Clinicopathologic profiling and oncologic outcomes of secretory carcinoma of the breast

Secretory carcinoma of the breast (SCB) is a rather rare entity of invasive breast cancer, the clinicopathologic characteristics and survival outcomes remain to be elaborated. A retrospective review was conducted in SEER database. A total of 190 SCB patients identified in SEER were eligible for inclusion in the analysis. Median age at diagnosis was 56 years (range 2–96 years). Both sexes and bilateral breast could be affected. Intriguingly, the incidence of SCB tended towards to decreasing in recent decades. Small tumor burden was observed with a mean tumor size of 2.13 cm. In a subgroup with sufficient details, positive staining of estrogen receptor (ER) and progesterone receptor (PR) was 58% and 40%, respectively. The vast majority of patients were of well to moderate differentiation (86.86%) and negative regional lymph nodes involvement (70.71%). Nearly half of the patients took radiotherapy and chemotherapy. Seniors were inclined to have an inferior breast cancer specific survival (BCSS) than their younger counterparts (P = 0.018). Patients underwent breast conserving surgery (BCS) and radiotherapy had much better BCSS than its mastectomy counterparts (P = 0.014). Collectively, SCB is a clinical indolent invasive breast cancer with excellent prognosis. BCS in conjunction with radiotherapy would be a rational alternative for this distinct entity.


Results
Patient demographics. The demographic characteristics of the 190 SCB patients was summarized in Fig. 1. Median age at diagnosis was 56 years (range 2-96 years) (data not shown). Both sexes could be affected by SCB, with an approximate male to female ratio of 1:30 (data not shown). The proportion of patients diagnosed under the age of 30 years was 13.16% (Fig. 1A). Intriguingly, the number of patients was stable increasing as time went on, with a peak occurring at the beginning of twenty-first century, while declined sharply thereafter (Fig. 1B). Laterality was found to be comparable between the left and right breast, with 103 patients in left, 85 in right and 2 bilateral, respectively (data not shown). Primary tumor site was highest likely located in the upperouter quadrant (UOQ) irrespective of laterality (Fig. 1C).
Disease and treatment characteristics. In order to better understand the clinicopathologic features of SCB, a subgroup of 99 patients with sufficient and explicit information were derived and listed in Table 1. Median age at diagnosis was 57 years (range: 8-89 years). Most patients were female white ethnicity and had tumors no more than 2 cm (cm), with an average tumor size of 2.13 cm. The vast majority of patients were of negative regional lymph nodes involvement (70.71%) and well to moderate differentiation (86.86%). Positive staining of estrogen receptor (ER) and progesterone receptor (PR) was 58% and 40%, respectively. BCS was performed in 53 patients. The uptake of radiotherapy and chemotherapy was 45.45% and 41.41%, respectively. Hormone therapy was unavailable in SEER database.
Oncologic outcomes. For all patients, the median follow-up time was 97 months (range 0-436 months).
5-year BCSS was 95.79%, 10-year and 20-year BCSS both were 93.16% ( Fig. 2A). 5-year OS was 89.47%, 10-year OS was 81.58% and 20-year OS was 76.84% (Fig. 2B). Age-specific survivals were presented in (Fig. 2C,D). www.nature.com/scientificreports/ There was statistical significance in age-specific BCSS (P = 0.018) and OS (P < 0.001), and worse prognosis was indicated with growing age. For the subgroup cohort, the median follow-up time was 82 months (range 0-263 months). No statistical significance was observed with regard to BCSS (P = 0.365) and OS (P = 0.603) categorized by hormone receptor status (Fig. 3A,B). Similar baseline characteristics of patients underwent BCS and radiotherapy and mastectomy were shown in Table 2. Although OS (P = 0.185) was comparable between the two subsets, patients who underwent BCS and radiotherapy had much better BCSS than its mastectomy counterparts (P = 0.014) (Fig. 3C,D). Table 1. Clinicopathologic characteristics and type of treatment of all patients included. pT1 pathological tumor size ≤ 2 cm, pT2 2 cm < pathological tumor size ≤ 5 cm, pT3 pathological tumor size > 5 cm, pN0 negative regional lymph node, pN1, 1 to 3 regional lymph node metastasis, pN2 4 to 9 regional lymph node metastasis, Nuclear grade I well differentiation, Nuclear grade II moderate differentiation, Nuclear grade III poor differentiation, ER estrogen receptor, PR progesterone receptor, BCS breast conserving surgery.

