon.3338 [DOI] [PubMed] [Google Scholar]
- 30. Gajra A, McCall L, Muss HB, et al. The preference to receive chemotherapy and cancer-related outcomes in older adults with breast cancer CALGB 49907 (alliance). J Geriatr Oncol 2018;9:221–7. 10.1016/j.jgo.2018.02.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Pressoir M, Desné S, Berchery D, et al. Prevalence, risk factors and clinical implications of malnutrition in French comprehensive cancer centres. Br J Cancer 2010;102:966–71. 10.1038/sj.bjc.6605578 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Srokowski TP, Fang S, Hortobagyi GN, et al. Impact of diabetes mellitus on complications and outcomes of adjuvant chemotherapy in older patients with breast cancer. J Clin Oncol 2009;27:2170–6. 10.1200/JCO.2008.17.5935 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Aaldriks AA, van der Geest LGM, Giltay EJ, et al. Frailty and malnutrition predictive of mortality risk in older patients with advanced colorectal cancer receiving chemotherapy. J Geriatr Oncol 2013;4:218–26. 10.1016/j.jgo.2013.04.001 [DOI] [PubMed] [Google Scholar]
- 34. Raji MA, Kuo Y-F, Freeman JL, et al. Effect of a dementia diagnosis on survival of older patients after a diagnosis of breast, colon, or prostate cancer: implications for cancer care. Arch Intern Med 2008;168:2033–40. 10.1001/archinte.168.18.2033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Canoui-Poitrine F, Reinald N, Laurent M, et al. Geriatric assessment findings independently associated with clinical depression in 1092 older patients with cancer: the ELCAPA cohort study. Psychooncology 2016;25:104–11. 10.1002/pon.3886 [DOI] [PubMed] [Google Scholar]
- 36. Lichtman SM, Cirrincione CT, Hurria A, et al. Effect of pretreatment renal function on treatment and clinical outcomes in the adjuvant treatment of older women with breast cancer: alliance A171201, an ancillary study of CALGB/CTSU 49907. J Clin Oncol 2016;34:699–705. 10.1200/JCO.2015.62.6341 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Mislang AR, Biganzoli L. Adjuvant systemic therapy in older breast cancer women: can we optimize the level of care? Cancers (Basel) 2015;7:1191–214. 10.3390/cancers7030833 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Clark GM. The biology of breast cancer in older women. J Gerontol 1992;47 Spec No:19–23. [PubMed] [Google Scholar]
- 39. Jonczyk MM, Jean J, Graham R, et al. Surgical trends in breast cancer: a rise in novel operative treatment options over a 12 year analysis. Breast Cancer Res Treat 2019;173:267–74. 10.1007/s10549-018-5018-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Yamada A, Kumamaru H, Shimizu C, et al. Systemic therapy and prognosis of older patients with stage II/III breast cancer: a large-scale analysis of the Japanese breast cancer registry. Eur J Cancer 2021;154:157–66. 10.1016/j.ejca.2021.06.006 [DOI] [PubMed] [Google Scholar]
- 41. Sang Y, Yang B, Mo M, et al. Treatment and survival outcomes in older women with primary breast cancer: a retrospective propensity score-matched analysis. Breast 2022;66:24–30. 10.1016/j.breast.2022.09.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Tamirisa N, Lin H, Shen Y, et al. Association of chemotherapy with survival in elderly patients with multiple comorbidities and estrogen receptor-positive, node-positive breast cancer. JAMA Oncol 2020;6:1548–54. 10.1001/jamaoncol.2020.2388 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Ring A, Battisti NML, Reed MWR, et al. Bridging the age gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer. Br J Cancer 2021;125:209–19. 10.1038/s41416-021-01388-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Christman K, Muss HB, Case LD, et al. Chemotherapy of metastatic breast cancer in the elderly. The Piedmont oncology Association experience. JAMA 1992;268:57–62. [PubMed] [Google Scholar]
- 45. Jacquet E, Lardy-Cléaud A, Pistilli B, et al. Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients. Eur J Cancer 2018;95:93–101. 10.1016/j.ejca.2018.03.013 [DOI] [PubMed] [Google Scholar]
- 46. Paridaens RJ, Dirix LY, Beex LV, et al. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European organisation for research and treatment of cancer breast cancer cooperative group. J Clin Oncol 2008;26:4883–90. 10.1200/JCO.2007.14.4659 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the pre-operative “Arimidex” compared totamoxifen (PROACT) trial. Cancer 2006;106:2095–103. 10.1002/cncr.21872 [DOI] [PubMed] [Google Scholar]
- 48. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375:1925–36. 10.1056/NEJMoa1607303 [DOI] [PubMed] [Google Scholar]
- 49. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 2017;35:3638–46. 10.1200/JCO.2017.75.6155 [DOI] [PubMed] [Google Scholar]
- 50. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 2018;379:1926–36. 10.1056/NEJMoa1810527 [DOI] [PubMed] [Google Scholar]
- 51. Nightingale G, Schwartz R, Kachur E, et al. Clinical pharmacology of oncology agents in older adults: a comprehensive review of how chronologic and functional age can influence treatment-related effects. J Geriatr Oncol 2019;10:4–30. 10.1016/j.jgo.2018.06.008 [DOI] [PubMed] [Google Scholar]
- 52. López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013;153:1194–217. 10.1016/j.cell.2013.05.039 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Zhang W, Jia L, Cai G, et al. Model construction for biological age based on a cross-sectional study of a healthy Chinese Han population. J Nutr Health Aging 2017;21:1233–9. 10.1007/s12603-017-0874-7 [DOI] [PubMed] [Google Scholar]
- 54. Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 2018;19:371–84. 10.1038/s41576-018-0004-3 [DOI] [PubMed] [Google Scholar]
- 55. Wildiers H, Heeren P, Puts M, et al. International society of geriatric oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol 2014;32:2595–603. 10.1200/JCO.2013.54.8347 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Biganzoli L, Battisti NML, Wildiers H, et al. Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European society of breast cancer specialists (EUSOMA) and the International society of geriatric oncology (SIOG). Lancet Oncol 2021;22:e327–40. 10.1016/S1470-2045(20)30741-5 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
bmjopen-2023-078782supp001.pdf (1.2MB, pdf)
bmjopen-2023-078782supp002.pdf (89.7KB, pdf)
Data Availability Statement
Data are available in a public, open access repository.