1 INTRODUCTION

Breast cancer is a heterogeneous age-specific malignancy that commonly affects women.1 Studies have shown that elderly adults have a higher incidence of breast cancer and are at higher risk of under treatment and overtreatment.2, 3 Conversely, younger women with breast cancer are more likely to have malignant tumors and poor prognosis.4 An effective therapeutic option for breast cancer is crucial to improve the survival and prognosis of breast cancer patients.

Chemotherapy is an effective therapeutic option for invasive breast cancer. In the past, chemotherapy was considered as an effective adjuvant therapy after surgery.5 Recently, neoadjuvant chemotherapy has been recommended as a treatment for patients with advanced breast cancer and greater tumor size.6, 7 Neoadjuvant chemotherapy is beneficial for reducing tumor size and preventing tumor cell extension.8 Pathological response is generally used to estimate the effectiveness of neoadjuvant chemotherapy, based on the extent of residual tumor cells in the breast lesion. Patients with no or <5% residual invasive malignant tumor cells without mitosis achieve pathological complete response (pCR).9 Several studies have used various definitions of pCR. German study groups defined pCR in breast cancer as an absence of residual invasive or noninvasive tumor cells in the breast or axillary nodes (ypT0 ypN0).10 The University of Texas MD Anderson Cancer Center and the Neo-Breast International Group define pCR as the absence of invasive or noninvasive residuals in the breast and absence of invasive residuals in the axillary nodes (ypT0/is ypN0).11, 12

Although pCR does not constitute a definite surrogate endpoint for long-term survival in breast cancer prognosis, patients who attain pCR typically have better prognostic outcomes than those who do not.13, 14 Furthermore, preclinical studies have demonstrated a strong association between pCR and long-term improvement in prognostic outcomes in breast cancer patients, especially for those with more aggressive subtypes and high-risk breast cancer.15-17 For instance, studies have reported that human epidermal growth factor receptor 2 (HER2)-positive breast cancer with pCR is associated with a considerably longer survival interval.13 Therefore, pCR is regarded as the primary endpoint for estimating the prognostic outcomes, including disease-free and OS, of patients undergoing neoadjuvant therapy.

Studies investigating the effect of age on pCR are lacking, especially lack of knowledge of the effects of neoadjuvant therapy and different age groups on survival outcome. Hence, this study investigated the effectiveness of neoadjuvant chemotherapy in patients with invasive breast cancer in different age groups and evaluated the impact of age group on disease-free and OS according to different treatment responses.

2 METHODS 2.1 Dataset

Data were retrospectively collected from the cancer registry database of Kaohsiung Medical University Hospital in Taiwan following protocol with institutional review board approval (KMUIRB990174). Patients with distant metastatic breast cancer and those who had not received any systemic treatment were excluded. The comparison of demographic characteristics between neoadjuvant and adjuvant systemic treatment subgroup in breast cancer registry databases is summarized in Table S1. Although the neoadjuvant subgroup had significantly higher proportion in HER2-positive patients, no significant differences were found in estrogen receptor (ER) and progesterone receptor (PR) between the adjuvant and neoadjuvant subgroups. Thus, according to the comparison results between the adjuvant and neoadjuvant subgroups in database, HER2 status between case controls should be matched to avoid selection bias. Female patients with breast cancer who received neoadjuvant chemotherapy and surgical treatment between January 2011 and December 2017 were examined. The censor date of study was December 31, 2018, to ensure at least a 1-year follow-up interval for the study population. The cases were patients aged >50 years, and the controls were patients aged ≤50 years or under. HER2 status (determined from biopsy specimens) was used as the matching criterion to control the combination therapeutic effects of target therapy and chemotherapy in neoadjuvant settings. Overall, 96 elder cases and 96 younger controls were included after 1:1 case–control matching. The cancer characteristics examined included HER2 status, preoperative primary tumor size, preoperative regional lymph node status, preoperative clinical stage, histological type, histological grade, ER status, and PR status. The staging of preoperative primary tumor size, preoperative regional lymph node status, and preoperative clinical stage were defined according to the American Joint Committee on Cancer (AJCC) staging 7th edition. The preoperative clinical stage IV patients indicate regional metastases breast cancer. Breast-conserving surgery, radiotherapy, and hormone therapy were included as treatment characteristics. All of the HER2-positive patients received combined neoadjuvant target therapy and chemotherapy; thus, target therapy was not included in additional treatments as a factor.

