Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies.

Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.

Immune microenvironment in patients with mismatch-repair-proficient oligometastatic colorectal cancer exposed to chemotherapy: the randomized MIROX GERCOR cohort study.

In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri-operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein-1 (PD-1, invasive front, stromal, intra-epithelial compartments), and programmed death-ligand 1 (PD-L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD-L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD-L1 expressions on immune cells were predictive of better disease-free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD-L1 expression and tumor-infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.

PARP inhibition in treatment of pancreatic cancer.

INTRODUCTION: Tumor control and survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) has improved with more effective polychemotherapies. The identification of novel therapeutic targets is strongly needed in order to propose maintenance therapies that improve quality of life while maintaining tumor control. AREAS COVERED: PDAC with mutations in homologous recombination repair genes such as BRCA are particularly sensitive to platinum agents. Recently, the potential role of poly(ADP-ribose) polymerase (PARP) inhibitors was suggested. The POLO study has shown that olaparib was efficient and well-tolerated as maintenance therapy in patients with germline BRCA1/2 mutation and a metastatic PDAC controlled after a platinum-based induction chemotherapy. EXPERT OPINION: The demonstration of olaparib efficacy in patients with metastatic PDAC and BRCA germline mutation has paved the way for maintenance with a targeted therapy. Further studies are needed to assess; the potential role for PARPI in earlier forms of PDAC, those with somatic or more rare BRACness signatures, to overcome primary or secondary resistances to PARPi, and to combine them with other antitumoral agents.

Maintenance therapies in metastatic pancreatic cancer: present and future with a focus on PARP inhibitors.

Metastatic pancreatic ductal adenocarcinomas (PDACs) are now more effectively controlled using chemotherapy combinations such as FOLFIRINOX and gemcitabine plus nab-paclitaxel (NabP) regimens with a subset of patients who achieve a sustained tumor stabilization or response. The next challenge is to design maintenance therapies that result in continued tumor control with minimal toxicity. Quality of life should always be a priority in these patients with prolonged survival. Gradually tapering off the intensity of chemotherapy by suppressing drug(s) in the combination is one option. Thus, maintenance with 5-fluorouracil or gemcitabine as single agents after FOLFIRINOX or gemcitabine-NabP induction, respectively, seems to be a promising approach to minimize neurotoxicity while maintaining efficacy. Another option is to introduce maintenance drug(s) with different anti-tumoral actions. The recent example of olaparib in patients with BRCA mutated PDAC provides a promising proof-of-concept of a switch maintenance strategy in this setting.

Molecular description of ANGPT2 associated colorectal carcinoma.

Angiopoietin-2 (ANGPT2) is a prognostic factor in metastatic colorectal cancer (CRC). Nevertheless, it remains to be elucidated which molecular characteristics make up the ANGPT2-related poor-prognosis CRC subset. Public transcriptomic datasets were collected from Gene Expression Omnibus GEO and with the TCGAbiolinks R-package for the TCGA. After appropriate normalization, differential expression analysis was performed using Benjamini and Hochberg method for false discovery rate. Plasma from two prospective clinical trials were used to investigate the clinical impact of ANGPT2-related biomarkers. In the 935 samples included in four annotated platforms (GPL) and derived from localized CRC, ANGPT2hi expression conferred a worst overall survival (HR = 1.20; p = 0.02). CRC stage, ANGPT2hi expression but not Consortium Molecular Subtype (CMS) predict overall survival in multivariate analysis. ANGPT2 expression was not correlated with a specific CMS nor to RAS, RAF, MSI, p53, CIN, CIMP genomic alterations. Gene expression analysis revealed that ANGPT2hi CRC subset is characterized by angiogenesis-related gene expression, presence of myeloid cells, stromal organization and resistance to chemotherapy. A prognostic model was proposed using seric levels of ANGPT2, STC1 and CD138 in 97 mCRC patients. Our results provide evidence that ANGPT2 is a prognostic factor in localized CRC and defined a specific CRC subset with potential clinical implementation.