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Effect of postoperative radiotherapy in women with localized pure mucinous breast cancer after lumpectomy: a population-based study

Effect of postoperative radiotherapy in women with localized pure mucinous breast cancer after... Purpose: Pure mucinous breast cancer is a rare subtype of invasive breast cancer with favorable prognosis, in which the effect of postoperative radiotherapy remains unclear. We aimed to investigate the prognostic value of postopera- tive radiotherapy in women with localized pure mucinous breast cancer after lumpectomy. Methods: We conducted a retrospective cohort study to compare the effectiveness of postoperative radiotherapy (RT ) and omitting postoperative radiotherapy (non-RT ) in patients with first primary T1-2N0M0 ( T ≤ 3 cm) pure mucinous breast cancer who underwent lumpectomy between 1998 and 2015 using the Surveillance, Epidemiology, and End Results (SEER) database. Breast cancer-specific survival (BCSS) was compared between RT and non-RT groups using Kaplan–Meier method and Cox proportional hazards regression model. Propensity score matching (PSM) was carried out to balance cohort baselines. In addition, an exploratory analysis was performed to verify the effectiveness of RT in subgroup patients. Results: Of 7832 eligible patients, 5352 (68.3%) underwent lumpectomy with postoperative RT, 2480 (31.7%) received lumpectomy without postoperative RT. The median follow-up duration was 92 months. The median age was 66 years in the RT group and 76 years in the non-RT group.The 15-year BCSS was 94.39% (95% CI, 93.08% to 95.35%) in the RT group versus 91.45%(95% CI, 88.93% to 93.42%) in the non-RT group (P < 0.001). The adjusted hazard ratio for BCSS was 0.64 (95% CI, 0.49 to 0.83; P = 0.001) for RT group versus non-RT group. After propensity score match- ing, similar results were yielded. Adjuvant RT reduced the 15-year risk of breast cancer death from 7.92% to 6.15% (P = 0.039). The adjusted hazard ratio for BCSS were 0.66 (95%CI, 0.47 to 0.92; P = 0.014) for RT group versus non-RT group. The benefit of RT was well consistent across subgroup patients. Conclusion: Among women with T1-2N0M0 (tumor size ≤ 3 cm) pure mucinous breast cancer, the addition of RT after lumpectomy was significantly associated with a reduced incidence of breast cancer death compared with non- RT, and the magnitude of benefit may be modest. This suggests that postoperative RT is recommended in the treat - ment of localized pure mucinous breast cancer. Qiuping Mo, Yongzhen Wang and JinLan Shan have contributed equally to this work and share first authorship. *Correspondence: wangxiaochen@zju.edu.cn Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mo et al. Radiation Oncology (2022) 17:119 Page 2 of 13 Keywords: Breast neoplasm, Radiotherapy, Adjuvant, Lumpectomy, Prognosis, Mucinous Introduction was an independent protective factor for both overall Mucinous breast carcinoma accounting for approxi- survival (OS) and BCSS in patients with pure mucinous mately 1 to 6% of all breast cancer is divided into two breast cancer. However, this retrospective study was hete- pathological subtypes: pure mucinous breast cancer togeneous in nature because inclusion criteria involved in and mix mucinous breast carcinoma [1]. Pure mucinous advanced patients, and the cohort included mastectomy breast cancer exclusively consists of tumor tissue with and lumpectomy [22]. A recent SEER research presented extracellular mucin production over 90%, whereas mix that postoperative radiotherapy following lumpectomy mucinous breast cancer usually mixes infiltrating ductal improved the 10-year BCSS rates from 94.5 to 97.6% in epithelial component with mucinous areas covering from patients aged ≥ 65  years diagnosed with T1–2N0 and 50 to 90% [2]. The comparisons of biological features and hormone receptor-positive pure mucinous breast cancer. clinical prognosis have been identified previously among Yet regrettably, patients aged < 65 years were not included pure mucinous breast cancer, mix mucinous breast car- in this study. Besides, patients with tumor size larger cinoma and invasive breast cancer of no special type [1, than 3 cm were more likely to receive endocrine therapy, 3–13]. Pure mucinous breast cancer usually occurs in which may confuse results [23]. Obviously, it is necessary elderly patients, especially in postmenopausal women [8]. to adequately assess individualized roles of postoperative The tumor size of pure mucinous breast cancer ranges RT in this special subtype of breast carcinoma. Hence, we from less than 1  cm to more than 20  cm, with an aver- proceeded to a large population-based study using SEER age of 3 cm [14]. On account of fewer genetic mutations, to investigate the effect of postoperative RT on BCSS in pure mucinous breast cancer has a stabilized luminal A women undergoing lumpectomy with T1-2N0M0 (tumor phenotype with higher expression of hormone receptor size ≤ 3 cm) stage pure mucinous breast cancer. and a lower rate of positive human epidermal growth fac- tors 2 (HER-2) [5, 15, 16]. A mechanical barrier made of Methods abundant pools of extracellular mucus around cellular Patients population island restricts carcinoma cell invasion, leading to less This retrospective study was performed utilizing SEER axillary lymph node or distant metastases. Axillary node database (November 2018 submission) which released involvement, although rare, appears to be the worst prog- cancer data from 18 registries of national cancer insti- nostic factor followed by tumor size, age, progesterone tute and covered approximately 28% of the US population receptor(PR), HER-2 status and nuclear grade [3, 17–20]. [24]. A case-listing session was derived from SEER*Stat It has reported that the 5-year, 10-year disease-free sur- version 8.3.5. vival (DFS) were up to 94% [1], 92% [9] for patients with We selected all female cases of histological diag- node-negative pure mucinous breast cancer, respectively. nosed first primary pure mucinous breast cancer with Hence, pure mucinous breast cancer presents distinct the International Classification of Diseases for Oncol - clinicopathological characteristics with especially favora- ogy, 3rd Revision (ICD-O-3) code 8480/3 from January ble prognosis. 1998 through December 2015. Patients with T1-2N0M0 At present, the recommendations of locoregional treat- (tumor size less than 3  cm) stage were eligible. And ment for patients with operable pure mucinous breast patients were required to receive lumpectomy with or cancer from the latest National Comprehensive Cancer without postoperative RT. The exclusion criteria were Network are the same as that for patients with typical listed as follows: diagnosed from death certificate or breast cancer [21]. However, it is difficult to evaluate the autopsy only; no active or complete follow-up data; died effect of local regional treatment on survival outcome in at the start of the follow-up; unknown T, N, M stage; with prospective cohort studies or randomized trials owing to nodal positive disease or metastases disease at diagnosis; the relatively low incidence rate and a limited follow-up without operation or unknown surgery; without RT or prognosis of pure mucinous breast cancer. Guidelines on unknown RT; non-postoperative radiotherapy; bilateral radiotherapy of pure mucinous breast cancer are extrap- cancer or unknown laterality; unknown tumor size. The olated from evidence based on other common invasive flowchart for