Abstract PD8-06: The genomic landscape of metastatic special histologic types of breast cancer
Authors: Fresia Pareja, Simon SK Lee, Francisco Beca, Lorenzo Ferrando, Pier Selenica, David N Brown, Hannah Y Wen, Hong Zhang, Edi Brogi, Pedram Razavi, Sarat Chandarlapaty, Britta Weigelt, Jorge S Reis-Filho
Journal: Cancer Research (2020)

Abstract Introduction: Breast cancer (BC) is heterogeneous and comprises diverse entities with distinctive phenotypes, biology and clinical presentations. There are 21 special histologic types, accounting for approximately 20% of invasive BCs. Large-scale sequencing studies have focused preferentially on common histologic forms, and data on the genomic landscape of special histologic types, particularly in the metastatic setting, are scarce. Here, we sought to define the repertoire of somatic genetic alterations of metastatic special histologic types of BC. Materials and methods: We conducted a reanalysis of MSK-IMPACT targeted sequencing data of 346 special histologic types of BC from Razavi et al (Cancer Cell 2018), including invasive lobular (ILC; primary, n=129; metastasis, n=150), mucinous (primary n=11, metastasis n=5), micropapillary (primary n=8, metastasis n=13) and metaplastic carcinomas (primary, n=6; metastasis, n=11). Somatic single nucleotide variants (SNVs) and copy number alterations (CNAs) were inferred using a validated bioinformatics pipeline, and mutational signatures were assessed with SigMA. Genetic alterations of metastatic special histologic type BCs were compared to those of primary tumors and metastatic invasive ductal carcinomas of no special type (IDC-NSTs) matched by age, menopausal status and estrogen receptor (ER)/HER2 status at a 1:2 ratio for ILCs and at a 1:3 ratio for the remaining BCs. Results: The most frequently mutated genes in metastatic ILCs were CDH1 (71%), PIK3CA (49%), ESR1 (20%) and KMT2C (19%). ESR1 mutations were more frequent in metastatic than in primary ILCs (20% vs 3%; P&amp;lt;0.01). Metastatic ILCs, as compared to matched metastatic IDC-NSTs, had a higher frequency of mutations in CDH1 (71% vs 2%; P&amp;lt;0.001), KMT2C (19% vs 10%; P&amp;lt;0.05), TBX3 (16% vs 5%; P&amp;lt;0.001), ERBB2 (12% vs 3%; P&amp;lt;0.01) and FOXA1 (10% vs 2%; P&amp;lt;0.05), and a lower frequency of mutations in TP53 (16% vs 36%; P&amp;lt;0.001) and GATA3 (6% vs 16%; P&amp;lt;0.01). GATA3, NCOR1 and ESR1 (each, 40%) were the most frequently mutated genes in metastatic mucinous BCs. ESR1 and NCOR were numerically more frequent in metastatic than in primary mucinous BCs (40% vs 0%; P&amp;gt;0.05). Metastatic mucinous BCs had a numerically higher frequency of mutations in ESR1 (40% vs 6%; P&amp;gt;0.05) and GATA3 (40% vs 0%; P&amp;gt;0.05), and lower frequency of TP53 mutations (20% vs 53%; P&amp;gt;0.05) than matched metastatic IDC-NSTs. PIK3CA and TP53 were the most recurrently mutated genes in metastatic micropapillary BCs and were numerically more frequent in metastatic than in primary tumors (PIK3CA, 61% vs 25%; TP53, 46% vs 25%; P&amp;gt;0.05). PIK3CA was more frequently mutated in metastatic micropapillary BCs than IDC-NSTs (61% vs 23%; P&amp;lt;0.05). Metastatic metaplastic BCs most frequently harbored mutations in TP53 (72%) and PIK3CA (45%), with comparable frequencies in primary metaplastic BCs. ATM (27% vs 3%; P&amp;lt;0.05), MAP3K13 and YAP1 (27% vs 0%; P&amp;lt;0.05) were more frequently mutated in metastatic metaplastic BCs than in matched IDC-NSTs. No differences in the frequency of CNAs were seen between metastatic BCs of special histologic type and matched primary tumors or metastatic IDC-NSTs. Akin to metastatic IDC-NSTs, aging or APOBEC were the predominant mutational SNV signatures in metastatic ILCs, micropapillary and metaplastic BCs. Conclusions: The repertoire of somatic genetic alterations of primary and metastatic special histologic type BCs markedly overlaps. Nonetheless, there is an enrichment of mutations in ESR1 in metastatic BCs of typically ER-positive special histologic type. Metastatic BCs of special histologic type show an enrichment of similar genetic alterations as primary tumors, such as a higher frequency of mutations in CDH1, FOXA1 and TBX3 in ILCs, a lower frequency of PIK3CA and TP53 mutations in mucinous BCs and a higher frequency of PIK3CA and TP53 mutations in micropapillary and metaplastic BCs. Citation Format: Fresia Pareja, Simon SK Lee, Francisco Beca, Lorenzo Ferrando, Pier Selenica, David N Brown, Hannah Y Wen, Hong Zhang, Edi Brogi, Pedram Razavi, Sarat Chandarlapaty, Britta Weigelt, Jorge S Reis-Filho. The genomic landscape of metastatic special histologic types of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD8-06.