Adolescent and young adults (AYAs) with cancer are likely to have germline genetic variants associated with cancer predisposition that may present targets for approved therapeutic agents, according to an article appearing in the European Journal of Cancer.
However, an audit of germline and tumour testing procedures in patients being treated at a large institution revealed few patients actually received testing.
Terri Patricia McVeigh MD, Clinical Research Fellow at the Cancer Genetics Unit, and colleagues at the Royal Marsden NHS Foundation Trust, London, UK reviewed data regarding clinicopathological features, clinical assessments, as well as, information regarding germline and tumour genetic testing from AYAs with advanced solid tumours who were managed in the specialist drug development unit (DDU), at the Royal Marsden Hospital between 2002 and 2016. Currently, eligibility for clinical trials is discussed at a weekly Patient Allocation Meeting, where factors, such as tumour type, and results of germline and somatic assessment are considered, with the aim of allocating patients to trials investigating the utility of agents targeting the gene in question or a key pathway in which it is involved.
This review, which aimed to determine whether germline genetic assessment had been done and the effect on treatment of tumour molecular profiling included 219 patients aged 15 to 39 years; 139 patients were female and 80 were male.
The common cancer types in the study included 41 (19%) patients with sarcoma, 27 (12%) with cervical cancer, 25 (11%) with breast, 23 (11%) ovarian, and 21 (10%) of patients with colorectal cancers. Cancers occurring at a lower frequency included melanoma, cholangiocarcinoma, hepatocellular carcinoma, and adrenal cortical cancer, as well as cancers of the brain, head and neck, lung, bladder, kidney, endometrium and others. Germ cell cancers were recorded in 4 (2%) patients.
Documentation of family history of AYAs with cancer is often unsatisfactory
No family history information had been documented in either the referral documents or clinical notes for 81 (37%) of AYA patients initiating treatment for cancer. A family history positive for cancer, including a first degree relative with cancer, was documented for 24 patients; of these, nearly half (10 patients) were noted to a have potentially shared genetic aetiology. Of 42 patients with at least one second-degree relative with cancer, 19 had a cancer with potentially shared genetic susceptibility. The family history of 40 patients was recorded as ‘non-contributory’ in the clinical notes, with no detail given as to whether the information sought was limited to first- degree relatives, or whether a history of other cancers was present in the family.
The investigators found that germline testing had been carried out in just 34 (16%) of these patients. Under current testing criteria, an additional 32 (15%) would have been eligible for germline testing based solely on their personal history of cancer alone.
Some AYAs without a family history of cancer should have germline genetic testing
Of the 34 patients undergoing germline test, a pathogenic variant was detected in the majority, or 22 (64%) patients. The pathogenic variants most commonly reported were BRCA1, in 15 patients and BRCA2 in 3 patients; these genetic variants occurred in 8 patients with ovarian, and 10 patients with breast cancer. The genetic reports were not available for review in approximately one-third (12) of patients.
In most cases genetic testing was undertaken only after formal consultation with a genetic specialist. Just 3 patients had analysis of BRCA1 and BRCA2 as part of the mainstreaming genetic testing pathway; 18 additional patients would have been eligible under current guidelines for mainstreamed BRCA1/BRCA2 analysis. One case in point was an individual who was assessed by a clinical geneticist at the time of diagnosis but did not fulfill the testing criteria at the time of her review and died before criteria for testing were loosened.
Tumour-based genetic testing may identify clinically targetable mutations
Tumour testing for somatic putative targetable variants was done in fewer than 46 (21%) of the AYAs undergoing cancer treatment. Thirteen tumours were tested using the 48-gene panel, which yielded no somatic variants with allele frequency greater than 5% (major variant); however, one major variant at 5% was identified in 26 (58%) tumours. The most commonly detected somatic mutations were in TP53 (13 samples, 28%); PIK3CA (8, 18%); KRAS (4, 9%), and MET (5 samples, 11%). Increasing the panel size to 113 genes increased the yield of variants.
Genomic/somatic mutation information allowed clinical trial participation
Thirteen (72%) of the 18 patients with pathogenic BRCA1/BRCA2 variants were allocated to a trial evaluating the efficacy of a Poly-ADP-ribose polymerase (PARP) inhibitor, and 4 other BRCA mutation carriers entered trials investigating an agent involved in dsDNA damage response pathways. Out of all 46 patients undergoing tumour molecular characterisation, 9 entered trials based on their underlying germline defect, and 7 participated in trials of agents targeting identified somatic mutations or genes in a related pathway.
Potentially actionable somatic mutations were identified in 15 individuals; however, either no suitable trials or no slots within appropriate trials were available. Allocation to a trial was not altered by tumour profiling in 3 patients, but they could be assigned on their tumour histology or immunophenotype. Three patients were enrolled in an immunotherapy trial based upon the crude number of mutations identified, which was considered a surrogate marker of high mutational load.
The authors pointed out that a significant proportion of AYAs with advanced cancer have targetable somatic or germline mutations. It is critical for heritable cancer predisposition to be recognised in AYA patients, as it may have significant implications for the treatment and surveillance of the patient and also inform management of at-risk relatives. Ideally, diagnosis of a cancer predisposition syndrome should occur at an early stage in the patient's treatment, to guide decision-making.
Overall, 40% of this cohort would have qualified for germline genetic testing using today's criteria based on their personal history alone, and it is likely that a greater proportion still would also qualify if accurate family history information had been recorded.
Involvement of a cancer geneticist routinely in the multidisciplinary care of this unique young cohort would help optimise the overall treatment of the patient and their family, particularly in cases where the patient has limited life expectancy.
Support by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research was disclosed. Dr McVeigh is also supported by the Health Research Board/Health Service Executive and Dr Sundar was supported by the National Medical Research Council Research Fellowship.
McVeigh TP, Sundar R, Diamantis N, et al. The role of genomic profiling in adolescents and young adults (AYAs) with advanced cancer participating in phase I clinical trials. EJC 2018; 95:20-29. DOI: https://doi.org/10.1016/j.ejca.2018.02.028