2.2 Outcome estimation

Neoadjuvant chemotherapy response was determined according to the pathological response of breast tumors after treatment completion. Patients with no invasive or noninvasive breast residuals and no invasive residuals in the axillary nodes were considered to have achieved pCR10-12; otherwise, they were labeled as non-pCR. Disease progression and OS were used for the evaluation of the effects of neoadjuvant chemotherapy response, age group, tumor characteristics, and additional treatments in a 5-year follow-up. The disease progression of both groups was tracked from the date of first diagnosis to the date of first recurrence/metastasis or the end of the study. The OS outcome was dependent on patient survival status. The survival interval was tracked from the date of first diagnosis to the date of death or the end of the study. Patients lost to follow-up before the end of the study were considered censored.

2.3 Statistical analysis

The tumor characteristics, neoadjuvant chemotherapy response, additional treatments, and survival status of patients in different age groups are presented as means and standard deviations or as frequencies and percentages. The distribution of tumor characteristics between the age groups was estimated using an independent t test, a chi-squared test, or Fisher's exact test, as appropriate. Logistic regression analysis was used to investigate the effects of age group and cancer characteristics on neoadjuvant treatment response. The Kaplan–Meier method was used to visualize and compare the cumulative survival rate of patients by age group, and the log-rank test was used to estimate the difference between the age groups in terms of survival status according to neoadjuvant chemotherapy response. p <0.05 was considered statistically significant. All analyses were performed using Stata version 13.0 (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX, USA: StataCorp LP).

3 RESULTS

A total of 192 female patients with breast cancer were investigated. The baseline characteristic distribution of the patients by age group is presented in Table 1. The mean age of the younger group was 43.2 ± 6.7 years, while the mean age of the elder group was 58.7 ± 5.8 years. After 1:1 matching, 49% of patients in each group had HER2-positive breast cancer. A significantly higher proportion of ER-negative (elder vs. younger, 32.3% vs. 19.8%; p = 0.048) and PR-negative (elder vs. younger, 49.0% vs. 31.3%; p = 0.012) were found in the elder group. Moreover, the elder group obtained significantly higher proportion in the triple-negative subgroup (elder vs. younger, 13.5% vs. 5.2%; p = 0.048).

TABLE 1. Baseline characteristics of the study population (N = 192) Variables Younger group Elder group p (<50 years) (≥50 years) Cases 96 96 Age (year) 43.2 ± 6.7 58.7 ± 5.8 <0.001 Her2 status (matched) 1.000 Negative 49 (51.0%) 49 (51.0%) Positive 47 (49.0%) 47 (49.0%) Preoperative primary tumor size 0.108 cT1 3 (3.1%) 1 (1%) cT2 28 (29.2%) 22 (22.9%) cT3 28 (29.2%) 19 (19.8%) cT4 37 (38.5%) 52 (54.2%) Unknown 0 (0%) 2 (2.1%) Preoperative regional lymph node 0.577 cN0 16 (16.7%) 10 (10.4%) cN1 52 (54.2%) 51 (53.1%) cN2 20 (20.8%) 25 (26.0%) cN3 7 (7.3%) 7 (7.3%) Unknown 1 (1.0%) 3 (3.1%) Preoperative clinical stage 0.059 I 0 (0%) 1 (1.0%) II 23 (24.0%) 13 (13.5%) III 35 (36.5%) 28 (29.2%) IV (regional metastases) 38 (39.6%) 52 (54.2%) Unknown 0 (0%) 2 (2.1%) Histological type 0.311 Non-IDC 1 (1.0%) 3 (3.1%) IDC 95 (99.0%) 93 (96.9%) Histological grade 0.679 1 5 (5.2%) 3 (3.1%) 2 52 (54.2%) 60 (62.5%) 3 21 (21.9%) 18 (18.8%) Unknown 18 (18.8%) 15 (15.6%) ER status 0.048 Negative 19 (19.8%) 31 (32.3%) Positive 77 (80.2%) 65 (67.7%) PR status 0.012 Negative 30 (31.3%) 47 (49.0%) Positive 66 (68.8%) 49 (51.0%) Molecular subtype Her2 overexpression 13 (13.5%) 17 (17.7%) 0.427 TNBC 5 (5.2%) 13 (13.5%) 0.048 Treatment response (pCR) 9 (9.4%) 7 (7.3%) 0.602 Conserving surgery 53 (55.2%) 62 (64.6%) 0.185 Postoperative nodal status 2 (33.3%) 36 (37.5%) 0.540 With radiotherapy 44 (45.8%) 23 (24.0%) 0.001 With hormone therapy 71 (74.0%) 54 (56.3%) 0.010 Disease progression 48 (50.0%) 56 (58.3%) 0.247 Expired 14 (14.6%) 18 (18.8%) 0.439 Notes: p values were estimated using an independent t test, Fisher's exact test, or a chi-squared test. Bold fonts indicates statistical significance.

