Qiusheng Guo, Tian Lan, and Yunyan Lu contributed equally to this work.
This article is available under a Creative Commons License (Attribution 4.0 International, as described at
There is little evidence determining whether elderly patients (from 70 to 90 years old) with triple-negative breast cancer (TNBC) could benefit from adjuvant chemotherapy (AC). This study explores the effect of AC in these population following surgery. A total of 4610 patients were identified in the Surveillance, Epidemiology, and End Results database (2010–2018). Multiple imputation by chained equations was performed to impute missing data. Inverse probability of treatment weighting (IPTW) was applied to reduce the selection bias. IPTW-adjusted Kaplan–Meiers survival analysis and Cox proportional hazards models were performed to compare breast cancer-specific survival (BCSS) and overall survival (OS) in the two treatment groups. The patients were classified into the chemotherapy (
Breast cancer is the most common female malignancy worldwide [
The global population is aging at a sharp rate. By 2030, 20% of all adults are estimated to be 65 and above [
There are few population-based retrospective studies evaluating the impact of AC in older women with TNBC. One study was derived from the National Cancer Database, and the other was derived from the Swedish National Breast Cancer Register [
TNBC data were extracted by using the SEER-stat software (SEER*Stat 8.3.9) from the SEER 18 regions database [Incidence-SEER 18 Research Plus Data, 18 Registries, Nov 2020 Sub (2000–2018)] that covers approximately 34.6% of the U.S. population [
The SEER database provided the following clinicopathological factors: patient-associated demographics, clinicopathologic features, treatment-related variables, and prognostic information. Patient-associated demographics included age (70–79 or 80–89), year at diagnosis (2010–2014 or 2015–2018), marital status (married or unmarried), race (white, black, or others), and median household income (<$40,000, $40,000–$49,999, $50,000–$59,999, $60,000–$69,999, or >$70,000). Tumor-related information was grade, tumor size, lymph node status, and TNM stage. Treatment data consisted of surgery (breast-conserving surgery or mastectomy) and radiation.
Multiple imputations by chained equations were performed using the mice R package to impute missing data for the grade (14.3% missing), lymph node status (6.1% missing), marital status (5.0% missing), tumor size (1.4% missing), stage (0.7% missing), and race (0.4% missing), with the assumption that the missing data were missing at random [
To reduce the selection bias in this retrospective and non-random study, the observed differences in baseline features between the two treatment groups were controlled with the inverse probability of treatment weighting (IPTW) method. IPTW had superior performance over propensity score matching, such as retaining all the cases in the subsequent analysis [
A multivariate logistic regression was used to calculate propensity scores, the probability of receiving a treatment (chemotherapy or observation in this study), in each imputed dataset.
The independent variables in this model were year at diagnosis, age, marital status, median household income, race, grade, tumor size, lymph node status, surgery, and radiation. Then Rubin’s rules were applied to combine the estimated propensity scores from the 30 imputed datasets. Standardized mean difference (SMD) of less than 0.1 is considered as a good match of covariates between two treatment groups [
Adjusted survival analysis was conducted using the Kaplan–Meier curves and the Log-rank test based on IPTW [
At last, we reported the E-value by performing additional sensitivity analyses to estimate the assessment of robustness to biases, such as unmeasured or uncontrolled confounding. A high E-value revealed that the strong confounder associations would be needed to explain away the observed treatment-outcome relationship. Two-sided statistical significance was set as
Flowchart for the selection of older patients with triple-negative breast cancer (TNBC) after surgery in the SEER database (2010–2018).
