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The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration

Karloski, Eve; Dudley, Beth; Diergaarde, Brenda; Blanco, Amie; Everett, Jessica N; Levinson, Elana; Rangarajan, Tara; Stanich, Peter P; Childers, Kimberly; Brown, Sandra; Drogan, Christine; Cavestro, Giulia Martina; Gordon, Kelly; Singh, Aparajita; Simeone, Diane M; Reich, Hannah; Kastrinos, Fay; Zakalik, Dana; Hampel, Heather; Pearlman, Rachel; Gordon, Ora K; Kupfer, Sonia S; Puzzono, Marta; Zuppardo, Raffaella Alessia; Brand, Randall E
BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS:Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS:The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS:Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.
PMID: 38809542
ISSN: 1097-0142
CID: 5663572

Somatic Mutational Analysis in EUS-Guided Biopsy of Pancreatic Adenocarcinoma: Assessing Yield and Impact

Dong, Sue; Agarunov, Emil; Fasullo, Matthew; Kim, Ki-Yoon; Khanna, Lauren; Haber, Gregory; Janec, Eileen; Simeone, Diane; Oberstein, Paul; Gonda, Tamas
OBJECTIVES/OBJECTIVE:We sought to determine the yield of somatic mutational analysis from EUS-guided biopsies of pancreatic adenocarcinoma compared to that of surgical resection and to assess the impact of these results on oncologic treatment. METHODS:We determined the yield of EUS sampling and surgical resection. We evaluated the potential impact of mutational analysis by identifying actionable mutations and its direct impact by reviewing actual treatment decisions. RESULTS:Yield of EUS sampling was 89.5%, comparable to the 95.8% yield of surgical resection. Over a quarter in the EUS cohort carried actionable mutations, and of these, over one in six had treatment impacted by mutational analysis. CONCLUSIONS:EUS sampling is nearly always adequate for somatic testing and may have substantial potential and real impact on treatment decisions.
PMID: 38546128
ISSN: 1572-0241
CID: 5645102

Surveillance of Individuals at High Risk of Developing Pancreatic Cancer: A Prevalence Meta-analysis to Estimate the Rate of Low-yield Surgery

Paiella, Salvatore; Secchettin, Erica; Lionetto, Gabriella; Archibugi, Livia; Azzolina, Danila; Casciani, Fabio; Simeone, Diane M; Overbeek, Kasper A; Goggins, Michael; Farrell, James; Ponz de Leon Pisani, Ruggero; Tridenti, Maddalena; Corciulo, Maria Assunta; Malleo, Giuseppe; Arcidiacono, Paolo Giorgio; Falconi, Massimo; Gregori, Dario; Bassi, Claudio; Salvia, Roberto; Capurso, Gabriele
OBJECTIVE:To quantify the rate of low-yield surgery, defined as no high-grade dysplastic precursor lesions or T1N0M0 pancreatic cancer at pathology, during pancreatic cancer surveillance. BACKGROUND:Global efforts have been made in pancreatic cancer surveillance to anticipate the diagnosis of pancreatic cancer at an early stage and improve survival in high-risk individuals (HRIs) with a hereditary predisposition. The negative impact of pancreatic cancer surveillance when surgery is performed for low-grade dysplasia or a non-neoplastic condition is not well quantified. MATERIALS AND METHODS:A systematic search and prevalence meta-analysis was performed for studies reporting surgery with final diagnoses other than those defined by the Cancer of the Pancreas Screening (CAPS) goals from January 2000 to July 2023. The secondary outcome was the pooled proportion of final diagnoses matching the CAPS goals (PROSPERO: #CRD42022300408). RESULTS:Twenty-three articles with 5027 patients (median 109 patients/study, interquartile range 251) were included. The pooled prevalence of low-yield surgery was 2.1% (95% CI: 0.9-3.7, I2 : 83%). In the subgroup analysis, this prevalence was nonsignificantly higher in studies that only included familial pancreatic cancer subjects without known pathogenic variants, compared with those enrolling pathogenic variant carriers. No effect modifiers were found. Overall, the pooled prevalence of subjects under surveillance who had a pancreatic resection that contained target lesions was 0.8% (95% CI, 0.3-1.5, I2 : 24%]. The temporal analysis showed that the rate of low-yield surgeries decreased in the last decades and stabilized at around 1% (test for subgroup differences P <0.01). CONCLUSIONS:The risk of "low-yield" surgery during pancreatic cancer surveillance is relatively low but should be thoroughly discussed with individuals under surveillance.
PMID: 37681303
ISSN: 1528-1140
CID: 5620512

