Abstract P6-02-10: Prevalence of breast cancer predisposing variants in patients with breast carcinoma in situ
Authors: Fostira Florentia , Nasikas Dimitrios , Apostolou Paraskevi , Dellatola Vassiliki , Fokianou Anna , Kontogianni Panagiota , Alevizou Romina , Filippidou Sofia , Maniatis Dimitrios , Papadopoulos Lazaros , Pavlakis Emmanouil , Ntasiou Panagiota , Karageorgopoulou Sofia , Xepapadakis Grigorios 
Published: March 2023

Abstract
Background. Carcinoma in situ (CIS) of the breast is a non-obligatory pre-malignant breast lesion and a highly suspected precursor of invasive cancer. Although the selection criteria for referral to genetic testing are well established for patients diagnosed with invasive breast cancer, these are not clear for patients diagnosed with CIS. Our goal is to assess the prevalence of predisposing pathogenic variants in key genes, as well as to describe factors in patients with CIS that might be associated with genetic predisposition. Methods. A total of 267 patients solely diagnosed with CIS (mean age 43.65 years, range 18-74) through years 2010-2022, were referred for genetic testing and were analyzed, following their informed consent, implementing a 42-gene panel. Of these, 81.5%, 12.4% and 5.8% were ductal, lobular and mixed CIS, respectively. Patients having a synchronous invasive breast cancer diagnosis were not included in the study. Of patients with known grade, 52.28%, 28.9% and 18.8% were grade 3, 2 and 1, respectively. Strong family history for breast cancer (&gt;2 close family relatives) was positive in 28% (75/267) of patients, while 67.8% of CIS were hormone receptor positive. Results. A total of 12.7% (34/267) of patients carried pathogenic variants in seven clinically actionable genes, i.e. CHEK2 (10), BRCA2 (9), BRCA1 (5), ATM (5), PALB2 (2), MSH6 (2) and TP53 (1). Mean age at diagnosis of carriers was 42.1 years (range 29-61 years, p=0.26), 60% of patients had a grade 3 CIS diagnosis (OR 1.1, 95% 0.589-2.1, p=0.73), 96% had a hormone positive diagnosis (OR 1.4, 95% 0.78-2.50, p=0.24), while 73.5% (25/34) reported as having at least two close family relatives with breast cancer (OR 2.9, 95% 1.6-5.1, p=0.0001). The vast majority of carriers had a ductal CIS (DCIS) diagnosis, i.e. 91.2% (31/34) although this did not reach statistical significance (OR 1.087, 95% 0.64-1.82, p=0.72), probably due to small numbers. Notably, carriers were more likely to have a diagnosis with comedo characteristics, although this parameter has not been monitored closely for the whole cohort. Conclusion. Herein, an important fraction of patients with breast CIS carried pathogenic variants in clinically actionable genes, with the most frequent being CHEK2, BRCA2, BRCA1 and ATM. Notably, the prevalence is comparable to that of patients with invasive breast cancer. Strong family history for breast cancer was strongly associated with the identification of predisposing variants. Other factors, such as high grade, hormone positivity, age at diagnosis and others might also be associated with predisposition to CIS, but larger, prospective, studies are needed to confirm these. This is one of the few studies evaluating the inherited predisposition associated with both high and moderate penetrant breast cancer genes, highlighting that individuals with CIS diagnosis and strong family history for breast cancer should be offered the option to genetic testing via multigene panel.
Citation Format: Florentia Fostira, Dimitrios Nasikas, Paraskevi Apostolou, Vassiliki Dellatola, Anna Fokianou, Panagiota Kontogianni, Romina Alevizou, Sofia Filippidou, Dimitrios Maniatis, Lazaros Papadopoulos, Emmanouil Pavlakis, Panagiota Ntasiou, Sofia Karageorgopoulou, Grigorios Xepapadakis. Prevalence of breast cancer predisposing variants in patients with breast carcinoma in situ [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 P6-02-10.