Secretory Carcinoma Of Breast Research Articles

Pure secretory carcinoma in situ: a case report and literature review

BackgroundSecretory breast carcinoma is an exceptionally rare type of breast carcinoma. Only 5 cases of pure secretory carcinoma in situ have been reported in English literature. Herein, we reported a rare case of pure secretory breast carcinoma in situ.Case presentationThe patient is a 38-year-old female with bloody discharge from the left nipple. Microscopically, the terminal-duct lobular units were enlarged and filled with tumor cells. The tumor cells were arranged in cystic, microcystic, solid and papillary pattern and formed a honeycomb-like appearance. The presence of intracellular and extracellular eosinphilic PAS-positive material was the most remarkable feature. Immunohistochemically, myoepithelial markers highlighted the complete presence of myoepithelial cells around the tumour nests. Tumour cells were strongly positive for S-100 and CK5/6, negative for ER, PR and HER2. Fluorescence in situ hybridization analysis showed ETV6-NTRK3 fusion.ConclusionSecretory carcinoma in situ shares the same morphological, immunohistochemical and molecular features with invasive secretory carcinoma except that the papillary growth pattern is more common in the introductal components. Cautions should be taken to distinguish secretory carcinoma in situ from other introductal lesions. Our report is an important supplement to the morphology spectrum of secretory breast carcinoma.

Pan-Trk immunohistochemistry reliably identifies ETV6-NTRK3 fusion in secretory carcinoma of the salivary gland.

Secretory carcinoma of the salivary gland is a newly recognized entity that morphologically resembles breast secretory carcinoma and has a characteristic t(12;15)(p13;q25) ETV6-NTRK3 translocation. Fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) analyses can detect the ETV6-NTRK3 fusion; however, both tests are expensive and not widely available. In this study, we aimed to determine whether pan-Trk immunohistochemistry (IHC) could detect ETV6-NTRK3 fusions as reliably as RT-PCR and FISH. We performed pan-Trk IHC in 70 salivary gland cancer samples, including secretory carcinomas, acinic cell carcinomas, and hybrid carcinomas. Nineteen tumors exhibited positive pan-Trk staining, including 16 secretory carcinomas, 2 hybrid carcinomas with a secretory carcinoma component, and 1 acinic cell carcinoma. Pan-Trk IHC staining was localized in the nucleus in 16 (84.2%) cases and in the cytoplasm and/or membrane in 3 (15.8%) cases. RT-PCR analysis for the ETV6-NTRK3 transcript was conducted in 45 samples; the fusion transcript was present in 11 of 12 secretory carcinomas and absent in 32 acinic cell carcinomas and 1 mucoepidermoid carcinoma. Pan-Trk IHC was positive in 10 of 11 salivary tumors that were positive for ETV6-NTRK3 by RT-PCR and negative in all 34 tumors that were negative for the fusion by RT-PCR. Therefore, in comparison with RT-PCR, pan-Trk IHC had a sensitivity of 90.9% and specificity of 100%. In conclusion, our data showed that pan-Trk IHC is a reasonable screening test for diagnosing secretory carcinoma of the salivary gland.

Abstract 1926: Ba/F3 NTRK cell panel, a powerful cell model for NTRK inhibitor discovery and development

