10620 Background: Up to 10% of patients with cancer harbor pathogenic germline variants (PVs) in one or more cancer susceptibility genes. Genetic cancer risk assessment (GCRA) is an important tool for the management of patients with cancer. It allows the identification of candidates for structured screening protocols, risk reduction strategies, targeted therapies and cascade testing. Knowledge about the prevalence and spectrum of PVs is limited among underrepresented populations. We studied the prevalence of germline PVs in a cohort of Mexican patients with cancer. Methods: Between April 2017 and September 2022, patients with diagnosis of cancer who met clinical criteria for GCRA according to international guidelines (NCCN) and were enrolled in the international Clinical Cancer Genomics Community Research Network (CCGCRN) registry at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran were included. Cancer risk counseling and germline multi-gene panel testing were performed. Post-test counseling and cascade testing with known PV analysis was offered. Results: 1322 patients met inclusion criteria (probands n = 1027, relatives n = 295). Among the probands, 72.4% (744/1027) were women, median age at cancer diagnosis was 48.2 years (range 1-88) and 9.8% (n = 101) had more than one primary tumor. 14.5% (149/1027) of probands had a positive result in which 152 PV were identified ( BRCA1 n = 39, BRCA2 n = 33, ATM n = 11, CHEK2 n = 11, MLH1 n = 11, TP53 n = 7, PALB2 n = 7, NF1 n = 6, MSH2 n = 5, MSH6 n = 3, PTEN n = 3, APC n = 2, BRIP1 n = 2, CDH1 n = 2, RB1 n = 2 and 1 PV in the genes: CDKN2A, MAX, MUTYH, NBN, PTCH1, RAD50, SDHA and SDHB). The frequency of PV according to cancer diagnosis was: breast 15.5% (82/527), prostate 2% (4/198), ovarian 15.6% (12/77), colorectal 26.6% (16/60) and pancreatic 11.9% (5/42). The frequency of recurrent, potentially founder PVs in their respective genes was as follows: BRCA1 del(exons9-12) 30.7% (12/39) and CHEK2 c.707T > C 81.8% (9/11). Among the relatives referred for cascade testing the frequency of PV was 40% (118/295), 18.6% (55/295) had personal history of cancer with a median age at diagnosis of 47 years. Conclusions: Our results show a wide spectrum and a variable frequency of PVs among one of the largest examined cohorts of Mexican patients with cancer, with a high frequency of PVs among cases of breast, ovarian, and colorectal cancer. In contrast to reports from other populations, there was very low frequency of PVs among patients with prostate cancer. The outcomes of this study add to our understanding of the genetic epidemiology of cancer in the Mexican population, and support creating GCRA programs to improve access to multi-gene panel testing among underrepresented patients in limited resource settings.

Background: Breast cancer incidence is increasing globally, and a significant proportion of the disease has been linked to genetic susceptibility. Genetic knowledge and skills are essential for achieving optimal cancer care and prevention. However, in low- and middle-income countries the availability of physicians and other providers specializing in cancer genetics is very limited, and cancer genetics is not included in most undergraduate or graduate medical programs. Providing physicians-in-training with education on hereditary breast and ovarian cancer (HBOC) syndromes has the potential to improve the early identification of patients at a higher risk of breast cancer. This study aimed to assess the effect of a short HBOC course given to fellows from a single teaching hospital in Mexico City. Methods: We evaluated the basal practice patterns and knowledge on HBOC among fellows enrolled in internal medicine, general surgery, medical oncology and clinical genetics fellowship programs using a validated cancer genetics questionnaire composed of 13 questions and graded on a 0-100% scale. Fellows received a cancer genetics course (three lectures) from oncologists and geneticists with training in cancer genetics, and changes in knowledge post-course were evaluated using the same questionnaires. Descriptive statistics were utilized to describe the included subjects, and T-tests were used to compare pre and post questionnaire scores. Results: 110 fellows with a median age of 26.9 years (range 24-31) completed the basal questionnaire. 48.9% were enrolled in internal medicine, 21.8% in general surgery, 13.6% in medical oncology and 7.2% in clinical genetics. All respondents reported to routinely interrogate patients about their family history of cancer, and 70% said they had referred patients to the genetics clinic at their institution. The average score on the basal survey was 62% (SD 17). After the cancer genetics course was completed, 85 fellows answered the questionnaire. We found a relative increase in knowledge from pre to post-intervention of 12% (post-intervention average score 70% [SD 14]), which was statistically significant (p <0.01). After the course, 36% of fellows said they would feel capable to provide recommendations to patients at risk of HBOC, compared to 17% before the course (p <0.01). Conclusions: Although knowledge about HBOC among Mexican fellows is suboptimal, we found that providing short educational courses on cancer genetics may lead to a significant increase in knowledge on HBOC, as well as to an increase in confidence regarding recommendations. This study reinforces the need to develop focused and cost-effective educational strategies in low- and middle-income countries where specialists in cancer genetics are scarce, in order to provide physicians-in-training with knowledge and tools to recognize, refer, and counsel patients at risk of HBOC. Citation Format: Yanin Chavarri Guerra, Hector De la Mora Molina, Rosa Elena Caballero Landinez, Arantxa Lagunas Salazar, Andrea De la O Murillo, Rafael Reyes Arciniega, Enrique Soto Perez de Celis, Jose Luis Rodriguez Olivares, Osvaldo M Mutchinick, Jazmin Arteaga Vazquez. An educational cancer genetics course to increase knowledge on hereditary breast cancer syndromes among physicians-in-training at a teaching hospital in Mexico City [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-15-02.

