Abstract PD8-05: Genomic profiling of metastatic invasive lobular carcinoma reveals unique genomics and therapeutic opportunities
Authors: Sokol ES , Basudan A , Lee AV , Stephens PJ , Frampton GM , Oesterreich S , Hartmaier RJ 
Published: February 2018

Abstract
Background
Invasive lobular carcinoma (ILC) is a common breast cancer histological subtype comprising ˜10-15% of all cases. ILC possesses many unique features when compared to invasive ductal carcinoma (IDC). First, ILC has distinct genomic alterations expanding beyond the defining event of CDH1 loss to other genes such as TBX3, FOXA1, and AKT signaling related genes. Second, ILC responds differently to chemotherapeutics and endocrine therapies despite similar clinical staging. Third, ILC tumors spread to a distinct set of organs compared to IDC tumors, commonly forming distant metastases in the ovary, colon, omentum, and stomach. However, the genomics of metastatic ILC have yet to be fully explored.
Methods
Comprehensive hybrid-capture based genomic analysis of 286-395 cancer related genes was performed on 5523 histologically defined ILC (n=613) and IDC (n=4910) tumors. Of these, 29% and 21% were from distant metastatic sites for ILC and IDC, respectively. Additionally, histology based ER-status was available for a subset of tumors allowing a subgroup of ER-positive, HER2-negative IDC (ER-IDC) samples to be identified (n=655).
Results
We examined the genetic differences between ILC and IDC in the context of both local and metastatic disease. Overall, the genomic profiles of ILC are enriched for alterations in CDH1, TBX3, PIK3CA, and RUNX1 in agreement with previous studies. Alterations in genes involved in AKT signaling (PIK3CA, PTEN, and AKT1) are also enriched in ILC (64% v. 49%; p&lt;10-7). Interestingly, NF1 loss of function alterations are enriched in metastatic ILC compared to ER-IDC (12.2% v. 3.6%, p&lt;0.001) but not in local disease (4.8% v. 4.1%, p=0.72). NF1 is a negative regulator of RAS-cyclic AMP pathway and suggests that NF1 driven RAS signaling is an important driver of metastasis in ILC.
We next examined metastatic ILC samples for alterations enriched at specific metastatic tissue sites. Two metastatic sites were exclusive to ILC samples compared to ER-IDC: GI (19.4%) and the female reproductive tract (11.7%). Within metastatic ILC, alterations in ESR1 showed strong tissue site bias towards liver metastases with 29% harboring an alteration in ESR1 (range: 8-13% in other sites, excluding ovary). Interestingly, ESR1 alterations were never observed in 14 ovary metastases, potentially reflecting an effect of local estrogen production on ILC ovarian metastases. In support of this, ILC ovarian metastases occur in younger women with a median age of 53.5 compared to 63.5 across all other sites.
Lastly, high tumor mutation burden (TMB) is strongly associated with metastatic ILC with 8.9% of metastatic ILC classified as TMB-high (320 mutations/Mb) compared to 2.1% of ILC in the breast. A similar but less pronounced finding was also observed for ER-IDC (1.6% versus 0.8%). This suggests that checkpoint blockage therapies may be a more common option in metastatic ILC than previously appreciated.
Conclusions
Genomic profiling of metastatic ILC reveals numerous potential therapeutic options enriched in this disease. Inhibition of RAS signaling driven by NF1 loss and TMB-high directed immunotherapeutics may be potential therapeutic options for a substantial portion of metastatic ILC patients.
Citation Format: Sokol ES, Basudan A, Lee AV, Stephens PJ, Frampton GM, Oesterreich S, Hartmaier RJ. Genomic profiling of metastatic invasive lobular carcinoma reveals unique genomics and therapeutic opportunities [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-05.