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Influence of advanced age on the prognosis of triple-negative breast cancer patients: A surveillance, epidemiology, and end results-based study


 Department of Thyroid and Breast Surgery, Yangzhou University Affiliated Northern Jiangsu People's Hospital, Yangzhou, China

Date of Submission14-Jan-2021
Date of Decision25-Apr-2021
Date of Acceptance09-Jul-2021
Date of Web Publication11-Nov-2022

Correspondence Address:
Deyuan Fu,
Yangzhou University Affiliated Northern Jiangsu People's Hospital, Yangzhou
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_90_21

 > Abstract 


Introduction: Age at diagnosis has shown significant effect on the prognosis in breast cancer patients. However, whether age is an independent risk factor remains controversial. Furthermore, population-based estimates of age on the prognosis impact in triple-negative breast cancer are still lacking. The aim of this study was to analyze the influence of age and other factors on the prognosis and survival of triple-negative breast cancer patients.
Materials and Methods: We used the surveillance, epidemiology, and end results program data from 2011 to 2014. A retrospective cohort study was conducted to investigate prognosis factors in triple-negative breast cancer. Patients were divided into two groups according to age at diagnosis: 75 + years (the elderly patients) and < 75 years (reference group). The clinicopathologic characteristics of different age groups were compared using Chi-square tests. Overall survival (OS) and breast cancer-specific survival were analyzed using the Kaplan–Meier method. Prognostic factors were compared using the Cox proportional hazards model. We also analyzed the difference of distant metastasis at initial diagnosis on every group.
Results: A total of 21,429 triple-negative breast cancer patients were included in our study. The mean breast cancer-specific survival time of triple-negative breast cancer was 70.5 months for the reference group and 62.4 months for the elderly group. Survival analysis showed that the breast cancer-specific survival rate was 78.9% for the reference group and 67.4% for the elderly group. The mean OS time was 69.0 months for the reference group and 52.3 months for the elderly group. The 5-year OS of triple-negative breast cancer patients was 76.4% for the reference group and 51.3% for the elderly group. The prognosis of elderly patients is much poor than reference group. Univariate Cox regression analysis showed that age, race, marital status, histological grade, stage, T, N, M, surgery, radiotherapy, and chemotherapy were risk factors for triple-negative breast cancer (TNBC) (P < 0.05). Multivariate Cox regression analysis showed that age, race, marital status, histological grade, stage, T, N, M, surgery, radiotherapy, and chemotherapy were independent risk factors for TNBC (P < 0.05).
Conclusions: Age is an independent risk factor for the prognosis of TNBC patients. Elderly triple-negative breast cancer patients displayed obvious lower 5-year survival rate compared to reference group, even though they have better grade stage, minor tumor, less lymph node metastasis. The lower rate of marital status, radiotherapy, chemotherapy, surgery, and higher rate of metastasis at diagnosis must contribute to their poor outcome.

Keywords: Advanced age, prognosis, surveillance, epidemiology, and end results, survival analysis, triple-negative breast cancer



How to cite this URL:
Tan H, Fu D. Influence of advanced age on the prognosis of triple-negative breast cancer patients: A surveillance, epidemiology, and end results-based study. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=361025




 > Introduction Top


Breast cancer is the second most common type of cancer in women and the second leading cause of cancer-related death in women. The mortality rate is inclining significantly in low-income countries[1] due to the lack of multidisciplinary approaches and the poor management of breast cancer with effective individualized treatments, such as target therapy, surgery, chemotherapy, and radiotherapy. Triple-negative breast cancer (TNBC), a molecular subtype defined by the lack of hormonal receptor and human epidermal growth factor receptor-2 (HER-2) expression, accounts for about 10% to 20% of all breast cancers and is associated with a more aggressive disease outcome.[2],[3]

However, the effect of age on TNBC has been controversial. A study involving 412 patients showed that age was not an independent factor affecting the prognosis of TNBC patients.[4] Previous studies mostly focused on very young patients while few studies on elderly patients.[5],[6] Our study focused on the impact of advanced age on the prognosis of TNBC patients.


