Secretory carcinoma of the breast with multiple distant metastases in the brain and unfavorable prognosis: a case report and literature review

Secretory carcinoma of the breast is one of the rarest subtypes, accounting for less than 0.15 % of all infiltrating breast carcinomas [2]. It was first described in 1966 by McDivitt and Stewart as a rare breast neoplasia identified in female children and adolescents, with an average age of nine [1]. However, it is now clear that secretory carcinoma can occur in adults of both sexes [7‐9]. The typical clinical presentation of secretory carcinoma of the breast is a slow-growing, painless, well-circumscribed, palpable mass that can occur anywhere but is more common in the outer upper quadrant of the breast [10]. Microscopically, secretory carcinoma of the breast has been shown to be arranged with a solid, microcystic and tubular structure composed of cells that produce abundant intracellular and extracellular milk-like secretory material intensively positive for alcian blue or PAS. Tumor cells have low-grade features with small to medium size, oval to round nuclei, scant mitotic activity, and abundant granular eosinophilic cytoplasm. Occasionally, a papillary pattern can be the dominant architecture. Immunohistochemically, tumor cells are positive for S100 staining and triple-negative for ER, PR and HER2 [2, 11, 12]. In addition to the breast, secretory cancer can occur in other organs that contain secretory glands, such as parotid gland, salivary gland, sweat gland, lacrimal gland and thyroid [13‐18]. Secretory carcinoma that occurs in other organs shows the same combined structures of cribriform patterns, solid patterns, microcystic patterns, and the extracellular secretion which is positive for Alcian blue or PAS.

Tognon et al. were the first to report in 2002 that secretory carcinoma of the breast harbored a recurrent balanced chromosomal translocation, t(12;15) (p13; q25), which leads to the formation of ETV6-NTRK3 fusion [12]. In addition to secretory carcinomas occurring in the breast, salivary gland [14] and thyroid [18], ETV6-NTRK3 gene fusion is also encountered in several neoplasms, including ALK-negative inflammatory myofibroblastic tumors, the cellular variant of congenital mesoblastic nephroma, congenital fibrosarcoma and radiation-induced papillary thyroid carcinoma [19, 20]. Meanwhile, some novel gene mutations of secretory carcinomas occurring in the salivary glands have been recently reported. Sasaki et al. [21] found a case with a CTNNA1-ALK fusion, and Black et al. [22] reported another case harboring two gene fusions, ETV6-RET and EGFR-SEPT14, expanding the molecular characterization of secretory carcinoma beyond the ETV6-NTRK3 gene mutation. A large-scale parallel sequencing analysis of 9 cases of secretory breast cancer, including one ductal carcinoma in situ, showed that there were no additional typical mutations in breast cancer except ETV6-NTRK3 gene mutation in all cases, while the mutation burden was very low [23].

Secretory carcinoma of the breast has generally been described as one with a favorable prognosis. However, several cases have presented distant metastases. To date, a total of 14 cases of secretory carcinoma of the breast with distant metastasis have been reported in the literatures (10 females and 4 males; 2 cases with disseminated metastases, 6 cases with multiple organ metastases), with ages ranging from 8 to 73 years (mean 36 years). The most common metastatic organs were the lung (9 cases), liver (4 cases), and bone (4 cases), with the other metastatic sites being the skin (2 cases), kidney (1 case), mediastinum (1 case), pancreas (1 case) and pleural (1 case). A total of 8 cases were reported to become fatal due to the metastatic secretory carcinoma. Mortality ranged from 6 to 240 months after initial diagnosis (mean survival time was 74.6 months) [5, 24‐33]. As summarized by Hoda et al., there were no obvious clinicopathological features of secretory carcinomas, such as the patient’s gender, tumor location, imaging findings, follow-up treatment of surgery and/or chemotherapy, axillary node status, or the expression status of ER, PR and HER2, to indicate the distant invasion ability of the tumor [24]. Tavassoli and Norris [7] suggested that three features may indicate a favorable prognosis for patients with secretory carcinoma of the breast: (1) tumor size less than 2 cm; (2) age of less than 20 years at diagnosis; and (3) circumscribed margins. Unfortunately, none of these three features were present in our case. Moreover, relatively high Ki-67 proliferation index (40 %) and nuclear grade (intermediate) of tumor cells have been suggested to be associated with the poor prognosis of this patient, in consideration of the correlations between these two indicators and the prognosis of other breast cancers [34, 35]. Sequencing analysis has revealed only ETV6-NTRK3 mutation, with no additional molecular alterations in any of the reported cases of secretory carcinoma of the breast, whether with or without distant metastasis [24, 28, 30, 31]. Detection of additional gene mutations, such as TERT promoter mutation and CDKN2A/b deletion, may be helpful as an indicator for prediction of the invasive course of secretory breast cancer.

Due to the paucity of reported cases for secretory carcinoma, no consensus guidelines for treatment are available. However, surgery is considered the mainstay of treatment for secretory carcinoma. The demonstration of late local recurrence has led many to propose mastectomy for patients with this disease [36]. In adults, a simple mastectomy, at minimum, is recommended. Modified radical mastectomy has been favored by some authors in cases with tumor sizes greater than 2 cm and poor gross circumscription [37]. Adjuvant chemotherapy and radiation have been used as treatments; however, these therapies have had little to no success [28]. As a novel treatment strategy, targeted therapy of patients with NTRK fusion-positive cancers with a TRK inhibitor, such as larotrectinib or entrectinib, has been shown to be associated with high response rates [38]. Shukla et al. reported a successful targeted therapy experience using larotrectinib to treat refractory ETV6-NTRK3 fusion-positive secretory breast carcinoma in a 14-year-old girl [39]. An excellent clinical response to pan-TRK inhibitors was also observed in two additional patients with ETV6-NTRK3 fusion-positive secretory breast carcinoma (an 8-year-old girl and a 26-year-old man) [24].

In our patient, 4 cycles of EC regimens and 2 cycles of DC regimens neoadjuvant chemotherapy were first used due to the large size of the tumor (12 cm) and late clinical stage (T4N1M0/IIIB). The tumor had a partial response to EC regimens therapy but progressed on DC regimens. To avoid losing the opportunity for surgical treatment, a modified radical mastectomy was performed immediately. A total of 4 cycles of FEC regimens and 8 cycles of intensive chemotherapy were continuously given. Radiotherapy was carried out on the chest wall and drainage areas. The patient was then switched to intensive chemotherapy with oral Capecitabine for 8 cycles. Regrettably, the patient did not receive targeted therapy with a TRK inhibitor due to no such drugs available for clinical use in China at that time. Multiple brain metastases were found 10 months later, and the overall survival of the patient was 19 months.