patient selection was shown in Fig. 1. breast cancer. Although scholars have done some retro- spective studies, the effect of postoperative radiotherapy Study covariates in patiens with pure mucinous breast cancer is uncertain According to administrations of lumpectomy and post- so far. Previous study showed that adjuvant radiotherapy operative RT, a total of 7832 eligible patients under the M o et al. Radiation Oncology (2022) 17:119 Page 3 of 13 Fig. 1 Patient selection diagram inclusion criteria were stratified into RT group and non- extracted. Among them, the T stage was adjusted by the RT group. We subsequently reviewed variable informa- 6th American Joint Committee on Cancer (AJCC) TNM tion of each case on patient baseline demographics, such Staging System. Tumor grade was categorized into four as age at diagnoses, year of diagnoses, race, marital status levels on the biasis of the degree of differentiation: grade at diagnoses. Then, tumor clinicopathological character - I, well differentiated; grade II, moderately differentiated; istics, including tumor laterality, tumor grade, T stage, grade III, poorly differentiated; grade IV, undifferentiated tumor size, estrogen receptor (ER) and PR status, were or anaplastic. Borderline ER/PR status defined as having Mo et al. Radiation Oncology (2022) 17:119 Page 4 of 13 Table 1 Demographic and tumor characteristics among all Table 1 (continued) patients with pure mucinous breast cancer RT radiotherapy, SD standard deviation, IQR interquartile range; DSW, divorced, separated and widowed RT Non-RT P* *Categoric variables were analyzed by the Pearson x test, and continuous variables (age, tumor size) were analyzed by the t tests or Mann–Whitney tests Characteristics No % No % Including Asian or Pacific Islander, American Indian, Alaska Native and unknown race Patients 5352 68.3 2480 31.7 Including unmarried or domestic partner, single (never married) Age of diagnosis, years Including divorced, separated and widowed Mean (SD) 64.4 (12.5) 72.8 (13.3) < 0.001 Median (IQR) 66.0 (56.0–74.0) 76.0 (65.0–83.0) < 0.001 < 50 749 14.1 194 7.8 < 0.001 1–10% positivity by immunohistochemistry were merged 50–59 1008 18.8 232 9.4 into positive ER/PR status [25, 26]. In this study, we did 60–69 1495 27.9 386 15.6 not evaluate HER-2 status because of lacking data before ≥ 70 2100 39.2 1668 67.2 Era of diagnosis 1998–2004 2027 37.9 845 34.1 0.002 Statistical analysis 2005–2009 1515 28.3 772 31.1 Categoric variables were compared across treatment 2010–2015 1810 33.8 863 34.8 groups using the Pearson chi-squared test, and continu- Race ous variables were analyzed by two independent sample White 4292 80.2 2079 83.8 < .001 t-tests or Wilcoxon rank sum test. The primary endpoint Black 453 8.5 225 9.1 of this study was BCSS. BCSS was defined as an interval Other 607 11.3 176 7.1 from the data of pure mucinous breast cancer diagnosis Marital status to death as a result of breast cancer. Using Kaplan–Meier Married 2892 54.0 984 39.7 < 0.001 survival analysis, BCSS were estimated with log-rank Non-married 680 12.7 258 10.4 tests in unmatched groups and matched groups. Haz- DSW 1680 30 1106 44.6 ard Ratio (HR) and 95% confidence interval (95%CI) Unknown 172 3.2 132 5.3 were calculated by Cox proportional hazards model to Laterality estimate the effect of RT. The multivariable Cox pro - Left 2782 52.0 1317 53.1 0.354 portional hazards regression analysis incorporated vari- Right 2570 48.0 1163 46.9 ables that were significant or approximately significant in Tumor size ( T stage), cm univariate analyses. The proportional-hazards assump - Mean (SD) 1.4 (0.7) 1.4 (0.7) 0.092 tion was checked based on Schoenfeld residuals after fit - Median (IQR) 1.3 (0.9–1.8) 1.3 (0.9–1.8) 0.139 ting a Cox model. And all of the Cox models obeyed the ≤ 1.0 ( T1) 2034 38.0 909 36.7 0.488 proportional risk hypothesis. PSM was used to control 1.1–2.0 ( T1) 2456 45.9 1170 47.2 confounding bias in the retrospective study. Propensity 2.1–3.0 ( T2) 862 16.1 401 16.1 scores of being receipt of RT were calculated by using a Tumor grade multivariable logistic regression model. The independ - I 2977 55.6 1366 55.1 0.002 ent variables are being those that were statistically sig- II 1478 27.6 627 25.3 nificant for correlation with treatment modality. Patients III 135 2.5 52 2.1 treated with RT were matched 1:1 to patients managed IV 8 0.2 4 0.2 without RT on propensity scores by using nearest neigh- unknown 754 14.1 431 17.4 bor matching algorithm. The threshold value of Caliper ER status matching was set to 0.2. A standardized difference of Positive 5002 93.5 2176 87.7 < 0.001 less than 0.1 was considered an indifferent imbalance Negative 88 1.6 30 1.2 between comparison groups. Further, exploratory analy- Unknown 262 4.9 274 11.0 sis and tests of interaction were undertaken to evaluate PR status the effect of adjuvant RT among subgroups according to Positive 4503 84.1 1953 78.8 < 0.001 patient and tumor characteristics. Negative 510 9.5 206 8.3 Statistical analyses were performed with SPSS, version Unknown 339 6.4 321 12.9 24.0 (SPSS Inc., Chicago, IL, USA) and STATA, version Chemotherapy 15 (Stata Corp., College Station, TX, USA). Two-tailed No/Unknown 4854 90.7 2371 95.6 < 0.001 P < 0.05 was considered statistically significant. Yes 498 9.3 109 4.4 M o et al. Radiation Oncology (2022) 17:119 Page 5 of 13 Fig. 2 Utilization of postoperative radiotherapy versus omission over time in patients with T1-2N0M0(tumor size ≤ 3 cm) pure mucinous breast cancer from SEER Database, 1998–2015 of covariates was well balanced between propensity- Results matched groups (Table 2). Patient demographics and tumor characteristics Comparisons of patient demographics and tumor char- Survival analyses of BCSS acteristics between RT and non-RT group were sum- Overall, the median follow-up time was 92 months (inter- marized in Table  1. A total of 7832 eligible patients quartile range, 48 to142 months), and 239 breast cancer- with pure mucinous breast cancer were identified in special deaths were observed. The Kaplan–Meier survival the cohort (mean [SD] age, 67.1 [13.3] years), of whom estimate showed that 5-year, 10-year, 15-year BCSS rates 5352 (68.3%) received lumpectomy and postoperative were 99.01% (95% CI, 98.68% to 99.26%), 96.95% (95% CI, RT, 2480(31.7%) were treated with lumpectomy without 96.29% to 97.49%), 94.39% (95% CI, 93.08% to 95.35%) for RT. Among patients underwent lumpectomy, those who patients treated with RT respectively, whereas the cor- received RT were on average 9 years younger than those responding were 97.38% (95% CI, 96.57–98.01%), 94.50% who did not (P < 0.001). The median age (interquartile (95% CI, 93.08–95.64%), 91.45%(95% CI, 88.93–93.42%) range) was 66  years (56–74) in RT group and 76  years for non-RT respectively. The difference between RT and (65–83) in non-RT group. The main pathological fea - non-RT curve was statistically significant (log-rank test, ture of patients was hormone receptor positive (91.9%) P < 0.001; Fig.  3A). The univariate Cox proportional haz - and well differentiated (55.5%). The minority of patients ards regression model showed the HR of BCSS for RT received chemotherapy(7.8%). There was no signifi - versus non-RT was 0.51 (95% CI, 0.39–0.66; P < 0.001). cant difference between treatment groups in tumor size For the purpose of controlling the potential confound- (P = 0.433). There was little change in the utilization of ing factors in adjuvant RT effectiveness, the multivariable postoperative RT through the