 > Materials and Methods Top


Data source and patient selection

We extracted data from the surveillance, epidemiology, and end results (SEER) 18 registry research database. The SEER program is the largest publicly available cancer dataset. It is a population-based cancer registry covering approximately 26.4% of the US population across several disparate geographic regions. A data use agreement submission was required to access the SEER Research Data File. We submitted the data agreement form to the SEER administration. After acceptance of the agreement, SEER*Stat 8.3.8(Seer, Inc., Bethesda, USA) and data files were downloaded directly from the SEER website.

SEER*Stat version 8.3.8 was used to generate a case listing. We extracted cases of women breast cancer diagnosed with TNBC subtype. Patients diagnosed by either autopsy or death certificate were excluded. Patients must have complete dates of survival months and the follow-up must be active. The analysis was restricted to patients with a diagnosis confirmed by histopathology, and only duct, lobular, and other carcinomas based on the primary site were included (International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes 8500–8543). Patients only have one primary malignant breast cancer only. Tumor stage was registered according to breast-adjusted american joint committee on cancer (AJCC) 6th stage (Stages I-IV).

We generated a case listing with information on the following variables: year of diagnosis, age at diagnosis, race/ethnicity, marital status at diagnosis, grade, ICD-O-3 Hist/behav, breast-adjusted AJCC 6th T, N, M (1988–2015), reason no cancer-directed surgery, radiation recode, chemotherapy recode (yes, no/unk), SEER combined mets at DX-bone/brain/liver/lung (2010+), SEER cause-specific death classification, vital status, and survival (months). Race was classified as white, black, or other. Marital status was categorized as married, unmarried (including single, divorced, separated, widowed), and unknown.

Statistical analysis

Descriptive statistics were used to examine the following fundamental characteristics of TNBC patients: year of diagnosis, age, race, marital status, grade, histology, breast-adjusted AJCC 6th T, N, M (1988–2015), surgery, radiotherapy, chemotherapy, breast cancer-specific survival (BCSS), and overall survival (OS). Year of diagnosis, age, race, marital status, grade, histology, breast-adjusted AJCC 6th T, N, M (1988–2015), surgery, radiotherapy, chemotherapy were used to calculate hazard ratios (HRs) and 95% confidence intervals in the univariate and multivariate Cox model.

The variables were stratified by age groups. We used the Chi-square test to calculate P values for comparing the frequency distributions among the two groups. BCSS was the mainly study outcome, and generate survival curves were generated by using the Kaplan–Meier method. We analyzed the differences between the curves using the log-rank test. A Cox proportional hazards regression model was used to assess the independent risk factors for BCSS. A P value below 0.05 was considered statistically significant. All reported P values were two tailed. All statistical analyses were performed using SPSS 22.0 (IBM Corporation, Amen Monk, NY, USA).


 > Results Top


A total of 21,429 TNBC patients were included in our study [Table 1].
Table 1: Clinicopathologic feature of triple-negative breast cancer

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Clinicopathological features

(1) The rate of elderly patients in white was higher than in black and other races (13.4% vs. 8.6%, 10.8%). (2) Compared with the reference group, the elderly group had significantly lower proportion of marriage status (33.2%, vs. 56.4%), higher proportion of low Grade (Grade I + II: 25.7% vs. 16.2%), higher proportion of small tumors (T0 + T1:43.3% vs. 41.8), higher nonlymphatic metastasis rate (65.1% vs. 62.2%), higher metastasis rate at diagnosis (6.9% vs. 5.2%), higher Stage 0 + I rate (25.7% vs. 16.2%), lower Stage III + IV rate (70.9% vs. 80.4), lower surgical rate (89.2% vs. 92.3%), lower radiotherapy rate (39.4% vs. 51.8%), lower chemotherapy rate (30.0% vs. 82.7%), higher rate of lung metastasis at diagnosis (2.9% vs. 2.3%), higher rate of other cause of death (37.6% vs. 11.9%) (All of above: P <0.05). There was no difference in the proportion of year of diagnosis, bone metastasis at diagnosis, liver metastasis at diagnosis, and brain metastasis at diagnosis (P > 0.05) [Table 1].

