I. Walker

The National Lung Matrix Trial: Translating the Biology of Stratification in Advanced Non-Small Cell Lung Cancer

The National Lung Matrix Trial is currently the largest stratified medicine study in lung cancer. Utilizing a next-generation sequencing screening platform and an adaptive umbrella trial design, we will explore the activity of multiple biomarker/targeted therapy options in order to expand the precision medicine opportunities for patients with non-small-cell lung cancer.

Lessons for molecular diagnostics in oncology from the Cancer Research UK Stratified Medicine Programme.

The implementation of stratified medicine in modern cancer care presents substantial opportunity to refine diagnosis and treatment but also numerous challenges. Through experience in a UK tumor profiling initiative, we have gained valuable insights into the complexities and possible solutions for routine delivery of stratified cancer medicine.

A collaborative approach to enabling stratified cancer medicine in the UK

Embedding stratified cancer medicine into the patient pathway will require adaptation of the diagnostic pathway to incorporate predictive molecular analysis, presenting challenges of accessing tumour samples of sufficient quality and quantity for analysis and ensuring the timeliness, accuracy, and clinical validity of results. In 2010, Cancer Research UK (CRUK), in partnership with AstraZeneca and Pfizer, set up the Stratified Medicine Programme (SMP1) to work collaboratively with a small number of hospital and genetics laboratories to demonstrate the feasibility of testing large volumes of samples, while working towards more standardised and efficient processes. By June 2013, 9010 patient samples had been sent for genetic testing and here we present an overview of our experience and the wealth of insights that have been generated into the complexities of attempting this transformation of National Health Service (NHS) care.

Somatic cancer genetics in the UK: real-world data from phase I of the Cancer Research UK Stratified Medicine Programme

Introduction Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. Methods A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3–5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups. Results 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers. Conclusion Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx.

529 The Cancer Research UK Stratified Medicine Programme: From national screening to national trial

Background: The increasing demand for analysis of multiple predictive genetic markers in tumour samples to guide therapeutic decision-making requires the rapid validation and uptake of new knowledge and technology, as well as collaboration between clinical teams, cellular pathology and molecular genetics laboratories. Material and Methods: Between 2011 and 2013, formalin-fixed paraffinembedded tumour samples from patients consented through a network of hospitals underwent targeted mutation analysis. This was initially performed using Sanger sequencing and similar methods but following cross-validation an amplicon-based targeted next generation sequencing panel was implemented. Clinical information based on the requirements of the national cancer registration dataset was also centrally collated for each participant. The current second phase of the initiative has a sole focus on patients with advanced lung cancer, and aims to expand the geographical reach to perform molecular pre-screening of samples to help determine patient eligibility for the National Lung Matrix Trial, a multi-arm stratified phase II clinical trial of novel therapeutics. Results: 10,754 patients (98% of those approached) consented to analysis of material during phase one, with 9010 samples submitted for analysis. The table shows the overall results of analysis for the first 7850 samples. Analysis by histological subtype enriches for certain mutations, with 925 pulmonary adenocarcinomas showing 36.5% KRAS mutations, 11.6% EGFR mutations and 2.5% ALK gene rearrangements and 56 mucinous colorectal adenocarcinomas showing 43.5% BRAF mutations and 50% KRAS mutations. Conclusions: A centralised national testing network for genetic analysis of formalin-fixed paraffin-embedded tumour samples is feasible and acceptable to patients and clinicians, with applications beyond genotyping for currently licensed oncologic therapies. Acknowledgements: Funding for the Stratified Medicine Programme is acknowledged from Cancer Research UK and programme founding partners AstraZeneca and Pfizer.