period between 1998 and Cox proportional hazards regression analysis was further 2015(Fig. 2). In order to eliminate the imbalance between applied. After the prognostic analysis was adjusted for groups that may affect results, PSM was subsequently the following clinicopathological parameters: tumor size, conducted. After PSM between the RT group and non- tumor grade, PR status, age at diagnosis, race and married RT group, 2149 pairs were generated. The distribution status, we observed postoperative RT was independently Mo et al. Radiation Oncology (2022) 17:119 Page 6 of 13 Table 2 Demographic and tumor characteristics among propensity-matched population with pure mucinous breast cancer RT Non-RT Standardized difference Characteristics No % No % Patients 2149 50.0 2149 50.0 Age of diagnosis, years Mean (SD) 70 (11.9) 71 (12.9) 0.081 < 50 163 7.6 194 9.0 0.050 50–59 233 10.8 232 10.8 0.000 60–69 463 21.5 380 17.7 0.096 ≥ 70 1290 60.0 1343 62.5 0.051 Era of diagnosis 1998–2004 792 36.9 731 34.0 0.061 2005–2009 585 27.2 673 31.3 0.090 2010–2015 772 35.9 745 35.3 0.011 Race White 1769 82.3 1782 82.9 0.015 Black 186 8.7 202 9.4 0.026 Other 194 9.0 165 7.7 0.047 Marital status Married 932 43.3 956 44.5 0.022 Non-married 215 10.0 227 10.6 0.020 DSW 902 42.0 880 40.9 0.022 Unknown 100 4.7 86 4.0 0.033 Laterality Left 1124 52.3 1139 53.0 0.014 Right 1025 47.7 1010 47.0 0.014 Tumor size ( T stage), cm Mean (SD) 1.4 (0.7) 1.4 (0.7) 0.000 ≤ 1.0 ( T1) 817 38.0 822 38.3 0.006 1.1–2.0 ( T1) 985 45.8 1009 47.0 0.024 2.1–3.0 ( T2) 347 16.1 318 14.8 0.036 Tumor grade I 1164 54.2 1212 56.4 0.044 II 566 26.3 558 26.0 0.007 III 45 2.1 46 2.1 0.000 IV 4 0.2 4 0.2 0.000 unknown 370 17.2 329 15.3 0.052 ER status Positive 1912 89.0 1952 90.8 0.060 Negative 34 1.6 30 1.4 0.012 Unknown 203 9.4 167 7.8 0.058 PR status Positive 1732 80.6 1754 81.6 0.027 Negative 182 8.5 186 8.7 0.005 Unknown 235 10.9 209 9.7 0.039 Chemotherapy No/Unknown 2019 94.0 2040 94.9 0.039 Yes 130 6.0 109 5.1 0.039 RT radiotherapy, SD standard deviation, DSW divorced, separated and widowed M o et al. Radiation Oncology (2022) 17:119 Page 7 of 13 Fig. 3 Kaplan–Meier curves comparing BCSS between treatment groups for (A) all patients; (B) propensity-matched patients associated with better BCSS benefit (adjusted HR, 0.64; during 2010–2015. However, as we can see from the 95%CI, 0.49–0.83; P = 0.001). Moreover, the results also Fig.  4, there were no statistically significance in global indicated that tumor size, age ≥ 70  years, negative PR test for interaction (P > 0.05). expression and DSW (divorced, separated, widowed) marital status were risk predictors which independently Discussion associated with BCSS(Table 3). Among women with early-stage breast cancer receiving In the propensity-matched cohort, the survival analy- lumpectomy, the addition of RT is a standardized treat- sis of BCSS also showed a significant difference between ment based not only on its benefit in reducing ipsilateral the two groups (log-rank test, P = 0.039; Fig.  3B). The breast cancer recurrence, but also on its ability to signifi - BCSS rate for RT group was marginally better than non- cantly improve BCSS [27, 28]. In this large population- RT group. The 5-year BCSS was 98.85% (95%CI, 98.24– based study, by using matched approach among patients 99.25%)in RT group and 94.93% (95%CI, 93.46–96.08%) who received lumpectomy with T1-2N0M0 (T ≤ 3  cm) in non-RT group. The 10-year BCSS was 95.96% (95%CI, pure mucinous breast cancer, our result clearly indi- 94.66–96.95%) in RT group and 94.93% (95%CI, 0.93.46– cated that adjuvant irradiation following lumpectomy 96.08%) in non-RT group.The 15-year BCSS rate was was significantly associated with BCSS benefit. The 93.82% (95%CI, 91.75–95.38%) in RT group and 92.02% cumulative 15-year BCSS rate was 94.39% for women (95%CI, 89.39–94.03%) in non-RT group. The univariate with pure mucinous breast cancer received adjuvant analyses also confirmed that the RT group indicated a RT after lumpectomy, and 91.45% for patients treated significantly favorable prognosis (HR, 0.71; 95%CI, 0.51– with lumpectomy alone (HR = 0.51; 95% CI, 0.39–0.66; 0.98; P = 0.041; Table  4). After adjusted age, race, mari- P < 0.001; Table  3). After adjustment for potential con tal status and tumor size, the result of multivariable Cox founding factors, it was translated that the relative reduc- analysis did not change substantially (adjusted HR, 0.66; tion of breast cancer-special death was 34%, and the 95%CI, 0.47–0.92; P = 0.014; Table 4). absolute risk reduction at 15 years was 1.8%. In addition, The salutary effect of adjuvant RT on BCSS was further heterogeneity tests of the interaction term were not sig- assessed in different subgroups among the matched pop - nificant among the matched population, suggesting that ulation who underwent lumpectomy, and the HR inter- the protective prognostic value of adjuvant RT were con- actions were tested (Fig. 4). The benefit of RT seemed to sistent among different populations. be significant in some patients. The HR was 0.64 (95%CI, Our research has several potential strengths. To our 0.43–0.95) for patients aged 70  years and older, 0.44 best knowledge, this is a large cohort used to evaluate the (95%CI, 0.24–0.81) for married women, 0.44 (95%CI, effect on postoperative RT following lumpectomy among 0.27–0.71) for patients with 1.1–2.0  cm tumor size, 0.63 patients with early-stage pure mucinous breast cancer. (95%CI, 0.44–0.91) for patients with positive ER disease, Our study only aims to patient with tumor size less than 0.60 (95%CI, 0.40–0.90) for patients with positive PR 3  cm, which minimizes the impact of endocrine therapy tumor, 0.31 (95%CI, 0.10–0.96) for patients diagnosed on results. Propensity score matching was generated to Mo et al. Radiation Oncology (2022) 17:119 Page 8 of 13 Table 3 Univariate and multivariate prognostic analyses of BCSS in all patients Characteristics Univariate Multivariate HR 95%CI P aHR 95%CI P Treatment groups Non-RT 1.00 1.00 RT 0.51 0.39–0.66 < 0.001 0.64 0.49–0.83 0.001 Age of diagnosis, years < 50 1.00 1.00 50–59 1.08 0.58–2.03 0.803 1.11 0.59–2.10 0.746 60–69 1.46 0.83–2.57 0.192 1.51 0.84–2.68 0.166 ≥ 70 3.51 2.12–5.80 < 0.001 3.05 1.80–5.17 < 0.001 Era of diagnosis 1998–2004 1.00 2005–2009 1.04 0.77–1.41 0.789 2010–2015 0.88 0.55–1.41 0.606 Race White 1.00 1.00 Black 1.49 1.00–2.22 0.047 1.44 0.96–2.15 0.076 Other 0.52 0.30–0.91 0.022 0.70 0.39–1.20 0.213 Marital status Married 1.00 1.00 Non-married 0.92 0.56–1.51 0.736 0.98 0.59–1.61 0.931 DSW 2.25 1.71–2.96 < .001 1.56 1.17–2.08 0.002 Unknown 1.90 1.02–3.55 0.045 1.36 0.72–2.56 0.339 Laterality Left 1.00 Right 0.95 0.74–1.23 0.690 Tumor size ( T stage), cm ≤ 1.0 ( T1) 1.00 1.00 1.1–2.0 ( T1) 1.85 1.35–2.53 < 0.001 1.92 1.40–2.63 < .001 2.1–3.0 ( T2) 2.95 2.05–4.24 < 0.001 3.02 2.09–4.36 < .001 Tumor grade I 1.00 1.00 II 1.35 1.00–1.82 0.049 1.31 0.97–1.77 0.079 III/IV 1.95 1.05–3.63 0.034 1.91 1.02–3.59 0.043 unknown 1.19 0.85–1.68 0.305 1.16 0.83–1.64 0.390 ER status Positive 1.00 Negative 1.65 0.78–3.53 0.120 Unknown 1.24 0.83–1.85 0.300 PR status Positive 1.00 1.00 Negative 1.56 1.08–2.26 0.020 1.47 1.01–2.13 0.045 Unknown 1.37 0.95–1.98 0.100 1.19 0.82–1.72 0.368 Chemotherapy No/Unknown 1.00 Yes 0.75 0.46–1.21 0.460 HR hazard ration, aHR adjust hazard raion, CI confidence interval M o et al. Radiation Oncology (2022) 17:119 Page 9 of 13 Fig. 4 Forest plot depicting hazard ratios of adjuvant radiotherapy following lumpectomy versus lumpectomy alone for