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Background The recent approval of PARP inhibitor, olaparib, in HER2-negative breast cancer expands the therapeutic options for patients with germline BRCA1/2 alterations. The role of somatic BRCA alteration as a predictive biomarker in breast cancer is currently unclear. NCCN guidelines call for germline testing in all young patients ( Methods Hybrid-capture based comprehensive genomic profiling of 395 cancer-related genes using the FoundationOne assay (Foundation Medicine, MA) was performed on 12,508 breast carcinomas. Somatic/germline/zygosity status for BRCA1/2 variants was analyzed as described in Sun, 2018 (PMID: 29415044). High genome-wide loss-of-heterozygosity (gLOH) was classified as ≥16% LOH. Subgroups were analyzed on histological {Invasive Ductal Carcinoma (IDC), Invasive Lobular Carcinoma (ILC)} and molecular subtypes [ER-positive (ER+), HER2-amplified (HER2+), TNBC], patient age [≤45, 46-60, 61+], and gender. Results Consistent with previous reports, the frequency of BRCA1/2 alterations was highest in young patients ( The fraction of somatic BRCA mutations (sBRCA) was 38%, with the lowest fraction of sBRCA in TNBC and young patients (30%, 30% overall, 36%, 42% for BRCA1) and highest in HER2+, ILC, and older patients (46%, 52%, 51%); the absolute frequency of sBRCA is approximately 3.5%. In tumors with ESR1 mutations, we detected concurrent BRCA mutation in 6.4% (85/1319), with 48% predicted somatic. Almost all tumors with BRCA mutations had biallelic inactivation, with LOH of the second allele irrespective of predicted germline status (90% of gBRCA and 86% of sBRCA under LOH). gLOH score was used as a phenotypic measure of homologous recombination deficiency (HRD): patients harboring biallelic BRCA alterations had elevated rates of gLOH with 89% of gBRCA and 84% of sBRCA tumors harboring a high gLOH score, vs 47% with heterozygous BRCA, 34% with no BRCA alteration, and 80% for patients with BRCA deletion. Conclusions Thirty-eight percent of deleterious BRCA alterations in breast are predicted somatic, including 36% of BRCA1 alterations in TNBC. Germline testing would miss these alterations even though they are frequently under LOH and are associated with high gLOH, a biomarker with predictive value in ovarian cancer. While patients with ER+ and HER2+ tumors have low rates of gBRCA alterations, the overall BRCA mutation rate, including somatic alterations, is appreciable at 8.3% and 5.3%. Our findings demonstrate that sBRCA alterations are associated with a comparable HRD phenotype to gBRCA altertions and suggests that PARP inhibitors may have potential value for a wider range of breast cancer patients. Citation Format: Sokol ES, Frampton GM, Ross J, Ali S, Chung J, Oesterreich S. BRCA1/2 alterations are present at significant rates across breast cancer subtypes and are associated with a high genome-wide loss of heterozygosity signature [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-05.

Introduction: The lack of estrogen receptor (ER) expression is the primary cause of de novo resistance of breast cancers to endocrine therapy. In contrast, in most cases of acquired endocrine resistance, ER is expressed and other mechanisms of resistance have been proposed, such as ER mutations. Pre-clinical studies demonstrated a small number of specific point mutations that can enhance ER function. However, the studies on clinical samples performed in the 1990's were limited by small sample size, lack of detailed clinical correlation and lacked the sensitivity of next-generation sequencing (NGS). Therefore, in this study we sought to comprehensively investigate the frequency and functional significance of ER mutations throughout the progression of breast cancer from primary disease to advanced metastatic disease using targeted NGS. Methods: In this retrospective study, a total of 249 tumor specimens were analyzed. The specimens include 134 ER positive and, as controls, 115 estrogen receptor negative tumors. The estrogen receptor positive samples consist of 58 primary breast cancers and 76 metastatic sample. All tumors were sequenced with high coverage using NGS targeting the coding sequence of ER and an additional 181 cancer-related genes. Results: Recurring somatic mutations at codons 537 and 538 within the ligand-binding domain of the estrogen receptor were detected in ER positive metastatic tumors. Overall, the frequency of these mutations was 12% (95% CI 6%-21%) in metastatic patients compared with none in the primary cases. In total there were 9 recurring somatic mutations; Y537C (11%), Y537N (33%), Y537S (22%) and D538G (33%). In addition in a small number of paired primary and metastatic samples from the same patient, these mutations were found only in the metastatic specimens. In a subset of heavily pre-treated patients the frequency was 20% (5/25, 95% CI 7%-41%). ER activating mutations were not detected in any stage of ER negative disease. ER alterations were not mutually exclusive with any of the other commonly altered genes and of the most frequently altered genes, all but ER alterations displayed similar frequencies across primary and metastatic specimens. Functional studies in cell line models demonstrated that these ER mutations render ER constitutively active and confer resistance to hormone deprivation, tamoxifen and fulvestrant. Conclusions: Herein, we reveal functional ER mutations as potential drivers of endocrine resistance during the progression of ER positive breast cancer. The absence of detectable mutations in the primary tumors suggests clonal evolution as the mechanism of resistance. Thus, these mutations have the potential to be an important genetic biomarker of endocrine resistance in ER positive metastatic breast cancer and could assist in clinical decision making as disease progresses. Our findings also underscore the value of repeated biopsies of metastatic lesions. Lastly, since the frequencies of these mutations are substantial when sensitive testing methods are used in the correct clinical context, pre-clinical and clinical studies to identify novel therapeutics that can overcome this resistance are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-06.

