39P Genomic landscape of metaplastic breast cancer from the AACR GENIE database

Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer characterized by its heterogeneous histopathology, aggressive nature, propensity to present at advanced stages, and high prevalence of triple-negative receptor status. However, unlike most triple-negative breast cancers, they are resistant to standard chemotherapy. Given these unique clinical characteristics, we aimed to evaluate the genetic alterations and oncogenic signaling pathways involved in MpBC. We queried the AACR GENIE version 15.0 database using the cBioPortal platform. We report the frequency of genetic alterations and describe the involvement of oncogenic signaling pathways defined in prior work using The Cancer Genome Atlas (TCGA). We identified 245 patients from 253 samples defined as MpBC. Median age at the time of sequencing was 58 years (IQR 48-67). The median mutation count per sample was 7 (IQR 3-11). The highest frequency of mutations was observed in TP53 (n=130, 51.4%), followed by PIK3CA (n=81, 32.0%), KMT2C (n=36, 17.9%), and FAT1(n=29, 13.7%). Copy number alterations were reported in 103 samples, most frequently in MYC (20.4%), RECQL4 (18.4%), RAD21 (16.5%), and AGO2 (13.6%). The involvement of all ten oncogenic signaling pathways is reported across the MpBC cohort, and frequencies are described in the table. Most patients (83.3%, n=204) were found to have concomitant involvement of two or more oncogenic pathways.Table: 39PFrequency of involvement of TCGA PanCancer pathways in MpBC cohortOncogenic signaling pathwayNumber of patients involved (n)Frequency (n/245; in percentage)Cell cycle14860.4%PI3K14860.4%TP5314659.6%RTK-RAS11647.3%NOTCH7631.0%HIPPO4116.7%MYC3213.1%WNT3112.6%TGF-Beta124.9%NRF293.7% Open table in a new tab Current therapeutic approaches have poorer outcomes in patients with MpBC as compared to other breast cancer subtypes. We found that MpBC is associated with high-frequency genes associated with aggressive behavior and chemoresistance, including TP53 mutations and MYC amplifications. PIK3CA is also prevalent in MpBC and potentially targetable. Our findings may inform the development of novel targeted therapeutic regimens and improve outcomes for this rare but aggressive breast cancer subtype.