Abstract P6-06-02: Germline CDH1 mutations in lobular carcinoma in situ
Authors: Reyes SA , Sakr RA , Schizas M , Towers R , Park AY , Ng CKY , Weigelt B , Reis-Filho JS , King TA 
Published: May 2016

Abstract
BACKGROUND: Germline CDH1 mutations are responsible for the increased risk of both gastric cancer and invasive lobular breast cancer (ILC) in families with hereditary diffuse gastric cancer syndrome; yet germline CDH1 mutations in women with ILC without a family history (FH) of gastric cancer are rare. Lobular carcinoma in situ (LCIS) is both a risk factor and non-obligate precursor of ILC and recent data suggest that germline CDH1 mutations may be present in up to 8% of patients with bilateral LCIS +/- ILC; raising questions about the role of genetic testing in this context. The purpose of this study was to determine the frequency of germline CDH1 mutations in a large prospectively followed cohort of patients with pathologically confirmed bilateral LCIS.
METHODS: Patients with a biopsy proven history of LCIS, entering surveillance or presenting for surgery (prophylactic or therapeutic mastectomy), between 2005 and 2013 were prospectively identified and enrolled in IRB approved protocols at Memorial Sloan-Kettering Cancer Center for the collection of tissue and/or germline DNA (IRB 01-135, 99-030). All biopsies were reviewed to confirm LCIS and mastectomy specimens were subject to extensive sampling of all quadrants. Cases with confirmed bilateral LCIS were chosen for the primary analysis. Cases where bilateral mastectomy tissue sampling confirmed only unilateral LCIS were included for comparison. Germline DNA was anonymized and analyzed for CDH1 mutations using targeted capture sequencing with baits for all exons of CDH1 on HiSeq2000. Germline single nucleotide variants were called using GATK HaplotypeCaller and insertions/deletions by Varscan and Scalpel. Mutations were manually inspected using the Integrative Genomics Viewer (IGV). Clinical data were abstracted prior to anonymization.
RESULTS: Germline DNA was available for 114 patients; 78 underwent bilateral mastectomy for breast cancer (BC), 8 chose prophylactic mastectomy and 28 patients with biopsy proven bilateral LCIS were identified in surveillance. Following mastectomy, tissue sampling confirmed bilateral LCIS in 67/86 (78%) patients, and ruled out bilateral LCIS in 19 patients; yielding 95 patients with bilateral LCIS for the primary analysis. Median age at LCIS diagnosis for bilateral and unilateral cases respectively was 48yrs (range 36-70) and 44 yrs (range 38-63). One patient with bilateral LCIS also reported a FH of gastric cancer. Pathogenic germline CDH1 mutations (D72N (missense) and E35* (nonsense)) were identified in 2/95 (2%) patients with bilateral LCIS, one of whom also had invasive breast cancer (ILC). A germline CDH1 mutation was not identified in the patient with bilateral LCIS and a FH of gastric cancer, nor were CDH1 mutations identified among the 19 patients with unilateral LCIS.
CONCLUSIONS: In this cohort of 95 patients with pathologically documented bilateral LCIS +/- BC, the overall frequency of CDH1 germline mutations was 2%; considerably lower than previously reported. To our knowledge this is the largest series to address this question and these findings do not support germline testing for CDH1 mutations in women with bilateral LCIS.
Citation Format: Reyes SA, Sakr RA, Schizas M, Towers R, Park AY, Ng CKY, Weigelt B, Reis-Filho JS, King TA. Germline CDH1 mutations in lobular carcinoma in situ. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-06-02.