Goggins, Michael

ABSTRACT Background Retrospective evaluations of multidisciplinary team (MDT) review of pancreatic cystic lesions (PCL) demonstrate improved PCL management. Endoscopic ultrasound (EUS) evaluates PCL for worrisome features; however, its influence on MDT is unclear and may be attenuated by anchoring/confirmation bias. We aimed to evaluate the impact of EUS and the overall performance of MDT evaluation of PCL. Methods Four mock MDT sessions at two institutions were presented imaging from 40 consecutive PCL cases (20 “high‐risk” with advanced neoplasia, 20 “low‐risk” with pathologic low‐grade dysplasia or ≥ 3 years of non‐progression on surveillance), with and without upfront EUS/FNA (cytology, CEA, Amylase), in a randomized, crossover design. Group 1 adjudicated without EUS, Group 2 adjudicated with EUS, and Group 3 adjudicated with EUS after initially adjudicating without it. Results The cohort included branch‐duct ( n = 20), mixed type ( n = 6), and main duct ( n = 4) IPMN, MCN ( n = 5), and non‐mucinous PCL ( n = 5). Group 2 (EUS) correctly identified mucinous PCL with 97% sensitivity and 70% specificity, significantly higher than Group 1 (No EUS) (Sensitivity 91%, Specificity 20%; p = 0.04). Group 3 (Unblinded to EUS) performed significantly worse in mucinous PCL identification compared with Group 2, indicating cognitive bias (Sensitivity 97%, Specificity 10% ( p = 0.0003)). Group 2 correctly identified high‐risk PCL that required surgical intervention with 85% sensitivity and 85% specificity, significantly higher than Group 1 (Sensitivity 60%, Specificity 75%; p = 0.0016) and Group 3 (Sensitivity 73%, Specificity 80%, p = 0.0485). Conclusion While susceptible to cognitive bias, EUS significantly improves MDT assessment of PCL. MDT establishes a high bar for iterative additions of biomarkers to PCL analysis.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract Purpose: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network–defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, to compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum, and germline DNA from 140 stage I to IV pancreatic ductal adenocarcinoma (PDAC) cases and 140 controls from three tertiary care institutions, with controls frequency matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, with median age 67.3 (minimum: 45, maximum: 90) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 [95% confidence interval (CI), 87.8–95.6]. Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC = 96.3, P = 0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC = 95, P = 0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC = 96.4 (94–98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Abstract Objective: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded EDRN defined phase 2 Biomarker Bakeoff study of eight promising biomarker panels using pancreatic cancer ductal adenocarcinoma (PDAC) case and general population healthy control samples from three institutions. The scientific questions were to determine whether panels could discriminate PDAC cases from controls with Receiver Operating Characteristic Area Under the Curve (AUC) &gt; 0.8, compare panel performance head-to-head via 95% confidence intervals (CI), and determine whether the panel improved upon serum CA19-9 alone. A secondary goal was to perform modeling to discover a new panel consisting of individual biomarkers. Methods: Eligible biomarkers were required to have had a prior EDRN defined phase 2 validation study published and be ready for validation in a sample set from multiple institutions. Three institutions submitted a total of 140 cases and 140 controls frequency matched to cases on age and sex. Four consortium member institutions submitted for validation eight panels consisting of ten plasma, serum and DNA genotyping biomarkers in addition to CA19-9. Locked panel formulas were submitted prior to specimen distribution. The primary metric was AUC with bootstrapped 95% CIs. LASSO penalized regression was used for exploratory panel building. Nested cross validation and internal-external validation were performed, and optimism-corrected performance estimates were computed. Results: The overall sample (N=280) was 51% female, median age of 67 years, and 94% were of non-Hispanic white race and ethnicity. Controls had median BMI 27.3, 56% never smokers, and 12% type II diabetes mellitus (DM2); cases (staged I to IV) had median BMI 26.6, 42% never smokers, and 26% DM2. Overall panel AUC estimates ranged from 89.9 to 96.3 and all were significantly larger than the null hypothesis value of 0.8 (p&lt;0.05). The apparent serum CA19-9 AUC was 91.7 (87.8, 95.6). Two panels were significantly different from serum CA19-9, a panel with FUT2/3 genotype with serum CA19-9 (p=0.002) and a panel containing tissue factor pathway inhibitor (TFPI), tenascin C (TNC), and plasma CA19-9 (p=0.01). In subset analyses by PDAC stage, no panel improved upon the null hypothesis value of 0.8 in stage I (p&gt;0.05), all panels improved upon the null hypothesis value of 0.8 in stage II and III (p&lt;0.05), and only serum CA19-9 did not improve upon the null hypothesis value of 0.8 in stage IV. All biomarkers but two microRNAs were retained in a LASSO model that had optimism corrected AUC=96.4 (95% CI: 94.0, 98.9). Conclusions: All submitted panels performed well overall in this blinded study, with the panel containing FUT2/3 genotype performing the best. Panel discovery improved upon serum CA19-9, though optimism corrected AUC 95% CIs overlap with those of apparent CA19-9 performance. Further work is needed to prioritize promising biomarkers and to improve detection of early stage PDAC. Citation Format: Ann L. Oberg, William R. Bamlet, Grant Izmirlian, Seetharaman Balasenthil, Surinder K. Batra, Masataka Hayashi, Daniel Herman, Michael A. Hollingsworth, Maneesh Jain, Ann M. Killary, Brianna M. Krusen, Suyu Liu, Gopalakrishnan Natarajan, Subrata Sen, Lynette M. Smith, Sudhir Srivastava, Brian M. Wolpin, Kenneth S. Zaret, Michael G. Goggins. Pancreatic Cancer Detection Consortium biomarker bake-off: A consortium Phase 2 blinded biomarker validation and panel discovery study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B070.

Abstract Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case–control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10−8 in the meta-analysis; Pinteraction = 2.1 × 10−9 in the case–control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

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: 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.