early-stage pure mucinous breast cancer in the propensity-matched population Mo et al. Radiation Oncology (2022) 17:119 Page 10 of 13 Table 4 Univariate and multivariate prognostic analyses of BCSS after PSM Characteristics Univariate Multivariate HR 95%CI P aHR 95%CI P Treatment groups Non-RT 1.00 1.00 RT 0.71 0.51–0.98 0.039 0.66 0.47–0.92 0.014 Age of diagnosis, years < 50 1.00 1.00 50–59 0.81 0.30–2.17 0.678 0.91 0.34–2.45 0.919 60–69 1.52 0.68–3.39 0.311 1.71 0.75–3.88 0.152 ≥ 70 2.73 1.32–5.62 0.006 2.83 1.32–6.05 0.002 Era of diagnosis 1998–2004 1.00 2005–2009 1.02 0.70–1.50 0.902 2010–2015 0.87 0.48–1.57 0.649 Race White 1.00 1.00 Black 1.60 0.99–2.61 0.055 1.67 1.02–2.74 0.042 Other 0.55 0.26–1.19 0.130 0.68 0.31–1.47 0.325 Marital status Married 1.00 1.00 Non-married 1.18 0.62–2.22 0.614 1.18 0.62–2.25 0.620 DSW 2.14 1.48–3.08 < .001 1.60 1.10–2.35 0.015 Unknown 1.99 0.94–4.22 0.072 1.66 0.78- 3.52 0.189 Laterality Left 1.00 Right 1.03 0.74–1.42 0.879 Tumor size ( T stage), cm ≤ 1.0 ( T1) 1.00 1.00 1.1–2.0 ( T1) 2.09 1.38–3.18 0.001 2.19 1.44–3.33 < .001 2.1–3.0 ( T2) 3.46 2.15–5.59 < .001 3.58 2.21–5.79 < .001 Tumor grade I 1.00 II 1.12 0.76–1.67 0.550 III/IV 1.80 0.78–4.13 0.168 unknown 0.87 0.57–1.38 0.594 ER status Positive 1.00 Negative 1.84 0.68–5.00 0.228 Unknown 1.19 0.71–1.82 0.598 PR status Positive 1.00 Negative 1.22 0.72–2.07 0.452 Unknown 1.19 0.77–1.85 0.421 Chemotherapy No/Unknown 1.00 Yes 0.56 0.25–1.27 0.169 HR hazard ration, aHR adjust hazard raion, CI confidence interval M o et al. Radiation Oncology (2022) 17:119 Page 11 of 13 reduce the confounding factors, leading to the baseline personalized management for patients [5]. The PIK3CA was comparable between treatment groups. In addition, mutation rate is 30–40% in ER-positive invasive ductal the heterogeneity of RT effect was tested in subgroup carcinoma and 7% in pure mucious breast cancer. The interaction, which further verified the benefit of BCSS p53 mutation rate is 20% in ER positive invasive ductal was attributable to radiotherapy rather than a baseline carcinoma, but only within 5% in pure mucinous breast imbalance in clinicopathologic features. cancer. The probability of 1q gains and 16q losses is Only a few studies have assessed the role of postopera- 10% in pure mucinous breast caner, which is 50% lower tive RT in this special type of breast cancer. Histological than that of ER-positive invasive ductal carcinoma [16]. types of breast cancer, as prognostic risk factors, have In addition, pure mucious breast cancer had a relatively rarely been evaluated in randomized trials related to lower percentage of high 21-gene recurrence score radiation therapy [29]. Single-center experiences did not patients than the infiltrating ductal carcinoma [32]]. In demonstrate that adjuvant RT improve recurrence free the future, for those with specific types of breast cancer, it survival among patient with pure mucinous breast can- is required to further study the prediction of clinical ben- cer [11]. In several Single-center retrospective studies, efit from radiation therapy, and the identification of low- they were also failed to show that receiving adjuvant RT risk patients in whom radiation can be safely omitted. could improve the OS or DFS in pure mucinous breast Nevertheless, we must acknowledge several limitations cancer [1, 3, 6, 11, 19, 30, 31]. These negative results may of this study. There are inherent biases in retrospective be related to small sample sizes and limited follow-up study inevitably. The SEER database at present cannot periods in retrospective studies.A previous SEER analy- provide the code on surgical margins, lymphovascular sis including 11,422 patients with pure mucinous breast invasion, Ki-67 and hormone therapy. Data are missing cancer between 1973 and 2002, with a mean follow-up in some cases for fundamental variables such as tumor period of 84  months, showed that the addition of radio- size, grade, TNM stage, hormone receptor status. For- therapy was not significantly asscosiated with prognosis tunately, missing data in TNM stage and tumor size less using multivariable Cox regression analysis [3]. On the than 5% of the total data. The radiotherapy treatment was contrast, another SEER database study, including 8048 not assigned at random. Although the propensity score I-IV stage pure mucinous breast cancer from 2004 to matching method is efficient for reducing the confound - 2014, found that radiotherapy was an independent fac- ing bias, a significant proportion of samples are censored tor for both OS and BCSS [22]. The opposing results may in the paired matching process. be related to the rapid development of radiotherapy and breast conserving surgery in the 1990s. A recent SEER Conclusion research presented that radiotherapy following lumpec- In patients with localized pure mucinous breast can- tomy improved BCSS in pure mucious breast cancer cer receiving lumpectomy, our results indicated that the patients aged ≥ 65  years diagnosed with T1–2N0 [23]. management with adjuvant RT slightly improved BCSS Here, we assessed BCSS benefit of adjuvant RT follow - compared with its omission. The adjvuant radiotherapy ing lumpectomy compared with lumpectomy alone in is an appropriate therapeutic option for patients received T1-2N0M0(tumor size ≤ 3  cm) pure mucinous breast lumpectomy with localized pure mucinous breast cancer. cancer by using propensity score matching method and multivariable Cox regression analysis. Combined with Abbreviations the above, we believe that adjuvant RT is a value option RT: Radiotherapy; SEER: The surveillance, epidemiology, and end results data- for patients underwent lumpectomy with pure mucinous base; PSM: Propensity score matching; BCSS: Breast cancer-specific survival; PR: Progesterone receptor; ER: Estrogen receptor; HER-2: Human epidermal breast cancer, even in those with low-risk factors. growth factors 2; DFS: Disease-free survival; OS: Overall survival; AJCC: Ameri- In the cohort, the risk prediction stratified score bas - can joint committee on cancer; HR: Hazard ratio; 95%CI: 95% Confidence ing on clinical features and molecular biomarkers is low interval . among patients with pure mucinous breast cancer, which Author contributions might explain why absolute reductions in 15-year risk MQP contributed to study conception and design, data collection and of breast cancer death tend to be modest. Besides, we analysis, manuscript writing. WYZ wrote and edited the manuscript. SJL,WXC reviewed the manuscript.WXC acquired the funding. All authors contributed believe patterns of intrinsic tumorigenesis of pure muci- to the submitted version. MQP, WYZ and SJL have contributed equally to nous breast cancer may contribute to the result. This this work and share first authorship. All authors read and approved the final special type of breast cancer is distinct from other ER- manuscript. positive/HER2-negative form of breast cance in terms Funding of the tumorigenicity of mutated genes, suggesting that This work was supported by the Zhejiang Provincial Natural Science Founda- the genomic profiling of unusual variants of breast can - tion of Chian (grant no.Y19H160283). cer should be taken into account in developing suitable Mo et al. Radiation Oncology (2022) 17:119 Page 12 of 13 population-based study from China. Ann Surg Oncol. 2012;19(9):3019–27. Declarations https:// doi. org/ 10. 1245/ s10434- 012- 2322-6. 12. 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Effect of postoperative radiotherapy in women with localized pure mucinous breast cancer after lumpectomy: a population-based study

