The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small-molecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment. Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for single-driver mutations have been implemented. Improvements in DNA- and RNA-based next-generation sequencing technologies enable analysis of a group of genes in one assay; however, turnaround times remain relatively long. Consequently, rapid screening technologies are being implemented alongside next-generation sequencing. Further challenges in the evolving landscape of biomarker testing in NSCLC are actionable primary and secondary resistance mechanisms to targeted therapies. Therefore, comprehensive testing on re-biopsies, collected at the time of disease progression, in combination with testing of circulating tumour DNA may provide important information to guide second- or third-line therapies. Furthermore, longitudinal biomarker testing can provide insights into tumour evolution and heterogeneity during the course of the disease. We summarise best practice strategies for Europe in the changing landscape of biomarker testing at diagnosis and during treatment.

Background : Multimodal therapeutic strategies have improved the outcome of peritoneal metastases (PM). However, objective assessment of therapy response remains difficult in PM, since radiological studies have a poor accuracy for low-volumetric disease. There is an obvious need for a histological gold standard allowing assessment of tumor response to treatment in PM. Content : We propose to perform peritoneal punch biopsies with a diameter of 3 to 5 mm in all four abdominal quadrants. We propose a four-tier Peritoneal Regression Grading Score (PRGS), defined as Grade 1: complete response (absence of tumor cells), Grade 2: major response (major regression features, few residual tumor cells), Grade 3: minor response (some regressive features but predominance of residual tumor cells), Grade 4: no response (tumor cells without any regressive features). Acellular mucin and infarct-like necrosis should be regarded as regression features. We recommend reporting the mean and the worst value of the regression grades obtained. When complete tumor response is suspected intraoperatively, a peritoneal cytology should be sampled. Summary : A generic, unique score for the assessment of histological tumor response to chemotherapy in PM makes sense because of the clinical impact of histological response to therapy and because the organ of metastasis (peritoneum) is the same. By adopting PRGS, different centers will be able to use a uniform terminology and grading that will allow meaningful comparison of their results. Outlook : PRGS has now to be validated in several gastrointestinal and gynecological cancer types and may be useful both in clinical and research settings.

Sporadic or hereditary colorectal cancer (CRC) with microsatellite instability (MSI) is frequently characterized by inflammatory lymphocytic infiltration and tends to be associated with a better ou...

Metastatic colorectal cancer (mCRC) is one of the major causes of cancer-related death. Despite the substantial progress in mCRC management, it remains important to identify new therapeutic options and biological markers for personalized medicine. Here, we investigated the expression of claudin-1 (CLDN1), a major tight junction transmembrane protein, in the different colorectal cancer (CRC) molecular subtypes and then assessed the anti-tumor effect of a new anti-CLDN1 monoclonal antibody (mAb). Gene expression profiling and immunochemistry analysis of normal and tumor tissue samples from patients with stage IV CRC were used to determine CLDN1 gene expression. Then, the 6F6 mAb against CLDN1 extracellular part was generated. Its effect on CRC cell cycle, proliferation, survival and migration was assessed in vitro, using a 3D cell culture system, flow cytometry, clonogenic and migration assays. In vivo, 6 F6 mAb efficacy was evaluated in nude mice after subcutaneous xenografts or intrasplenic injection of CRC cells. Compared with normal mucosa where it was almost exclusively cytoplasmic, in CRC samples CLDN1 was overexpressed (p < 0.001) and mainly localized at the membrane. Moreover, it was differentially expressed in the various CRC molecular subtypes. The strongest expressions were found in the consensus molecular subtype CMS2 (p < 0.001), the transit-ampliflying (p < 0.001) and the C5 subtypes (p < 0.001). Lower CLDN1 expression predicted a better outcome in the molecular subtypes C3 and C5 (p = 0.012 and p = 0.004, respectively). CLDN1 targeting with the 6 F6 mAb led to reduction of survival, growth and migration of CLDN1-positive cells. In preclinical mouse models, the 6F6 mAb decreased tumor growth and liver metastasis formation. Our data indicate that CLDN1 targeting with an anti-CLDN1 mAb results in decreased growth and survival of CRC cells. This suggests that CLDN1 could be a new potential therapeutic target.

Poly(adenosine diphosphate–ribose) polymerase 1 (PARP-1) and the balance between BRCA1 and 53BP1 play a key role in the DNA repair and cell stress response. PARP inhibitors show promising clinical activity in metastatic triple negative (TN) or BRCA-mutated breast cancer. However, a comprehensive analysis of PARP-1 activity, BRCA1 promoter methylation and 53BP1 expression in tumours without known BRCA1 mutation has not yet been carried out.

Rare peritoneal cancers represent complex clinical situations requiring a specific and multidisciplinary management. Because of their rarity, lack of awareness and knowledge often leads to diagnostic delays and misdiagnosis. And patients are not systematically referred to expert centers as they should be. Clinicians and researchers also face unique challenges with these rare cancers, because it is hard to conduct adequately powered, controlled trials in such small patient population. This is how an observational patient registry constitutes a key instrument for the development of epidemiological and clinical research in the field of these rare cancers. It is the appropriate tool to pool scarce data for epidemiological research and to assess the impact of diagnostic and therapeutic strategies. We aimed to provide the outlines and the framework of the RENAPE observational registry and share our experience in the establishment of a national patient registry. The RENAPE observational registry has been launched in 2010 thanks to institutional supports. It concerns only patients with a histological diagnosis confirming a peritoneal surface malignancy. A web secured clinical database has been implemented based on data management procedures according to the principles of international recommendations and regulatory statements. A virtual tumor bank is linked in order to the conduct translational studies. Specialized working groups have been established to continuously upgrade and evolve the common clinical and histological data elements following the last classifications and clinical practices. They contribute also to standardize clinical assessment and homogenize practices. The RENAPE Registry may improve awareness and understanding of the rare peritoneal tumors into the incidence, prevalence, recurrence, survival and mortality rates, as well as treatment practices thereby enabling therapeutic intervention to be evaluated and ultimately optimized. ClinicalTrials.gov Identifier: NCT02834169