Abstract
Histologic special types of breast cancer (BC) account for ~20% of BCs. Large sequencing studies of metastatic BC have focused on invasive ductal carcinomas of no special type (IDC-NSTs). We sought to define the repertoire of somatic genetic alterations of metastatic histologic special types of BC. We reanalyzed targeted capture sequencing data of 309 special types of BC, including metastatic and primary invasive lobular carcinomas (ILCs; n = 132 and n = 127, respectively), mixed mucinous (n = 5 metastatic and n = 14 primary), micropapillary (n = 12 metastatic and n = 8 primary), and metaplastic BCs (n = 6 metastatic and n = 5 primary), and compared metastatic histologic special types of BC to metastatic IDC-NSTs matched according to clinicopathologic characteristics and to primary special type BCs. The genomic profiles of metastatic and primary special types of BC were similar. Important differences, however, were noted: metastatic ILCs harbored a higher frequency of genetic alterations in TP53, ESR1, FAT1, RFWD2, and NF1 than primary ILCs, and in CDH1, PIK3CA, ERBB2, TBX3, NCOR1, and RFWD2 than metastatic IDC-NSTs. Metastatic ILCs displayed a higher mutational burden, and more frequently dominant APOBEC mutational signatures than primary ILCs and matched metastatic IDC-NSTs. ESR1 and NCOR mutations were frequently detected in metastatic mixed mucinous BCs, whereas PIK3CA and TP53 were the most frequently altered genes in metastatic micropapillary and metaplastic BCs, respectively. Taken together, primary and metastatic BCs histologic special types have remarkably similar repertoires of somatic genetic alterations. Metastatic ILCs more frequently harbor APOBEC mutational signatures than primary ILCs and metastatic IDC-NSTs.
Highlights
Breast cancer (BC) is heterogeneous and comprises various entities with divergent phenotype, biology, and clinical presentation[1,2]
No statistically significant differences were observed in the fraction of the genome altered (FGA) of metastatic mixed mucinous, micropapillary, or metaplastic BCs compared to their primary counterparts, or to age, menopausal status, and estrogen receptor (ER)/HER2 status-matched metastatic IDC-NSTs (Supplementary Fig. 4c–e), potentially due to the small sample size of special types of BC other than invasive lobular carcinomas (ILCs) analyzed in the study
Here, through the reanalysis of targeted sequencing data of primary and metastatic forms of histologic special types of BC, we have demonstrated that the repertoire of somatic genetic alterations in metastatic forms of histologic special subtypes of BC is generally similar to that of their primary counterparts
Summary
Breast cancer (BC) is heterogeneous and comprises various entities with divergent phenotype, biology, and clinical presentation[1,2]. Large sequencing studies have focused on invasive ductal carcinoma of no special type (IDC-NSTs), the most common histologic form of BC4–9, and data on the genomic landscape of histologic special types, in the metastatic setting, are scarce These studies have shown that the repertoire of somatic genetic alterations found in metastatic BCs is remarkably similar to that of primary tumors, TP53, ESR1, ARID1A, ERBB2, GATA3, KMT2C, NCOR1, NF1, and RB1 have been found to be significantly more frequently mutated in metastatic disease[7,10,11]. Through the reanalysis of targeted sequencing data generated with an FDA-approved multigene sequencing assay[11], we sought to define the repertoire of somatic genetic alterations of metastatic ILCs, mixed mucinous, micropapillary, and metaplastic BCs, and determine whether the landscape of somatic mutations and copy number alterations (CNAs) of metastatic special types of BC is distinct from that of their primary counterparts or of metastatic IDC-NSTs
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