Yurgelun, Matthew B.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.

Patients with familial adenomatous polyposis (FAP) are at increased risk of developing cancer, with the most common sites being colorectal, duodenal/ampullary and thyroid. In the last decade, an alarming increase in gastric cancer has been reported in the Western FAP population. These cancers are often diagnosed at an advanced stage with poor prognosis, even in patients undergoing regular upper endoscopic surveillance. Most gastric cancers in Western patients with FAP occur in the proximal stomach, where a carpeting of fundic gland polyposis hampers visualization of gastric cancer and its precursor lesions during endoscopic surveillance. Although fundic gland polyps are the most prevalent proximal polyp, several different dysplastic lesions can be found in the stomachs of patients with FAP. including fundic gland polyps with dysplasia, foveolar-type adenomas, pyloric gland adenomas, and intestinal-type adenomas. Although adenomas are the most likely precursors to gastric cancer, the exact lesions responsible for gastric cancer in FAP are not yet fully understood. This review focuses on gastric polyposis and the characteristics of gastric cancer in Western patients with FAP, including risk factors, lesion detection, surveillance and management of gastric polyposis, and areas for future research.

Gastric cancer is a significant global health concern, with CDH1-associated gastric cancer representing a small but important subset of cases. Historically, individuals with CDH1 pathogenic germline variants were advised to undergo prophylactic total gastrectomy due to the high reported risk of gastric cancer and the limited sensitivity of upper endoscopy in detecting signet ring cell carcinoma (SRCC). However, emerging data suggest that the cumulative lifetime risk of advanced gastric cancer among CDH1 germline pathogenic variant carriers is lower than previously thought, and early-stage SRCC detected on endoscopy does not necessarily indicate imminent—or even eventual—progression to advanced cancer. The near-universal presence of T1a SRCC in gastrectomy specimens from asymptomatic CDH1 pathogenic variant carriers calls into question the reflexive recommendation for gastrectomy, including upon detection of SRCC during surveillance. Furthermore, the morbidity and quality-of-life impact associated with total gastrectomy require careful consideration. Active endoscopic surveillance has shown promise as an alternative management strategy for gastrectomy in patients lacking indicators of >T1a SRCC, though current data are limited by short follow-up periods and selection bias. This review synthesizes recent findings on the natural history of CDH1-associated gastric cancer and evaluates the risks and benefits of gastrectomy versus active endoscopic surveillance, with the goal of helping clinicians provide personalized and evidence-based recommendations for patients with CDH1 pathogenic variants.

Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1 , BRCA2 , CDH1 , PALB2 , PTEN , and TP53 , and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

Abstract Background: Uptake of genetic testing for cancer susceptibility in family members of cancer patients is suboptimal. The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated two strategies of remote genetic education and testing in relatives of pancreatic ductal adenocarcinoma (PDAC) patients. Methods: Eligible participants had: a first-degree relative with PDAC or had a known pathogenic germline variant (PGV) in one of thirteen PDAC predisposition genes (APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53) and a first- or second-degree relative with PDAC. Participants were cluster-randomized by family into one of two arms. Arm 1 included an interactive telemedicine session with a genetic counselor, followed by genetic testing at a commercial laboratory. Arm 2 involved remote online genetic education and testing at the commercial laboratory without the interactive session. The primary outcome was uptake of genetic testing across study arms, which was compared by permutation tests and mixed-effects logistic regression models. Results: Between 5/8/2019 and 6/1/2021, 424 families were randomized, including 601 participants (n=296 Arm 1; n=305 Arm 2). The uptake of genetic testing was 87% (257/296) in Arm 1 and 93% (284/305) in Arm 2 (p=0.014). Participants in Arm 1 were significantly less likely to obtain genetic testing compared to Arm 2 (Adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). BRCA2, ATM, CDKN2A and PALB2 were the most common PDAC susceptibility genes in which PGVs were identified. Conclusions: Remote methods of genetic education and testing are successful alternatives to traditional germline susceptibility testing. Citation Format: Nicolette J. Rodriguez, C. Sloane Furniss, Matthew B. Yurgelun, Chinedu Ukaegbu, Pamela E. Constantinou, Ileana Fortes, Alyson Caruso, Alison N. Schwartz, Jill E. Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott H. Nelson, Sydney Okumura, Alicia Y. Zhou, Tara B. Coffin, Hajime Uno, Miki Horiguchi, Allyson J. Ocean, Florencia McAllister, Andrew M. Lowy, Scott M. Lippman, Alison P. Klein, Lisa Madlensky, Gloria M. Petersen, Judy E. Garber, Michael G. Goggins, Anirban Maitra, Sapna Syngal. A randomized study of two Strategies of remote Genetic Education, Risk Assessment, and Testing (GENERATE) for family members of patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A029.

