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Geriatric Early-Stage Triple-Negative Breast Cancer Patients in Low-risk Population: Omitting Chemotherapy Based on Nomogram

  • Author Footnotes
    † Chen Zhou and Li Xu contributed equally to this article.
    Chen Zhou
    Footnotes
    † Chen Zhou and Li Xu contributed equally to this article.
    Affiliations
    Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu, China

    Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu, China
    Search for articles by this author
  • Author Footnotes
    † Chen Zhou and Li Xu contributed equally to this article.
    Li Xu
    Footnotes
    † Chen Zhou and Li Xu contributed equally to this article.
    Affiliations
    Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu, China

    Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu, China
    Search for articles by this author
  • Zhenggui Du
    Correspondence
    Address for correspondence: Zhenggui Du and Qing Lv, Department of Breast Surgery, Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, 37 Guoxue Street, 610041, Chengdu, China.
    Affiliations
    Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu, China

    Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu, China
    Search for articles by this author
  • Qing Lv
    Correspondence
    Address for correspondence: Zhenggui Du and Qing Lv, Department of Breast Surgery, Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, 37 Guoxue Street, 610041, Chengdu, China.
    Affiliations
    Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu, China

    Clinical Research Center for Breast Diseases, West China Hospital, Sichuan University, Chengdu, China
    Search for articles by this author
  • Author Footnotes
    † Chen Zhou and Li Xu contributed equally to this article.
Published:September 01, 2022DOI:https://doi.org/10.1016/j.clbc.2022.08.013

      Abstract

      Background

      Considering old age and comorbidities, the actual benefit of chemotherapy in older patients with early triple-negative breast cancer (TNBC) remains uncertain. We aimed to select appropriate patients who could avoid chemotherapy in this population.

      Methods

      A total of 6482 patients more than 65 years old with T1-2N0-1M0 TNBC in 2010-2015 were extracted from SEER program. Multivariate logistic regression was performed to identify independent factors associated with chemotherapy usage. Survival analysis was performed using Kaplan-Meier plots and log-rank tests. Independent prognostic factors were identified by multivariate Cox analysis. A nomogram predicting breast cancer-specific survival (BCSS) and a risk stratification model were constructed.

      Results

      A total of 3379 (52.13%) patients received chemotherapy while 3103 (47.87%) did not. Age, married status, grade, T-stage, N-stage, radiation and breast-conserving surgery (BCS) were significantly associated with chemotherapy usage (all P < .05). Chemotherapy significantly improved OS (HR = 0.606, P < .001) and BCSS (HR = 0.763, P = .006) in the entire population. A nomogram was built by incorporating independent risk factors (age, T-stage, N-stage, grade and radiation). Based on the score of the nomogram, the risk stratification model demonstrated that chemotherapy improved OS (P < .001) and BCSS (P < .001) of patients in the high-risk group (score >180), but not in the low-risk group (score ≤75).

      Conclusion

      Chemotherapy is beneficial for geriatric patients with T1-2N0-1M0 TNBC in this study, and the risk stratification model indicates the feasibility of sparing chemotherapy in low-risk subgroup without sacrificing survival, providing clinicians tools to weigh the risk–benefit of chemotherapy and customize the individualized treatment accordingly.

      Keywords

      Abbreviations:

      AIA/API (American Indian/Alaska Native/Asian or Pacific Islander), AJCC (American Joint Committee on Cancer seventh edition), BCSS (breast cancer-specific survival), C-index (concordance index), ER (estrogen receptor), HER2 (human epidermal growth factor-2), HR (hazard ratio), OS (overall survival), PR (progesterone receptor), SEER (Surveillance, Epidemiology, and End Results), SPSS (Statistical Package for the Social Sciences), TNBC (triple-negative breast cancer), 95% CI (95% confidence interval)