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Abstract

Purpose: Pure mucinous breast cancer is a rare subtype of invasive breast cancer with favorable prognosis, in which the effect of postoperative radiotherapy remains unclear. We aimed to investigate the prognostic value of postopera- tive radiotherapy in women with localized pure mucinous breast cancer after lumpectomy. Methods: We conducted a retrospective cohort study to compare the effectiveness of postoperative radiotherapy (RT ) and omitting postoperative radiotherapy (non-RT ) in patients with first primary T1-2N0M0 ( T ≤ 3 cm) pure mucinous breast cancer who underwent lumpectomy between 1998 and 2015 using the Surveillance, Epidemiology, and End Results (SEER) database. Breast cancer-specific survival (BCSS) was compared between RT and non-RT groups using Kaplan–Meier method and Cox proportional hazards regression model. Propensity score matching (PSM) was carried out to balance cohort baselines. In addition, an exploratory analysis was performed to verify the effectiveness of RT in subgroup patients. Results: Of 7832 eligible patients, 5352 (68.3%) underwent lumpectomy with postoperative RT, 2480 (31.7%) received lumpectomy without postoperative RT. The median follow-up duration was 92 months. The median age was 66 years in the RT group and 76 years in the non-RT group.The 15-year BCSS was 94.39% (95% CI, 93.08% to 95.35%) in the RT group versus 91.45%(95% CI, 88.93% to 93.42%) in the non-RT group (P < 0.001). The adjusted hazard ratio for BCSS was 0.64 (95% CI, 0.49 to 0.83; P = 0.001) for RT group versus non-RT group. After propensity score match- ing, similar results were yielded. Adjuvant RT reduced the 15-year risk of breast cancer death from 7.92% to 6.15% (P = 0.039). The adjusted hazard ratio for BCSS were 0.66 (95%CI, 0.47 to 0.92; P = 0.014) for RT group versus non-RT group. The benefit of RT was well consistent across subgroup patients. Conclusion: Among women with T1-2N0M0 (tumor size ≤ 3 cm) pure mucinous breast cancer, the addition of RT after lumpectomy was significantly associated with a reduced incidence of breast cancer death compared with non- RT, and the magnitude of benefit may be modest. This suggests that postoperative RT is recommended in the treat - ment of localized pure mucinous breast cancer. Qiuping Mo, Yongzhen Wang and JinLan Shan have contributed equally to this work and share first authorship. *Correspondence: wangxiaochen@zju.edu.cn Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mo et al. Radiation Oncology (2022) 17:119 Page 2 of 13 Keywords: Breast neoplasm, Radiotherapy, Adjuvant, Lumpectomy, Prognosis, Mucinous Introduction was an independent protective factor for both overall Mucinous breast carcinoma accounting for approxi- survival (OS) and BCSS in patients with pure mucinous mately 1 to 6% of all breast cancer is divided into two breast cancer. However, this retrospective study was hete- pathological subtypes: pure mucinous breast cancer togeneous in nature because inclusion criteria involved in and mix mucinous breast carcinoma [1]. Pure mucinous advanced patients, and the cohort included mastectomy breast cancer exclusively consists of tumor tissue with and lumpectomy [22]. A recent SEER research presented extracellular mucin production over 90%, whereas mix that postoperative radiotherapy following lumpectomy mucinous breast cancer usually mixes infiltrating ductal improved the 10-year BCSS rates from 94.5 to 97.6% in epithelial component with mucinous areas covering from patients aged ≥ 65  years diagnosed with T1–2N0 and 50 to 90% [2]. The comparisons of biological features and hormone receptor-positive pure mucinous breast cancer. clinical prognosis have been identified previously among Yet regrettably, patients aged < 65 years were not included pure mucinous breast cancer, mix mucinous breast car- in this study. Besides, patients with tumor size larger cinoma and invasive breast cancer of no special type [1, than 3 cm were more likely to receive endocrine therapy, 3–13]. Pure mucinous breast cancer usually occurs in which may confuse results [23]. Obviously, it is necessary elderly patients, especially in postmenopausal women [8]. to adequately assess individualized roles of postoperative The tumor size of pure mucinous breast cancer ranges RT in this special subtype of breast carcinoma. Hence, we from less than 1  cm to more than 20  cm, with an aver- proceeded to a large population-based study using SEER age of 3 cm [14]. On account of fewer genetic mutations, to investigate the effect of postoperative RT on BCSS in pure mucinous breast cancer has a stabilized luminal A women undergoing lumpectomy with T1-2N0M0 (tumor phenotype with higher expression of hormone receptor size ≤ 3 cm) stage pure mucinous breast cancer. and a lower rate of positive human epidermal growth fac- tors 2 (HER-2) [5, 15, 16]. A mechanical barrier made of Methods abundant pools of extracellular mucus around cellular Patients population island restricts carcinoma cell invasion, leading to less This retrospective study was performed utilizing SEER axillary lymph node or distant metastases. Axillary node database (November 2018 submission) which released involvement, although rare, appears to be the worst prog- cancer data from 18 registries of national cancer insti- nostic factor followed by tumor size, age, progesterone tute and covered approximately 28% of the US population receptor(PR), HER-2 status and nuclear grade [3, 17–20]. [24]. A case-listing session was derived from SEER*Stat It has reported that the 5-year, 10-year disease-free sur- version 8.3.5. vival (DFS) were up to 94% [1], 92% [9] for patients with We selected all female cases of histological diag- node-negative pure mucinous breast cancer, respectively. nosed first primary pure mucinous breast cancer with Hence, pure mucinous breast cancer presents distinct the International Classification of Diseases for Oncol - clinicopathological characteristics with especially favora- ogy, 3rd Revision (ICD-O-3) code 8480/3 from January ble prognosis. 1998 through December 2015. Patients with T1-2N0M0 At present, the recommendations of locoregional treat- (tumor size less than 3  cm) stage were eligible. And ment for patients with operable pure mucinous breast patients were required to receive lumpectomy with or cancer from the latest National Comprehensive Cancer without postoperative RT. The exclusion criteria were Network are the same as that for patients with typical listed as follows: diagnosed from death certificate or breast cancer [21]. However, it is difficult to evaluate the autopsy only; no active or complete follow-up data; died effect of local regional treatment on survival outcome in at the start of the follow-up; unknown T, N, M stage; with prospective cohort studies or randomized trials owing to nodal positive disease or metastases disease at diagnosis; the relatively low incidence rate and a limited follow-up without operation or unknown surgery; without RT or prognosis of pure mucinous breast cancer. Guidelines on unknown RT; non-postoperative radiotherapy; bilateral radiotherapy of pure mucinous breast cancer are extrap- cancer or unknown laterality; unknown tumor size. The olated from evidence based on other common invasive flowchart for patient selection was shown in Fig. 1. breast cancer. Although scholars have done some retro- spective studies, the effect of