Abstract P4-05-04: Advanced breast cancer (ABC) in young women (YW): A comprehensive genomic profiling (CGP) study
Authors: Sokol Ethan S 
Published: March 2020

Background: ABC in YW is an aggressive disease with a higher mortality rate than that seen in older women (OW). Pre-menopausal women face challenges in balancing treatment with reproductive health and are often excluded from promising clinical trials. Studies from NCI SEER suggest that the rate of YW breast cancer has nearly doubled in the last 40 years from 1.5 to 2.9 cases per 100,000. In this study, we compare the genomic alterations (GA) in ABC in YW vs OW across ancestry groups.

Methods: Hybrid-capture based CGP of at least 315 cancer-related genes was performed on 21,440 clinically advanced breast cancers in 4,303 YW (&lt;45) and 17,137 OW (≥45). Predominant ancestry was assessed using a SNP-based approach (Connelly et al, 2018). Subgroups were analyzed on histological (Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC) and molecular subtypes (ER-positive (ER+), HER2-amplified (HER2+), TNBC).

Results: Our cohort of young women (YW) exhibit different frequencies of genetic driver events compared to older women (OW) (25 genes with a corrected p &lt; 0.01) including a lower frequency of alterations in PIK3CA (23% in YW v 36% in OW, p = 8E-63), TBX3 (1.1% v 3.9%, p = 1E-16), and RUNX1 (1.2% v 2.4%, p = 6E-08) and a higher frequency of BRCA1 (8.5% in YW vs 3.2% in OW; p = 1E-32), BRCA2 (6.3% v 4.3%, p = 9E-08), and GATA3 (12.5% v 8.4%, p = 5E-16). When accounting for histological and molecular subtype, many of the same trends hold (Table 1). For example, PIK3CA alterations were observed at a significantly reduced rate in YW in ER+, HER2+, and TNBC disease. Although BRCA1 mutations are generally associated with TNBC, we observed a significantly higher frequency of alterations in YW with ILC (4.7% v 0.8%, p = 0.01) and ER+ disease (5.9% v 2.2%; p = 0.003). ESR1 point mutations were lower in YW v OW (6% v 13%, p = 3E-38), possibly reflecting differences in therapy. Unexpectedly, the distribution of ESR1 LBD alterations differed between the cohorts, with Y537S as the most common alteration in YW (40% v 24% in OW; p = 1E-06).

YW with ILC showed a significantly higher rate of biopsy from the female reproductive tract (40% v 7.5% in OW, p =0.0001). TNBC tumors exhibited a higher rate of brain metastasis rate in YW (23% v 6% in OW, p = 0.003). HER2 tumors exhibited a lower rate of metastases to the skin in YW (8% v 14%, p = 0.02). No significant differences were observed in sites of distant metastasis in the ER+ subtype (all p &gt;0.08).

YW ABC was depleted in European ancestry (OR = 0.56, p = 2e-56) and strongly enriched in Asian and American ancestry (OR = 1.7 and 1.9, respectively, p &lt; 6E-15) relative to the cohort of OW. No genes exhibited significant differences in frequency across ancestry groups (p &gt;0.05). Across ancestry groups, BRCA1/2, ESR1, GATA3, and TBX3 show similar patterns between YW and OW. Patterns of metastatic tissue tropism were also largely similar across ancestry groups.

   significance YW v OW in groupGenefreq YWfreq OWoverallILCIDCER+HER2+TNBCPIK3CA23.1%36.3%P&lt;0.0001nsP&lt;0.0001P&lt;0.0001P&lt;0.001P&lt;0.01TBX31.1%3.9%P&lt;0.0001p&lt;0.05P&lt;0.0001P&lt;0.01P&lt;0.01nsRUNX11.2%2.4%P&lt;0.0001nsP&lt;0.01nsP&lt;0.001nsBRCA18.5%3.2%P&lt;0.0001P&lt;0.01P&lt;0.0001P&lt;0.01nsP&lt;0.01BRCA26.3%4.3%P&lt;0.0001p&lt;0.05nsnsnsnsGATA312.5%8.4%P&lt;0.0001nsP&lt;0.0001P&lt;0.0001nsnsESR16.0%12.6%P&lt;0.0001P&lt;0.01P&lt;0.0001P&lt;0.0001P&lt;0.01ns

Conclusions: CGP of ABC in YW vs OW revealed consistent genetic differences across molecular and histological subtypes, which may impact targeted therapies. YW have a lower frequency of alterations in PIK3CA across all molecular subtypes, potentially limiting the utility of PI3K-alpha inhibitors, such as alpelisib. The high frequency of BRCA1/2 alterations across subtypes may predict sensitivity to PARP inhibitors. While there are differences in the relative prevalence of ancestry groups in our population, we did not observe significant differences in driver alterations or tissue tropism across these groups.

Citation Format: Ethan S Sokol. Advanced breast cancer (ABC) in young women (YW): A comprehensive genomic profiling (CGP) study [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 P4-05-04.