Our Uncommon Cancers Theme aims to address the challenges associated with research into and treatment of cancers classified as ‘uncommon’. The BRC is supporting research that will further our understanding of the biological causes and drivers of uncommon cancers and advance methods of diagnosis, treatments and patient outcomes Improving outcomes in melanoma Research at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London (ICR) has been instrumental in the development of major new treatment options, which have significantly improved outcomes for melanoma patients. ICR research into the BRAF gene laid the groundwork for the development of the targeted drugs dabrafenib and vemurafenib for melanoma and subsequent global clinical trials led by Professor James Larkin, which led to changes in standard of care for patients. Research led by Professor Larkin has also contributed to the approval of drugs called immune checkpoint inhibitors, which harness the immune system to treat melanoma and renal cell carcinoma. Novel test to identify ‘high-risk’ Myeloma Researchers from The Royal Marsden and the ICR, led by Dr Martin Kaiser, have developed a ground-breaking genetic test that can accurately identify a group of multiple myeloma patients classed as ‘high-risk’. Around 20 per cent of multiple myeloma patients are classified as being high risk and typically have poor outcomes, however very little is known about which treatments are most effective for these patients. This novel test will have an important role in a the national clinical trial MUK nine, which wants to assess how effective new combinations of treatments are in patients with high risk myeloma. This trial, which is being led by the University of Leeds, is the first in the UK where newly diagnosed multiple myeloma patients will be genetically screened and grouped according to their risk classification, with high risk patients proceeding to take part in the trial. In addition to improving our understanding of the genetics of melanoma, it is hoped that this trial will provide the evidence needed to change clinical practice from a one-size-fits-all approach to patients receiving treatments tailored to their genetics. Whole body MRI for Myeloma Whole body MRI is a new imaging technique that can define the spread and rate of cancer growth more accurately than standard MRI scans. Researchers from the ICR and The Royal Marsden have led the development of DW-MRI nationally and internationally and have successfully applied this to a variety of tumour types for disease detection. The Royal Marsden researchers also led an international panel of experts in the fields of radiology, medical physics and haematology to design a new clinical protocol for whole-body MRI in myeloma - the Myeloma Response Assessment and Diagnosis System (MY-RADS). This followed guidance from the National Institute for Health and Care Excellence (NICE) that whole-body MRI should be used as a standard, first-line treatment for myeloma patients. The MY-RADS protocol aims to standardise and reduce variation in how whole-body MRI images are taken, interpreted and used to assess how patients are responding to treatment. Although whole body MRI scans for myeloma provide more accurate results, it takes significantly longer for radiologists to interpret the results. In collaboration with Imperial College, The Royal Marsden and ICR researchers are currently leading the MALIMAR trial to find out if computers can be ‘taught’ to detect disease sites on whole body MRI scans to aid radiologists and speed up the process of interpreting scans – ultimately improving access for myeloma patients across the NHS. Progress in paediatric cancers Researchers from The Royal Marsden and ICR led an early-stage study to test the feasibility of a DNA reading tool to find genetic mutations in paediatric solid tumour patients at the point of diagnosis and relapse. This tool could be used to find genetic mutations, or ‘biomarkers’, that cause disease and identify new targets for drugs. This tool was piloted on a national scale in 2016 through a Childhood Cancer and Leukaemia group and in collaboration with Great Ormond Street Hospital and is now being used to sequence DNA from paediatric patients with solid tumours across the country. NHS England has agreed that the panel can be offered to paediatric patients with solid tumours through the North London Genomic Laboratory Hub. After receiving further funding from CRUK, a biomarker testing programme is being introduced to hospitals across the UK and through the CRUK Experimental Cancer Medicine Centre Network. The programme is also being used in international clinical trials to find new drug targets, such as eSMART, which is being carried out in the UK at The Royal Marsden’s paediatric drug development unit. In neuroblastoma, a paediatric cancer, MYCN amplification is strongly associated with unfavourable outcome. ICR researchers showed that a new drug, fadraciclib, may target MYCN-amplified neuroblastoma and therefore could be an important new treatment for this cancer. The drug, which has already passed safety trials in adults, was jointly discovered by ICR scientists in collaboration with the company Cyclacel. Clinical trials for fadraciclib will be carried out as part of the international eSMART clinical trial. Improving outcomes for sarcoma patients In adult rare cancers, our sarcoma researchers successfully leveraged their global industrial collaborations to accelerate regulatory approval of life-extending targeted drugs (tazemetostat, avapritinib and ripretinib, FDA 2020).