Short- and long-term recurrence of early-stage invasive ductal carcinoma in middle-aged and old women with different treatments: A nationwide population-based cohort study

Most new cases and the highest mortality rates of breast cancer occur among middle-aged and old women. The recurrence rate of early-stage invasive ductal carcinoma (IDC) among women aged ≥ 50 years and receiving different treatments remains unclear. Methods Therefore, this study was conducted to determine these rates. We used Surveillance, Epidemiology, and End Results (SEER) data for this nationwide population-based cohort study. All women aged ≥ 50 years and diagnosed with early-stage IDC between 2000 and 2015 were identied and divided into three treatment groups, namely, breast conservation therapy (BCT), mastectomy alone (MAS), and mastectomy with radiation therapy (MAS + RT). The recurrence rates of IDC among these groups were then compared.


Results
The BCT group had a lower short-term recurrence risk than the MAS and MAS + RT groups (hazard ratio

Conclusion
The results provide valuable evidence of the most reliable treatment strategy for this population. Further studies including more variables and validation in other countries are warranted to con rm our ndings.

Background
Breast cancer presents a great burden to public health and an important threat to women. According to breast cancer statistics in the United States, approximately 12% of all American women will develop invasive breast cancer in their lifetime [1]. Indeed, 276,480 new cases of female invasive breast cancer and 42,170 deaths from this disease are expected to occur in the country in 2020 [1]. Second only to that of lung cancer, the mortality rate of breast cancer is higher than the mortality rates of other types of cancer [1]. In Taiwan, breast cancer is the most common female cancer, and this cancer was third leading cause of female cancer-related deaths in 2019 [2]. The incidence rate of breast cancer is approximately 188-194 per 100,000 women [2].
Breast cancer is more common in middle-aged and old women than in younger women, and most deaths are recorded in women aged ≥ 65 years [3]. In 2017, women aged > 50 years made up 81% of all new female cases of invasive breast cancer in the United States [4]. In Taiwan, 66.6% of the women diagnosed with breast cancer in 2017 were aged > 50 years [5]. Invasive ductal carcinoma (IDC) is the most common type of invasive breast cancer (80%); invasive lobular carcinoma (7-15%) ranks a distant second in terms of invasiveness [6]. According to statistics in Taiwan, IDC comprises approximately 85.7% of all newly diagnosed breast cancer cases [5]. Therefore, the development of suitable treatment strategies, especially for early-stage IDC, is an important issue for the female population. Common treatments for early-stage IDC include (1) breast conservation therapy (BCT), which involves breast-conserving surgery (BCS) plus postsurgical radiation, (2) mastectomy alone (MAS), and (3) mastectomy with radiation therapy (MAS + RT) [7].
A previous nationwide population-based study by the Surveillance, Epidemiology, and End Results (SEER) database revealed that women with early-stage IDC receiving BCT have better 5-and 10-year survival rates than those receiving MAS or MAS + RT [7]. However, this study included women aged ≥ 18 years, and the characteristics of this population may differ from those of middle-aged and old women. Few studies on recurrence rates following different treatments in middle-aged and old women with early-stage IDC have been published. Local recurrence is important to overall survival because local failure predicts distant metastasis in the future [8]. We conducted this nationwide population-based cohort study to assess the short-and long-term recurrence rates of early-stage IDC in middle-aged and old women following different treatments. Our hypothesis is that women receiving BCT will have a lower recurrence rate than those receiving MAS or MAS + RT.

Data sources
We used SEER data reported by the National Cancer Institute for this study [9]. The SEER is a national population-based report of the most recent cancer incidence, prevalence, demographic characteristics, diagnosis time, tumor characteristics, surgery, RT, mortality, survival, and lifetime risk statistics in the United States [10]. It is published annually by the Surveillance Research Program of the National Cancer Institute in an effort to reduce the cancer burden among the United States population [10]. In the initial phase of the survey, seven registries (SEER 7) with epidemiologically signi cant population subgroups of racial and ethnic minorities were published. Since then, the database has been incrementally expanded to include 18 cancer registries (SEER 18) [11]. The SEER data can be applied for the analyses online.

