The Different Outcomes Between Breast-Conserving Surgery Plus Radiotherapy and Mastectomy in Breast Ductal Carcinoma In Situ with Microinvasion

Background: Ductal carcinoma in situ with microinvasion (DCIS-MI) is a subtype of breast cancer with good prognosis, for which both breast conserving surgery plus radiotherapy (BCS+RT) and mastectomy are feasible surgical methods, but their effects on the prognosis of patients are still unclear. Methods: We used the Surveillance, Epidemiology and End Results (SEER) database to extracted DCIS-MI patients who underwent BCS+RT or mastectomy between 2000 and 2014. Participants were divided into BCS+RT group and mastectomy group. We compared the breast cancer-specic survival (BCSS) and overall survival (OS) of the two groups using Kaplan -Meier method and Cox proportional hazard regressions before and after propensity score matching (PSM) with the landmark. Results: We selected 5432 patients, among which 2834 patients (52.17%) were in the BCS+RT group and 2598 patients (47.83%) were in the mastectomy group. With a 101 months median follow-up time in the overall cohort, both univariate and multivariate analysis showed that BCS + RT group showed signicantly higher OS and BCSS compared with patients in the mastectomy group (P<0.001). After PSM, the BCS+RT and mastectomy groups consisted of 1902 patients, respectively. multivariate analysis also showed that compared with mastectomy, the BCS+RT showed signicantly higher OS and BCSS (HR = 0.676, 95% CI = 0.540-0.847, P<0.001; HR = 0.565,95% CI = 0.354-0.903, P= 0.017). In addition, the subgroup analysis showed that BCS + RT is at least equivalent to mastectomy with respect to OS and BCSS in any subgroup. Conclusion: For patients with DCIS-MI, the prognosis of BCS+RT was superior to mastectomy.


Introduction
Ductal carcinoma in situ with microinvasion (DCIS-MI) is a special type of breast cancer, accounting for 0.6-3.4% of breast cancer [1,2]. It refers to cancer cells breaking through the basement membrane to in ltrate adjacent tissues, but the maximum lesion scope is less than 1mm [3,4]. According to the American Joint Committee on Cancer (AJCC), lesions that meet this de nition are regarded as a subtype of stage T1 breast cancer and classi ed as T1mic stage [5]. Most scholars believe that DCIS-MI is the intermediate stage of DCIS and invasive ductal carcinoma (IDC), with a prognosis between the two [6-9]. However, some scholars believe that DCIS-MI has the same prognosis as DCIS [10,11]. The early-stage proposed by DCIS-MI lacks a uni ed diagnostic standard, the disease is relatively rare, and the study sample size is small. Therefore, there are many controversies in the treatment.
Currently, many studies have demonstrated that for early breast cancer, patients receiving BCS + RT have the same prognosis as patients receiving mastectomy [12][13][14]. Mamtani et al. compared the prognosis of BCS + RT and mastectomy in patients with DCIS and found that BCS + RT was superior to mastectomy in OS or DFS of DCIS [15].
Both BCS + RT and mastectomy are currently available surgical methods for DCIS-MI. However, considering the good prognosis of DCIS-MI and patients' postoperative life quality, it is worth exploring whether BCS + RT is the best choice for DCIS-MI. At present, there are few studies on the surgical methods of DCIS-MI [16][17][18].The prognosis of BCS + RT or mastectomy for patients with DCIS-MI is still unclear.We conducted this study to determine which surgical procedure is better for patients with DCIS-MI. This study compared the long-term outcomes of patients with DCIS-MI receiving BCS + RT and mastectomy using the SEER database.

Patients
This study was conducted using the SEER database published in November 2018. Patients who were diagnosed with DCIS-MI from 2000 to 2014 were eligible for recruitment. The inclusion criteria included: (1) 20-79 years old; (2) A mastectomy or breast-conserving surgery was performed. Exclusion criteria included :(1) Patients with tumor metastasis; (2) patients combined with other malignant tumors; (3) Patients who did not receive radiotherapy after breast-conserving surgery.

Data collection and outcome measures
We collected the following factors: year of diagnosis, age, race, marital status, histological grade, lymph node status, estrogen receptor (ER), progesterone receptor (PR), surgical method, chemotherapy and radiotherapy. Our study's main outcomes were OS and BCSS, OS was de ned as the time from the date of diagnosis to the date of death, and BCSS was measured from the date of diagnosis to the date of death due to breast cancer.

Statistical analysis
Propensity score matching(PSM) was applied to create a matched pair between the two groups to eliminate the selection bias of this study population [19]. We performed PSM for all the variables included in the study. Landmark analysis was used to eliminate a lead time bias among the propensity-matched cohort [20]. With the landmark, analysis was restricted to patients who survived to 6 months without death .X 2 test was used to compare the distribution of the clinical and pathological features between the two groups before and after PSM. The OS and BCSS survival curves were plotted through the Kaplan-Meier method and compared by the log-rank test. The cox regression model was used for the univariate and multivariate analyses of the BCSS and OS. All P values were twosided, and P < 0.05 was considered signi cant. The SPSS 20.0 (IBM SPSS Statistics, Chicago, IL, US)was used for these analyses.

Ethics statement
The informed consent is not required for that the study obtained data from the SEER database.

