Efficiency of olaparib in colorectal cancer patients with an alteration of the homologous repair protein.

International audiencePrecision medicine is defined by the administration of drugs based on the tumor's particular genetic characteristics. It is developing quickly in the field of cancer therapy. For example, KRAS, NRAS and BRAF genetic testing demonstrates its efficiency for precision medicine in colorectal cancer (CRC). Besides for these well-known mutations, the purpose of performing larger genetic testing in this pathology is unknown. Recent reports have shown that using the poly ADP ribose polymerase (PARP) inhibitor olaparib in patients with homologous repair enzyme deficiency gave positive clinical results in breast, ovarian and prostate cancers. We have reported here the cases of 2 patients with multi-treated metastatic CRC who underwent somatic and constitutional exome analyses. The analyses revealed a loss of function mutation in a homologous repair enzyme resulting in the loss of heterozygosity for both patients (Check2 for the first patient and RAD51C for the second one). Both patients were treated with off-label usage of olaparib. While the first patient showed clinical benefit, reduction of carcinoembryonic antigen tumor marker and radiologic response, the second patient quickly presented a progression of the tumor. Additional genetic analyses revealed a frameshift truncating mutation of the TP53BP1 gene in the patient who progressed. Interestingly, deficiency in TP53BP1 was previously described to confer resistance to olaparib in mice breast cancer models. Our findings suggest that exome analysis may be a helpful tool to highlight targetable mutations in CRC and that olaparib may be efficient in patients with a homologous repair deficiency

An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers

PARP inhibitors yield interesting outcomes for patients with ovarian tumors harboring BRCA1 or BRCA2 mutation, but also with other tumors with homologous repair (HR) deficiency. About 40% of variants are variants of unknown significance (VUS), blocking the use of PARP inhibitors. In this study, we analyzed NGS data from 78 metastatic patients treated with PARP inhibitors. We tested NGS data and in silico predictions to classify VUS as potentially benign or deleterious. Among 41 patients treated with olaparib, three had tumors harboring benign and 26 pathogenic variants, while 12 had VUS. Progression-Free Survival (PFS) analysis showed that benign variants did not respond to olaparib whereas pathogenic variants were associated with a median PFS of 190 days. Surprisingly, median PFS of patients with VUS-carrying tumors suggested that some of them may be sensitive to PARP inhibitors. By testing different in silico predictions and variant allelic frequency, we obtained an algorithm predicting VUS sensitivity to PARP inhibitors for patients with a Performance Status below 3. Our work suggests that VUS in HR genes could be predicted as benign or deleterious, which may increase the number of patients eligible for PARP inhibitor treatment. Further studies in a larger sample are warranted to validate our prediction algorithm

Detection of KRAS, NRAS and BRAF somatic mutations in circulating tumor DNA using two assays of Next Generation Sequencing (NGS) for patients with metastatic colorectal cancer

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Transcriptome-wide identification of transient RNA G-quadruplexes in human cells

In vivo existence of guanine-rich four-stranded RNA structures (G4-RNAs) has been a matter of debate. Here the authors developed a protocol, G4RP-seq, to capture and identify transcriptome-wide G4-RNA, providing insights into the formation of transient G4-RNA in live human cells

The enhancement of radiotherapy efficacy with docetaxel-titanate nanotubes as a new nanohybrid for localized high risk prostate cancer

International audienceFrom 30% to 50% of high risk prostate cancer patients who undergo radiation therapy (RT) will have a biochemical failure. These failures are either due to a poor local control or to distant disease which may also be related to a local failure. Taxane-based chemotherapy has proved to be useful in prostate cancer. Combining chemotherapy, such as docetaxel (DXL), with RT can enhance its efficiency, however systemic injection of the classical formulation leads to 95% uptake by healthy tissues whereas 2−5% only reach tumors; adverse side effects are a crucial problem. Moreover, multidrug resistance mechanisms often limit drug efficacy by decreasing tumor cell intracellular concentration of drugs. There is interest to develop nanocarrier of DXL to maintain drug inside cancer cells by improving its efficacy. In a previous in vitro study, we have highlighted that titanate nanotubes (TiONTs) which have a needle shape can enter and stay inside cancer cells until 10 days without cytotoxic effects induction. We suggest in this study to develop TiONt-DXL nanocarrier and to evaluate its in vivo biodistribution as well as its efficacy in association with RT on a prostate cancer model

Use of dedicated gene panel sequencing using next generation sequencing to improve the personalized care of lung cancer

IF 5.008International audienceAdvances in Next Generation Sequencing (NGS) technologies have improved the ability to detect potentially targetable mutations. However, the integration of NGS into clinical management in an individualized manner remains challenging. In this single-center observational study, we performed a dedicated NGS panel studying 41 cancer-related genes in 50 consecutive patients with metastatic non-small-cell lung cancer between May 2012 and October 2014. Molecular analysis could be performed in 48 patients with a good quality check. One hundred and thirty-three mutations, whose twenty-four unique mutations, were detected. At least one mutation was found in 46 patients. In 58% of cases, the Molecular Tumor Board (MTB) was able to recommend treatment with a targeted agent based on the evaluation of the tumor genetic profile and treatment history. Nine patients (18%) were subsequently treated with a MTB-recommended targeted therapy; four patients experienced a clinical benefit with a partial response or stabilization lasting more than 4 months. In this case series involving patients with metastatic non-small cell lung cancer, we show that including integrative clinical sequencing data into routine clinical management was feasible and could impact on patient therapeutic proposal

Detail of observed <i>TP53</i> gene mutations.

<p>Detail of observed <i>TP53</i> gene mutations.</p