      Introduction

      Triple-negative breast cancer (TNBC), a subtype of breast carcinoma defined as lack of estrogen receptor (ER) and progesterone receptor (PR) protein expression and human epidermal growth factor-2 (HER2) amplification, is acknowledged to reveal with more aggressive tumor behavior and tends to be more likely to relapse and metastasize even in early stage.
      • Malorni L
      • Shetty PB
      • De Angelis C
      • et al.
      Clinical and biologic features of triple-negative breast cancers in a large cohort of patients with long-term follow-up.
      For the lack of endocrine therapy and anti-HER2 therapy, chemotherapy has become an exclusive choice of systematic strategy and plays a vital importance on the treatment process of TNBC. Due to its aggressive biological features, even for patients with early-stage TNBC, chemotherapy based on taxane and anthracycline regimens is also recommended as adjuvant strategy after breast surgery, in which process patients gain recurrence and mortality reduction.
      • Gradishar WJ
      • Moran MS
      • Abraham J
      • et al.
      Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.
      ,
      Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials.
      According to a cohort study involving in early-stage TNBC patients >50years in England
      • Jauhari Y
      • Dodwell D
      • Gannon MR
      • et al.
      The influence of age, comorbidity and frailty on treatment with surgery and systemic therapy in older women with operable triple negative breast cancer (TNBC) in England: a population-based cohort study.
      that not all patients received chemotherapy although they had relatively a higher N stage at diagnosis. Older age, more comorbidities and greater frailty were associated with lower rates of chemotherapy use. Furthermore, chemotherapy usage in elderly is significantly less than that in younger patients in clinical treatment process due to poorer health conditions, more incompliance and more toxic side effects.
      • 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.
      ,
      • Dreyer G
      • Vandorpe T
      • Smeets A
      • et al.
      Triple negative breast cancer: clinical characteristics in the different histological subtypes.
      In a word, the abundance of chemotherapy in geriatric TNBC patients was common in practical clinical procedures.
      Whether chemotherapy is obligatory in elderly patients with early TNBC has not reached a consensus worldwide yet. According to the most recent NCCN guideline,
      • Gradishar WJ
      • Moran MS
      • Abraham J
      • et al.
      Breast Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.
      as for geriatric patients, it's still hard to make definite recommendations as a result of limited data, and risks should be assessed according to patients' personal condition when deciding whether to use chemotherapy.
      • Dotan E
      • Walter LC
      • Baumgartner J
      • et al.
      NCCN Guidelines® Insights: Older Adult Oncology, Version 1.2021.
      Other than breast cancer, survival outcome is also tightly associated with other factors. Among geriatric adults with early breast cancer who survived more than 5 years after diagnosis, cardiovascular disease became the leading cause of death rather than breast cancer itself,
      • Abdel-Qadir H
      • Austin PC
      • Lee DS
      • et al.
      A population-based study of cardiovascular mortality following early-stage breast cancer.
      and they were more likely to suffer from chemotherapy-related complications and death.
      • Muss HB
      • Berry DA
      • Cirrincione C
      • et al.
      Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: the cancer and leukemia group b experience.
      ,
      • Ferreira de Souza T
      • Quinaglia ACST
      • Osorio Costa F
      • et al.
      Anthracycline therapy is associated with cardiomyocyte atrophy and preclinical manifestations of heart disease.
      Moreover, elderly patients have more comorbidities, which may result in less effectiveness of chemotherapy and more non-breast cancer mortality.
      • Gray E
      • Marti J
      • Wyatt JC
      • Brewster DH
      • Hall PS
      • group Sa
      Chemotherapy effectiveness in trial-underrepresented groups with early breast cancer: a retrospective cohort study.
      ,
      • Land LH
      • Dalton SO
      • Jensen MB
      • Ewertz M
      Impact of comorbidity on mortality: a cohort study of 62,591 Danish women diagnosed with early breast cancer, 1990-2008.
      In a word, the OS of breast cancer patients is associated with not only breast cancer but comorbidities and treatment regimen related complications. As a result, in geriatric population, we should focus on both BCSS and the impact of other factors on OS of patients as well. Many researches have also drawn controversial conclusions as to the effectiveness of chemotherapy in early-stage TNBC patients with older age. Chandler et al.
      • Chandler Y
      • Jayasekera JC
      • Schechter CB
      • Isaacs C
      • Cadham CJ
      • Mandelblatt JS
      Simulation of chemotherapy effects in older breast cancer patients with high recurrence scores.
      demonstrated that elderly breast cancer patients could only have small benefit from chemotherapy even they had a high recurrence risk. Moreover, studies reported that elderly patients have less recurrence, metastasis and better survival prognosis than younger counterparts when the 2 groups had equal clinicopathological features of the primary tumor despite the older group having received less chemotherapy.
      • Qiu JD
      • Xue XY
      • Li R
      • Wang JD
      Clinicopathological features and prognosis of triple-negative breast cancer: a comparison between younger (<60) and elderly (>/=60) patients.
      Nevertheless, among early-stage TNBC patients, a paradoxical conclusion of was drawn that elderly stage II TNBC patients could benefit from chemotherapy.
      • Kozak MM
      • Xiang M
      • Pollom EL
      • Horst KC
      Adjuvant treatment and survival in older women with triple negative breast cancer: a surveillance, epidemiology, and end results analysis.
      These prompted that merely a portion of geriatric patients could really gain survival benefits from chemotherapy based on the enormous benefit from locoregional therapy in early-stage breast cancer.
      • Rosen PR
      • Groshen S
      • Saigo PE
      • Kinne DW
      • Hellman S
      A long-term follow-up study of survival in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma.
      ,
      • Battisti NML
      • Joshi K
      • Nasser MS
      • Ring A
      Systemic therapy for older patients with early breast cancer.
      In other words, geriatric patients who receive adjuvant chemotherapy should be carefully selected, but there's still a lack of appropriate assessment measures to identify the necessity of chemotherapy in this population.
      Although some patients could benefit from chemotherapy, the comorbidities and complications induced by chemotherapy have a vital impact on survival outcome of elderly patients. Considering the relatively better prognosis of early-stage TNBC and the finite tolerance of chemotherapy in elderly population, the clinical decisions should be made on the basis of scientific evaluation of benefits and risks. However, there's still lack of specific tool to stratify different groups which have a higher risk of suffering from adverse prognosis and could benefit from chemotherapy. This study aimed to discuss whether elderly patients with primary TNBC in early stage can benefit from chemotherapy based on the data from the Surveillance, Epidemiology, and End Results (SEER) program and to establish a risk stratification model using a nomogram to assess the exact benefits patients can gain from chemotherapy, suggesting the possibility of omitting chemotherapy in certain subgroup.

