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.
Talia Golan and Milind Javle
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.