Study design, setting, and participants
We used the SEER 18 database to conduct a nationwide population-based cohort study. Initially, all patients diagnosed with breast cancer as the primary cancer between 2000 and 2015 were identi ed ( Fig. 1). The exclusion criteria were as follows: (1) male; (2) aged < 50 years; (3) ductal carcinoma in situ; (4) American Joint Committee on Cancer (AJCC) cancer staging was not T1-2, N0-1, or M0; (5) diagnosis was made only by autopsy or death certi cation; (6) survival < 1 month; (7) incomplete data (race, cancer stage, estrogen receptor [ER], progesterone receptor [PR], and marital status); (8) did not receive RT after BCS and did not receive MAS. Finally, middle-aged and old women (age ≥ 50 years) diagnosed with earlystage IDC as the primary cancer between 2000 and 2015 were identi ed for the analyses. According to the AJCC, the de nitions of early-stage IDC are as follows: (1) cancer stage: T1-2, N0-1, or M0; (2) positive lymph nodes ≤ 3 (patients with > 4 positive lymph nodes were excluded because RT is almost suggested in these patients); (3) tumor size < 5 cm [12]. Patients were divided into three treatment groups as follows:  (Table 1). Race was classi ed as white, black, and others. Marital status was classi ed as married, never married, widowed, and others. Tumor size was classi ed as ≤ 2 cm, 2-3 cm, 3-4 cm, and 4-5 cm. Tumor grade was classi ed as I, II, III, and IV on the basis of histological ndings. Positive lymph node(s) was classi ed as 0, 1, 2, and 3. ER and PR status were classi ed as positive and negative. Data are presented as n (%) or mean ± standard deviation. IDC, invasive ductal carcinoma; BCT, breast conservative treatment; MAS, mastectomy; RT, radiotherapy; ER, estrogen receptor; PR, progesterone receptor.
The primary outcomes were short-term recurrence rate (< 1 year) and long-term recurrence rate (≥ 1 year). Recurrence times were tracked beginning on the day breast cancer was rst diagnosed. Recurrence was de ned as local tumor recurrence in the breast (after BCT), chest wall (after MAS), ipsilateral/parasternal/infra-or supraclavicular lymph nodes, and skin of the chest wall (not breast) [13].

Ethics statement
This study protocol was approved by the Institutional Review Board of Kaohsiung Medical University (Approval No. KMUHIRB-EXEMPT(II)-20190018). Informed consent was waived because we used deidenti ed secondary data from the SEER. The waiver does not affect the rights and welfare of the patients.

Statistical analysis
For descriptive statistics, we used frequencies and percentages to represent categorical variables and means with standard deviations (SDs) to represent continuous variables. For inferential statistics, we used the chi-squared test to investigate associations between the three treatment groups and categorical variables in the demographic and clinical characteristics. One-way ANOVA (analysis of variance) was used to investigate associations between the three treatment groups and continuous variables in the demographic characteristics. Kaplan-Meier analysis and log-rank tests were used to compare differences in the recurrence curves of the three treatment groups. The Cox proportional hazard model was used to investigate predictors for recurrence. We used SAS9.4 to obtain descriptive and inferential statistics and STATA SE13.0 to draw the recurrence curves. The signi cance level was set to 0.05 (twotailed).

Results
Overall, 184,964 patients were included in this study (  Table 4 and Fig. 2). In addition, in the short-term recurrence analysis, only age 80-89 years was an independent predictor of recurrence (Table 3). Age ≥ 90 years, black race, tumor grade II, and PR-negative tumors reasonably predicted long-term recurrence (Table 4).   Subgroup analysis of short-term recurrence showed that the BCT group has a lower recurrence rate at 6 months (Supplementary Table 1 and Supplementary Fig. 1) than the other groups. Long-term recurrence analysis showed that the BCT group has a higher recurrence rate than the MAS and MAS + RT groups at the 10-and 15-year follow-ups (Supplementary Table 2 and Supplementary Fig. 2). Competing risk analysis with adjustment for demographic and clinical characteristics revealed that the BCT group (reference) has a lower short-term recurrence risk than the MAS (HR: 1.90, p < 0.001) and MAS + RT (HR: 2.08, p = 0.048) groups. Moreover, the BCT group (reference) had a higher long-term recurrence risk than the MAS (HR: 0.28, p < 0.001) and MAS + RT (HR: 0.42, p < 0.001) groups.