Abstract NTRK (Neurotrophic tyrosine kinase receptor)family, also named as TRK (Tropomyosin receptor kinase),is composedof three transmembrane protein receptors, TrkA, TrkB and TrkC,which play important rolesin neuronal differentiation and survival. Over-activation of NTRK1, NTRK2 and NTRK3 due to chromosomal rearrangement and mutations, was found in congenital fibrosarcoma, secretory breast carcinoma cancer and other types ofcancer. The identification of NTRK fusions as diver cancer genes has led to rapid development of anticancer therapeutic agents, including LOXO101, LOXO195 and TPX0005.Ba/F3 line is a popular system for studying both kinases and their inhibitors, because some protein kinases can render the Ba/F3 cells to be depended on the activation of the kinases instead of IL-3 supplement, while their inhibitors can antagonize the kinase-dependent growth effects. Our group used Ba/F3 cells togenerate a celllinepanel with 14 different NTRK fusion genes or mutations for NTRK inhibitor screening and development. Inaddition to use the cell lines for in vitro assays, thetransformed Ba/F3 linescan grow well in immune-deficient miceas in vivo models. LOXO101—a NTRK inhibitor—was used to test tumor growth inhibition, the results showedthat threewild-type fusion cell lineswere sensitive to LOXO101, but not other tumor models containing NTRK gatekeeper mutations. All the tumor models were sensitive to TPX0005, another NTRK inhibitor. Ourdata indicatethatthe celllinepanel of Ba/F3is apowerful cell model for new NTRK inhibitor discovery and development. Citation Format: Feng Hao, Zhaoshuai Bai, Guoqian Wang, Feng He, Changpeng Liu, Jinying Ning. Ba/F3 NTRK cell panel, a powerful cell model for NTRK inhibitor discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1926.

Non‐secretory breast carcinomas lack NTRK rearrangements and TRK protein expression

Anti-TRK targeted therapies offer opportunities to treat patients with advanced NTRK1/2/3-rearranged cancers. Beyond NTRK-rearranged secretory breast carcinomas, little is known about NTRK rearrangements and the expression of TRK proteins in non-secretory breast carcinomas. We search for TRK proteins expressions using pan-TRK immunohistochemistry and NTRK1, NTRK2 and NTRK3 rearrangements using fluorescent in situ hybridization (FISH) tests in a set of tissue microarray included breast carcinomas. Only 1/339 invasive breast carcinomas, the only example of secretory subtype, was positive using pan-TRK immunohistochemistry and harboured a NTRK-rearrangement (NTRK1 positive FISH test). According to our results, druggable NTRK rearrangements and related-TRK proteins expression are not encountered in non-secretory breast carcinomas.

Neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) genes

The neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) genes (1-3) are proto-oncogenes that when activated are encountered in a wide array of tumours. The recent advent of very specific and...

Clinicopathologic and molecular characteristics of 44 patients with pure secretory breast carcinoma.

ObjectiveSecretory breast carcinoma (SBC) is a rare type of breast malignancy, accounting for less than 0.02% of all infiltrating breast malignancies. The pure SBC, a type of SBC without another type of breast malignant neoplasm, is particularly rare. This study aimed to investigate the clinicopathologic and molecular features of pure SBC.MethodsThe main pathological parameters such as estrogen receptor (ER), progesterone receptor (PR), and human epithelial growth factor receptor 2 (C-erbB-2) were detected by immunohistochemistry (IHC), and the clinicopathologic and prognostic difference were compared with invasive ductal carcinoma (IDC). Fluorescent in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR) was performed to identify the ETV6-NTRK3 rearrangement of SBC. ResultsWe found that the positivity rates of ER, PR, C-erbB-2, p53, and S-100 were 47.7% (21/44), 52.3% (23/44), 36.4% (16/44), 27.3% (12/44), and 95.5% (42/44), respectively, which were higher than those reported in previous studies. Special periodic acid-Schiff analysis was performed in 36 patients, and the value of the Ki-67 index ranged from 1% to 50% (mean value: 10%). Interestingly, most patients with pure SBC harbored an ETV6-NTRK3 rearrangement with an 88.6% (39/44) expression rate. Compared with IDC, the tumor size of most patients with SBC was larger than 2 cm (P = 0.024). Ultrasound showed benign lesions, and the total misdiagnosis rate was higher (P = 0.020). Although the pathological classification was mostly triple-negative breast cancers (P = 0.036), there was less metastasis (P = 0.029), and the overall prognosis was better than that of the IDC group. ConclusionsAlthough axillary lymph node metastasis, local recurrence, or distant metastasis may occur, SBC is also considered an indolent neoplasm with a good prognosis. Once diagnosed, surgical treatment should be performed as soon as possible, followed by appropriate adjuvant chemotherapy, irradiation, and endocrine therapies.