This abstract was withdrawn by the authors.

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 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.

Background: ERBB2 is an EGFR family member encoding the ligand independent receptor tyrosine kinase HER2. ERBB2 amplification is well understood to drive oncogenesis, with breast carcinoma as the exemplar. To explore the oncogenic potential of ERBB2 non-amplification genomic alterations, we have retrospectively reviewed the genomic profiles and clinical history of 37 patients with different cancers harboring such alterations Materials and Methods: We explored the spectrum of ERBB2 somatic mutations across of 2,250 patients that underwent hybrid-capture based comprehensive genomic profiling (CGP) utilizing next-generation sequencing (NGS) at a single CLIA-certified, CAP-accredited, New York Statue Regulated central laboratory (Foundation Medicine, Inc.). The population consists of patients from 5 different cancer centers. This retrospective review was IRB approved. Cancer type, ERBB2 mutation type, co-existing mutations, number of chemotherapy lines, date of metastasis, relapse date and deceased date were collected. Clinically relevant genomic alterations were denoted as those suggesting benefit from an FDA-approved targeted therapy or mechanism driven clinical trial. Results: Out of the 37 patients with ERBB2 mutations, 18/37 (49%) were males, and 19/37 (51%) were females. Among cancer types, 12/37(32%) had lung cancer, colon 6/37(16%), bladder 5/37(13.5%), breast 4/37(11%), and other cancers 6/37 (6%). The median number of chemotherapy lines administered among all patients was 3. The alterations in ERBB2 were distributed as follows: 54% (20/37) in the kinase domain, 30%(11/37) in the extracellular domain (ECD) and 11% (4/37) in the non-kinase intracellular domain, and 5% (2/37) truncations. Of ECD domain mutations, 81% (9/11) were at the S310 position. 198 non-ERBB2 alterations co-occurred in this cohort, 89 of which were clinically relevant genomic alterations. In this population, colorectal carcinoma had the highest mutational load followed by duodenum/jejunum, bladder, skin malignancies, gallbladder, cervix, tonsil, breast and stomach. We partitioned overall survival (OS) into two parts and expressed it as the sum of progression free survival (PFS) and survival post-progression (SPP) and it was calculated among the deceased patients 18/37(49%). The median patient survival in this cohort was 25 months. Among individual tumor types, lung cancer had the lowest OS, which was 9 months (M), followed by breast (35 M), colon (41 M), and bladder (44 M). Conclusion: In this retrospective study the incidence of ERBB2 non-amplification alterations in a variety of solid tumors was 1.6%. Outcomes data in this small cohort will be assessed for prognostic implications of these alterations, and any treatment episodes with HER2- targeted therapy will be reported. A prospective histology-independent, aberration-specific study is necessary to decipher the effect of anti-HER2 targeted against these alterations. Citation Format: Sharon Wesley Dev Sahadevan, Zachary Chalmers, Garret M. Frampton, Navneet Dhillon, Kim Kramer, Philip J. Stephens, George W. Daneker, Jeffrey S. Ross, Vincent A. Miller, Maurie Markman, Siraj M. Ali, Ricardo H. Alvarez. Clinical evaluation of patients with advanced solid tumors harboring ERBB2-somatic mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A80.