A.J. van Puffelen; M.A. Pruis; E. Cuppen & M.P.J.K. Lolkema

Suppose you are a patient with metastatic cancer and you are running out for treatment options in the regular setting, but you are still in a good condition; you are a so called ‘last resort patient’.  In general, there a two options: you can wait and see and the medical care is focused on symptom management, so called Best Supportive Care (BSC). The second option is to opt for participation in an early-phase clinical trial. Then you will receive an experimental treatment with  a (small) chance on benefit that could prolong your life.

Early-phase clinical trials can be divided into three categories;  (1)all-comer design trials, (2) enrichment design trials, i.e. targeted or biomarker-guided trials, and (3) master protocol trials, i.e. basket and umbrella trials [1]. With the onset of precision oncology and personalized targeted medicine, the proportion of the latter two categories increases considerably. These trials might be beneficial for patient outcomes, because it targets a specific feature of the tumor [2]. To identify trials that match a patient’s cancer characteristics, molecular testing of the tumor material will often be required.

Back to the patient: You have decided that you want to participate in an early-phase trial, hoping for an anti-tumor effect and because you contribute to clinical research in order to help future patients. After discussing this with your medical specialist, you’ve learned that there are some options, but we need to know first if the specific features are present in your tumor. So a biopsy is taken and sent to the laboratory for testing for the specific feature, which is targeted with the agent under testing  in the trial. This is the prescreening. A couple of weeks later, you receive the results, and in case these are positive, you can start with the actual screening for the trial. It could take up to two months or even longer, after the initial discussion with your medical specialist, before you start with treatment. It could also be the case, that the test is negative, and you have to look for another option, maybe also with an independent prescreening. This costs a lot of time, time which is very precious in this stage of disease. So instead of using a trial and error approach to see if a patient fits in trial A and then B and then C, shouldn’t we turn this around and first characterize the complete tumor and then ask the question which available trials match the individual’s tumor characteristics?

Technological advances make this possible. With Whole Genome Sequencing (WGS) the complete tumor DNA from an individual tumor biopsy can be characterized in detail. This may help to better understand the mutational and driver landscape of a cancer genome and can give an explanation for the functional and/or clinical implications [3]. For the patient, it can identify relevant biomarkers which can lead to more treatment options in clinical trials.

In our recent research [4] we showed that WGS on fresh frozen tumor biopsies, is a feasible tool for the selection of personalized experimental therapy for the last resort patient. In 84% of the 31 patients who underwent a tumor biopsy for WGS, at least one actionable event was found. One third (11/31) of the patients received matched experimental treatment, based on the results of WGS. Also, the turnaround time between the biopsy procedure and return of the WGS test results,  is less than two weeks, which is an acceptable time and the patient only needs to go once through this procedure to have all options available. Thus, WGS  could fulfil the role of a universal genomic prescreening test, what is beneficiary for the patient.

The question is how large these prescreening must be: do we need WGS, or could a smaller set of genes, like TSO500, gain the same level of insight? One advantage of WGS is that it does not miss anything, because there is no predefined set of tests for genes, a so called panel. The choice for the panel depends heavily on the tumor type and the willingness to look for (very) rare alteration. With WGS analysis all genomic information is readily available for clinical practice and the results are not depending on the specific choice for a test or panel by the treating clinician[4].

With WGS we find more leads for a possible treatment, but this specific treatment also should be available in practice. This could form a dilemma.  Treatments are registered for specific indications which cannot be easily switched. For example: with WGS we find a PIK3CA mutation in a prostate carcinoma, which could be a driver. In breast cancer, patients with this mutation could receive a treatment with Alpelisib, but for our prostate cancer patient this is not available in the regular setting or in a trial. What is then the actionability of WGS?  On the other hand, all the collected data from individual tumor material, helps researchers with building up knowledge; this is possible because of the bioinformatics and reporting pipelines are open source.Also, it could accelerate the setup of novel clinical trials for testing regular treatments for other indications or for developing agents for newly discovered targets. This means more treatment options, which is beneficiary for the patient and will improve the actionability of WGS.

The use of WGS also raises the topic about incidental findings about genetic  predispositions, which may not only be relevant for the patient, but also for their relatives. Potentially, this could have a huge impact for these individual persons.  They should be aware of this possibility of incidental findings and how they want to be informed about it. Therefore, they need to be properly informed, starting upfront.  This is an important responsibility for the clinician and should be part of the whole procedure.

Altogether, we find that WGS is a feasible and valuable tool in the last resort setting, for finding more treatment options with the chance on prolonging the life of these patient group. Therefore, we feel it should be made available for every last resort patient. Also, the knowledge we gather with WGS can bring us a step closer to our goal to find an effective and suitable treatment for every single patient, not based on ‘one size fits all’ but adjusted to the characteristics of the patient and the tumor.

Link to article

Literature

1. Bui NQ, Kummar S. Evolution of early phase clinical trials in oncology. J Mol Med. 2018;96:31–8.
2. Fontes Jardim DL, Schwaederle M, Wei C, Lee JJ, Hong DS, Eggermont AM, et al. Impact of a biomarker-based strategy on oncology drug development: a metaanalysis of clinical trials leading to FDA approval. J Natl Cancer Inst. 2015;107:1–11.
3. Nelson AC, Yohe SL. Cancer whole-genome sequencing: the quest for comprehensive genomic profiling in routine oncology care. J Mol Diagn. 2021;23:784–7
4. Pruis MA, Groenendijk FH, Badloe KS, van Puffelen A, Robbrecht D, Dinjens WNM, et al. Personalised selection of experimental treatment in patients with advanced solid cancer is feasible using whole-genome sequencing. British J Cancer 2022.