Secretory breast carcinoma: A report of two cases

Secretory breast carcinoma was first described by McDivitt and Stewart in 1966, who reported seven cases of this tumoural strain in children and therefore named it “juvenile carcinoma”. However, a couple of decades later, Tavassoli and Norris reported a series of 19 cases and found that most occurred in adults, and therefore they proposed changing its name to “secretory carcinoma.” Since then, approximately 100 cases have been reported in the world literature. We present two cases treated with total mastectomy and sentinel node biopsy with excellent outcome. To our knowledge, only a few cases have been reported in Latin American patients.

Molecular characterization of cancers with NTRK gene fusions

Targeted inhibitors of neurotropic tyrosine kinases are highly effective in selected patients with gene fusions involving NTRK1, NTRK2, or NTRK3. These fusions are consistently detected in rare cancer types (e.g., secretory breast carcinoma and congenital infantile fibrosarcoma), but the occurrence of NTRK fusions in common cancers and their relationship to other therapy biomarkers are largely unexplored. Tissue samples from 11,502 patients were analyzed for 53 gene fusions and sequencing of 592 genes, along with an immunohistochemical evaluation of TrkA/B/C and PD-L1. Thirty-one cases (0.27% of the entire cohort) had NTRK fusions. The most common fusions were ETV6:NTRK3 (n = 10) and TPM3:NTRK1 (n = 6). Gliomas had the highest number of NTRK fusions (14/982, 1.4%), most commonly involving NTRK2 (n = 9). Seventeen non-glioma cases with NTRK fusions included carcinomas of the lungs, thyroid, breast, cervix, colon, nasal cavity, cancer of unknown primary and soft tissue sarcomas. Strong and uniform Trk expression detected with a pan-Trk immunohistochemistry characterized 7/8 NTRK1 fusion cases and 8/9 NTRK2 fusion cases, while NTRK3 fused cases were positive in 6/11 (55%) of cases. 29% of NTRK fusion cases had no other pathogenic genomic alteration. PD-L1 expression was observed in 23% of NTRK fused cases while high tumor DNA microsatellite instability was detected in two cases. We confirm the rarity of NTRK genes fusions outside the brain malignancies. NTRK inhibitors alone or combined with immune checkpoint inhibitors may be a therapeutic option for a substantial proportion of these patients. Strategies for detection of the NTRK fusion-driven cancers may include immunohistochemistry, but gene fusion detection remains the most reliable tool.

Secretory Breast Carcinoma: A Case Report with MRI Findings

Secretory Breast Carcinoma: A Case Report with MRI Findings

Inhibiting TRK Proteins in Clinical Cancer Therapy.

Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions.

Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6–NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4–NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6–NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4–NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4–NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4–NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.

Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis.

Chromosomal rearrangements that facilitate tumor formation and progression through activation of oncogenic tyrosine kinases are frequently observed in cancer. The ETV6-NTRK3 (EN) fusion has been implicated in various cancers, including infantile fibrosarcoma, secretory breast carcinoma, and acute myeloblastic leukemia, and has exhibited in vivo and in vitro transforming ability. In the present study, we analyzed transcriptome alterations using DNA microarray and RNA-Seq in EN-transduced NIH3T3 fibroblasts to identify the mechanisms that are involved in EN-mediated tumorigenesis. Through functional profile assessment of EN-regulated transcriptome alterations, we found that upregulated genes by EN were mainly associated with cell motion, membrane invagination, and cell proliferation, while downregulated genes were involved in cell adhesion, which correlated with the transforming potential and increased proliferation in EN-transduced cells. KEGG pathway analysis identified the JAK-STAT signaling pathway with the highest statistical significance. Moreover, Ingenuity Pathway Analysis and gene regulatory network analysis identified the STAT1 transcription factor and its target genes as top EN-regulated molecules. We further demonstrated that EN enhanced STAT1 phosphorylation but attenuated STAT1 acetylation, eventually inhibiting the interaction between the NF-κB p65 subunit and acetylated STAT1. Consequently, nuclear translocation of NF-κB p65 and subsequent NF-κB activity were increased by EN. Notably, inhibition of STAT1 phosphorylation attenuated tumorigenic ability of EN in vitro and in vivo. Taken together, here we report, for the first time, STAT1 as a significant EN-regulated transcription factor and a crucial mediator of EN-induced tumorigenesis.