postoperative radiotherapy Study covariates in patiens with pure mucinous breast cancer is uncertain According to administrations of lumpectomy and post- so far. Previous study showed that adjuvant radiotherapy operative RT, a total of 7832 eligible patients under the M o et al. Radiation Oncology (2022) 17:119 Page 3 of 13 Fig. 1 Patient selection diagram inclusion criteria were stratified into RT group and non- extracted. Among them, the T stage was adjusted by the RT group. We subsequently reviewed variable informa- 6th American Joint Committee on Cancer (AJCC) TNM tion of each case on patient baseline demographics, such Staging System. Tumor grade was categorized into four as age at diagnoses, year of diagnoses, race, marital status levels on the biasis of the degree of differentiation: grade at diagnoses. Then, tumor clinicopathological character - I, well differentiated; grade II, moderately differentiated; istics, including tumor laterality, tumor grade, T stage, grade III, poorly differentiated; grade IV, undifferentiated tumor size, estrogen receptor (ER) and PR status, were or anaplastic. Borderline ER/PR status defined as having Mo et al. Radiation Oncology (2022) 17:119 Page 4 of 13 Table 1 Demographic and tumor characteristics among all Table 1 (continued) patients with pure mucinous breast cancer RT radiotherapy, SD standard deviation, IQR interquartile range; DSW, divorced, separated and widowed RT Non-RT P* *Categoric variables were analyzed by the Pearson x test, and continuous variables (age, tumor size) were analyzed by the t tests or Mann–Whitney tests Characteristics No % No % Including Asian or Pacific Islander, American Indian, Alaska Native and unknown race Patients 5352 68.3 2480 31.7 Including unmarried or domestic partner, single (never married) Age of diagnosis, years Including divorced, separated and widowed Mean (SD) 64.4 (12.5) 72.8 (13.3) < 0.001 Median (IQR) 66.0 (56.0–74.0) 76.0 (65.0–83.0) < 0.001 < 50 749 14.1 194 7.8 < 0.001 1–10% positivity by immunohistochemistry were merged 50–59 1008 18.8 232 9.4 into positive ER/PR status [25, 26]. In this study, we did 60–69 1495 27.9 386 15.6 not evaluate HER-2 status because of lacking data before ≥ 70 2100 39.2 1668 67.2 Era of diagnosis 1998–2004 2027 37.9 845 34.1 0.002 Statistical analysis 2005–2009 1515 28.3 772 31.1 Categoric variables were compared across treatment 2010–2015 1810 33.8 863 34.8 groups using the Pearson chi-squared test, and continu- Race ous variables were analyzed by two independent sample White 4292 80.2 2079 83.8 < .001 t-tests or Wilcoxon rank sum test. The primary endpoint Black 453 8.5 225 9.1 of this study was BCSS. BCSS was defined as an interval Other 607 11.3 176 7.1 from the data of pure mucinous breast cancer diagnosis Marital status to death as a result of breast cancer. Using Kaplan–Meier Married 2892 54.0 984 39.7 < 0.001 survival analysis, BCSS were estimated with log-rank Non-married 680 12.7 258 10.4 tests in unmatched groups and matched groups. Haz- DSW 1680 30 1106 44.6 ard Ratio (HR) and 95% confidence interval (95%CI) Unknown 172 3.2 132 5.3 were calculated by Cox proportional hazards model to Laterality estimate the effect of RT. The multivariable Cox pro - Left 2782 52.0 1317 53.1 0.354 portional hazards regression analysis incorporated vari- Right 2570 48.0 1163 46.9 ables that were significant or approximately significant in Tumor size ( T stage), cm univariate analyses. The proportional-hazards assump - Mean (SD) 1.4 (0.7) 1.4 (0.7) 0.092 tion was checked based on Schoenfeld residuals after fit - Median (IQR) 1.3 (0.9–1.8) 1.3 (0.9–1.8) 0.139 ting a Cox model. And all of the Cox models obeyed the ≤ 1.0 ( T1) 2034 38.0 909 36.7 0.488 proportional risk hypothesis. PSM was used to control 1.1–2.0 ( T1) 2456 45.9 1170 47.2 confounding bias in the retrospective study. Propensity 2.1–3.0 ( T2) 862 16.1 401 16.1 scores of being receipt of RT were calculated by using a Tumor grade multivariable logistic regression model. The independ - I 2977 55.6 1366 55.1 0.002 ent variables are being those that were statistically sig- II 1478 27.6 627 25.3 nificant for correlation with treatment modality. Patients III 135 2.5 52 2.1 treated with RT were matched 1:1 to patients managed IV 8 0.2 4 0.2 without RT on propensity scores by using nearest neigh- unknown 754 14.1 431 17.4 bor matching algorithm. The threshold value of Caliper ER status matching was set to 0.2. A standardized difference of Positive 5002 93.5 2176 87.7 < 0.001 less than 0.1 was considered an indifferent imbalance Negative 88 1.6 30 1.2 between comparison groups. Further, exploratory analy- Unknown 262 4.9 274 11.0 sis and tests of interaction were undertaken to evaluate PR status the effect of adjuvant RT among subgroups according to Positive 4503 84.1 1953 78.8 < 0.001 patient and tumor characteristics. Negative 510 9.5 206 8.3 Statistical analyses were performed with SPSS, version Unknown 339 6.4 321 12.9 24.0 (SPSS Inc., Chicago, IL, USA) and STATA, version Chemotherapy 15 (Stata Corp., College Station, TX, USA). Two-tailed No/Unknown 4854 90.7 2371 95.6 < 0.001 P < 0.05 was considered statistically significant. Yes 498 9.3 109 4.4 M o et al. Radiation Oncology (2022) 17:119 Page 5 of 13 Fig. 2 Utilization of postoperative radiotherapy versus omission over time in patients with T1-2N0M0(tumor size ≤ 3 cm) pure mucinous breast cancer from SEER Database, 1998–2015 of covariates was well balanced between propensity- Results matched groups (Table 2). Patient demographics and tumor characteristics Comparisons of patient demographics and tumor char- Survival analyses of BCSS acteristics between RT and non-RT group were sum- Overall, the median follow-up time was 92 months (inter- marized in Table  1. A total of 7832 eligible patients quartile range, 48 to142 months), and 239 breast cancer- with pure mucinous breast cancer were identified in special deaths were observed. The Kaplan–Meier survival the cohort (mean [SD] age, 67.1 [13.3] years), of whom estimate showed that 5-year, 10-year, 15-year BCSS rates 5352 (68.3%) received lumpectomy and postoperative were 99.01% (95% CI, 98.68% to 99.26%), 96.95% (95% CI, RT, 2480(31.7%) were treated with lumpectomy without 96.29% to 97.49%), 94.39% (95% CI, 93.08% to 95.35%) for RT. Among patients underwent lumpectomy, those who patients treated with RT respectively, whereas the cor- received RT were on average 9 years younger than those responding were 97.38% (95% CI, 96.57–98.01%), 94.50% who did not (P < 0.001). The median age (interquartile (95% CI, 93.08–95.64%), 91.45%(95% CI, 88.93–93.42%) range) was 66  years (56–74) in RT group and 76  years for non-RT respectively. The difference between RT and (65–83) in non-RT group. The main pathological fea - non-RT curve was statistically significant (log-rank test, ture of patients was hormone receptor positive (91.9%) P < 0.001; Fig.  3A). The univariate Cox proportional haz - and well differentiated (55.5%). The minority of patients ards regression model showed the HR of BCSS for RT received chemotherapy(7.8%). There was no signifi - versus non-RT was 0.51 (95% CI, 0.39–0.66; P < 0.001). cant difference between treatment groups in tumor size For the purpose of controlling the potential confound- (P = 0.433). There was little change in the utilization of ing factors in adjuvant RT effectiveness, the multivariable postoperative RT through the period between 1998 and Cox proportional hazards regression analysis was further 2015(Fig. 2). In order to eliminate the