AACR 2016 - Precision medicine in paediatric cancer
29 April 2016, Nadina Grosios, Director Consultancy
One of the topics that featured at length in this year’s annual meeting of the American Association for Cancer Research (AACR) was paediatric oncology. Progress and challenges were discussed in aspects across the spectrum from genomics, epigenetics, novel targets and clinical trials to screening, surveillance and survivorship. Despite the high success rate in treating most haematological paediatric cancers, for relapsed disease and for solid paediatric tumours there is still a great unmet clinical need. Half of all chemotherapies used for children’s cancers are over 25 years old (www.kidsvcancer.org). Moreover, even though characterising the genetics of paediatric tumours has been fundamental in our understanding of cancer genetics in general, precision medicine and targeted therapies have had much less influence in paediatric oncology. The situation may however be gradually improving.
Beyond large scale genomics projects intending to catalogue genetic alteration in adult and paediatric cancers, there are currently underway several multidisciplinary initiatives investigating the application of genome-scale sequencing in different clinical settings with the aim to ultimately help identify “potentially actionable findings”, i.e., a) germline mutations affecting the patient, relatives, or both, b) tumour-specific alterations altering the histopathological diagnosis, change risk status, or both, and c) medically targetable somatic mutations (Schnepp et al., 2015).
One of the first such studies in paediatrics, the Peds-MiOncoSeq study, was highlighted by David Malkin (The Hospital for Sick Children, Toronto). It involved 102 children and young adults with relapsed, refractory or rare cancers and used exome (but not whole exome) and transcriptome sequencing to reveal actionable findings in 46% of the patients (Mody et al., 2015). This led to a clinical action in 25% of the cases that in 10% of patients resulted in durable clinical responses and in another 10% germline findings influenced clinical care by means of formal counselling and genetic screening.
The Baylor College of Medicine Advancing Sequencing into Childhood Cancer Care (BASIC3) project, presented by Williams Parsons (Texas Children’s Cancer Centre/ Baylor College of Medicine), enrolled children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumours. Its first formal report concluded that using combined tumour and germline Whole Exome Sequencing (WES), approximately 40% of newly diagnosed paediatric solid tumour patients (out of the 121 patients with adequate samples) had diagnostic and/ or potentially actionable findings. More specifically, 27% of patients harboured somatic mutations of established or potential clinical utility and approximately 8% had pathogenic or likely pathogenic germline mutations in adult and paediatric cancer susceptibility genes (Figure 1).
Katherine Janeway (Boston Children's Cancer and Blood Disorders Centre/ Dana-Farber) described the Individualized Cancer Therapy (iCAT) study; a multicentre precision medicine clinical trial that enrolled 100 patients aged 30 years or younger with high-risk recurrent or refractory extra-cranial solid tumours. This study identified potentially actionable findings in 43% of these patients and the expert panel convened made appropriate clinical recommendations in 31 patients (31%) and three patients received matched therapy (Figure 2).
A common finding of these studies, confirming similar results from previous work, is that germline mutations are found in approximately 8-10% of children and adolescents with cancer. Furthermore, as a few of the presenters pointed out, family history is not always predictive of the underlying cancer predisposing condition. As with adult tumours this type of work has identified alteration in existing (e.g. Wnt, BRAF, MEK, FGFR, ALK, PI3K/ mTOR) but also novel (e.g. SMARCA4, PAX3-FOXO1) genes that could be exploited in terms of targeted therapy. To date this however has proven to be a key challenge in the treatment of children with cancer. One of the barriers to the administration of matched targeted therapy identified by the iCAT study was that paediatric oncologists were unable to find or enrol their patients in a suitable clinical trial, resulting in only 3 of the 31 patients being able to receive a matched therapy.
That is a gap that many, including the National Cancer Institute (NCI), are trying to address. The NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) is a precision medicine 24-arm clinical trial exploring treating patients based on the molecular profiles of their tumours. It is funded through the Precision Medicine Initiative® (PMI) in the USA and opened for adult recruitment in August 2015. It is expected to start enrolling paediatric cancer patients by the end of 2016.
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