Secretory carcinoma of breast: a clinicopathologic analysis of 3 cases

Secretory carcinoma of breast: a clinicopathologic analysis of 3 cases

Successful Targeted Therapy of Refractory Pediatric ETV6-NTRK3 Fusion-Positive Secretory Breast Carcinoma.

Successful Targeted Therapy of Refractory Pediatric ETV6-NTRK3 Fusion-Positive Secretory Breast Carcinoma.

Clinicopathologic and molecular characterization of mammary analogue secretory carcinoma of salivary gland origin

BackgroundMammary analogue secretory carcinoma (MASC) is a newly recognized salivary gland tumor that harbors a characteristic balanced chromosomal translocation t (12; 15) (p13; q25) resulting in an ETV6-NTRK3 fusion gene. MethodsRetrospective study of 111 salivary gland carcinomas revealed 37 cases with secretory features and growth patterns resembling secretory carcinoma of breast. These 37 cases were originally diagnosed as acinic cell carcinoma, adenocarcinoma not otherwise specified and cystadenocarcinoma. Positive immunostaining for S-100 protein and mammaglobin, followed by detection of ETV6 gene rearrangement by FISH and/or ETV6-NTRK3 fusion transcript by RT-PCR were used to identify MASCs. ResultsIn the cohort of 37 salivary carcinomas with secretory features we have identified 10 cases of MASC. All 10 MASCs were positive for mammaglobin, S-100 protein and SOX10, while staining for DOG1 and p63 protein were mostly absent. In 7/10 cases, both FISH and RT-PCR were positive while three remaining cases showed break of ETV6 gene by FISH analysis and the RT-PCR was negative. Clinical follow-up data were obtained in 6 out of 10 patients with MASC. In 3 patients cervical lymph node metastases developed, one patient with high grade transformed MASC died with multiple distant bone metastases, and local recurrence was observed in three patients. ConclusionOur clinicopathological data are in keeping with previous studies; in most cases, MASC is a low-grade malignancy with overall favorable prognosis. In rare cases, however, MASC with high-grade transformation may behave aggressively, and these patients could benefit from targeted biological treatment using tyrosine kinase inhibitors.

Abstract 536: Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis

Abstract Chromosomal rearrangements that facilitate tumor formation and progression through activation of oncogenic tyrosine kinase are frequently observed in cancer. The ETV6-NTRK3 (EN) fusion has been implicated in various cancers, including infantile fibrosarcoma, secretory breast carcinoma and acute myeloblastic leukemia, and has exhibited in vivo and in vitro transforming ability. In the present study, we analyzed transcriptome alterations using RNA-Seq in EN-transduced NIH3T3 fibroblasts to identify the mechanisms that are involved in EN-mediated tumorigenesis. Through functional profile assessment of EN-regulated transcriptome alterations, we found that EN up-regulated genes mainly associated with cell motion, membrane invagination, and cell proliferation, while down-regulated genes are involved in cell adhesion, which described the transforming potential and increased proliferation in EN-transduced cells. Notably, KEGG pathway analysis identified the JAK-STAT signaling pathway with the highest statistical significance. Moreover, Ingenuity Pathway Analysis and gene regulatory network analysis identified the Stat1 transcription factor and its target genes as top EN-regulated molecules. We further demonstrated that EN enhanced STAT1 phosphorylation but attenuated STAT1 acetylation, thereby inhibiting the interaction between NF-κB p65 and acetylated STAT1. Consequently, nuclear translocation of NF-κB p65 and subsequent anti-apoptotic NF-κB activity were increased by EN. Taken together, here we report, for the first time, STAT1 as a significantly EN-regulated transcription factor and a crucial mediator of EN-induced tumorigenesis. [This work was supported by a National Research Foundation grant of Korea (NRF-2014M3A9B5073918) funded by the Korea government.] Citation Format: Jinah Park, Junil Kim, Poul H. Sorensen, Seong-Jin Kim. Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 536. doi:10.1158/1538-7445.AM2017-536

