Abstract P3-06-08: Mucinous and neuroendocrine breast cancers: A spectrum of genetically-related lesions distinct from common forms of estrogen receptor-positive breast cancers
Authors: Pareja F , Da Cruz Paula A , Selenica P , Lee JY , Marchio C , Brown D , Geyer FC , Brogi E , Vincent-Salomon A , Weigelt B , Reis-Filho JS 
Published: May 2019

Abstract
Introduction: Mucinous (MBCs) and neuroendocrine breast carcinomas (NBCs) are special histologic types of estrogen receptor (ER)-positive breast cancers. Together, MBCs and NBCs account for approximately 5% of invasive breast cancers. NBCs are defined by the expression of neuroendocrine markers (i. e., chromogranin and/ or synaptophysin), whereas MBCs consist of nests of cancer cells floating in pools of extracellular mucin and can be either hypocellular/type A (MBC-A) or hypercellular/type B (MBC-B). MBC-B may display neuroendocrine differentiation. We compared the repertoire of somatic genetic alterations in MBCs-A and MBCs-B, and in NBCs, and evaluated whether they differ from ER-positive/ HER2-negative invasive ductal carcinomas of no special type (IDC-NSTs).
Materials and methods: Reanalysis of the targeted capture or whole exome sequencing data of 22 MBCs (12 MBCs-A and 10 MBCs-B), and of 15 NBCs was performed. The BAM files were retrieved and somatic mutations were detected with MuTect, indels with Strelka, Varscan2, Scalpel and Lancet, and copy number alterations using FACETS. The mutational repertoire of MBCs-A and MCBs-B was compared to that of NBCs, and of ER-positive/ HER2-negative IDC-NSTs from The Cancer Genome Atlas (TCGA) breast cancer study (n=310).
Results: The most frequently mutated genes in MBCs-A were SF3B1 and FRG1B (17%, each); in MBCs-B were GATA3 and KMT2C (30%, each), and in NBCs were FOXA1 and TBX3 (20%, each) and KMT2C (20%). No significant differences were observed in single gene comparisons between MBCs-A, MBCs-B and NBCs (Fisher's exact tests, p&gt;0.05). When compared with ER-positive/HER2-negative IDC-NSTs from TCGA, NBCs harbored a higher frequency of mutations targeting FOXA1 (20% vs 2.9%, Fisher's exact test, p&lt;0.05) and TBX3 (20% vs 2.9%, Fisher's exact test, p&lt;0.05), and a lower frequency of TP53 mutations (0% vs 23.9%; Fisher's exact test, p&lt;0.05). We observed a lower frequency of PIK3CA mutations in both MBCs-A (8.3% vs 40%, Fisher's exact test, p&lt;0.05) and MBCs-B (0% vs 40%; Fisher's exact test, p&lt;0.01) compared to ER-positive/HER2-negative IDC-NSTs. Although not statistically significant, PIK3CA mutations were numerically less frequent in NBCs than in ER+/HER2- IDC-NSTs (13.3% vs 40%; Fisher's exact test, p&gt;0.05). Concurrent 1q gains and 16q losses, the hallmark copy number alterations of ER-positive/HER2-negative breast cancer were found in 47% of the ER-positive/HER2-negative IDC-NSTs from TCGA, but only present in 20% of NBCs and in none of the MBCs-A or MBCs-B.
Conclusion: Type A MBCs, type B MBCs and NBCs harbor similar patterns of genetic alterations, including a low frequency of PIK3CA mutations and of concurrent 1q gains/ 16q deletions. Taken together, our data suggest that both MBCs and the vast majority of NBCs constitute a spectrum of histologically and genomically related subtypes, distinct from ER-positive/HER2-negative IDC-NSTs.
Citation Format: Pareja F, Da Cruz Paula A, Selenica P, Lee JY, Marchio C, Brown D, Geyer FC, Brogi E, Vincent-Salomon A, Weigelt B, Reis-Filho JS. Mucinous and neuroendocrine breast cancers: A spectrum of genetically-related lesions distinct from common forms of estrogen receptor-positive breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-08.