Targeting pancreatic cancer metabolic dependencies through glutamine antagonism

Encarnación-Rosado, Joel; Sohn, Albert S W; Biancur, Douglas E; Lin, Elaine Y; Osorio-Vasquez, Victoria; Rodrick, Tori; González-Baerga, Diana; Zhao, Ende; Yokoyama, Yumi; Simeone, Diane M; Jones, Drew R; Parker, Seth J; Wild, Robert; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
PMID: 37814010
ISSN: 2662-1347
CID: 5604832

Author Correction: Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Werba, Gregor; Weissinger, Daniel; Kawaler, Emily A; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Wang, Lidong; Lim, Heather B; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H; Lund, Amanda W; Welling, Theodore H; Dolgalev, Igor; Tsirigos, Aristotelis; Simeone, Diane M
PMID: 37400453
ISSN: 2041-1723
CID: 5539082

Are All Cysts Created Equal?: Pancreatic Cystic Neoplasms in Patients with Familial or Genetic Risk Factors for Pancreatic Cancer

Haimi, Ido; Dettwyler, Shenin; Everett, Jessica; Simeone, Diane M
Pancreatic cystic lesions (PCLs) have become more prevalent over time, particularly in asymptomatic individuals. Current screening guidelines for incidental PCLs offer a unified approach to surveillance and management, predicated on "worrisome features." Although PCLs are common in the general population, their prevalence may be higher in high-risk individuals (HRI, unaffected patients with specific familial and/or genetic risk factors). As more PCLs are diagnosed and more HRI identified, it is important to promote research that bridges data gaps and introduces nuance to risk assessment tools, ensuring tailoring of guidelines to the needs of HRI with varying pancreatic cancer risk factors.
PMID: 37245935
ISSN: 1558-1950
CID: 5541862

Racial, Ethnic, and Sex-based Disparities among High-risk Individuals Undergoing Pancreatic Cancer Surveillance

Katona, Bryson W; Klute, Kelsey; Brand, Randall E; Everett, Jessica N; Farrell, James J; Hawthorne, Kieran; Kaul, Vivek; Kupfer, Sonia S; Paiella, Salvatore; Simeone, Diane M; Sussman, Daniel A; Zogopoulos, George; Lucas, Aimee L; Kastrinos, Fay
UNLABELLED:Since its inception two years ago, the international, multicenter Pancreatic Cancer Early Detection (PRECEDE) Consortium has enrolled high-risk individuals (HRI) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Herein we aim to evaluate enrollment disparities in PRECEDE. Data on HRIs enrolled between May 2020 and March 2022 were collected, with HRIs defined as participants enrolled in PRECEDE meeting guideline-based criteria for PDAC surveillance. Of 1,273 HRIs enrolled, 1,113 were eligible for inclusion, with 47.2% meeting familial pancreatic cancer criteria without a known pathogenic variant (PV) and the remainder having a pathogenic variant in a PDAC-risk gene (CDKN2A, STK11, PRSS1, BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). Study participants were predominantly from the United States (82.7%), the most common age range at enrollment was 60-69 years (37.4%), and a non-PDAC cancer was present in 32.4%. There were racial/ethnic- and sex-based disparities among enrolled subjects, as the majority of participants were female (65.9%) and self-reported white (87.7%), with only 2.9% having Hispanic ethnicity. While more than 97% of participants consented to utilize imaging data and biosamples for research, there was no difference in rate of consent based on race/ethnicity, sex, or age, thereby demonstrating uniform participation in research activities among all subgroups after enrollment. Ensuring that diversity of HRIs in PDAC surveillance programs mirrors the communities served by participating centers is important. Substantial racial/ethnic- and sex-based disparities persist among recently enrolled HRIs undergoing PDAC surveillance, and therefore reducing these disparities will be a major focus of the PRECEDE Consortium moving forward. PREVENTION RELEVANCE:Pancreatic cancer surveillance is critical to decreasing pancreatic cancer mortality; therefore, it is important that pancreatic cancer surveillance studies enroll diverse patients. We demonstrate that substantial racial/ethnic- and sex-based disparities exist amongst enrollment in the international PRECEDE consortium, highlighting the dire need for future efforts to reduce these disparities. See related Spotlight, p. 305.
PMID: 37259800
ISSN: 1940-6215
CID: 5539832

