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DNA Repair Dysfunction in Pancreatic Cancer: A Clinically Relevant Subtype for Drug Development

Talia Golan and Milind Javle

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate of ≤7% across all stages. The limited success of conventional therapies for PDAC is at least partially attributable to its genetic heterogeneity. Precision targeting of known PDAC subtypes may positively affect the outcome of this disease. An important actionable subtype in this cancer is associated with DNA repair dysfunction, including cases with germline BRCA mutations. This subtype can be targeted by inhibitors of poly(ADP-ribose) polymerase (PARP). BRCA mutation–associated PDAC may be the first biomarker-driven subtype in this disease that can be successfully targeted. However, DNA repair defects can extend beyond the narrow spectrum of BRCA1/2 mutations in PDAC and are present in a large proportion of patients with familial PDAC. This review describes the subgroup of patients with PDAC with aberrant DNA repair and discusses diagnostic and therapeutic options.

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Management of BRCA Mutation Carriers With Pancreatic Adenocarcinoma

Talia Golan and Pascal Hammel

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate of ≤7% across all stages. Most patients are diagnosed with advanced disease and median overall survival is limited. The limited success of conventional therapies for PDAC is at least partially attributable to its genetic heterogeneity. Extensive genomic efforts have been made to subtype PDAC. The DNA damage repair (DDR) deficiency subtype, also known as unstable genome/DSBR (DNA double-strand break repair) subtype, is one of the most clinically relevant biologic abnormalities in PDAC. Increased PDAC risk was found to be associated with inherited syndromes, which are present in approximately 10% of patients with PDAC. Recent updates to the ASCO and NCCN guidelines recommend risk assessment for all individuals with PDAC, irrespective of personal or family history or ethnicity. Germline BRCA mutations associated with DNA repair dysfunction is one of the best illustrations of actionable biologic subtypes in PDAC. This genetic alteration can indeed be targeted by PARP inhibitors (PARPi). Treatment implications for germline BRCA carriers with PDAC include the use of platinum-based therapy and the validation of PARPi administration as a maintenance strategy in platinum-sensitive patients. In the era of precision medicine, this is the first convincing example of targeting identified germline hereditary mutations in PDAC.

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Short- and Long-Term Survival in Metastatic Pancreatic Adenocarcinoma, 1993–2013

Talia Golan, Tal Sella, Ofer Margalit, Uri Amit, Naama Halpern, Dan Aderka, Einat Shacham-Shmueli, Damien Urban, and Yaacov Richard Lawrence

Background: During the past 2 decades, numerous clinical trials have focused on improving outcomes in patients with metastatic pancreatic cancer (mPDAC). The efficacy of new treatments has been demonstrated among highly selected patients in randomized phase III trials; hence, it is not clear to what extent these advances are reflected within the broader mPDAC population. Materials and Methods: Survival statistics were extracted from the SEER database for patients diagnosed with mPDAC between 1993 and 2013. Survival was analyzed using the Kaplan-Meier method and proportional hazard models. Results: The study population consisted of 57,263 patients diagnosed with mPDAC between 1993 and 2013; 52% were male, with a median age of 69 years (range, 15–104). Superior prognosis correlated with younger age, being married, tumor located within the head of the pancreas, lower grade disease, and more recent year of diagnosis. Median overall survival (OS) remained stable at 2 months between 1993 and 2013. Improvements in OS were seen for younger patients (age <50 years) and those with a more recent year of diagnosis (2009–2013). The percentage of patients who died within 2 months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%; P<.0001). The percentage of patients surviving ≥12 months improved from 4.9% in 1993 to 12.7% in 2013 (P<.0001). Conclusions: In recent years a modest improvement in OS has been seen among younger patients with mPDAC. The percentage of patients living beyond 1 year has significantly increased over time; however, the percentage of those dying within 2 months remains substantial.

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The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals

George Zogopoulos, Ido Haimi, Shenin A. Sanoba, Jessica N. Everett, Yifan Wang, Bryson W. Katona, James J. Farrell, Aaron J. Grossberg, Salvatore Paiella, Kelsey A. Klute, Yan Bi, Michael B. Wallace, Richard S. Kwon, Elena M. Stoffel, Raymond C. Wadlow, Daniel A. Sussman, Nipun B. Merchant, Jennifer B. Permuth, Talia Golan, Maria Raitses-Gurevich, Andrew M. Lowy, Joy Liau, Joanne M. Jeter, James M. Lindberg, Daniel C. Chung, Julie Earl, Teresa A. Brentnall, Kasmintan A. Schrader, Vivek Kaul, Chenchan Huang, Hersh Chandarana, Caroline Smerdon, John J. Graff, Fay Kastrinos, Sonia S. Kupfer, Aimee L. Lucas, Rosalie C. Sears, Randall E. Brand, Giovanni Parmigiani, Diane M. Simeone, and on behalf of the PRECEDE Consortium

Background: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. Methods: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18–90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. Results: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC–; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC–) were independent predictors of harboring a pancreatic cyst. Conclusions: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC– risk groups by surveillance protocols.