Abstract Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS-wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P = .38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P = .02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P = .13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P = .46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758

Abstract Background: Roughly 7–10% of patients with pancreatic ductal adenocarcinoma (PDAC) have a deleterious germline variant. Although identification of germline variants in family members has implications for cancer surveillance and can lead to early cancer detection and interception for PDAC, as well as other cancers, cascade genetic testing rates are low. The GENetic Education, Risk Assessment and TEsting (GENERATE) study evaluates novel methods of providing genetic education and testing for individuals at risk for hereditary PDAC. Methods: Eligible participants had: (1) a first- or second-degree relative with a diagnosis of PDAC and a known familial germline variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 (Known Familial Mutation (KFM)), (2) or were first-degree relatives of PDAC patients (no KFM). Participants were recruited through six academic centers, patient advocacy organizations and online outreach. Enrollment occurred through the study website (www.GENERATEstudy.org). All study participation, including genetic testing via a at home saliva sample kit, was done remotely. Participants were cluster randomized at the family level into one of two arms. Arm 1 (Doxy.me plus Color Genomics) included remote genetic education and testing through a video-based telemedicine platform (Doxy.me) and physician-mediated testing through Color Genomics. Arm 2 included remote genetic education and testing through Color Genomics only. Results: Between 5/8/2019–6/01/2021, 423 families were randomized, comprising 595 participants. Recruitment occurred through patient invitation via healthcare providers (n=128, 21.5%), family members (n=271, 45.5%), friends, advocacy groups, and online outreach (n=223, 37.5%). Participants were referred from the six GENERATE academic centers (n=270, 45.4%) and other institutions (n=325, 54.6%). Study participants were 52.5 years on average, primarily identified as White (n=577, 97%) and from the Northeast (n=184, 30.9%), Midwest (n=154, 25.9%), South (n=158, 26.6%) and West (n=99, 16.6%). Participants were randomized into each arm (n=296 Doxy.me plus Color Genomics; n=299 Color Genomics only). To date, 527 (88.6%) participants have ordered genetic testing. The uptake of genetic testing was 253/296 (85.5%) in the Doxy.me plus Color Genomics arm and 274/299 (91.6%) in the Color Genomics only arm (p=0.049, generalized mixed-effects model). A total of 82 PDAC associated pathogenic variants were identified. The most frequently detected variants were BRCA2 (n=32), ATM (n=25) and PALB2 (n=6). Additionally, 13 non-PDAC associated pathogenic variants and 20 low penetrance variants were detected. Conclusions: Remote methods of genetic education and testing are successful alternatives to traditional cascade testing, with genetic testing rates nearly 90%. Participant follow up will assess if satisfaction with decision making, cancer-risk distress, knowledge gained, family communication, and uptake of surveillance were impacted by the mode of delivery of pre-test genetic education. Citation Format: Nicolette J. Rodriguez, Constance S. Furniss, Matthew B. Yurgelun, Chinedu Ukaegbu, Pamela E. Constantinou, Alison N. Schwartz, Jill Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott Nelson, Sydney Okumura, Sherman Law, Alicia Y. Zhou, Tara B. Coffin, Hajime Uno, Allyson Ocean, Florencia McAllister, Andrew M. Lowy, Scott M. Lippman, Alison P. Klein, Lisa Madlensky, Gloria M. Petersen, Judy E. Garber, Michael G. Goggins, Anirban Maitra, Sapna Syngal. Comparison of novel healthcare delivery models on the uptake of genetic education and testing in families with a history of pancreatic cancer: The GENetic Education, Risk Assessment and TEsting (GENERATE) study [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-013.

Abstract Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. Prevention Relevance: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.