69 Background: Lynch syndrome (LS) is the most frequent hereditary cancer syndrome among patients with colorectal cancer. Screening tests such as immunohistochemistry (IHC) for mismatch repair (MMR) proteins and PREMM5 model help to identify patients at risk of germline pathogenic variants (PVs). However, there has been a disparity in that evaluation of these screening tools and their correlation with pathogenic variants (PVs) has been limited in Hispanic populations. Methods: Patients with colorectal cancer referred for genetic cancer risk assessment were enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry from October 2017 to February 2021 at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Genetic testing was performed by full sequencing of the MMR genes ( MLH1, PMS2, MSH2, MSH6 and EPCAM) and other cancer-associated genes ( APC, BRCA1, BRCA2, TP53, NF1, ATM, CHEK2, PALB2, BRIP1) and multiplex ligation dependent probe amplification to detect copy number variants (CNV) was performed for selected genes. Demographic, clinical characteristics and IHC results were obtained from clinical records. MMR PV probability was calculated using PREMM5. Results: Sixty-nine patients with colorectal cancer were included; mean age at diagnosis was 50 (26-82) years and 39/69 (56%) were women. A MMR gene PV was identified in 23/69 patients (33%); most frequently in MLH1 n = 14, followed by MSH2 n = 2, MSH6 n = 2 and PMS2 n = 1. Four recurrent PVs in MLH1 and MSH2 represented 22% of PVs. CNVs were identified in 4/23 (17.4%) patients with LS. PVs in other genes were identified in 8.6% of the cases: 2 ATM, 1 APC, 1 PALB2, 1 BRIP1 and 1 BRCA1. IHC results were available in 52/69 cases (75.4%) and MMR protein deficiency was found in 16/17 (94%) carriers and in 14/31 (45%) non-carriers (sensitivity 94.1% and specificity 54.8%). The area under the ROC curve for PREMM5 score was 0.94 (95% CI 0.88-0.99) with a mean score 31.6 (2.4-50) in patients with LS and 4.1 (0.9-50) in non-carriers. The diagnosis of a second primary colon cancer was more frequent among LS (30% vs 2.5%; p < 0.01). Conclusions: We found a high frequency of MMR gene PVs among patients referred for GCRA with personal history of colon cancer, and only a small proportion with PVs in other genes. Our results showed a good performance of PREMM5 model and a high sensitivity of MMR IHQ in a Mexican population, indicating that these are tools that can be used to prioritize patient selection for germline testing.

540 Background: The reported frequency of germline pathogenic variants (PVs) in patients with pancreatic cancer is 8-10%. Depending on the setting, pancreatic cancer-associated germline PVs in the BRCA and CDKN2A genes are the most commonly detected. The mismatch repair genes (MMR; Lynch syndrome) , TP53, STK11, ATM and PALB2 are also associated with an increased risk of pancreatic cancer . The identification of PVs in patients with pancreatic cancer is important as there may be a benefit of targeted therapies, such as PARP inhibitors for cases with defective double strand break repair or response to immunotherapy with defective MMR and high tumor mutational burden. Additionally, identification of predisposing PVs can enable screening and prevention for other family members through cascade testing. According to international guidelines, all patients diagnosed with exocrine pancreatic cancer are candidates for genetic testing. However, there is an underrepresentation of ethnic/ racial minorities, including Hispanic patients, in genetic studies. Methods: Between April 2017 and May 2020, patients with diagnosis of pancreatic adenocarcinoma who were treated at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and enrolled in the international Clinical Cancer Genomics Community Research Network registry were included in this analysis. Genetic testing was performed by full sequencing of the following genes: BRCA1, BRCA2, TP53, NF1, ATM, CHEK2, PALB2, CDKN2A, BRIP1, RAD50, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2 and EPCAM, as well as multiplex ligation-dependent probe amplification for selected genes and BRCA1 ex9-12del (Mexican founder mutation) screening with a three-primer polymerase chain reaction. Pedigrees, clinical and demographic data were obtained from the clinical records. Results: Forty-two patients with a diagnosis of pancreatic adenocarcinoma were included, with a median age at diagnosis of 57 years (range, 43-79), and 23/42 (55%) were women. The proportion of cases with operable, unresectable and metastatic disease at diagnosis was similar (33.3% for each group). The frequency of PVs was 11.9% ( ATM n =2, TP53 n =1, PALB2 n =1 and CHEK2 n =1). With a median follow-up 20 months 29/42 patients had died at the time of analysis (69%), the median overall survival was 16 months (range 3-84 months). No PVs were detected in the 4/42 patients who met the definition of familial pancreatic cancer (9.5%). Conclusions: Our results confirm the presence of PVs in cancer susceptibility genes in Mexican patients with pancreatic cancer, which is similar to that reported in other populations. However, it is notable that no BRCA PVs were identified in this small sample, as they are the most common PV found in other populations. Given to the heterogeneity of the PVs identified, our study supports the use of multi- gene panel testing in Hispanic patients with pancreatic cancer.