imbalance between applied. After the prognostic analysis was adjusted for groups that may affect results, PSM was subsequently the following clinicopathological parameters: tumor size, conducted. After PSM between the RT group and non- tumor grade, PR status, age at diagnosis, race and married RT group, 2149 pairs were generated. The distribution status, we observed postoperative RT was independently Mo et al. Radiation Oncology (2022) 17:119 Page 6 of 13 Table 2 Demographic and tumor characteristics among propensity-matched population with pure mucinous breast cancer RT Non-RT Standardized difference Characteristics No % No % Patients 2149 50.0 2149 50.0 Age of diagnosis, years Mean (SD) 70 (11.9) 71 (12.9) 0.081 < 50 163 7.6 194 9.0 0.050 50–59 233 10.8 232 10.8 0.000 60–69 463 21.5 380 17.7 0.096 ≥ 70 1290 60.0 1343 62.5 0.051 Era of diagnosis 1998–2004 792 36.9 731 34.0 0.061 2005–2009 585 27.2 673 31.3 0.090 2010–2015 772 35.9 745 35.3 0.011 Race White 1769 82.3 1782 82.9 0.015 Black 186 8.7 202 9.4 0.026 Other 194 9.0 165 7.7 0.047 Marital status Married 932 43.3 956 44.5 0.022 Non-married 215 10.0 227 10.6 0.020 DSW 902 42.0 880 40.9 0.022 Unknown 100 4.7 86 4.0 0.033 Laterality Left 1124 52.3 1139 53.0 0.014 Right 1025 47.7 1010 47.0 0.014 Tumor size ( T stage), cm Mean (SD) 1.4 (0.7) 1.4 (0.7) 0.000 ≤ 1.0 ( T1) 817 38.0 822 38.3 0.006 1.1–2.0 ( T1) 985 45.8 1009 47.0 0.024 2.1–3.0 ( T2) 347 16.1 318 14.8 0.036 Tumor grade I 1164 54.2 1212 56.4 0.044 II 566 26.3 558 26.0 0.007 III 45 2.1 46 2.1 0.000 IV 4 0.2 4 0.2 0.000 unknown 370 17.2 329 15.3 0.052 ER status Positive 1912 89.0 1952 90.8 0.060 Negative 34 1.6 30 1.4 0.012 Unknown 203 9.4 167 7.8 0.058 PR status Positive 1732 80.6 1754 81.6 0.027 Negative 182 8.5 186 8.7 0.005 Unknown 235 10.9 209 9.7 0.039 Chemotherapy No/Unknown 2019 94.0 2040 94.9 0.039 Yes 130 6.0 109 5.1 0.039 RT radiotherapy, SD standard deviation, DSW divorced, separated and widowed M o et al. Radiation Oncology (2022) 17:119 Page 7 of 13 Fig. 3 Kaplan–Meier curves comparing BCSS between treatment groups for (A) all patients; (B) propensity-matched patients associated with better BCSS benefit (adjusted HR, 0.64; during 2010–2015. However, as we can see from the 95%CI, 0.49–0.83; P = 0.001). Moreover, the results also Fig.  4, there were no statistically significance in global indicated that tumor size, age ≥ 70  years, negative PR test for interaction (P > 0.05). expression and DSW (divorced, separated, widowed) marital status were risk predictors which independently Discussion associated with BCSS(Table 3). Among women with early-stage breast cancer receiving In the propensity-matched cohort, the survival analy- lumpectomy, the addition of RT is a standardized treat- sis of BCSS also showed a significant difference between ment based not only on its benefit in reducing ipsilateral the two groups (log-rank test, P = 0.039; Fig.  3B). The breast cancer recurrence, but also on its ability to signifi - BCSS rate for RT group was marginally better than non- cantly improve BCSS [27, 28]. In this large population- RT group. The 5-year BCSS was 98.85% (95%CI, 98.24– based study, by using matched approach among patients 99.25%)in RT group and 94.93% (95%CI, 93.46–96.08%) who received lumpectomy with T1-2N0M0 (T ≤ 3  cm) in non-RT group. The 10-year BCSS was 95.96% (95%CI, pure mucinous breast cancer, our result clearly indi- 94.66–96.95%) in RT group and 94.93% (95%CI, 0.93.46– cated that adjuvant irradiation following lumpectomy 96.08%) in non-RT group.The 15-year BCSS rate was was significantly associated with BCSS benefit. The 93.82% (95%CI, 91.75–95.38%) in RT group and 92.02% cumulative 15-year BCSS rate was 94.39% for women (95%CI, 89.39–94.03%) in non-RT group. The univariate with pure mucinous breast cancer received adjuvant analyses also confirmed that the RT group indicated a RT after lumpectomy, and 91.45% for patients treated significantly favorable prognosis (HR, 0.71; 95%CI, 0.51– with lumpectomy alone (HR = 0.51; 95% CI, 0.39–0.66; 0.98; P = 0.041; Table  4). After adjusted age, race, mari- P < 0.001; Table  3). After adjustment for potential con tal status and tumor size, the result of multivariable Cox founding factors, it was translated that the relative reduc- analysis did not change substantially (adjusted HR, 0.66; tion of breast cancer-special death was 34%, and the 95%CI, 0.47–0.92; P = 0.014; Table 4). absolute risk reduction at 15 years was 1.8%. In addition, The salutary effect of adjuvant RT on BCSS was further heterogeneity tests of the interaction term were not sig- assessed in different subgroups among the matched pop - nificant among the matched population, suggesting that ulation who underwent lumpectomy, and the HR inter- the protective prognostic value of adjuvant RT were con- actions were tested (Fig. 4). The benefit of RT seemed to sistent among different populations. be significant in some patients. The HR was 0.64 (95%CI, Our research has several potential strengths. To our 0.43–0.95) for patients aged 70  years and older, 0.44 best knowledge, this is a large cohort used to evaluate the (95%CI, 0.24–0.81) for married women, 0.44 (95%CI, effect on postoperative RT following lumpectomy among 0.27–0.71) for patients with 1.1–2.0  cm tumor size, 0.63 patients with early-stage pure mucinous breast cancer. (95%CI, 0.44–0.91) for patients with positive ER disease, Our study only aims to patient with tumor size less than 0.60 (95%CI, 0.40–0.90) for patients with positive PR 3  cm, which minimizes the impact of endocrine therapy tumor, 0.31 (95%CI, 0.10–0.96) for patients diagnosed on results. Propensity score matching was generated to Mo et al. Radiation Oncology (2022) 17:119 Page 8 of 13 Table 3 Univariate and multivariate prognostic analyses of BCSS in all patients Characteristics Univariate Multivariate HR 95%CI P aHR 95%CI P Treatment groups Non-RT 1.00 1.00 RT 0.51 0.39–0.66 < 0.001 0.64 0.49–0.83 0.001 Age of diagnosis, years < 50 1.00 1.00 50–59 1.08 0.58–2.03 0.803 1.11 0.59–2.10 0.746 60–69 1.46 0.83–2.57 0.192 1.51 0.84–2.68 0.166 ≥ 70 3.51 2.12–5.80 < 0.001 3.05 1.80–5.17 < 0.001 Era of diagnosis 1998–2004 1.00 2005–2009 1.04 0.77–1.41 0.789 2010–2015 0.88 0.55–1.41 0.606 Race White 1.00 1.00 Black 1.49 1.00–2.22 0.047 1.44 0.96–2.15 0.076 Other 0.52 0.30–0.91 0.022 0.70 0.39–1.20 0.213 Marital status Married 1.00 1.00 Non-married 0.92 0.56–1.51 0.736 0.98 0.59–1.61 0.931 DSW 2.25 1.71–2.96 < .001 1.56 1.17–2.08 0.002 Unknown 1.90 1.02–3.55 0.045 1.36 0.72–2.56 0.339 Laterality Left 1.00 Right 0.95 0.74–1.23 0.690 Tumor size ( T stage), cm ≤ 1.0 ( T1) 1.00 1.00 1.1–2.0 ( T1) 1.85 1.35–2.53 < 0.001 1.92 1.40–2.63 < .001 2.1–3.0 ( T2) 2.95 2.05–4.24 < 0.001 3.02 2.09–4.36 < .001 Tumor grade I 1.00 1.00 II 1.35 1.00–1.82 0.049 1.31 0.97–1.77 0.079 III/IV 1.95 1.05–3.63 0.034 1.91 1.02–3.59 0.043 unknown 1.19 0.85–1.68 0.305 1.16 0.83–1.64 0.390 ER status Positive 1.00 Negative 1.65 0.78–3.53 0.120 Unknown 1.24 0.83–1.85 0.300 PR status Positive 1.00 1.00 Negative 1.56 1.08–2.26 0.020 1.47 1.01–2.13 0.045 Unknown 1.37 0.95–1.98 0.100 1.19 0.82–1.72 0.368 Chemotherapy No/Unknown 1.00 Yes 0.75 0.46–1.21 0.460 HR hazard ration, aHR adjust hazard raion, CI confidence interval M o et al. Radiation Oncology (2022) 17:119 Page 9 of 13 Fig. 4 Forest plot depicting hazard ratios of adjuvant radiotherapy following lumpectomy versus lumpectomy alone for early-stage pure mucinous breast cancer in the propensity-matched population Mo et al. Radiation Oncology (2022) 17:119 Page 10 