Abstract PD8-01: Comprehensive genomic profiling (CGP) of metastatic invasive lobular carcinomas reveals heterogeneity in immune biomarkers and resistance alterations across biopsy sites
Authors: Sokol Ethan , Jin Dexter X , Ross Jeffrey , Frampton Garrett M , Oesterreich Steffi 
Published: February 2021

Introduction Metastatic breast cancer is a clinically challenging disease with poor outcomes. Invasive lobular carcinoma (ILC) is a rarer subtype of breast cancer with distinct patterns of metastasis, including frequent GI and female reproductive (FR) metastases (mets). Due to their relative rarity, little is known about the genomic characteristic of ILC across met sites. Here we explore the genomic landscape of 1909 ILC, stratified by met site, with an examination of immune checkpoint inhibitor (ICPI) biomarkers, therapeutic alterations, and resistance mutations.

Methods CGP was carried out at Foundation Medicine with hybrid capture for exons from up to 395 cancer-related genes plus select introns from up to 31 genes (PMID 24142049). Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb (PMID: 28420421). Ventana PD-L1 IC staining (SP142; positive &gt;= 1% staining) was available for a subset of samples. 1071 breast-biopsied and 1909 met-biopsied ILC and 6926 breast-biopsied and 1901 met-biopsied IDC were available for analysis.

Results High TMB (&gt;= 10 muts/mb) and PD-L1 IC staining are associated with response to ICPI. ILC mets overall had a greater rate of high TMB relative to IDC mets (21% v 9%, p = 7E-25) and breast-biopsied (breast) ILC (21% v 10%; p = 9E-15) with the highest frequency in GI (23%) and skin (21%). PD-L1 IC+ rates were lower in ILC mets (18%) relative to IDC mets (34%) and breast ILC (31%), but were variable across sites, with relatively high rates of positivity in GI (48%), skin (29%), and FR (18%) mets, and no positive staining in bone mets (0/37).

Alterations in PIK3CA were higher in ILC mets (58%) relative to IDC mets (34%) and generally exhibited a similar frequency across ILC met sites, with modestly lower prevalence in skin (48%, p = 0.005). Pathogenic alterations in BRCA1/2 were observed in 4.8% of ILC mets overall, with a lower frequency in GI mets (1.3%, p = 0.03).

A comparison of ILC breast biopsies to ILC mets revealed 19 genes with higher prevalence in at least one ILC met site, most with known roles in therapy resistance (eg ESR1, NF1, RB1, KRAS, ERBB2, BRAF), though significant heterogeneity was observed across sites. Met-enriched (ME) alterations were highest in ILC from the liver (71%) and lowest in FR (33%). ERBB2 mutations, which are may be targetable with HER2 kinase inhibitors, were predominantly found in liver mets (21%) with significantly lower prevalence in skin (11%), bone (10%), GI (3%), and FR (3%). ESR1 alterations were common in most ILC sites, with the highest prevalence in liver (26%) and low frequency in FR (4%). While FR ILC harbored few ME alterations, the rare alterations were primarily found in NF1 (5%) and NCOR1 (5%).

Conclusions CGP revealed significant heterogeneity in ILC mets across tissues. ICPI biomarkers were variable across sites with the highest frequency in ILC GI mets, offering additional potential treatment avenues for these tumors. Alterations in PIK3CA were common in ILC mets with high prevalence across sites, suggesting utility for PIK3CA inhibitors. Therapy-resistant alterations were common in ILC mets but varied across sites. Notably, ERBB2 alterations were most prevalent in ILC liver mets, but less common at other sites.

The high prevalence of therapeutic and resistance alterations suggests value in profiling metastatic lesions.

breast_ILCmet_ILCbreast_IDCmet_IDCgi_ILCliver_ILCfemale_repr_ILCbone_ILCskin_ILCsample count (N)1071190969261901154639114268199ICPI biomarkerTMB-H (&gt;=10muts/mb)10.2%21.0%4.4%9.2%23.4%18.9%14.0%19.0%21.1%PDL1-IC+ SP142 (subset)31.5% (39/124)17.8% (38/213)57.3% (480/837)34.2% (54/158)47.6% (10/21)11.6% (8/69)18.2% (2/11)0% (0/37)28.6% (6/21)Therapy AssociatedPIK3CA50.0%57.6%29.3%34.3%59.1%57.3%62.3%60.1%48.2%BRCA1/24.9%4.8%9.2%7.7%1.3%4.1%7.0%5.2%5.5%Met-EnrichedESR1_mut3.8%18.3%2.2%17.0%20.8%25.5%3.5%11.9%7.5%ERBB2_mut9.7%12.5%2.0%2.7%3.2%20.7%2.6%9.7%11.1%ARID1A_mut7.5%12.2%4.0%5.5%14.3%11.4%7.9%9.0%10.6%NF1_mut4.4%8.7%3.5%4.2%5.8%8.5%5.3%10.4%8.0%RB1_mut2.7%6.3%4.3%3.5%7.8%5.9%2.6%4.5%11.6%KRAS2.3%5.5%3.9%3.6%5.2%6.7%2.6%6.3%2.0%PTEN_del3.1%4.1%5.7%4.7%1.9%4.7%4.4%1.9%8.0%FGFR20.7%3.1%2.9%2.6%1.3%4.1%1.8%4.1%2.0%NCOR1_mut1.2%2.9%1.1%1.1%3.2%3.0%5.3%1.9%1.0%SMAD42.0%2.9%1.2%1.9%1.9%4.7%1.8%2.6%1.5%BRAF1.6%2.1%1.2%1.4%0.0%1.4%2.6%4.5%2.5%FOXP1_mut0.4%1.6%0.3%0.3%2.6%1.1%0.0%1.9%1.0%APC_mut0.9%1.4%1.1%1.1%0.6%0.6%1.8%3.4%2.0%SOX90.3%1.3%0.5%0.4%0.0%1.1%0.0%1.5%0.5%CASP8_mut0.0%0.8%0.5%0.5%0.0%1.1%0.9%1.1%1.0%PTPN11_mut0.1%0.7%0.2%0.3%0.0%0.6%1.8%1.5%1.0%TERT_mut0.2%0.6%0.4%0.7%2.6%0.0%0.0%1.1%0.5%ALK_mut0.1%0.4%0.2%0.4%2.6%0.0%0.9%0.4%0.5%KMT2D_RE0.1%0.3%0.4%0.3%1.9%0.2%0.0%0.0%0.5%any_ME32.5%60.1%30.1%42.4%53.9%71.4%33.3%53.4%52.3%

Citation Format: Ethan Sokol, Dexter X Jin, Jeffrey Ross, Garrett M Frampton, Steffi Oesterreich. Comprehensive genomic profiling (CGP) of metastatic invasive lobular carcinomas reveals heterogeneity in immune biomarkers and resistance alterations across biopsy sites [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-01.