Synapse - RB1 genetic alterations in estrogen receptor–positive breast carcinomas: Correlation with neuroendocrine differentiation

RB1 genetic alterations in estrogen receptor–positive breast carcinomas: Correlation with neuroendocrine differentiation Journal Article

Authors:	Schwartz, C. J.; Marra, A.; Selenica, P.; Gazzo, A.; Tan, K.; Ross, D.; Razavi, P.; Chandarlapaty, S.; Weigelt, B.; Reis-Filho, J. S.; Brogi, E.; Pareja, F.; Wen, H. Y.
Article Title:	RB1 genetic alterations in estrogen receptor–positive breast carcinomas: Correlation with neuroendocrine differentiation
Abstract:	Genetic alterations in the retinoblastoma susceptibility gene (RB1) are present in up to 40% of triple-negative breast cancers (BCs) and frequent in tumors with neuroendocrine differentiation, including small cell neuroendocrine carcinoma. Data on RB1 genetic alterations in estrogen receptor (ER)–positive BCs are scarce. In this study, we sought to define the morphologic, immunohistochemical, and genetic features of ER-positive BCs harboring somatic alterations in RB1, with emphasis on neuroendocrine differentiation. ER-positive BCs with pathogenic RB1 genetic alterations were identified in <1% of cases (N = 55) from a cohort of 6026 BCs previously subjected to targeted next-generation sequencing, including 23 primary BCs (pBCs) and 32 recurrent/metastatic BCs (mBCs). In cases where loss of heterozygosity of the wild-type RB1 allele could be assessed (93%, 51/55), most pBCs (82%, 18/22) and mBCs (90%, 26/29) exhibited biallelic RB1 inactivation, primarily through loss-of-function mutation and loss of heterozygosity (98%, 43/44). Upon histologic review, a subset of RB1-altered tumors exhibited neuroendocrine morphology (13%, 7/55), which correlated with expression of neuroendocrine markers (39%, 9/23) in both pBCs (27%, 3/11) and mBCs (50%, 6/12). Loss of Rb protein expression was observed in BCs with biallelic RB1 loss only, with similar frequency in pBCs (82%, 9/11) and mBCs (75%, 9/12). All cases with neuroendocrine marker expression (n = 9) and/or neuroendocrine morphology (n = 7) harbored biallelic genetic inactivation of RB1 and exhibited Rb loss of expression. TP53 (53%, 29/55) and PIK3CA (45%, 25/55) were the most frequently comutated genes across the cohort. Overall, these findings suggest that ER-positive BCs with biallelic RB1 genetic alterations frequently exhibit Rb protein loss, which correlates with neuroendocrine differentiation in select BCs. This study provides insights into the molecular and phenotypic heterogeneity of BCs with RB1 genetic inactivation, underscoring the need for further research into the potential clinical implications associated with these tumors. © 2024 United States & Canadian Academy of Pathology
Keywords:	immunohistochemistry; adult; human tissue; protein expression; aged; major clinical study; missense mutation; mutation; bone metastasis; follow up; lymph node metastasis; antineoplastic agent; breast cancer; aromatase inhibitor; cohort analysis; cancer hormone therapy; tumor suppressor gene; liver metastasis; lung metastasis; partial mastectomy; genomics; heterozygosity loss; neoadjuvant chemotherapy; estrogen receptor; retinoblastoma protein; chromogranin; loss of function mutation; chromosome 11; skin metastasis; nonsense mutation; chemoradiotherapy; genetic heterogeneity; lumpectomy; neuroendocrine carcinoma; small cell carcinoma; synaptophysin; soft tissue metastasis; neuroendocrine; indel mutation; invasive ductal carcinoma; rb1 gene; rb1; high throughput sequencing; estrogen receptor positive breast cancer; human; female; article; simple mastectomy; tumor-related gene; invasive lobular breast carcinoma; thoracic metastasis
Journal Title:	Modern Pathology
Volume:	37
Issue:	8
ISSN:	0893-3952
Publisher:	Nature Research
Date Published:	2024-08-01
Start Page:	100541
Language:	English
DOI:	10.1016/j.modpat.2024.100541
PUBMED:	38897452
PROVIDER:	scopus
PMCID:	PMC11344677
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85197812773&doi=10.1016%2fj.modpat.2024.100541&partnerID=40&md5=e6a7d932d50cb6ea98c2652bd19400b4
Notes:	Article -- MSK Cancer Center Support Group (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Christopher Schwartz -- MSK author Lee Tan is listed under her middle name, Kiki, on the original publication -- Source: Scopus