A total of 1,415,230 patients with breast cancer were extracted from the SEER database between 2010 and 2018. We identified 4610 elderly female patients with nonmetastatic TNBC who received surgery according to the inclusion and exclusion criteria, of whom 1989 were treated with AC and 2621 with observation (
Baseline characteristics of old patients who received adjuvant chemotherapy vs observation after operation for triple-negative breast cancer in unweighted and weighted study populations
<0.001 | 0.727 | |||||
2010–2014 | 1533 (58.5) | 1034 (52.0) | 1444.0 (55.0) | 1061.3 (54.3) | ||
2015–2018 | 1088 (41.5) | 955 (48.0) | <0.001 | 1182.1 (45.0) | 891.6 (45.7) | 0.308 |
78.53 (5.34) | 74.47 (3.95) | 76.72 (5.31) | 76.50 (4.88) | |||
<0.001 | 0.807 | |||||
Unmarried | 1478 (59.7) | 905 (47.7) | 1339.0 (54.1) | 999.6 (53.7) | ||
Married | 998 (40.3) | 992 (52.3) | 1134.5 (45.9) | 862.9 (46.3) | ||
0.010 | 0.977 | |||||
<40,000 | 121 (4.6) | 110 (5.5) | 133.7 (5.1) | 100.2 (5.1) | ||
40,000–49,999 | 365 (13.9) | 280 (14.1) | 381.5 (14.5) | 275.0 (14.1) | ||
50,000–59,999 | 454 (17.3) | 322 (16.2) | 441.5 (16.8) | 315.6 (16.2) | ||
60,000–69,999 | 786 (30.0) | 521 (26.2) | 736.0 (28.0) | 550.9 (28.2) | ||
>70,000 | 895 (34.1) | 756 (38.0) | 933.3 (35.5) | 711.3 (36.4) | ||
0.931 | 0.901 | |||||
White | 2011 (77.0) | 1515 (76.6) | 2001.8 (76.4) | 1475.8 (75.9) | ||
Black | 404 (15.5) | 314 (15.9) | 420.5 (16.1) | 315.1 (16.2) | ||
Others | 198 (7.6) | 150 (7.6) | 196.2 (7.5) | 154.0 (7.9) | ||
<0.001 | 0.733 | |||||
I+II | 686 (29.7) | 331 (19.3) | 571.2 (24.9) | 413.1 (24.3) | ||
III | 1623 (70.3) | 1385 (80.7) | 1720.4 (75.1) | 1283.9 (75.7) | ||
<0.001 | 0.449 | |||||
T1 | 1513 (58.8) | 997 (50.6) | 1413.7 (54.8) | 1071.6 (55.3) | ||
T2 | 868 (33.7) | 875 (44.4) | 1000.4 (38.8) | 721.7 (37.2) | ||
T3 | 191 (7.4) | 100 (5.1) | 164.4 (6.4) | 145.6 (7.5) | ||
<0.001 | 0.77 | |||||
N0 | 1910 (79.3) | 1316 (67.8) | 1825.2 (74.5) | 1378.2 (72.8) | ||
N1 | 331 (13.7) | 409 (21.1) | 408.5 (16.7) | 343.1 (18.1) | ||
N2 | 97 (4.0) | 147 (7.6) | 127.5 (5.2) | 105.1 (5.6) | ||
N3 | 72 (3.0) | 70 (3.6) | 89.1 (3.6) | 66.8 (3.5) | ||
<0.001 | 0.958 | |||||
BCS | 1312 (50.1) | 1207 (60.7) | 1420.7 (54.1) | 1058.5 (54.2) | ||
Mastectomy | 1309 (49.9) | 782 (39.3) | 1205.3 (45.9) | 894.4 (45.8) | ||
<0.001 | 0.803 | |||||
None | 1144 (43.6) | 527 (26.5) | 980.2 (37.3) | 719.9 (36.9) | ||
Yes | 1477 (56.4) | 1462 (73.5) | 1645.9 (62.7) | 1233.0 (63.1) |
BCS: Breast-conserving surgery.
The results of multivariable logistic regression analysis predicting receipt of AC vs observation in the unweighted cohort are shown in
In the weighted cohort, the median follow-up was 38 months, and the interquartile range was 48 months (17–65). The IPTW-adjusted Kaplan–Meier analysis confirmed that BCSS in the AC group was longer than in the observation group (
Subgroup analyses were performed to further explore the IPTW-adjusted HRs of AC vs observation outcome based on year at diagnosis, age, marital status, race, stage, tumor size, lymph node, surgery, and radiation (
In the complete case analysis, the 5-year IPTW-adjusted rates of prognosis in the AC group were better than that in the observation group (BCSS: 81.75% vs 78.24%,
The E-value for an estimate is 1.92, indicating that the observed HR of 0.77 could be explained away by an unmeasured confounder that was associated with both AC and BCSS by a risk ratio of 1.92-fold each, above and beyond the measured confounders, but weaker confounding could not do so. The unmeasured confounder would not suffice to explain away the AC effect estimate. In addition, the E-value for OS HR is 2.40.
