Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas

Abstract

Secretory carcinomas of the breast are rare tumors with distinct histologic features, recurrent t(12;15)(p13;q25) translocation resulting in ETV6-NTRK3 gene fusion and indolent clinical behavior. Mammary analog secretory carcinomas arising in other sites are histopathologically similar to the breast tumors and also harbor ETV6-NTRK3 fusions. Breast secretory carcinomas are often triple (estrogen and progesterone receptor, HER2) negative with a basal-like immunophenotype. However, genomic studies are lacking, and whether these tumors share genetic features with other basal and/or triple negative breast cancers is unknown. Aside from shared ETV6-NTRK3 fusions, the genetic relatedness of secretory carcinomas arising in different sites is also uncertain. We immunoprofiled and sequenced 510 cancer-related genes in nine breast secretory carcinomas and six salivary gland mammary analog secretory carcinomas. Immunoprofiles of breast and salivary gland secretory carcinomas were similar. All the tumors showed strong diffuse MUC4 expression (n=15), and SOX10 was positive in all nine breast and in five out of six salivary gland tumors. All breast secretory carcinomas were triple negative or weakly ER-positive, and all tumors at both the sites expressed CK5/6 and/or EGFR, consistent with a basal-like phenotype. Sequencing revealed classic ETV6-NTRK3 fusion genes in all cases, including in carcinoma in situ of one breast tumor. Translocations were reciprocal and balanced in six out of nine breast and three out of six salivary gland tumors and were complex in three others. In contrast to most breast basal carcinomas, the mutational burden of secretory carcinomas was very low, and no additional pathogenic aberrations were identified in genes typically mutated in breast cancer. Five (56%) breast and two (33%) salivary gland tumors had simple genomes without copy number changes; the remainder had very few changes, averaging 1.3 per tumor. The ETV6-NTRK3 derivative chromosome was duplicated in one breast and one salivary gland tumor, and was the only copy number change in the latter. The findings highlight breast secretory carcinoma as a subtype more closely related to mammary analog secretory carcinoma than to basal/triple negative breast cancers of no special type. Lack of pathogenic mutations in common cancer-related genes suggests that ETV6-NTRK3 alone may suffice to drive these tumors and likely helps explain their indolent behavior.

Secretory carcinoma of the breast: clinicopathologic profile of 14 cases emphasising distant metastatic potential

“…In their immunohistochemical and genomic review of secretory carcinoma of the breast and mammary analogue secretory carcinoma, Krings et al reported 44% of their SCB cases (four of nine tumours) demonstrated weak to moderate ER expression. 25 Within our study cohort, seven patients (50%) were found to have tumours with ER expression. These patients tended to be older, and five of the seven patients received hormonal therapy (Table 1).…”

“…[51][52][53][54] Krings et al reported massively parallel sequencing analysis of nine secretory breast carcinomas and demonstrated very low mutation burdens and very few copy number alterations in these tumours. 25 In all cases of SCB with distant metastases in the literature, no additional molecular alterations were reported.…”

“…Identification of a recurrent chromosomal rearrangement in secretory carcinoma, t(12;15)(p13;q25), resulting in a fusion between E26 transformation‐specific translocation variant 6 ( ETV6 ) and neurotrophic receptor tyrosine kinase 3 ( NTK3 ), allowed for a potentially targeted approach to management . This fusion has thus far been reported in 95.2% (40 of 42) of the cases tested in the literature …”

“…21 This fusion has thus far been reported in 95.2% (40 of 42) of the cases tested in the literature. 14,[21][22][23][24][25][26][27][28][29][30] Here, we sought to characterise the clinical, pathological and molecular features of this unusual, typically indolent subtype of breast cancer further, with a focus on particularly aggressive clinical courses through a review of cases diagnosed and managed in a single large tertiary cancer centre during a period of 25 years.…”

CRTC1–MAML2 fusion in mucoepidermoid carcinoma of the breast

“…However, these studies have generally not included triple‐negative salivary gland‐like tumours that can arise in the breast, including secretory carcinomas, acinic cell carcinomas and adenoid cystic carcinomas, as well as MEC and even more rare types . Recent studies suggest that secretory carcinomas and adenoid cystic carcinomas of the breast are genetically more similar to their respective salivary gland counterparts than they are to other triple‐negative carcinomas . In contrast, acinic cell carcinomas arising in the breast harbour frequent TP53 mutations and complex patterns of copy number alterations which are not present in salivary gland acinic cell carcinomas, suggesting that these two tumours are not related despite their histological similarity .…”