Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting.

To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients. Somatic mutations had >80% biallelic inactivation frequency and were predominantly clonal, suggesting that BRCA1/2 loss occurs early in the development of these cancers. Clinical outcomes between placebo- and olaparib-treated patients with somatic BRCA1/2 mutations were similar to those with germline BRCA1/2 mutations, indicating that patients with somatic BRCA1/2 mutations benefit from treatment with olaparib.

Panel based MALDI-TOF tumour profiling is a sensitive method for detecting mutations in clinical non small cell lung cancer tumour.

BACKGROUND: Analysis of tumour samples for mutations is becoming increasingly important in driving personalised therapy in cancer. As more targeted therapies are developed, options to survey mutations in multiple genes in a single tumour sample will become ever more attractive and are expected to become the mainstay of molecular diagnosis in non-small cell lung cancer (NSCLC) in the future. MATERIALS AND METHODS: 238 non-small cell lung cancer (NSCLC) tumour samples were analysed using a custom panel of 82 mutation assays across 14 oncogenes including KRAS and EGFR using Sequenom iPlex Matrix Assisted Laser Desorption/Ionisation Time of Flight Mass Spectrometry (MALDI-TOF). We compared the data generated for KRAS mutations to those detected by Amplification Refractory Mutation System (ARMS) based DxS TheraScreen K-RAS Mutation Kit. RESULTS: The ARMS detected mutations in 46/238 tumour samples. For samples with mutations detected by both approaches, 99.1% overall agreement was observed. The MALDI-TOF method detected an additional 6 samples as KRAS mutation positive and also provided data on concomitant mutations including PIK3CA and TP53. CONCLUSIONS: The Sequenom MALDI-TOF method provides a sensitive panel-based approach which makes efficient use of patient diagnostic samples. This technology could provide an opportunity to deliver comprehensive screening of relevant biomarkers to the clinic earlier in disease management, without the need for repeat biopsy and allow for additional downstream analysis in NSCLC where available tissue may have been exhausted.

Targeted therapies in colorectal cancer-an integrative view by PPPM.

In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.

Circulating tumour-derived predictive biomarkers in oncology.

Molecular characterization of tumour material will become increasingly important in selecting patients for clinical trials and offering appropriate treatment for patients in clinical practice. Recent advances in the field have indicated that the molecular characteristics of a tumour can be determined from circulating tumour cells and circulating tumour DNA; thus, a simple blood sample could provide these data in a simple, convenient and efficient manner. This article discusses progress towards guiding treatment decisions through measuring tumour-derived factors in the circulation.