The findings of our study demonstrated that AC was related to improved BCSS and OS in older patients with nonmetastatic TNBC. It was interesting that chemotherapy improved OS, but not BCSS, in patients aged over 80 years. Less intensive chemotherapy should be applied with caution for patients aged over 80 years based on contradictory results. According to the present National Comprehensive Cancer Network guideline for patients under 70 years, chemotherapy should be considered for T1bN0M0 TNBC and exempt for T1aN0M0 TNBC. But our study presented that older patients with T1abN0M0 TNBC could not get survival benefits (BCSS and OS) from chemotherapy. De-escalation of chemotherapy may be an acceptable approach for these specific patients.
Clinicians should consider the physical status of patients, like function, falls, comorbidity, cognition, depression, and nutrition, when recommending chemotherapy for older TNBC women in terms of the American Society of Clinical Oncology Guideline [
Adoption rates of adjuvant chemotherapy for old patients with triple-negative breast cancer (TNBC) in the unweighted study population.
Multivariable logistic regression model predicting receipt of adjuvant chemotherapy vs observation in the unweighted study population
2010–2014 | 1.00 (Reference) | |
2015–2018 | 1.25 (1.09–1.43) | <0.001 |
Age, mean (SD) | 0.82 (0.80–0.83) | <0.001 |
Unmarried | 1.00 (Reference) | |
Married | 1.22 (1.06–1.41) | 0.006 |
<40,000 | 1.00 (Reference) | |
40,000–49,999 | 0.75 (0.53–1.06) | 0.106 |
50,000–59,999 | 0.61 (0.43–0.85) | 0.004 |
60,000–69,999 | 0.60 (0.43–0.83) | 0.002 |
>70,000 | 0.83 (0.60–1.15) | 0.272 |
White | 1.00 (Reference) | |
Black | 0.88 (0.73–1.07) | 0.194 |
Others | 1.04 (0.80–1.35) | 0.792 |
I+II | 1.00 (Reference) | |
III | 1.85 (1.56–2.19) | <0.001 |
T1 | 1.00 (Reference) | |
T2 | 2.00 (1.71–2.34) | <0.001 |
T3 | 0.96 (0.69–1.33) | 0.785 |
N0 | 1.00 (Reference) | |
N1 | 2.43 (2.00–2.97) | <0.001 |
N2 | 3.03 (2.15–4.27) | <0.001 |
N3 | 2.51 (1.64–3.84) | <0.001 |
BCS | 1.00 (Reference) | |
Mastectomy | 1.12 (0.84–1.49) | 0.453 |
None | 1.00 (Reference) | |
Yes | 2.39 (1.81–3.17) | <0.001 |
BCS: Breast-conserving surgery.
It remains controversial whether AC could provide a survival benefit in older patients with TNBC. Some studies conducted before 2000 presented that chemotherapy could decrease all cause mortality in lymph node-positive, ER-negative, older patients [
There were several studies associated with the SEER database focusing on elderly TNBC patients. Retrospective research based on the SEER database indicated a prognostic difference between patients aged 18–69 with TNBC and patients aged 70 or older, which may be caused by undertreatment [
I
Our study should be interpreted with the following limitations. First, some significant factors associated with clinical and geriatric assessment, including Ki67, the Charlson–Deyo index, and BRCA1/2, were unavailable in the SEER database. The regimen changes during 2010–2018, and the lack of detailed chemotherapy regimens information may lead to bias. Residual unmeasured covariates may have impacted the founding of our study. In the current study, the results of a sensitivity analysis revealed a moderately robust outcome that an unmeasured confounder should have at least a 1.92-fold stronger association with both chemotherapy and prognosis in comparison with the relationship between chemotherapy and survival. Second, despite the implementation of some statistical approaches, selection bias was inevitable due to the retrospective nature of this study. Although the difficult recruitment of these specific patients, further prospective randomized control trials should be warranted.
In conclusion, the study presented a BCSS and OS benefit from AC in old patients with TNBC. AC should remain a reasonable treatment approach for these specific patients. Clinicians should take into consideration the function, falls, comorbidity, cognition, depression, and nutrition to administrate de-escalated treatment with caution for patients over 80 years or with T1ab.
We acknowledge the efforts of the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries for creating the SEER database.
Conflicts of interest: The authors declare no conflicts of interest.
Funding: This study was supported by the grants from Hangzhou Science and Technology Program (20211231Y063), Hangzhou Health Science and Technology Program (A20220311) and Zhejiang Traditional Medicine and Technology Program (2023ZL115).
Data availability: The datasets are available in the SEER database [Incidence-SEER 18 Research Plus Data, 18 Registries, Nov 2020 Sub (2000–2018)]