Abstract HER2-12: HER2-12 Genomic and Transcriptomic Landscape of HER2-Low Breast Cancer
Authors: Bansal Rani , McGrath Julie , Walker Phil , Bustos Matias A. , Rodriguez Estelamari , Sammons Sarah L. , Accordino Melissa K. , Meisel Jane , Gatti-Mays Margaret , Hsu Emily , Lathrop Kate I. , Kaklamani Virginia , Oberley Matthew , Korn W. Michael , Graff Stephanie L. 
Published: March 2023

Abstract
Introduction: Breast cancer has pioneered precision medicine with prognostic and predictive subtypes, defined by immunohistochemistry (IHC). Novel therapeutic strategies have led to the emergence of HER2-Low (H2L) as a new entity, defined as tumors with HER2 IHC score of 1+ (&gt;10% cell stained), as well as those with 2+ (&gt;10% cell stained) with paired negative in-situ hybridization (ISH) assay. H2L has been reported to represent up to half of all breast cancer. Further investigation into the mutational landscape of H2L compared to historical subtypes is needed to understand the clinical and biologic factors driving mechanisms of resistance and to consider post-progression treatment options within H2L populations. Methods: The Caris Life Sciences database was used to identify H2L breast tumors by IHC and CISH and evaluated for mutations detected by DNA next-generation sequencing (NextSeq 592-gene panel or NovaSeq whole exome panel). PD-L1 expression was tested by IHC (SP142 IC ≥ 1%). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (high ≥ 10 mutations per Mb). Statistical significance was determined using Fisher’s-Exact/Mann Whitney/X2 test with Benjamini-Hochberg-correction-adjusted p value (q value) of &lt;0.05. Results: A total of 19789 breast tumors were included in this study. Using standard definitions, 12480 were defined as hormone receptor positive (HR+), 7309 hormone receptors negative (HRneg), 5564 were TNBC, and 1784 HER2 positive (HER2pos). 4349 cases were also identified as H2L, which included 3403 HR+H2L and 946 HRneg H2L. H2L was 22% (4349/19789) of total population; 27% (3403/12480) of the HR+ population and 12.9% (946/7309) of the HRneg population. Within the H2L tumors, when stratified by HR status, we observed in the HR+H2L tumors an increased frequency of amplifications in CCND1 (15.6% vs 5.0%), FGF3 (13.3% vs 4.7%), FGF4 (13.3% vs 4.2%), FGF19 (14.4% vs 4.7%), ZNF703 (15.6% vs 4.4 %), NSD3 (12.9% vs 5.2%), ADGRA2 (13.1% vs 5.3%), FGFR1 (11.7% vs 3.6%) and EMSY (5.2% vs 1.4%) compared to the HRnegH2L tumors. TP53 mutations were strikingly higher in the HRnegH2L group (74.4% vs 25.0%) compared to HR+H2L tumors. Markers of IO response also showed elevated positivity in PD-L1 (39.6% vs 19.5%) however, no difference was detected in TMB-H status in HRnegH2L tumors compared to HR+H2L tumors, all q&lt;0.05. The genomic landscape differed when comparing HR+HER2pos tumors to HR+H2L tumors. Significantly more prevalent alterations in HR+HER2pos included amplifications in RNF43 (4.4% vs 1.4%), RARA (13.6% vs 0.1%), MLLT6 (19% vs 0.0%), MYC (6.1% vs 2.7%), DDX5 (10.1% vs 2.0%), CLTC (10.4% vs 3.3%) as well as TP53 (64.0% vs 25.0%) mutations and PD-L1 expression (26.6% vs 19.5%). Furthermore, mutations in PTEN (2.5% vs 7.8%), MAP3K1 (2.8% vs 7.1%), ESR1 (4.4% vs 14.3%), CDH1 (5.2% vs 16.4%), AKT1 (0.0% vs 4.3%) were elevated in the HR+H2L tumors compared to the HR+HER2pos tumors, all q&lt;0.05. Interestingly, when the HRnegH2L tumors were compared to TNBC subtype differences were seen in the mutation rate of PIK3CA (33.5% vs 16.7%; q&lt;0.0001), a master regulator of cell growth, and tumor suppressor gene TP53 (74% vs 86%). Conclusions: With some exceptions, H2L breast cancer shared genomic features with its more classically defined subset of either HR+ or HRneg disease. Notable differences in PIK3CA (an actionable mutation) and TP53 (a prognostic alteration) warrant additional assessment, as do amplifications variable between HR+H2L and HR+Her2pos groups. Our findings add tremendously to the current understanding of the molecular profile of the H2L subgroup and comparison to the classically defined breast cancer subgroups. Genomic risk assessments after progression on novel therapeutics will be needed to better define implications for mechanisms of resistance.
Citation Format: Rani Bansal, Julie McGrath, Phil Walker, Matias A. Bustos, Estelamari Rodriguez, Sarah L. Sammons, Melissa K. Accordino, Jane Meisel, Margaret Gatti-Mays, Emily Hsu, Kate I. Lathrop, Virginia Kaklamani, Matthew Oberley, W. Michael Korn, Stephanie L. Graff. HER2-12 Genomic and Transcriptomic Landscape of HER2-Low Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-12.