The number of deaths due to breast cancer in the elderly group was 718 (62.4%), while other causes were 433 (37.6%). In the reference group, the number of deaths due to breast cancer was 718 (62.4%) and 433 (37.6%) due to other causes. There was a significant difference between the two groups (P < 0.05) [Table 2].
Table 2: Cause of death in the two groups

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Survival time of breast cancer-specific survival and overall survival

The mean estimate BCSS time for TNBC was 69.6 months, 70.5 months for the reference group, and 62.4 months for the elderly group. 5-year BCSS rate for TNBC was 77.6% [Figure 1], 78.9% for reference group, and 67.4% for elderly group [Figure 2]. The mean estimate OS time for TNBC was 67.0 months, 69.0 months for the reference group, and 52.3 months for the elderly group. 5-year OS rate for TNBC was 73.3% [Figure 3], 76.4% for reference group, and 51.3% for elderly group [Figure 4].
Figure 1: Kaplan–Meier analysis of 5-year breast cancer-specific survival for triple-negative breast cancer

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Figure 2: Kaplan–Meier analysis of 5-year breast cancer-specific survival for triple-negative breast cancer stratified by age

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Figure 3: Kaplan–Meier analysis of 5-year overall survival for triple-negative breast cancer

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Figure 4: Kaplan–Meier analysis of 5-year overall survival for triple-negative breast cancer stratified by age

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Univariate Cox regression analysis showed that age, race, marital status, histological grade, stage, T, N, M, surgery, radiotherapy, and chemotherapy were all risk factors for TNBC (P < 0.05), without year of diagnosis (P > 0.05) [Table 3]. Multivariate Cox regression analysis showed that age, race, marital status, histological grade, stage, T, N, M, surgery, radiotherapy, and chemotherapy were all independent risk factors for TNBC (P < 0.05), without year of diagnosis (P > 0.05) [Table 4].
Table 3: Univariate Cox regression analysis of breast cancer-specific survival for triple-negative breast cancer

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Table 4: Multivariate Cox regression analysis of breast cancer-specific survival for triple-negative breast cancer

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 > Discussion Top


TNBC is the most aggressive subtype of breast cancer, which is characterized by negative hormone receptor and lack of HER-2 overexpression or gene amplification. TNBC is often accompanied by larger tumor volume, poorer histological grade, more lymph nodes involved and is more prone to distant metastasis, also lack of FDA-approved targeted drugs.[7] Based on the dual influence factors of TNBC and age, out study analyzed the information of 21,429 cases (SEER database) diagnosed as TNBC at the first diagnosis and pathological diagnosis and classified the enrolled patients into <75 group (reference group) and 75+ group (elderly group). The difference in clinicopathological features and prognosis between these two groups was emphatically analyzed to explore the influence of age on the prognosis of TNBC.

Previous other researchers' studies showed that age was not an independent risk factor for TNBC patients (evaluation of local and distant patterns in patients with triple-negative breast cancer). However, our study shows the opposite. This may be related to the small sample size of their study (1930 vs. 21429 patients). At the same time, our study found that old age is considered as a moderately adverse prognostic factor in the diagnosis of breast cancer, which is contrary to some research conclusions and believes that youth is a poor prognostic factor of TNBC.[6] This could be caused by the difference of age boundaries.

Although the grade, tumor size, and lymph node metastasis of elderly TNBC patients are lower (indicating a good prognosis), elderly patients' lower rate of surgery and chemotherapy accompanied by high metastasis rate at diagnosis leading to poor BCSS (67.4% vs. 78.9%). It means that the surgery, chemotherapy, and metastasis rate at diagnosis have greater influence on elderly patients. Our study finds that metastasis at diagnosis is higher in elderly group than reference group. This is a new finding, and this finding may indicate that elderly patients will suffer from this status, leading a comparatively poor prognosis, even though these elderly patients have better histology grade, smaller tumor size, lesser lymph node metastasis.

