The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC.

Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

Background: Biliary tract cancers (BTCs) represent a heterogeneous group of aggressive solid tumors with limited therapeutic options, and include gallbladder cancer (GBC), ampulla of Vater cancer (AVC), intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). Methods & Results: In the current review, we will discuss recent results of clinical trials testing targeted therapies in BRAF-mutant BTCs, with a particular focus on the recently published Phase II ROAR trial and ongoing active and recruiting clinical trials. Conclusions: Although the extended use of molecular profiling has paved the way toward a new era in BTC management, targeted therapies are limited to iCCA so far, and the prognosis of patients with metastatic disease has substantially not changed in the last decade. In this discouraging scenario, BRAF inhibition is currently emerging as a novel treatment option in patients harboring BRAF mutations.

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.

Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting. A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included. Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs. These results confirm the effectiveness and safety of pemigatinib in a real-world setting.

The onset and selection of resistant clones during cancer treatment with chemotherapy or targeted therapy is a major issue in the clinical management of metastatic colorectal cancer patients. It is possible that a more personalized treatment selection, using reliable response-to-therapy predictive biomarkers, could lead to an improvement in the success rate of the proposed therapies. Although the process of biomarker selection and validation could be a long one, requiring solid statistics, large cohorts and multicentric validations, non-coding RNAs (ncRNAs) and in particular microRNAs, proved to be extremely promising in this field. Here we summarize some of the main studies correlating specific ncRNAs with sensitivity/resistance to chemotherapy, anti-VEGF therapy, anti-EGFR therapy and immunotherapy in colorectal cancer (CRC).