      Materials and Methods

      Data Collection and Study Population

      The SEER program provides information on cancer incidence and survival from 17 registries and 12 state of United States, covering approximately 34.6% of the U.S. population. This retrospective study used the SEER*STAT software version 8.3.6 (Information Management Services, Inc., Calverton, MD, USA) to filter the study population meeting the criteria as follows: 1) aged more than 65 years old; 2) diagnosed with T1-2N0-1M0 (American Joint Committee on Cancer seventh edition, AJCC T, 7th ed) primary breast cancer as their only cancer or first of consequent cancers between 2010 and 2015; 3) defined as negative statues of ER, PR and HER-2 status according to the record of subtypes in SEER database. Patients who died or lost to follow-up for less than 3 months or those with unknown variable information were excluded from the study cohort to avert potential bias.
      The variables accessible from SEER database were reviewed including demographic characteristics (year of diagnosis, age at diagnosis, race and marital status), tumor burden features (lateral, tumor location, grade, T and N stage), treatment strategies (breast surgery type, radiotherapy and chemotherapy) as well as survival status (survival time and cause of death). Age was transformed into categorical variables (65-69, 70-74, 75-79, 80-84, and ≥85). Based on the code information in SEER, tumor location was classified as outer quadrant and axillary tail, inner quadrant, and others. BCSS and OS were used to describe the prognostic outcomes of this study. BCSS was defined as the time from the date of diagnosis to the date of death for breast cancer based on the “cause-specific death classification” in SEER database. OS was defined as the time from the date of diagnosis to death due to any cause based on the “vital status recode” in SEER database.
      Patient informed consent was not required in this study because the data released by the SEER database are publicly available and the personal private information was unavailable. We agree to all the provisions stated in the SEER program.

      Statistical Analysis

      Eligible patients were divided into chemotherapy group and no chemotherapy group. The baseline demographics, tumor burden and treatment strategies were compared between chemotherapy and no chemotherapy groups using Pearson Chi-square test for categorical characteristics and Student's t test for continuous characteristics. Then multiple logistic regression analysis was applied to find out independent risk factors associated with chemotherapy usage. As for survival outcomes, Kaplan-Meier survival analysis and log-rank test were used to describe and compare BCSS and OS between the 2 groups. Then univariate Cox regression for all-cause mortality and breast cancer–specific mortality was performed in all the patients involved and the factors with P-value < .05 were again involved in multivariate Cox regression to explore the independent prognostic factors.
      To determine the prognosis of exempting chemotherapy, a nomogram was established to predict the 3- or 5-year BCSS of patients without chemotherapy by involving independent risk factors according to the results of multivariate Cox analysis. Internal validation in the no chemotherapy cohort and external validation in the chemotherapy cohort were performed. The concordance index (C-index) and calibration curves were applied to measure the discrimination and accuracy of the model by bootstrap validation method with 1000 resamples. Then survival outcomes among different risk levels were described and compared by Kaplan-Meier survival analysis and log-rank test in order to assess the benefit patients could gain from chemotherapy.
      Statistical analyses were conducted by SPSS 22.0 (Statistical Package for the Social Sciences, Chicago, Ill) and the packages (rms, hmisc, survival etc.) in R software version 3.6.1 (http://www.rproject.org). Statistical significance was determined with a 2-tailed P < .05.

