Abstract
Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1–7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9–63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients.
Highlights
Biliary tract cancers (BTCs) are a relatively rare group of malignancies arising from different anatomical locations of the biliary tree and including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer (GBC), and ampulla of Vater cancer (AVC)(Figure 1) [1,2].biliary tract cancers (BTCs) represents the second most frequent primary liver cancer after hepatocellular carcinoma (HCC), accounting for about 3% of all gastrointestinal tumors [3,4]
This topic is important if we look at BTC, where platinum-based chemotherapy represents the mainstay of palliative treatment following the results of the landmark ABC-02 trial and the more recent ABC-06 study [9,82,83]
Patients with advanced/metastatic BTC have a dismal prognosis and few therapeutic options, and there is an urgent need for novel treatment strategies in this setting
Summary
Biliary tract cancers (BTCs) are a relatively rare group of malignancies arising from different anatomical locations of the biliary tree and including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Comprehensive sequencing studies of BTC showed that nearly 40% of patients harbor a potentially targetable genetic alteration, emphasizing the genomic complexity of the disease, with several reports that have been focused on cell-cycle dysregulation, DNA damage repair (DDR) pathway deficiency, and genomic instability [13]. With a study design similar to OlympiAD, the randomized phase III EMBRACA trial compared talazoparib versus standard single-agent chemotherapy of the physician’s choice (capecitabine, eribulin, gemcitabine, or vinorelbine) in advanced breast cancer patients with germline BRCAm, observing that talazoparib provided a statistically significant benefit in terms of PFS (8.6 versus 5.6 months; Hazard Ratio 0.54; 95% CI, 0.41–0.71, p < 0.001) [21]. The second and even more significant mechanism is represented by PARP trapping activity; PARPi trap PARP at its DNA binding site preventing repair processes, hesitating in cell death by mitotic catastrophe [46,47]. The inhibition of this pathway can force cells to use alternative damage repair systems, namely non-homologous recombination processes [48,49], which are more error-prone and can result in large-scale genomic rearrangements, and in apoptotic cell death [50]
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