Overall, 9 (9.4%) elder patients and 7 (7.3%) younger patients achieved pCR after neoadjuvant chemotherapy; however, no statistical significance was found between the groups. Furthermore, a significantly smaller proportion of younger patients have received radiotherapy (elder vs. younger, 24% vs. 45.8%; p = 0.001) and hormone therapy (elder vs. younger, 56.3% vs. 74%; p = 0.010) in adjuvant settings.

Table 2 shows the association between age group, cancer characteristics, and neoadjuvant chemotherapy response identified using logistic regression analysis. In a univariate analysis, high histological grade (odds ratio [OR], 3.45; 95% CI, 1.04–11.42; p = 0.042) was associated with a significantly higher likelihood of achieving pCR. ER-positive status (OR, 0.13; 95% CI, 0.04–0.39; p <0.001) and PR-positive status (OR, 0.20; 95% CI, 0.06–0.63; p = 0.006) were associated with a lower likelihood of achieving pCR. Similar results were found in the fully adjusted multivariate model; however, only ER-positive status (OR, 0.16; 95% CI, 0.03–0.84; p <0.030) was associated with significantly lower odds of achieving pCR.

TABLE 2. Logistic regression analysis of neoadjuvant chemotherapy response Category Comparison Univariate model Full-adjusted model OR (95% CI) p OR (95% CI) p Age group >50 versus ≤50 years 0.76 (0.27–2.13) 0.602 0.54 (0.17–1.74) 0.300 Histological grade 3 versus 1–2 3.45 (1.04–11.42) 0.042 2.12 (0.58–7.72) 0.256 ER status Positive versus negative 0.13 (0.04–0.39) <0.001 0.16 (0.03–0.84) 0.030 PR status Positive versus negative 0.20 (0.06–0.63) 0.006 0.67 (0.12–3.91) 0.658 Preoperative primary tumor size cT3-4 versus cT1-2 1.21 (0.37–3.93) 0.752 0.81 (0.20–3.24) 0.766 Preoperative regional lymph node cN1-3 versus cT0 2.55 (0.32–20.18) 0.375 3.96 (0.4–38.82) 0.238 Metastatic cancer MBC versus EBC 0.64 (0.22–1.85) 0.412 0.63 (0.19–2.05) 0.440 Note: Bold fonts indicates statistical significance. Abbreviations: EBC, early breast cancer with preoperative clinical stage I to III; MBC, de novo regional metastases breast cancer with preoperative clinical stage IV.

Although no direct significant association was found between age group and treatment response, several significant results were found in treatment response stratification analysis. Kaplan–Meier analysis was used to further evaluate the impact of age group on disease-free survival (Figures 1) and OS (Figures 2) according to neoadjuvant chemotherapy response stratification. Among 16 pCR patients, elder patients showed significantly greater 5-year disease-free survival (DFS) than younger patients (DFS rate, 85.7% vs. 0%; p = 0.041). However, in 176 non-pCR patients, the elder age group showed poor DFS compared to the younger group (DFS rate, 16.6% vs. 32.3%; log-rank test, p = 0.031). Similar findings were noted in OS analysis. Among 16 pCR patients, elder patients showed greater 5-year OS than younger patients (OS rate, 100.0% vs. 66.7%; p = 0.564). In 176 non-pCR patients, the elder age group showed poor OS compared to younger group (DFS rate, 52.7% vs. 67.9%; p = 0.057). The sensitivity analysis for DFS (Figure S1) and OS (Figure S2) using cutoff values of 40 and 60 to estimate the differential result compared with cutoff values of 50 in diagnosis age. The sensitivity analysis results for PFS showed that the subgroup with cutoff value of 40 in diagnosis age have no statistically significant results in both pCR (Figure S1A) and non-pCR (Figure S1C) stratum. Similar results were found in OS analysis for cutoff value of 40 in diagnosis age (Figure S2A,C). Although the sensitivity analysis results showed that the subgroup with cutoff value of 60 in diagnosis age have no statistically significant results in pCR strata (Figure S2B), the non-pCR strata (Figure S2D) showed similar statistically significant findings with the subgroup with cutoff value of 50 in diagnosis age.