      Results

      Patient Characteristics

      According to SEER database, a total of 7618 geriatric patients were diagnosed with T1-2N0-1 TNBC. Patients diagnosed with M1(n = 177), with unknown race (n = 34), marital status (n = 387), grade (n = 223), surgical method (n = 211), cause of death (n = 13), and lose of follow-up at 3 months (n = 91) were excluded. Among the 6482 patients involved, 3379 (52.13%) received chemotherapy while the other 3103 (47.87%) did not (Figure 1). Many baseline variables between chemotherapy group and no chemotherapy group were significantly different (P < .001) (Table 1). In accordance with multivariate logistic regression (Table 2), patients who received chemotherapy were more likely to be younger (P < .001) and married (OR=1.32; 95% CI: 1.18-1.49, P < .001). As for tumor burden and treatment strategies, patients who had heavier tumor burden, reflected as higher grade [Grade II: (OR=2.60; 95% CI: 1.81-3.72, P < .001); Grade III/IV: (OR=4.51; 95% CI: 3.17-6.40, P < .001)], T2 (OR=2.6; 95% CI: 1.81-2.35, P < .001) and N1 stage (OR=3.11; 95% CI: 2.61-3.70, P < .001) and who received radiation (OR=1.52; 95% CI: 1.31-1.76, P < .001) were significantly associated with the applicant of chemotherapy, while the no chemotherapy group tended to receive mastectomy (OR=0.82; 95% CI: 0.70-0.96, P = .014).
      Table 1Demographic and Disease Characteristics of Patients
      VariablesTotal PatientsNo ChemotherapyChemotherapyP
      P < .05 was considered statistically significant.
      n648231033379
      Y of diagnosis (%)<.001
      20101043 (16.1)573 (18.5)470 (13.9)
      20111026 (15.8)528 (17.0)498 (14.7)
      20121130 (17.4)557 (18.0)573 (17.0)
      20131055 (16.3)481 (15.5)574 (17.0)
      20141107 (17.1)520 (16.8)587 (17.4)
      20151121 (17.3)444 (14.3)677 (20.0)
      Age (mean (SD))73.62 (6.92)76.82 (7.46)70.68 (4.77)<.001
      Age (%)<.001
      65-692304 (35.5)639 (20.6)1665 (49.3)
      70-741687 (26.0)652 (21.0)1035 (30.6)
      75-791142 (17.6)653 (21.0)489 (14.5)
      80-84790 (12.2)633 (20.4)157 (4.6)
      85+559 (8.6)526 (17.0)33 (1.0)
      Race (%).009
      White5051 (77.9)2463 (79.4)2588 (76.6)
      Black997 (15.4)433 (14.0)564 (16.7)
      AIA/API434 (6.7)207 (6.7)227 (6.7)
      Marital (%)<.001
      Unmarried3257 (50.2)1790 (57.7)1467 (43.4)
      Married3225 (49.8)1313 (42.3)1912 (56.6)
      Lateral (%).30
      Right3135 (48.4)1522 (49.0)1613 (47.7)
      Left3347 (51.6)1581 (51.0)1766 (52.3)
      Tumor location (%).02
      outer2924 (45.1)1367 (44.1)1557 (46.1)
      inner1348 (20.8)624 (20.1)724 (21.4)
      Others
      includes “Central portion of breast”, “Breast includes Nipple” and “Overlapping lesion of breast such as 3, 6, 9, 12 o'clock” as recorded in the SEER database.
      2210 (34.1)1112 (35.8)1098 (32.5)
      Grade (%)<.001
      I236 (3.6)184 (5.9)52 (1.5)
      II1593 (24.6)937 (30.2)656 (19.4)
      III/IV4653 (71.8)1982 (63.9)2671 (79.0)
      T (%)<.001
      T13904 (60.2)2077 (66.9)1827 (54.1)
      T22578 (39.8)1026 (33.1)1552 (45.9)
      N (%)<.001
      N05347 (82.5)2769 (89.2)2578 (76.3)
      N11135 (17.5)334 (10.8)801 (23.7)
      Breast Surgery (%)<.001
      BCS4237 (65.4)1921 (61.9)2316 (68.5)
      mastectomy2245 (34.6)1182 (38.1)1063 (31.5)
      Radiation (%)<.001
      No3202 (49.4)1774 (57.2)1428 (42.3)
      Yes3280 (50.6)1329 (42.8)1951 (57.7)
      Abbreviations: AIA = American Indian/Alaska native; API = Asian or Pacific Islander; BCS = breast conserving surgery; IDC = invasive ductal carcinoma.
      a P < .05 was considered statistically significant.
      b includes “Central portion of breast”, “Breast includes Nipple” and “Overlapping lesion of breast such as 3, 6, 9, 12 o'clock” as recorded in the SEER database.
      Table 2Multivariate Logistic Regression for Chemotherapy
      VariablesTotal Patients (n = 6482)Chemotherapy (n = 3379)OR (95% CI)P
      P < .05 was considered statistically significant.
      Y of diagnosis
      201010434701 (reference)
      201110264981.30 (1.06-1.60).010
      201211305731.45 (1.19-1.77)<.001
      201310555741.62 (1.32-1.98)<.001
      201411075871.51 (1.24-1.85)<.001
      201511216772.00 (1.64-2.44)<.001
      Age
      65-69230416651 [reference]
      70-74168710350.60 (0.52-0.69)<.001
      75-7911424890.27 (0.23-0.32)<.001
      80-847901570.08 (0.06-0.09)<.001
      85+559330.01 (0.01-0.02)<.001
      Race
      White505125881 (reference)
      Black9975641.07 (0.91-1.26).37
      AIA/API4342271.10 (0.87-1.39).42
      Marital
      Unmarried325714671 (reference)
      Married322519121.32 (1.18-1.49)<.001
      Lateral
      Right313516131 (reference)
      Left334717661.11 (0.98-1.24).08
      Tumor location
      outer292415571 (reference)
      inner13487241.09 (0.94-1.28).23
      Others
      includes “Central portion of breast”, “Breast includes Nipple” and “Overlapping lesion of breast such as 3, 6, 9, 12 o'clock” as recorded in the SEER database.
      221010980.94 (0.82-1.07).38
      Grade
      I23652
      II15936562.60 (1.81-3.72)<.001
      III/IV465326714.51 (3.17-6.40)<.001
      T
      T1390418271 (reference)
      T2257815522.06 (1.81-2.35)<.001
      N
      N0534725781 (reference)
      N111358013.11 (2.61-3.70)<.001
      Breast Surgery
      BCS423723161 (reference)
      mastectomy224510630.82 (0.70-0.96).01
      Radiation
      No320214281 (reference)
      Yes328019511.52 (1.31-1.76)<.001
      Abbreviations: AIA = American Indian/Alaska native; API = Asian or Pacific islander; BCS = breast conserving surgery; IDC = invasive ductal carcinoma.
      a P < .05 was considered statistically significant.
      b includes “Central portion of breast”, “Breast includes Nipple” and “Overlapping lesion of breast such as 3, 6, 9, 12 o'clock” as recorded in the SEER database.

