Breaking oncological paradigms
James Fleck1 & Gabriel Macedo2: Anticancerweb 28(10), 2020
At first, Precision Medicine seemed like fiction, but it gradually became clinically useful for dealing with some types of tumor for which there was no standard treatment or for patients who expressed disease progression after two or more previous unsuccessful treatments. The cornerstone was the identification of a mutation (germline or somatic) that could become a biological target or a predictive biomarker for a new pharmacological action (actionability) in a specific tumor type. Some initial disappointment was due to the low percentage of actionable mutations identified in rare tumors or refractory diseases. More recently, some cutting-edge cancer drugs with a focus on genetic biomarkers, rather than any specific type of cancer, have gained approval and changed the way we diagnose and treat malignant tumors, creating the new tumor-agnostic cancer treatment scenario. Currently, an increasing number of clinical trials are using next-generation sequencing (NGS) to recruit eligible patients, which has resulted in important advances in the understanding of tumor molecular biology, also helping in the development of new anticancer drugs. The new therapeutic options must be considered under a highly qualified multidisciplinary supervision, which has been responsible for the development of Molecular Tumor Board (MTB) concept in highly qualified cancer centers, worldwide.
A Molecular Tumor Board should follow some basic rules: The multidisciplinary team must meet regularly, preferably through videoconferences, which is time saving and allows for participation of experts from multiple institutions. A well-designed administrative profile must be implemented to optimize cost efficiency. Continuous knowledge translation must be sought not only to increase data availability, but also to improve technical education. Surgeons should be informed about the acquisition of sufficient tissue, as well as the proper handling of the material at the time of diagnostic biopsy. An ad hoc report must be provided including the NGS results in the context of each patient's specific clinical assessment. The multidisciplinary team should categorize molecular analysis results according to levels of evidence, preferably supported by prospective randomized trials and FDA approval. Several international classifications and harmonized clinical interpretations from knowledgebases (https://search.cancervariants.org/#*) are already available and the report must clearly specify which one was used. MTB generally fosters very specific and sensitive questions, asking for a comprehensive assessment of the board, which should include various specialties, such as clinical oncologists, cancer surgeons, pathologists, molecular biologists, geneticists, bioethicists, bioinformaticians, research coordinators, pharmacists, data managers, among others. The growing availability of data will soon require improvements in bioinformatics and, eventually, the use of artificial intelligence. A long-term ICER / QALY analysis will indicate the best way to face global health burden, and MTB may come to play an essential role in personalized clinical assessment of cancer patients, improving indices like NNT (number needed to treat) and NNH (number needed to harm). Participation of all stakeholders should be encouraged, generating collective intelligence. The methodology will be standardized soon and the indications expanded, making precision medicine accessible to everyone.
1. James Fleck, MD, PhD is a Full Professor of Clinical Oncology at the Department of Internal Medicine FAMED – UFRGS
2. Gabriel Macedo, MSc, PhD is the Precision Medicine Program – Coordinator at Hospital de Clínicas de Porto Alegre
References:
1. Xuaniy Li & Jeremy Warner: A review of precision oncology knowledgebases for determining the clinical actionability of genetic variants, Front Cell Dev Biol 8: Article 48, Feb 11th, 2020
2. Luchini C, Lawlor R, Milella M and Scarpa A: Molecular Tumor Boards in Clinical Practice, Tends in Cancer 6 (9):738 – 44, 2020
3. Liberati A, Altman D, Tetzlaff J, et al: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339, July 21st, 2009
4. Roychowdhury S, Iyer M, Robinson D, et al: Personalized oncology through integrative high-throughput sequencing: a pilot study, Sci Transl Med 3: 111–121, 2011
5. Mateo J, Chakravarty D, Dienstmann R, et al: A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO scale for clinical actionability of molecular targets (ESCAT). Ann Oncol 29: 1895–1902, 2018
6. Li M, Datto M, Duncavage E, et al: Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists, J Mol Diagn 19: 4–23, 2017
7. Chakravarty D, Gao J, Phillips S, et al: OncoKB: A precision oncology knowledge base, JCO Precis Onco. 1: 1–16, 2017
8. Photo by National Cancer Institute on Unsplash
Precision medicine is a subject of great relevance and that has been growing in the last decade, it aims at a more precise and efficient treatment, with the help of different specialists. It takes into account the individual variability in genes, environment and lifestyle for each person. But this precision does not mean, literally, to create something specific for a single patient, but the ability to classify individuals into subpopulations, in "types of patients", which differ in their susceptibility to a particular disease, in biology and / or prognosis of these diseases or in response to specific treatment. Precision medicine relies not only on molecular biology, but also on the analysis of these complex data (big data analytics), using algorithms and artificial intelligence, and it is this combination that generates the possibility of preventive interventions and "personalization" of the treatment.
The traditional “one-size-fits-all” cancer treatment certainly holds the potential to become outdated in years to come as precision medicine keeps evolving. Cancer is an immensely heterogeneous disease that benefits from a tailored approach based mainly on pharmacogenetics, aiming at ensuring specific therapies for particular subsets of tumors (with variable sets of genetic mutations and protein expression). This personalized therapeutic strategy can offer key advantages as it may minimize treatment toxicity and maximize treatment efficacy. However, the delivery of precision medicine remains restricted by our capability to interpret the genomic alterations and match them with the most appropriate targeted agents or immunotherapies, which is what makes the formation of these Molecular Tumor Boards so valuable.
Precision Medicine is a tool in which genetics has a fundamental role for us to have a new expectation when it comes to cases of patients with tumors that had no treatment or patients with disease progression after unsuccessful treatments. Undoubtedly, this requires many steps to put it into practice, as a team full of experts. A Molecular Tumor Board can change the assessment made today in cancer patients around the world, which modifies several epidemiological indices if it is more and more widespread.
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