Five-year disease-free survival curve for different age groups of (A) patients who achieved pathological complete response (pCR) and (B) patients who did not achieve pCR after neoadjuvant chemotherapy

Five-year overall survival curve for different age group of (A) patients who achieved pathological complete response (pCR) and (B) patients who did not achieve pCR after neoadjuvant chemotherapy

4 DISCUSSION

The results demonstrate that of patients who achieved pCR, those in the elder age group had significantly better DFS than those in the younger age group. Of patients who did not achieve pCR, those in the younger age group had significantly better DFS than those in the older age group. Notably, these results from stratification according to the presence or absence of pCR were reversed in different age groups, possibly because of between-group differences in cancer characteristics.

In general, the age of 50 years is considered to be a major cutoff for various diseases in which age is a prominent factor, including female breast cancer, primarily due to the changes in the microenvironment in vivo during the aging process.18, 19 Moreover, 50 years old is commonly considered as a surrogate cut-point to distinguish menopause status for Taiwanese women, which is highly related to the survival outcome of breast cancer.20, 21 The baseline characteristic distribution (Table 1) shows that a significantly higher proportion of elder patients aged >50 years were ER-negative, PR-negative, or had the triple-negative subtype of breast cancer, which is consistent with past findings.22, 23

The results indicate that patients with ER-positive breast cancer had poor response to neoadjuvant chemotherapy. Rather than chemotherapy, the most effective therapeutic option for ER-positive breast cancer is endocrine therapy. Combining both therapies may stop the cell cycle in the G0 phase and then limit the sensitivity of cytotoxic chemotherapeutic agents, resulting in a negative effect.24, 25

A previous study has demonstrated that pCR following neoadjuvant chemotherapy is associated with favorable survival outcomes among patients with operable breast cancer and considered tumor response to be a good endpoint for survival.26 Although pCR was not associated with significant benefits in all patients, the elderly patients who achieved pCR had significantly greater DFS than the younger patients. Women aged >50 years face a significantly elevated risk of breast cancer and are at risk of both under treatment and overtreatment.3, 27, 28 This finding suggests that neoadjuvant chemotherapy could be beneficial for elder female breast cancer patients, and pCR should be regarded as a surrogate endpoint of DFS for breast cancer patients who are over the age of 50 years in neoadjuvant settings.

This study had several limitations. First, its retrospective nature limited the inclusion of previously reported covariates such as genomic information or tumor markers.29 However, we have included general associated variables commonly used in breast cancer research. Second, because database information on the neoadjuvant chemotherapy regimen was incomplete, we could not analyze the effects of different regimens for operable breast cancer in patients of different age groups. Moreover, the limited sample size in the pCR subgroup analysis might increase the type I and type II error of our study findings and hence, limiting the generalizability of the findings. Although preoperative neoadjuvant system treatment is currently not recommended for metastatic breast cancer, considering the retrospective nature of current study, preoperative neoadjuvant systematic treatment was a treatment option for locally advanced and regional stage IV breast cancer in our study.30, 31 Despite the limitations, this study provides useful information on the effectiveness of neoadjuvant chemotherapy for patients with breast cancer in different age groups and the effect of treatment response on survival outcomes.

This case–control matched study investigated the effectiveness of neoadjuvant chemotherapy in different age groups and determined the impact of treatment response on survival outcomes in Taiwanese female patients with breast cancer. Our results demonstrate that patients aged >50 years who achieved pCR after neoadjuvant chemotherapy was more likely to have better disease-free survival. However, younger patients showed no survival benefits regardless of pCR status.

CONFLICT OF INTEREST

All authors declare no conflict of interest.

Filename Description kjm212475-sup-0001-Figure S1.docxWord 2007 document , 703.6 KB

Figure S1 Sensitivity analysis of disease-free survival (DFS) using cutoff values of 40 and 60 years in diagnosis age. Five-year DFS curve for different age group of (A) patients who achieved pCR with cutoff value of 40 years, (B) patients who achieved pCR with cutoff value of 60 years, (C) patients who did not achieve pCR with cutoff value of 40 years, and (D) patients who did not achieve pCR with cutoff value of 60 years after neoadjuvant chemotherapy.

kjm212475-sup-0002-Figure S2.docxWord 2007 document , 641 KB

Figure S2 Sensitivity analysis of overall survival (OS) using cutoff values of 40 and 60 years in diagnosis age. Five-year OS curve for different age group of (A) patients who achieved pCR with cutoff value of 40 years, (B) patients who achieved pCR with cutoff value of 60 years, (C) patients who did not achieve pCR with cutoff value of 40 years, and (D) patients who did not achieve pCR with cutoff value of 60 years after neoadjuvant chemotherapy.

kjm212475-sup-0003-Table S1.docxWord 2007 document , 16.2 KB

Table S1 Demographic characteristics of adjuvant and neoadjuvant subgroup in breast cancer in cancer registry database.

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