      Survival Analyses and Prognostic Factors of BCSS and OS

      Cox analysis was applied to detect independent factors of adverse prognosis. Following the univariate Cox analysis (Supplemental Table 1), those variables with P-value <.05 were included in multivariate Cox analysis. Based on the multivariate Cox analysis (Table 3), younger age, American Indian/Alaska Native/Asian or Pacific Islander (AIA/API) race and married status were protective factors for OS, and for BCSS, younger age and AIA/API race were associated with better prognosis. Lower tumor burden (lower grade, T and N stage) as well as radiation and chemotherapy were protective factors against both all-cause mortality and breast cancer–specific mortality. After adjusting the independent risk factors, patients still presented to benefit from chemotherapy both in terms of OS (chemotherapy vs no chemotherapy: HR = 0.606; 95% CI, 0.525-0.699, P < .001) and BCSS (chemotherapy vs no chemotherapy: HR = 0.763; 95% CI, 0.630-0.925, P =.006).
      Table 3Multivariate Cox Regression for All-Cause Mortality and Breast Cancer–Specific Mortality
      VariablesOSBCSS
      HR, 95% CIpHR, 95% CIP
      Age<0.001<.001
      65-69refref
      70-741.203(1.002-1.444)0.051.238(0.982-1.560).07
      75-791.511(1.249-1.827)<0.0011.469(1.146-1.883).002
      80-842.280(1.877-2.770)<0.0011.699(1.292-2.234)<.001
      85+3.192(2.608-3.906)<0.0012.193(1.641-2.931)<.001
      Race0.002.011
      Whiterefref
      Black1.128(0.962-1.322)0.141.082(0.871-1.345).47
      AIA/API0.643(0.486-0.851)0.0020.544(0.358-0.827).004
      Marital-
      Unmarriedref-
      Married0.866(0.765-0.981)0.02-
      Tumor location.04
      outer-ref
      inner-1.210(0.971-1.509).09
      Others
      includes “Central portion of breast”, “Breast includes Nipple” and “Overlapping lesion of breast such as 3, 6, 9, 12 o'clock” as recorded in the SEER database
      -1.246(1.040-1.493).02
      Grade<0.001<.001
      Irefref
      II1.486(0.959-2.304)0.081.159(0.581-2.309).68
      III/IV2.059(1.344-3.153)0.0012.213(1.139-4.299).02
      T
      T1refref
      T21.918(1.696-2.169)<0.0012.476(2.073-2.958)<.001
      N
      N0refref
      N11.709(1.493-1.956)<0.0012.189(1.833-2.613)<.001
      Radiation
      Norefref
      Yes0.628(0.553-0.712)<0.0010.648(0.544-0.771)<.001
      Chemotherapy
      Norefref
      Yes0.606(0.525-0.699)<0.0010.763(0.630-0.925).006
      Abbreviations: AIA = American Indian/Alaska native; API = Asian or Pacific islander; BCSS = breast cancer-specific survival; C =, confidence interval; HR = hazard ratio; OS = overall survival.
      a includes “Central portion of breast”, “Breast includes Nipple” and “Overlapping lesion of breast such as 3, 6, 9, 12 o'clock” as recorded in the SEER database

      Construction and validation of the nomogram in the no chemotherapy group

      Compared to OS, BCSS is a better prognostic index to reflect the effect of chemotherapy on elderly patients. As a result, a nomogram was developed to predict 3-year and 5-year BCSS for patients without chemotherapy (Figure 2). According to the results from multivariate Cox analysis on the no chemotherapy group (Supplemental Table 2), 5 independent prognostic variables (age, grade, T-stage, N-stage and radiation) were incorporated into the nomogram. Based on the nomogram, points were signed for each variable and a cumulative point could be calculated based on patients' demographic characteristics, tumor burden and treatment strategy, with lower scores relating to better prognosis. The nomogram showed that patients who were younger, diagnosed with smaller tumors with lower grade, as well as node negative, and who received radiation were more likely to get a lower score.
      Figure 2
      Figure 2Nomogram for predicting 3- and 5-year BCSS in patients without chemotherapy.
      The nomogram was validated internally and externally using the no chemotherapy cohort (training set) and the chemotherapy cohort (validation set). The C-index of the nomogram in the internal validation was 0.785 (95% CI: 0.763-0.809) and 0.745 (95% CI: 0.726-0.769) in the external validation. Calibration curves for 3- and 5-year predictions of the model and observed outcomes were shown in Supplementary Figure 1, which showed a high consistency between the predicted outcomes and the actual survival outcomes. Both the internal validation and the external validation showed a sufficient accuracy of the model.

      Risk Stratification Model

      To further identify those who could benefit from chemotherapy, a risk stratification model was built based on scores calculated by the nomogram. The range of the scores in the risk stratification model was classified as low-risk (cumulative score ≤75, 1988/6482, 30.7%), intermediate-risk (cumulative score 75∼180, 3340/6482, 51.5%) and high-risk (cumulative score >180, 1154/6482, 17.8%). As shown in Kaplan-Meier plots (Figure 3), chemotherapy significantly improved OS [HR 0.415 (0.339-0.509), P < .001] and BCSS (HR 0.586 [0.454-0.758], P < .001) in the high-risk group, while the low-risk group couldn't benefit from chemotherapy (OS: HR 0.753 [0.550-1.032], P = .78; BCSS: HR 1.460 [0.900-2.367], P = .12). In the intermediate-risk group, chemotherapy presented as a protective factor for OS (HR 0.454 [0.382-0.539], P < .001) but not for BCSS (HR 0.843 [0.667-1.067], P = .15).
      Figure 3
      Figure 3Overall survival and breast cancer-specific survival curves plotted by the Kaplan–Meier method. OS = overall survival; BCSS = breast cancer-specific survival.

