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

Precision 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 RAD51 C 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.

Solid solution evolution during mechanical alloying in Cu–Nb–Al compounds

This work concerns the structural evolution of Cu70Nb20Al10(at%) alloy processed by mechanical alloying using a planetary ball mill in air atmosphere for different times(4 to 200 h). The morphological, structural, microstructural, and thermal behaviors of the alloy were investigated by scanning electron microscopy, energy-dispersive spectroscopy, X-ray diffraction, and differential scanning calorimetry. X-ray diffraction patterns were examined using the Rietveld refinement technique with the help of the MAUD software. A disordered FCC-Cu(Nb,Al) solid solution was formed after 8 h of milling. The crystallite size, microstrain, and lattice parameter were determined by the Rietveld method. With increasing milling time, the crystallite size of the final product-ternary-phase FCC-Cu(Nb,Al)-is refined to the nanometer scale, reaching 12 nm after 200 h. This crystallographic structure combines good mechanical strength and good ductility. An increase in microstrain and partial oxidation were also observed with increasing milling time.

EGFR amplification induces sensitivity to antiEGFR therapy in pancreatic acinar cell carcinoma

Pancreatic acinar cell carcinoma(PACC) is a rare cancer. When the tumor is metastatic, few therapeutic options are available. Precision medicine using next-generation sequencing is defined by the administration of drugs based on the tumor genetic mutations. The usage of precision medicine for finding new therapeutic options for rare cancers is an emerging field. We have reported here the case of a patient bearing a multitreated metastatic PACC. This patient underwent somatic and constitutional exome analyses. The analyses revealed in the liver metastasis an amplification of the EGFR gene. Accordingly, the patient was treated with off-label usage of panitumumab. We observed rapid response with necrosis of the liver metastasis, while no efficacy was observed in the primary tumor. An exome analysis of the primary tumor revealed amplification of HER2 and MET with EGFR amplification. Such amplifications are known as a resistance mechanism to anti EGFR therapy. Our results suggest that exome analysis may be helpful to highlight targets in rare cancers, such as PACC. EGFR amplification in this pathology should be determined and could be used as a biomarker to propose anti EGFR therapy.