OS in the elderly group was significantly lower than that in the reference group (51.3% vs. 76.4%). This may due to the higher rate of other cause of death (37.6% in the elderly patients vs. 11.9% in the reference group). The other cause of death rate in elderly group was significantly higher than reference group, resulting in significantly lower OS in the elderly patients. BCSS was also significantly lower than that of the reference group (67.4% vs. 78.9%). Univariate risk analysis also suggested that the risk of the elderly group was 1.777 times than that of the reference group; multivariate Cox regression analysis indicated that the risk of the elderly group was 1.553 times than that of the reference group. This also indicates that the elderly age was an independent risk factor for TNBC patients.

At the same time, a very interesting finding is that if not included surgery, radiotherapy and chemotherapy factors (these three factors in elderly patients had lower proportion than reference group, 89.2% vs. 92.3%, 39.4% vs. 51.8%, 30.0% vs. 82.7%, respectively), HR for elderly group was 1.887 times than the reference group (if included the above three factors in multivariate analysis, the risk of elderly group was reduced to 1.553 times than the reference group. It suggested that the lower surgery, radiotherapy, and chemotherapy performed rate in the elderly group resulted a large gap before and after the inclusion in Cox regression analysis. This finding suggests that the relatively poor prognosis of elderly patients is partly due to the low rates of surgery, radiotherapy, and chemotherapy in this group of patients due to their advanced age.

There is a literature report showed that race, histological grade, and AJCC stage were not independent prognostic factors for TNBC patients.[8] On the contrary, our analysis showed that race and histological grade were still independent prognostic factors (even though their HR is much lower than T, N, or M). This might due to their low number of cases (11,514). We enrolled 21,429 cases, which was much bigger than their.


 > Conclusions Top


Age is an independent risk factor for the prognosis of TNBC patients. Elderly TNBC patients displayed obvious lower 5- year survival rate. The lower rate of marital status, radiotherapy, chemotherapy, surgery, and higher rate of metastasis at diagnosis must contribute to their poor outcome.

Financial support and sponsorship

This research was supported by the National Natural Science Foundation of China (82072909).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Autier P, Boniol M, La Vecchia C, Vatten L, Gavin A, Héry C, et al. Disparities in breast cancer mortality trends between 30 European countries: Retrospective trend analysis of WHO mortality database. BMJ 2010;341:c3620.  Back to cited text no. 1
    
2.
Kumar P, Aggarwal R. An overview of triple-negative breast cancer. Arch Gynecol Obstet 2016;293:247-69.  Back to cited text no. 2
    
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Aysola K, Desai A, Welch C, Xu J, Qin Y, Reddy V, et al. Triple negative breast cancer – An overview. Hereditary Genet 2013;2013 Suppl 2:001.  Back to cited text no. 3
    
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Rayson D, Payne JI, Michael JC, Tsuruda KM, Abdolell M, Barnes PJ. Impact of detection method and age on survival outcomes in triple-negative breast cancer: A population – Based cohort analysis. J Clin Breast Cancer 2018;18:e955-60.  Back to cited text no. 4
    
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Liedtke C, Hess KR, Karn T, Rody A, Kiesel L, Hortobagyi GN, et al. The prognostic impact of age in patients with triple-negative breast cancer. Breast Cancer Res Treat 2013;138:591-9.  Back to cited text no. 5
    
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Pilewskie M, King TA. Age and molecular subtypes: Impact on surgical decisions. J Surg Oncol 2014;110:8-14.  Back to cited text no. 6
    
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DeVita VT, Hellman S, Rosenberg SA. DeVita, Hellman, and Rosenberg's Cancer Principles and Practice of Oncology Review [M]. 11th ed. USA: Lippincott Williams and Wilkins Publishers; 2018.  Back to cited text no. 7
    
8.
Chen QX, Wang XX, Lin PY, Zhang J, Li JJ, Song CG, et al. The different outcomes between breast-conserving surgery and mastectomy in triple-negative breast cancer : A population-based study from the SEER 18 database. Oncotarget 2017;8:4773-80.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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