Discussion
SCB is a rare subtype of invasive breast malignancy, previous studies have been largely limited by case reports and small case series 5 . In the present study, we examined the demographics, disease characteristics, patterns of treatment and survival outcomes for patients diagnosed with SCB in a large-sized cohort derived from SEER database. Despite initially discovered in juveniles, it was documented in a wide range of age groups and more frequently occur in adults later 14 . Till now, the two largest retrospective studies conducted by Horowitz et al. with 83 SCB patients published in 2012 15 . and Jacob et al. with 246 SCB patients published in 2016 5 had illustrated a median age at diagnosis of 53 years in SEER database and 56 years in the National Cancer Data Base. Consistent with prior studies, median age at diagnosis was 56 years in this study. Additionally, Jacob et al. 5 demonstrated a male to female ratio of 1:31, which was in agreement with that of 1:30 in our study. Nevertheless, a published experience of male to female ratio was approximately 1:6 16 , which might be a result of small simple size. Confirming the previous report, the most common location of SCB was the UOQ of the breast, resembling that of invasive ductal carcinoma 17 .
Of note, great advances have been established in our understanding of biological nature of breast cancer, while the incidence of SCB was prone to continuously declining in recent decades. This was a new finding in the present study and some possible reasons would be rational to explain this phenomenon. Typically, SCB was presented with a slow-growing, painless, well-circumscribed, mobile mass, similar to that of benign epithelial proliferating lesions 8,18,19 , which may increase the possibility of misdiagnosis. Furthermore, non-specific and sparse ultrasound and mammographic findings associated with limited diagnostic value of ETV6-NTRK3 resulted in difficulty to differentiate diagnosis of SCB 17,[20][21][22] .
There was no consistence on status of ER and PR receptor. The overwhelming majority of literature showed that SCB was negative for ER, PR, human epidermal growth factor (HER2), and positive for basal-cell markers, therefore could be classified as a peculiar subtype of TNBC 6,23,24 . Recent studies with large sample size concluded that SCB mimicked immunoprofile of hormone receptor positive cancer other than that of TNBC 5,11,25 , which was in stark contrast to the earlier reports. Our results were in support of the recent studies. In addition, other disease parameters were comparable with most previous studies, demonstrating that SCB usually presented as low grade, less likely to positive regional lymph node 26,27 .
Although axillary lymph node metastasis of SCB was described as high as approximately 15%-30% and patients with more than four lymph nodes were exclusively rare, the prognosis of SCB was excellent in published reports 8,28 . Horowitz et al. 15 29 . Currently, the primary management of SCB was surgery, because of the indolent clinical course and fairly good prognosis. The impact beyond surgery on survival outcomes was largely unknown. We demonstrated that BCS and radiotherapy was superior to mastectomy with comparable OS but better BCSS. Genomic study of SCB indicated that mutational burden and copy number variant of secretory carcinoma of the breast is very low 30 , which supported the BCS and radiotherapy might be sufficient to the treatment of this rare subtype. The current study has some limitations. One limitation of this study was that details of systematic therapy, such as hormonal therapy and targeted therapy, were unavailable. Thus, the contribution of systematic therapy on the outcomes needed to be further clarified in future study. Another limitation of this study was the subtype of patients based on immunohistochemistry was not fully available, namely the frequency of receptor status as well as distribution of subtype merited deeper investigation. Although limitations existed, our study indeed improved our understanding this rare entity of SCB patients, especially based on the well-balanced characteristics of compared subgroups.
In conclusion, our retrospective study with medium-sized sample size reinforced the indolent course and unexceptionable outcomes of SCB. Moreover, BCS and radiotherapy could be a reasonable treatment of SCB followed by adequate systematic therapy. More intensive supervision and follow-up should be emphasized to the senior SCB patients. Long-term surveillance should be emphasized and cooperative work are stringently needed to derived a precise conclusion. Future studies with large size and comprehensive details are urged to validate our results.

Methods
Study cohort. This study adopted data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 tumor registry database that was updated in November 2016. The SEER*Stat version 8.3.5 was used to case extraction. With site recode limited to breast, eligible patients were extracted based on the following inclusion criteria: pathologic diagnosis according to the International Classification of Disease for Definition of outcomes. Overall survival (OS), defined as the time from diagnosis to death from any cause. Cancer-specific survival (CSS), defined as the interval from initial diagnosis to death resulting from breast cancer.
Statistical analysis. Survival curves were established by using the method of Kaplan and Meier. The log-rank test was adopted to compare survival outcomes between different subgroups of patients. Categorical variables were compared using the Pearson's chi-square test or Fisher's exact test, as appropriate. All tests were Table 2. Clinicopathologic characteristics and chemotherapy of subgroups divided by type of surgery. pT1 pathological tumor size ≤ 2 cm, pT2 2 cm < pathological tumor size ≤ 5 cm, pT3 pathological tumor size > 5 cm, pN0 negative regional lymph node, pN1, 1 to 3 regional lymph node metastasis, pN2 4 to 9 regional lymph node metastasis, Nuclear grade I well differentiation, Nuclear grade II moderate differentiation, Nuclear grade III poor differentiation, ER estrogen receptor, PR progesterone receptor, BCS breast conserving surgery.