Co‐occurrence of breast cancer and neuroendocrine tumours: New genetic insights beyond Multiple Endocrine Neoplasia syndromes

Abstract

Objective Age‐standardized incidence of female breast cancer is 145.1 per 100000/year and 5.86 per 100000/year for neuroendocrine tumours (NET) in Canada. Evidence is scarce about gene variants that may predispose patients to develop both neoplasms. The objective of this study was to identify germline gene variants associated with this combination of tumours. Design and patients A retrospective chart review (2007‐2018) in a tertiary NET referral centre was completed. A series of 9 female patients with concurrent breast cancer and NET is presented. All patients underwent a 37 gene hereditary cancer next‐generation sequencing panel. Results Mean age was 61.4 years (35‐85) at breast cancer diagnosis and 63.4 years (51‐89) at NET diagnosis. Four patients had a pancreatic, three had a small bowel and two had a lung NET. Two patients were known cases of MEN1, and one patient was found to harbour a pathogenic variant in MEN1 and a variant of unknown significance (VUS) in ATM. A second patient was found to harbour a pathogenic variant in APC. A third patient was found to carry a pathogenic variant in PALB2 as well as a VUS in FANCM, MLH1 and STK11. Another patient was found to harbour a VUS in MSH2. One patient was found to carry a pathogenic variant in NTHL1. Conclusion The first cases of a PALB2, an APC and a NTHL1 pathogenic variants in patients with both breast cancer and NET were presented. NGS testing should be considered in specific patients with this combination of neoplasms, as certain germline variants beyond MEN1, have important implications for cancer surveillance.

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

“…Other less common germline events are also implicated: occasionally, PanNETs are associated with Lynch syndrome [74][75][76] or SDH-related disease [77], suggesting that immunohistochemistry for mismatch repair (MMR) proteins and SDHB may be helpful in screening young patients. Other germline mutations identified in multi-neoplasia syndromes include PALB2, APC, and NTHL1 [78]. Moreover, in 17% of sporadic PanNETs without apparent familial background, germline mutations in DNA damage repair genes, including MUTYH, CHEK2, BRCA2, PALB2, and BARD1, have been identified [79,80].…”

Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

“…The identification of pathogenic germline RAD51AC defects in a thymic neuroendocrine tumor [ 78 ], as well as a germline APC variant harboring breast carcinoma patient with a pulmonary neuroendocrine tumor [ 90 ] and a germline MSH2 variant of unknown significance in another breast carcinoma patient with well-differentiated pulmonary neuroendocrine tumor [ 90 ], expands the spectrum of non-syndromic manifestations of germline disease in well-differentiated thoracic neuroendocrine neoplasms.…”

“…While germline variants in patients with DIPNECH require further studies, the documentation of a common breast carcinoma history and associated germline defects in patients with pulmonary neuroendocrine disease is an interesting pathogenetic association as seen in other neuroendocrine neoplasms [ 90 , 94 ]. More importantly, these findings suggest that the spectrum of germline disease in thoracic neuroendocrine neoplasia is likely underestimated.…”

An Inherited Cancer Syndrome Due to a Germline Monoallelic EGFR Mutation with Loss of Heterozygosity in Lung and Breast Tumors

“…Besides, the co-occurrence of lung and breast cancers in the same person at the same time is indeed rare. Besides, data are extremely scarce about gene mutations that would predispose the incidence of two different cancers with different sources, simultaneously [7]. Herein, we report the effect of a germline EGFR mutation on the cooccurrence of lung and breast cancers in a 53-year-old patient with a family history of breast cancer in her sibling and a history of lung cancer in her parent.…”