Neuroendocrine Breast Carcinomas Share Prognostic Factors with Gastroenteropancreatic Neuroendocrine Tumors: A Putative Prognostic Role of Menin, p27, and SSTR-2A

Roininen, Nelli; Takala, Sini; Haapasaari, Kirsi‐Maria; Jukkola-Vuorinen, Arja; Mattson, Johanna; Heikkilä, Päivi; Karihtala, Peeter

doi:10.1159/000493348

Cited by 10 publications

(7 citation statements)

References 39 publications

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“…Additional potential cellular targets in EP-NECs have been identified, such as in breast NEC (which is rare), farletuzumab and mirvetuximab soravtansine (FOLR1), sacituzumab govitecan (TROP-2) and HDAC inhibitors (H3K36Me3) (Vranic et al 2019). Another study reported that nuclear and cytoplasmic thymidylate synthase, nuclear and cytoplasmic neuron-specific enolase and nuclear p27 were significantly overexpressed in neuroendocrine breast carcinoma (P < 0.01); cytoplasmic somatostatin receptor-2A (SSTR-2A) expression was associated with better distant disease-free survival (P = 0.013), cytoplasmic menin expression with worse relapse-free survival (P = 0.022) and nuclear p27 with longer breast cancer-specific survival (P = 0.022), compared with invasive ductal carcinomas (Roininen et al 2019). Others targets of potential relevance are now detailed.…”

Section: New Therapeutic Perspectivesmentioning

confidence: 99%

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

McNamara

Scoazec

Walter

2020

Endocrine-Related Cancer

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Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.

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Section: New Therapeutic Perspectivesmentioning

confidence: 99%

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

McNamara

Scoazec

Walter

2020

Endocrine-Related Cancer

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“…Recently, Roininen et al assessed the immunohistochemical expression of well characterized prognostic factors of gastroenteropancreatic neuroendocrine tumors (GEP-NET) such as neuron specific enolase, thymidylate synthase, CD56, p27, menin, and somatostatin receptor type 2, and found a striking similarity in NEBC and GEP-NET. On the contrary, notable differences were found when compared with invasive ductal carcinomas [31].…”

Section: Prognostic Factors and Prognosismentioning

confidence: 82%

Neuroendocrine Cancer of the Breast: A Rare Entity

Irelli

Sirufo

Morelli

et al. 2020

JCM

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Neuroendocrine breast cancer (NEBC) is a rare histotype of breast carcinoma that presents, in most cases, positive hormone receptors and negative HER2. Indeed, the analysis of gene expression profiles revealed that NEBC belongs mainly to the luminal subtype. Cases of HER2-positive and triple-negative NEBC are rare. The cardinal treatment of early NEBC is surgery, similar to the treatment of invasive non-special histological type carcinoma. The use of radiotherapy follows the criteria applied in infiltrating breast cancer of non-special histotype. In the post-operative phase, therefore after the surgical treatment of mammary quadrantectomy, or mastectomy associated with homolateral sentinel lymph node removal ± axillary dissection, based on the histopathological characteristics of the tumor, the use of chemotherapy (anthracycline + taxane) and/or hormone therapy, whether or not associated with anti-HER2 therapy (trastuzumab) is the rule. Literature data report the use of cisplatin and etoposide, as in small cell lung cancers. Most of the information currently available derive from single case reports or a series of clinical cases; it follows the difficulty of formulating definite recommendations on the correct management of this histological type of breast cancer. This review describes available knowledge on this rare entity to improve the diagnostic and therapeutic strategies and offer insights to stimulate exploration of the many aspects still unknown.

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“…Interestingly, in our recent study, low MEN1 protein expression was associated with poor local relapse-free survival in breast NETs [ 4 ]. Whether the low MEN1 expression was actually due to the pathogenetic or unknown variant was not, however, addressed [ 53 ]. Pathogenetic or unknown variants in chromatin remodelling genes DAXX and ATRX are also characteristic of PNETs, and they are also frequent in other NENs [ 13 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the mutational profiles of neuroendocrine breast tumours, invasive ductal carcinomas and pancreatic neuroendocrine carcinomas

et al. 2022

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The pathophysiology and the optimal treatment of breast neuroendocrine tumours (NETs) are unknown. We compared the mutational profiles of breast NETs (n = 53) with those of 724 publicly available invasive ductal carcinoma (IDC) and 98 pancreatic NET (PNET) cases. The only significantly different pathogenetic or unknown variant rate between breast NETs and IDCs was detected in the TP53 (11.3% in breast NETs and 41% in IDCs, adjusted p value 0.027) and ADCK2 (9.4% in breast NETs vs. 0.28% in IDCs, adjusted p value 0.045) genes. Between breast NETs and PNETs, different pathogenetic or unknown variant frequencies were detected in 30 genes. For example, MEN1 was mutated in only 6% of breast NETs and 37% in PNETs (adjusted p value 0.00050), and GATA3 pathogenetic or unknown variants were only found in 17.0% of breast NETs and 0% in PNETs (adjusted p value 0.0010). The most commonly affected oncogenic pathways in the breast NET cases were PI3K/Akt/mTOR, NOTCH and RTK-RAS pathways. Breast NETs had typically clock-like mutational signatures and signatures associated with defective DNA mismatch repair in their mutational landscape. Our results suggest that the breast NET mutational profile more closely resembles that of IDCs than that of PNETs. These results also revealed several potentially druggable targets, such as MMRd, in breast NETs. In conclusion, breast NETs are indeed a separate breast cancer entity, but their optimal treatment remains to be elucidated.

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Neuroendocrine Breast Carcinomas Share Prognostic Factors with Gastroenteropancreatic Neuroendocrine Tumors: A Putative Prognostic Role of Menin, p27, and SSTR-2A

Cited by 10 publications

References 39 publications

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

Neuroendocrine Cancer of the Breast: A Rare Entity

Comparison of the mutational profiles of neuroendocrine breast tumours, invasive ductal carcinomas and pancreatic neuroendocrine carcinomas

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