      Discussion

      This study used the data based on the SEER program to discuss the benefit of chemotherapy in elderly patients suffering from early TNBC. According to the NCCN guideline, although chemotherapy is recommended for early-stage TNBC patients, there's still a lack of evidence to determine whether to apply chemotherapy to geriatric patients. In this study, the whole population could benefit from chemotherapy in OS and BCSS, so chemotherapy is necessary on the whole review of this population. Nevertheless, especially for geriatric patients, factors other than breast cancer such as comorbidities or complications of chemotherapy are also closely associated with their adverse prognosis. In actual clinical procedure, elderly individuals receive less chemotherapy than younger,
      • Jauhari Y
      • Dodwell D
      • Gannon MR
      • et al.
      The influence of age, comorbidity and frailty on treatment with surgery and systemic therapy in older women with operable triple negative breast cancer (TNBC) in England: a population-based cohort study.
      • 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.
      • Dreyer G
      • Vandorpe T
      • Smeets A
      • et al.
      Triple negative breast cancer: clinical characteristics in the different histological subtypes.
      and the benefit of chemotherapy on different geriatric subgroups were different.
      • Battisti NML
      • Joshi K
      • Nasser MS
      • Ring A
      Systemic therapy for older patients with early breast cancer.
      According to the individual nomogram, the whole cohort was divided into 3 risk levels including a low risk group (scored ≤75), an intermediate-risk subgroup (scored 75∼180) and a high-risk group (scored >180). Surprisingly, we found that in the low-risk group, chemotherapy could hardly improve OS or BCSS, which indicated that chemotherapy could scarcely beneficial in this subgroup. This requires prospective research for further exploration and validation.
      In this study cohort, 47.87% (3103/6482) of elderly patients didn't receive adjuvant chemotherapy, which is consistent with previously reported records.
      • Liedtke C
      • Hess KR
      • Karn T
      • et al.
      The prognostic impact of age in patients with triple-negative breast cancer.
      The entire older population could benefit from adjuvant chemotherapy, as reflected by improved OS and BCSS. The rise of BCSS could indicate the positive treatment effect over side effects on elderly early TNBC patients, while as for OS, other than the influence of treatment therapy, the improvement of OS could be explained by better basic health condition of patients who had received chemotherapy. On the whole review of the results, chemotherapy should be considered by all the elderly patients suffering from T1-2N-1M0 TNBC in order to obtain a better treatment effect. According to the baseline information, patients having received chemotherapy tended to have stage T2 and N1 disease with higher histological grade than another group, which is in accordance with the characteristics of patients who had improved survival prognosis through adjuvant chemotherapy among early breast cancer.
      • Sineshaw HM
      • Freedman RA
      • DeSantis CE
      • Jemal A
      Treatment patterns among women diagnosed with stage i-iii triple-negative breast cancer.
      In chemotherapy group, patients with more tumor burden had better BCSS instead, which could further authenticate the treatment effect of chemotherapy. In addition, patients who had chemotherapy should be able to tolerate chemotoxity as well, indicating better basic health condition in chemotherapy group, which could explain better survival prognosis in this group. Contrarily, there are still nearly half of the patients didn't receive chemotherapy in this cohort. On the 1 hand, they were characterized as less tumor burden or with less aggressive tumor. On the other hand, considering their probably less optimistic health condition, with more comorbidities for instance, doctors might choose not to add chemotherapy to guarantee safety. In this study, younger and married patients were significantly associated with chemotherapy usage. Younger age is usually related to better condition and less comorbidity, which is the basis of tolerating chemotherapy. Sineshaw et al
      • Sineshaw HM
      • Freedman RA
      • DeSantis CE
      • Jemal A
      Treatment patterns among women diagnosed with stage i-iii triple-negative breast cancer.
      discovered that with tumor size less than 1 cm, the addition of chemotherapy in TNBC patients was related to younger age, higher tumor grade, larger tumor size, and fewer comorbidities. Carol et al.
      • Parise C
      • Caggiano V
      The influence of marital status and race/ethnicity on risk of mortality for triple negative breast cancer.
      reported a relative lower usage of chemotherapy comparing unmarried and married TNBC women, probably because married patients were well accompanied and they would consider their children and families and choose more active treatment therapy. It's easy to understand that patients with heavier tumor burden including higher grade, T or N stage were more likely to receive chemotherapy, which is accordant with other studies.
      • Jauhari Y
      • Dodwell D
      • Gannon MR
      • et al.
      The influence of age, comorbidity and frailty on treatment with surgery and systemic therapy in older women with operable triple negative breast cancer (TNBC) in England: a population-based cohort study.
      ,
      • Sineshaw HM
      • Freedman RA
      • DeSantis CE
      • Jemal A
      Treatment patterns among women diagnosed with stage i-iii triple-negative breast cancer.
      Tumor histologically presented in higher grade indicates more aggressive histologic types which are evaluated at high risk of poor prognosis.
      • Geyer FC
      • Pareja F
      • Weigelt B
      • et al.
      The spectrum of triple-negative breast disease: high- and low-grade lesions.
      As for treatment procedure, patients who chose breast conserving surgery would receive postoperative radiotherapy as well, and this group of older population should be in healthier condition as they had to tolerate radiology, and they would be able to go through chemotherapy as well.
      Other than the treatment effects, the complications and toxicity of chemotherapy couldn't be neglected, especially for geriatric patients. As a result, though chemotherapy benefited the whole population, the necessity of chemotherapy of these patients should be assessed. For those who have a lower risk of breast cancer related adverse prognosis or less tolerance to side effects, the risk of chemotherapy-related adverse prognosis could exceed the treatment effect, thereby causing secondary damage to patients. To further explore the exact population that could gain exact benefits from chemotherapy and help to guide the choice of treatment in clinical practice, a nomogram to forecast the BCSS of sparing chemotherapy was created by integrating independent risk factors including age, grade, T-stage, N-stage and radiation.
      According to the nomogram and the risk stratification model, patients categorized in low-risk group showed a nonsignificant advantage in BCSS and OS. Based on survival analysis, BCSS was a modicum lower in chemotherapy group. Though no significant difference was observed, the decrease in BCSS could be partly explained by side effects of chemotherapy. This result suggested that in low-risk group, risk of chemotherapy is over the benefit, probably reminding the feasibility of omitting chemotherapy in this group. These patients were characterized as younger, smaller tumor with lower histology grade and negative lymph node, or having received radiation. For elderly patients with early-stage TNBC, OS was significantly better in 65-75 subgroup, with non-significantly lower breast cancer specific mortality even more patients had received chemotherapy compared to patients more than 75years.
      • Gal O
      • Ishai Y
      • Sulkes A
      • Shochat T
      • Yerushalmi R
      Early breast cancer in the elderly: characteristics, therapy, and long-term outcome.
      These researches indicated less benefit from chemotherapy in younger elderly adults. As for tumor size, several researches had reached consensus that for early TNBC, chemotherapy is redundant in node-negative TNBC patients with tumor staged T1a and T1b, but for T1cN0 patients, chemotherapy could improve survival prognosis.
      • Du ZL
      • Wang Y
      • Wang DY
      • et al.
      Evaluation of a beneficial effect of adjuvant chemotherapy in patients with stage I triple-negative breast cancer: a population-based study using the SEER 18 database.
      Additionally, many studies concluded that early-stage TNBC patients with negative lymph nodes were with better prognosis than N1 stage population, as positive lymph nodes indicate poor local involvement.