of 13 Table 4 Univariate and multivariate prognostic analyses of BCSS after PSM Characteristics Univariate Multivariate HR 95%CI P aHR 95%CI P Treatment groups Non-RT 1.00 1.00 RT 0.71 0.51–0.98 0.039 0.66 0.47–0.92 0.014 Age of diagnosis, years < 50 1.00 1.00 50–59 0.81 0.30–2.17 0.678 0.91 0.34–2.45 0.919 60–69 1.52 0.68–3.39 0.311 1.71 0.75–3.88 0.152 ≥ 70 2.73 1.32–5.62 0.006 2.83 1.32–6.05 0.002 Era of diagnosis 1998–2004 1.00 2005–2009 1.02 0.70–1.50 0.902 2010–2015 0.87 0.48–1.57 0.649 Race White 1.00 1.00 Black 1.60 0.99–2.61 0.055 1.67 1.02–2.74 0.042 Other 0.55 0.26–1.19 0.130 0.68 0.31–1.47 0.325 Marital status Married 1.00 1.00 Non-married 1.18 0.62–2.22 0.614 1.18 0.62–2.25 0.620 DSW 2.14 1.48–3.08 < .001 1.60 1.10–2.35 0.015 Unknown 1.99 0.94–4.22 0.072 1.66 0.78- 3.52 0.189 Laterality Left 1.00 Right 1.03 0.74–1.42 0.879 Tumor size ( T stage), cm ≤ 1.0 ( T1) 1.00 1.00 1.1–2.0 ( T1) 2.09 1.38–3.18 0.001 2.19 1.44–3.33 < .001 2.1–3.0 ( T2) 3.46 2.15–5.59 < .001 3.58 2.21–5.79 < .001 Tumor grade I 1.00 II 1.12 0.76–1.67 0.550 III/IV 1.80 0.78–4.13 0.168 unknown 0.87 0.57–1.38 0.594 ER status Positive 1.00 Negative 1.84 0.68–5.00 0.228 Unknown 1.19 0.71–1.82 0.598 PR status Positive 1.00 Negative 1.22 0.72–2.07 0.452 Unknown 1.19 0.77–1.85 0.421 Chemotherapy No/Unknown 1.00 Yes 0.56 0.25–1.27 0.169 HR hazard ration, aHR adjust hazard raion, CI confidence interval M o et al. Radiation Oncology (2022) 17:119 Page 11 of 13 reduce the confounding factors, leading to the baseline personalized management for patients [5]. The PIK3CA was comparable between treatment groups. In addition, mutation rate is 30–40% in ER-positive invasive ductal the heterogeneity of RT effect was tested in subgroup carcinoma and 7% in pure mucious breast cancer. The interaction, which further verified the benefit of BCSS p53 mutation rate is 20% in ER positive invasive ductal was attributable to radiotherapy rather than a baseline carcinoma, but only within 5% in pure mucinous breast imbalance in clinicopathologic features. cancer. The probability of 1q gains and 16q losses is Only a few studies have assessed the role of postopera- 10% in pure mucinous breast caner, which is 50% lower tive RT in this special type of breast cancer. Histological than that of ER-positive invasive ductal carcinoma [16]. types of breast cancer, as prognostic risk factors, have In addition, pure mucious breast cancer had a relatively rarely been evaluated in randomized trials related to lower percentage of high 21-gene recurrence score radiation therapy [29]. Single-center experiences did not patients than the infiltrating ductal carcinoma [32]]. In demonstrate that adjuvant RT improve recurrence free the future, for those with specific types of breast cancer, it survival among patient with pure mucinous breast can- is required to further study the prediction of clinical ben- cer [11]. In several Single-center retrospective studies, efit from radiation therapy, and the identification of low- they were also failed to show that receiving adjuvant RT risk patients in whom radiation can be safely omitted. could improve the OS or DFS in pure mucinous breast Nevertheless, we must acknowledge several limitations cancer [1, 3, 6, 11, 19, 30, 31]. These negative results may of this study. There are inherent biases in retrospective be related to small sample sizes and limited follow-up study inevitably. The SEER database at present cannot periods in retrospective studies.A previous SEER analy- provide the code on surgical margins, lymphovascular sis including 11,422 patients with pure mucinous breast invasion, Ki-67 and hormone therapy. Data are missing cancer between 1973 and 2002, with a mean follow-up in some cases for fundamental variables such as tumor period of 84  months, showed that the addition of radio- size, grade, TNM stage, hormone receptor status. For- therapy was not significantly asscosiated with prognosis tunately, missing data in TNM stage and tumor size less using multivariable Cox regression analysis [3]. On the than 5% of the total data. The radiotherapy treatment was contrast, another SEER database study, including 8048 not assigned at random. Although the propensity score I-IV stage pure mucinous breast cancer from 2004 to matching method is efficient for reducing the confound - 2014, found that radiotherapy was an independent fac- ing bias, a significant proportion of samples are censored tor for both OS and BCSS [22]. The opposing results may in the paired matching process. be related to the rapid development of radiotherapy and breast conserving surgery in the 1990s. A recent SEER Conclusion research presented that radiotherapy following lumpec- In patients with localized pure mucinous breast can- tomy improved BCSS in pure mucious breast cancer cer receiving lumpectomy, our results indicated that the patients aged ≥ 65  years diagnosed with T1–2N0 [23]. management with adjuvant RT slightly improved BCSS Here, we assessed BCSS benefit of adjuvant RT follow - compared with its omission. The adjvuant radiotherapy ing lumpectomy compared with lumpectomy alone in is an appropriate therapeutic option for patients received T1-2N0M0(tumor size ≤ 3  cm) pure mucinous breast lumpectomy with localized pure mucinous breast cancer. cancer by using propensity score matching method and multivariable Cox regression analysis. Combined with Abbreviations the above, we believe that adjuvant RT is a value option RT: Radiotherapy; SEER: The surveillance, epidemiology, and end results data- for patients underwent lumpectomy with pure mucinous base; PSM: Propensity score matching; BCSS: Breast cancer-specific survival; PR: Progesterone receptor; ER: Estrogen receptor; HER-2: Human epidermal breast cancer, even in those with low-risk factors. growth factors 2; DFS: Disease-free survival; OS: Overall survival; AJCC: Ameri- In the cohort, the risk prediction stratified score bas - can joint committee on cancer; HR: Hazard ratio; 95%CI: 95% Confidence ing on clinical features and molecular biomarkers is low interval . among patients with pure mucinous breast cancer, which Author contributions might explain why absolute reductions in 15-year risk MQP contributed to study conception and design, data collection and of breast cancer death tend to be modest. Besides, we analysis, manuscript writing. WYZ wrote and edited the manuscript. SJL,WXC reviewed the manuscript.WXC acquired the funding. All authors contributed believe patterns of intrinsic tumorigenesis of pure muci- to the submitted version. MQP, WYZ and SJL have contributed equally to nous breast cancer may contribute to the result. This this work and share first authorship. All authors read and approved the final special type of breast cancer is distinct from other ER- manuscript. positive/HER2-negative form of breast cance in terms Funding of the tumorigenicity of mutated genes, suggesting that This work was supported by the Zhejiang Provincial Natural Science Founda- the genomic profiling of unusual variants of breast can - tion of Chian (grant no.Y19H160283). cer should be taken into account in developing suitable Mo et al. Radiation Oncology (2022) 17:119 Page 12 of 13 population-based study from China. Ann Surg Oncol. 2012;19(9):3019–27. Declarations https:// doi. org/ 10. 1245/ s10434- 012- 2322-6. 12. 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Journal

Radiation OncologySpringer Journals

Published: Jul 7, 2022

Keywords: Breast neoplasm; Radiotherapy; Adjuvant; Lumpectomy; Prognosis; Mucinous

References