Discussion
The present study showed that most breast cancer patients receive BCT, followed by MAS and MAS + RT.
Patients who received BCT were more likely to be of white race and have a smaller tumor size, lower tumor grade, fewer positive lymph nodes, and larger number of ER-and PR-positive tumors than patients in other groups. Compared with the MAS and MAS + RT groups, the BCT group had a lower short-term recurrence risk but a higher long-term recurrence risk, especially at the 10 and 15-year follow-ups. Age ≥ 90 years, black race, tumor grade II, and PR-negative tumors were independent predictors for long-term recurrence.
We con rmed that the BCT group has a higher long-term recurrence risk than the MAS and MAS + RT groups; this result sheds some light on what has been a long-disputed issue in the literature. A large observational study in Germany between 1998 and 2014 reported that BCT allows better local control (HR: 1.52; 95% CI: 1.09-2.11) than MAS [14]. In addition, the BCT cohort had a lower 10-year cumulative incidence of lymph node recurrence (2.0% vs. 5.8%, p < 0.001), lower 10-year distant-metastasis-free survival (85.5% vs. 89.4%, p = 0.013), and better 10-year overall survival (85.3% vs. 79.3%, p < 0.001) than the MAS cohort [14]. A retrospective study in China between 1999 and 2014 reported that BCT has locoregional recurrence-free survival rates similar to that of MAS but better distant metastasis-free survival and overall survival rates [15]. A prospective Swedish multicenter cohort study carried out between 2000 and 2004 reported that local recurrence rates do not differ between BCT and MAS in patients with clinically node-negative breast cancer [16]. A randomized study with a 20-year follow-up in Italy in 2002 reported that the cumulative incidence of local recurrence in women with early breast cancer receiving BCT is 8.8%, which is higher than that in women receiving MAS (2.3%) [17]. However, the above studies included patients of all ages, and the characteristics of the populations studied may differ from those of patients aged ≥ 50 years, as in the present study. In addition, because these previous studies included all types of breast cancer, their results may be different when compared with a study speci c to IDC, such as the present work. Therefore, further studies speci c to middle-aged and old women and early-stage IDC are needed to con rm our ndings.
Risk of recurrence has a great in uence on patients with breast cancer because this risk causes patients to live with a constant fear of death [18]. The reasons behind local recurrence remain largely unknown [18], but the possible mechanisms include the existence of cancer stem cells and transformation of cancer cells into a relatively aggressive phenotype [18]. Cancer stem cells and transformed cancer cells are highly metastatic and resistant to conventional therapies [18]. A high percentage of aggressive cells is a feature of recurrent breast cancers [18]. Many clinical predictors for recurrence, including ER-negative, PR-negative, human epidermal growth factor receptor 2 (HER-2)-positive, triple-negative breast cancers, age, race, menopausal status, smoking, mammographic features, tumor morphology, tumor size, tumor stage, lymph node metastases, and gene expression pro ling, have been proposed [18,19].
Age ≥ 90 years, which has not been fully studied in the literature, was identi ed to be an independent predictor for long-term recurrence in the present study. A large population-based study in the Netherlands in 2020 reported that patients aged 75-79 years were at higher risk of distant recurrence than patients aged 70-74 years (subdistribution HR: 1.25; 95% CI: 1.11-1.41); however, age ≥ 80 years did not show this higher risk [20]. The authors attributed their ndings to several reasons: (1) patients in the aged 75-79 years were undertreated, (2) the risk of death without recurrence increases with age, and (3) patients with a high competing mortality risk were overtreated [20]. Another population-based study in Germany in 2019 revealed that patients aged < 70 years have higher 5-and 10-year locoregional recurrence and distant metastasis rates than those aged ≥ 70 years (17% vs. 13%) [21]. More evidence is needed to clarify this nding. Black race was a risk factor for cancer recurrence in the present study, consistent with ndings in previous studies [19]. Racial disparities may be due to socioeconomic factors and a more aggressive tumor biology among African-Americans [19]. Tumor grade was also associated with poor outcomes [19]. The present study revealed that tumor grade II is associated with long-term recurrence.
While patients with tumor grades III and IV were at higher risk for long-term recurrence than those with tumor grade I, the difference between grades was not signi cant. PR-negative is a predictor for recurrence, and the results between the present and previous studies are consistent [19]. In general, breast cancers that are single hormone receptor-positive appear to have a poorer prognosis than those that are both ERand PR-positive [19]. The present study also revealed a higher long-term recurrence risk in patients with ER-negative breast cancer than in those with ER-positive breast cancer; however, the difference was not signi cant (HR: 1.13; 95% CI: 0.97-1.33).
The major strengths of the present study include its nationwide population-based design, large sample size, and clear delineation of the knowledge gap in research on the recurrence rate of early-stage IDC in women aged ≥ 50 years. The limitations are as follows. First, the data were obtained from various institutions and may have bias in terms of treatment and quality. Second, because the present study conducts a secondary analysis of data, the results can only suggest associations between variables rather than causal relationships. Third, some variables, including genetic data, lymphovascular invasion, size of metastatic lymph nodes, resection margins, adjuvant therapies (e.g., chemotherapy and endocrine therapy), and HER2, were not considered in the present study because data on these variables were made available only after 2010. Fourth, because the data used for our analyses are from the United States, their generalization to other countries requires further validation.

Conclusion
This nationwide population-based cohort study revealed that, among middle-aged and old women with early-stage IDC, the BCT group has a lower short-term recurrence risk but a higher long-term recurrence risk than the MAS and MAS + RT groups, especially at the 10-and 15-year follow-ups. The results ll the knowledge gap in research on the long-and short-term recurrence rates of IDC and provide valuable evidence of the most reliable treatment strategy for this population. Further studies, including more variables and validation in other countries, are warranted to con rm our ndings. Availability of data and materials

Abbreviations
The data of SEER are publicly available. Figure 1 Flowchart of this study. SEER, Surveillance, Epidemiology, and End Results; IDC, invasive ductal carcinoma; AJCC, American Joint Committee on Cancer; ER, estrogen receptor; PR, progesterone receptor; RT, radiotherapy; BCS, breast conservative surgery; BCT, breast conservative treatment (BCS+RT); MAS, mastectomy alone.