      • Hernandez-Aya LF
      • Chavez-Macgregor M
      • Lei X
      • et al.
      Nodal status and clinical outcomes in a large cohort of patients with triple-negative breast cancer.
      It's obvious that patients with smaller tumor and negative lymph node involvement have the opportunity to omit chemotherapy. Tumor grade reflects the differentiation of tumor cells, and a lower grade represents greater differentiation which indicates a less active behavior of tumor, especially in small tumor,
      • Rakha EA
      • Reis-Filho JS
      • Baehner F
      • et al.
      Breast cancer prognostic classification in the molecular era: the role of histological grade.
      and is also associated with better survival prognosis.
      • Zhao S
      • Ma D
      • Xiao Y
      • Jiang YZ
      • Shao ZM
      Clinicopathologic features and prognoses of different histologic types of triple-negative breast cancer: a large population-based analysis.
      Among aged patients, radiotherapy could improve their prognosis in very early stage.
      • Mogal HD
      • Clark C
      • Dodson R
      • Fino NF
      • Howard-McNatt M
      Outcomes after mastectomy and lumpectomy in elderly patients with early-stage breast cancer.
      In TNBC patients, postoperative radiotherapy significantly reduced the mortality in early-stage TNBC patients,
      • Wang J
      • Shi M
      • Ling R
      • et al.
      Adjuvant chemotherapy and radiotherapy in triple-negative breast carcinoma: a prospective randomized controlled multi-center trial.
      and Zhai et al.
      • Zhai Z
      • Zheng Y
      • Yao J
      • et al.
      Evaluation of adjuvant treatments for t1 n0 m0 triple-negative breast cancer.
      concluded that TNBC patients aged more than 70 could improve BCSS from radiotherapy, while chemotherapy couldn't, indicating an adequate treatment effect of radiotherapy and a possibility of sparing chemotherapy in elderly patients with early-stage TNBC. Therefore, omitting chemotherapy was considerable in patients assessed as low risk based on the nomogram.
      On the other hand, in the high risk group, both BCSS and OS were significantly enhanced, which is in accordance with the results of the whole cohort, suggesting the indispensable role among the treatment strategies. Although patients in this subgroup could also suffer from some "background factors" which could also affect survival outcomes such as comorbidities, chemoresistance, side effects, commercial burden et al., in overall sight the benefit of chemotherapy overweighed the risk. Contrary to factors in low risk group, these patients presented as older, without postoperative radiation, suffering from larger tumor, positive lymph node and higher tumor grade. Though aged patients are more likely to die from reasons other than breast cancer, higher breast cancer specific mortality was discovered in older group of geriatric population in early-stage TNBC.
      • Freedman RA
      • Keating NL
      • Lin NU
      • et al.
      Breast cancer-specific survival by age: worse outcomes for the oldest patients.
      Advanced T and N stage usually represent progress in disease and worse prognosis, which require more aggressive treatment strategy to achieve better prognosis.
      • Kashiwagi S
      • Yashiro M
      • Takashima T
      • et al.
      Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67.
      ,
      • Kim HA
      • Seong MK
      • Kim EK
      • et al.
      Evaluation of the survival benefit of different chemotherapy regimens in patients with t1-2n0 triple-negative breast cancer.
      Waqar et al.
      • Haque W
      • Verma V
      • Hsiao KY
      • et al.
      Omission of radiation therapy following breast conservation in older (≥70 years) women with T1-2N0 triple-negative breast cancer.
      observed that omission of adjuvant RT for women aged more than 70years with early-stage TNBC was associated with poorer OS, and without radiotherapy, chemotherapy could control locoregional recurrence as well,
      • Truong PT
      • Lesperance M
      • Culhaci A
      • Kader HA
      • Speers CH
      • Olivotto IA
      Patient subsets with T1-T2, node-negative breast cancer at high locoregional recurrence risk after mastectomy.
      which suggests there's necessity of giving chemotherapy to patients who spared radiotherapy. As for tumor grades, studies reported that TNBC performed in higher grade have better response to chemotherapy,
      • Walsh EM
      • Shalaby A
      • O'Loughlin M
      • et al.
      Outcome for triple negative breast cancer in a retrospective cohort with an emphasis on response to platinum-based neoadjuvant therapy.
      and for early TNBC patients with poorly differentiated or undifferentiated tumor, chemotherapy showed significantly beneficial in BCSS and OS.
      • Du ZL
      • Wang Y
      • Wang DY
      • et al.
      Evaluation of a beneficial effect of adjuvant chemotherapy in patients with stage I triple-negative breast cancer: a population-based study using the SEER 18 database.
      As a result, chemotherapy was recommended in this subgroup, but individual treatment strategy of patients should be decided by also combining both the stratification model and patients' background factors.
      As for intermediate-risk group, patients who received chemotherapy had a better OS but non-significant BCSS difference was observed. This may be explained by the fact that the improved OS was not reaped from chemotherapy but for better basic health conditions and longer life expectancy of patients who received chemotherapy. In geriatric population, patients with more comorbidities and in poorer health condition are more likely to die from non-cancer diseases.
      • Land LH
      • Dalton SO
      • Jensen MB
      • Ewertz M
      Impact of comorbidity on mortality: a cohort study of 62,591 Danish women diagnosed with early breast cancer, 1990-2008.
      ,
      • Derks MGM
      • van de Velde CJH
      • Giardiello D
      • et al.
      Impact of comorbidities and age on cause-specific mortality in postmenopausal patients with breast cancer.
      The reason for those sparing chemotherapy in intermediate risk group should be more comorbidities and in poorer health condition than those who received chemotherapy due to less tolerance to chemotherapy. Given the above consideration, though the effects of chemotherapy is confusing in this group, considering the positive effects in the whole population, the application of chemotherapy should be determined individually among the intermediate-risk group, but it worth prospective researches for further discussion.
      To our knowledge, this study is the first to discuss the benefit of chemotherapy in elderly patients suffering from early TNBC, and to establish a nomogram to evaluate and forecast the effectiveness of chemotherapy in different risk levels. This study is based on SEER program which provides a large number of samples from multicenter and help to establish the stratification model by nomograms. Nevertheless, this study had some limitations. Firstly, this was a retrospective study, the selection bias and confounding factors couldn't be avoided. Confounding factors such as tumor heterogenicity could affect the comparison between 2 groups. Secondly, the SEER database we used is lack of several variables such as comorbidities, chemoresistance and side effects which were important factors affecting survival prognosis of elderly patients. Additionally, for geriatric patients, frailty assessment was of vital importance, as frailty conditions could increase adverse outcomes which should be combined to assess the benefit of chemotherapy. As a result, the benefit of sparing chemotherapy was underestimated. Thirdly, the recurrence rate is not mentioned in SEER database. TNBC, known as a progressive subtype which tends to recurrent and relapse quickly, recurrence rate is also an important prognostic index. However, for elderly patients, survival prognosis is also a good outcome to evaluate the effectiveness of chemotherapy.
      According to our risk stratification model, we identified the low-risk subgroup which could safely omit chemotherapy without sacrificing OS and BCSS while in the high-risk subgroup, chemotherapy remained beneficial to their survival prognosis. The model integrated multiple independent risk factors which include age, T-stage, N-stage, tumor grade and radiation. By this risk stratification mode, clinicians and patients can well-founded determine the risk–benefit of chemotherapy in elderly TNBC patients and make the appropriate decision to proceed or spare chemotherapy based on an individualized threshold and patients' preferences. Further well-designed prospective randomized trials with more prognostic factors are expected to provide more convincing evidence of chemotherapy use in elderly patients suffering from early-stage TNBC.