Baseline characteristics
In total, 5432 patients with DCIS-MI from 2000 to 2014 were included in the study through the SEER database. We divided the patients into two groups :BCS + RT group (2834,52.17%) and mastectomy group (2598,47.83%). Table 1 summarizes the patient clinical characteristics of the two groups. Compared with mastectomy group, the patients in the BCS group were older (78.9% VS. 64.2%; P < 0.001)and had lower histological grade (grade I + II,65.6% VS. 56.4%; P < 0.001), less lymph node metastasis(N0, 96.7% VS. 87.5%; P < 0.001). Further, the BCS group had a higher ER(76.7% VS. 67.4%; P < 0.001) and PR (62.9% VS. 55.4%; P < 0.001) positive rates and were less likely to receive chemotherapy (6.2% VS. 14.8%; P < 0.001). After PSM, the two groups consisted of 1902 pairs. There was no signi cant difference in clinicopathological characteristics between the two groups.

Subgroup analysis of OS and BCSS
To further explore possible factors affecting the overall survival time for patients who had undergone two types of surgery, we performed a subgroup analysis of all patients after PSM. BCS + RT group showed signi cantly higher OS than mastectomy group for patients aged between 50-79 years, patients who married or not married, the white race group, patients with grade III + IV, patients with lymph nodal negative, patients with ER positive, patients with PR positive or negative and those who did not receive chemotherapy(all P < 0.05) (Fig. 3).Further, the BCT + RT group also showed BCSS bene t in patients who not married, patients with lymph nodal negative, patients with ER negative, and those who did not receive chemotherapy (Fig. 4). The OS and BCSS outcomes of mastectomy were not better than those of BCS + RT in any subgroup.

Discussion
DCIS-MI is a special type of breast cancer, and there is little evidence on the prognosis of patients with DCIS-MI undergoing BCS + RT and mastectomy. We found that the prognosis of patients with DCIS-MI after mastectomy is not better than those of BCS + RT in any subgroup by using the SEER database.
In the NCCN guidelines, DCIS-MI is classi ed as early-stage invasive breast cancer. All surgical options for earlystage invasive breast cancer are uni ed. There is no special explanation for the surgical options for DCIS-MI. In our study, 71.9% of patients with DCIS-MI were older than 50 years. Besides, patients with DCIS-MI had few lymph node metastases (92.3% without lymph nodal metastases), low histological grade (61.3% in GI + II), and high positive rates of ER and PR (72.3% and 59.3%), which was consistent with other studies [21,22]. These results indicate that DCIS-MI has a good prognosis.
Although the clinicopathological features of DCIS-MI all indicate a good prognosis, at present, there are still a large number of DCIS-MI patients undergoing mastectomy. In our study, 47.83% of the patients received mastectomy. In Eastern countries, the proportion of patients with DCIS-MI undergoing mastectomy is higher, even as high as 80% [23,24]. At present, the safety of mastectomy for DCIS-MI has been veri ed. Mamtani et al.studied the locoregional and distant recurrence after mastectomy for DCIS with or without microinvasion. It proved that locoregional recurrence after mastectomy for DCIS ± microinvasion is uncommon. Even in the age group with the highest recurrence rate, 10-year locoregional recurrence remains low at 4.2% [25]. DCIS-MI often has multiple minimally invasive foci, associated with a higher risk of ipsilateral recurrence [26,27]. showed that the BCS + RT group showed signi cantly higher OS and BCSS than patients in the mastectomy group.
In order to nd out which subgroups of people can bene t from BCS + RT, we also conducted a subgroup analysis and found that the OS and BCSS outcomes of mastectomy were not better than those of BCS + RT in any subgroup. Furthermore, we observed that 95.5% of patients received mastectomy without RT in our study. Thus we think that BCS + RT showed a better prognosis than mastectomy may due to RT. Studies have con rmed that RT can reduce the local recurrence of breast cancer. Rakovitch et al. proved that postoperative radiotherapy could reduce the local recurrence rate in patients with DCIS-MI [17]. The EORTC study also demonstrated that adjuvant radiotherapy after BCS could reduce the risk of ipsilateral invasive recurrence by approximately 50% during 10 years of follow-up [29].
Similar to the result of aother study, chemotherapy cannot improve the survival of DCIS-MI. Pu et al. proved that postoperative chemotherapy did not improve DFS in patients with DCIS-MI after mastectomy (HR = 1.50, 95%CI 0.29-7.87, P = 0.63) [30]. Chen et al. analyzed 3198 DCIS-MI patients and concluded that chemotherapy was an independent factor for worse BCSS (P = 0.008) and there was no statistical signi cance for OS (P = 0.248) in patients with DCIS-MI [31].In our study's overall cohort, 6.2% and 14.8% of patients in the BCS + RT group and the mastectomy group received chemotherapy, respectively. There was no signi cant difference in OS and BCSS between those who did not receive chemotherapy and those who received chemotherapy (all P > 0.05) after PSM. However, further studies are needed to verify whether chemotherapy is bene cial to patients with DCIS-MI.
Our study had several limitations. Firstly, there may be residual confounders even though the propensity-matched landmark analysis was used. Secondly, the SEER database did not provide detailed information on breast multiple lesions and lacks data on postoperative breast reconstruction and postoperative local recurrence. Finally, there is no information on endocrine therapy and targeted therapy in the SEER database.

Conclusion
This population-based study based on SEER database revealed that the prognosis of patients who were diagnosed with DCIS-MI receiving mastectomy was not better than those receiving BCS + RT. We think that BCS + RT is more suitable for the DCIS-MI patients. https://seer. cancer.gov/data/, Accessed June 23, 2020.

Abbreviations
-Con ict of Interest The author(s) declare that they have no competing interests.The authors declare that the research was conducted in the absence of any commercial or nancial relationships that could be construed as a potential con ict of interest.
-Funding Not applicable.  The forest plot of HR for OS between the BCS+RT group and mastectomy group according to different characteristics