POLQ inhibition elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma via cGAS/STING signaling

Oh, Grace; Wang, Annie; Wang, Lidong; Li, Jiufeng; Werba, Gregor; Weissinger, Daniel; Zhao, Ende; Dhara, Surajit; Hernandez, Rosmel E; Ackermann, Amanda; Porcella, Sarina; Kalfakakou, Despoina; Dolgalev, Igor; Kawaler, Emily; Golan, Talia; Welling, Theodore H; Sfeir, Agnel; Simeone, Diane M
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.
PMID: 36976649
ISSN: 1558-8238
CID: 5541482

A systematic review and meta-analysis of germline BRCA mutations in pancreatic cancer patients identifies global and racial disparities in access to genetic testing

Paiella, S; Azzolina, D; Gregori, D; Malleo, G; Golan, T; Simeone, D M; Davis, M B; Vacca, P G; Crovetto, A; Bassi, C; Salvia, R; Biankin, A V; Casolino, R
BACKGROUND:Germline BRCA1 and BRCA2 mutations (gBRCAm) can inform pancreatic cancer (PC) risk and treatment but most of the available information is derived from white patients. The ethnic and geographic variability of gBRCAm prevalence and of germline BRCA (gBRCA) testing uptake in PC globally is largely unknown. MATERIALS AND METHODS/METHODS:We carried out a systematic review and prevalence meta-analysis of gBRCA testing and gBRCAm prevalence in PC patients stratified by ethnicity. The main outcome was the distribution of gBRCA testing uptake across diverse populations worldwide. Secondary outcomes included: geographic distribution of gBRCA testing uptake, temporal analysis of gBRCA testing uptake in ethnic groups, and pooled proportion of gBRCAm stratified by ethnicity. The study is listed under PROSPERO registration number #CRD42022311769. RESULTS:A total of 51 studies with 16 621 patients were included. Twelve of the studies (23.5%) enrolled white patients only, 10 Asians only (19.6%), and 29 (56.9%) included mixed populations. The pooled prevalence of white, Asian, African American, and Hispanic patients tested per study was 88.7%, 34.8%, 3.6%, and 5.2%, respectively. The majority of included studies were from high-income countries (HICs) (64; 91.2%). Temporal analysis showed a significant increase only in white and Asians patients tested from 2000 to present (P < 0.001). The pooled prevalence of gBRCAm was: 3.3% in white, 1.7% in Asian, and negligible (<0.3%) in African American and Hispanic patients. CONCLUSIONS:Data on gBRCA testing and gBRCAm in PC derive mostly from white patients and from HICs. This limits the interpretation of gBRCAm for treating PC across diverse populations and implies substantial global and racial disparities in access to BRCA testing in PC.
PMID: 36822114
ISSN: 2059-7029
CID: 5448262

Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Werba, Gregor; Weissinger, Daniel; Kawaler, Emily A; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Wang, Lidong; Lim, Heather B; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H; Lund, Amanda W; Welling, Theodore H; Dolgalev, Igor; Tsirigos, Aristotelis; Simeone, Diane M
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
PMID: 36781852
ISSN: 2041-1723
CID: 5427092