      Conclusions

      Chemotherapy is beneficial in treating geriatric patients with T1-2N0-1M0 TNBC, but according to the risk stratification model, the low-risk subgroup who could probably omit postoperative chemotherapy on the premise of unaffected survival prognosis. This study calls for further prospective randomized clinical trials to confirm the effectiveness and safety of omitting chemotherapy in low-risk subgroup.

      Clinical Practice Points

      • Considering old age and basic commorbidities, the actual benefit of chemotherapy on geriatric patients with early stage triple negative breast cancer (TNBC) is uncertain.
      • Based on the considerable sample size in the Surveillance, Epidemiology, and End Results (SEER) database, we comprehensively analyzed the benefit of chemotherapy on older patients with T1-2N0-1M0 TNBC, and built a prediction model based on nomogram, and patients were divided into low, intermediate and high risk subgroups.
      • Patients in low-risk group (score ≤75) were considered to have the possibility to omit chemotherapy without sacrificing survival. This model could assist clinicians to weigh the risk–benefit of chemotherapy and customize the individualized treatment accordingly.

      Author Contributions

      Zhenggui Du contributed to conception and design of the study. Chen Zhou and Li Xu organized the database and Li Xu performed the statistical analysis. Chen Zhou, Li Xu and Qing Lv contributed to the manuscript writing and revision. All authors contributed to the article and approved the submitted version.

      Acknowledgments

      We thank the open access to the database from SEER. This work was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYJC18018), the Department of Science and Technology of Sichuan province, China ( 2022YFQ0003 ), Chengdu Science and Technology Program ( 2019-YF05-01082-SN ) and West China Hospital, Sichuan University ( 21HXFH011 ).

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Appendix. Supplementary materials

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