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

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.

Carcinoma análogo secretor de mama: revisión de diagnóstico y tratamiento a propósito de 2 casos

IntroductionMammary analogue secretory carcinoma (MASC) is a neoplastic tumour of the salivary glands, characterised by having important histological and immuno-histochemical similarities with secretory breast carcinoma. Until its description in 2010, MASC was often diagnosed as carcinoma of acinar cells due to their morphological overlapping. As there is a lack of evidence in the scientific literature concerning the optimal treatment of these tumours, the aim of this article is to present 2recently treated cases, and review the described literature about their diagnosis and treatment. Material and methodsThe first case concerns a 41 year-old male with MASC of the minor salivary gland of the hard palate, and the other a 56 year-old patient with the same diagnosis at the level of the submandibular gland. ResultsSurgical resection with lesion-free margins was performed in both cases. Clinical surveillance was decided for one case with free margins, while in the other one, it was decided to give adjuvant therapy with radiotherapy due to the narrow lesion free margin. Both patients are disease free and continue on clinical follow-up. DiscussionThe literature describes the existence of a salivary glands tumour with common morphological characteristics between acinar cell carcinoma and breast carcinoma, and immunohistochemically characterised by being positive to vimentin and S-100 protein, but it was not known as MASC until its description in 2010.The genetic alteration associated with MASC is the presence of a translocation t(12;15) (q25; Q13) in ETV6-NTRK3, making it a pathognomonic tumour marker. There is consensus in the surgical treatment of primary lesions, but there is no agreement as regards neck dissection. The value of post-surgical radiotherapy is difficult to assess by the few cases in the literature. ConclusionsMASC is a recently described salivary gland tumour characterised by ETV6 translocation. Due to its behaviour as a low grade malignant neoplasm, it is recommended that its treatment should be excision with surgical margins, but in some cases its behaviour can be aggressive.

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumors of the Salivary Gland.

The salivary gland section in the 4th edition of the World Health Organization classification of head and neck tumors features the description and inclusion of several entities, the most significant of which is represented by (mammary analogue) secretory carcinoma. This entity was extracted mainly from acinic cell carcinoma based on recapitulation of breast secretory carcinoma and a shared ETV6-NTRK3 gene fusion. Also new is the subsection of "Other epithelial lesions," for which key entities include sclerosing polycystic adenosis and intercalated duct hyperplasia. Many entities have been compressed into their broader categories given clinical and morphologic similarities, or transitioned to a different grouping as was the case with low-grade cribriform cystadenocarcinoma reclassified as intraductal carcinoma (with the applied qualifier of low-grade). Specific grade has been removed from the names of the salivary gland entities such as polymorphous adenocarcinoma, providing pathologists flexibility in assigning grade and allowing for recognition of a broader spectrum within an entity. Cribriform adenocarcinoma of (minor) salivary gland origin continues to be divisive in terms of whether it should be recognized as a distinct category. This chapter also features new key concepts such as high-grade transformation. The new paradigm of translocations and gene fusions being common in salivary gland tumors is featured heavily in this chapter.

Secretory breast carcinoma with liver metastatic: report of a case

Secretory breast carcinoma with liver metastatic: report of a case