Tumor-agnostic, histology-independent cancer therapy
James Fleck: Anticancerweb 29 (06), 2020
Fortunately, we are at the beginning of a new era in cancer assessment and treatment. Molecular biology has been responsible for a great improvement in the recognition of the microenvironmental characteristics of cancer, which goes far beyond cellular and tissue morphology. High-throughput sequencing studies of human cancer suggest genetic instability as a hallmark of tumor biology, not only in hereditary diseases, but also in a special group of non-hereditary malignancies. High microsatellite instability (MSI-H) / mismatch repair-deficiency (MMR-d) and high tumor mutational burden (TMB-H) are predictive markers for immunotherapy in a wide variety of tumors not necessarily histologically related. The genetic signature of mismatch repair-deficient tumors harbor 10 to 100 times more mutations than mismatch repair-proficient tumors. MMR-d is associated with mutations in repetitive DNA sequences (microsatellites) showing high microsatellite instability. MMR-d is observed in a wide range of histology-independent primary tumors, like endometrial cancer, gastric cancer and colorectal cancer, among others. Mutations, produced mainly by DNA-frame deletions or insertions result in mutant neoantigens. When neoantigens are presented by the major histocompatibility complex, the tumor could be better recognized by the host immune system. In response, trying to protect themselves, the MMR-d / MSI-H tumor cells increase the expression of programmed death ligand-1 (PD-L1). In addition, a greater number of tumor infiltrating lymphocytes (TIL) exhibits upregulated checkpoint proteins, including programmed death-1 (PD-1). Despite the attempt to protect, both phenotypic expressions make these tumors particularly susceptible to immunotherapy with checkpoint inhibitors PD1 / PD-L1.
Recently published in October, 2019 in the Journal of Clinical Oncology, the results of phase II Keynote-158 study demonstrated a RECIST response rate of 34.3% using pembrolizumab (anti-PD-1) in patients with previously treated unresectable or metastatic MMR-d / MSI-H tumors. Approximately, one third of the patients with objective response had a complete response. The median overall survival among 27 MMR-d / MSI-H different tumor types was 23.5 months. Kaplan-Meier analysis showed that more than three quarters of the responders had durable responses, which leads to an estimated 24-months overall survival rate of 48.9%. Immune-mediated adverse events and infusion reactions were reported in 23.2 % of the patients, but most were grade 1 and 2. The results observed in this study supported the tumor-agnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer. Tumor mutational burden (TMB) has also been used as a prognostic and predictive marker. However, some drawbacks still limit the adoption of TMB for clinical decision making. Target panel sequencing might overestimate TMB due to panel design biases and there is no clear definition of what should be called a high TMB (TMB-H), ranging from 10 to 20 mutations / megabase. Currently, inconsistency has been overcome using whole-exome sequencing (WES) or improving the robustness of the TMB through a new statistical model with a predictive Bayesian structure, called ecTMB (estimation and classification of TMB). Regardless of the method used to assess tumor mutational burden, the microenvironmental phenotype will soon be guiding personalized cancer treatment, further improving cost-benefit ratio.
RECIST = Response Evaluation Criteria in Solid Tumors
References:
1. Aurelien Marabelle, Dung T. Le, Paolo A. Ascierto, et al: Efficacy of Pembrolizumab in Patients with Non-colorectal High Microsatellite Instability/ Mismatch Repair–Deficient Cancer: Results from the Phase II KEYNOTE-158 Study, J Clin Oncol 38:1-10, 2019
2. Lijing Yao, Yao Fu, Marghoob Mohiyuddin & Hugo Y. K. Lam: ecTMB: a robust method to estimate and classify tumor mutational burden, Nature, 10:4983, 2020
These studies shed more light to the fact that advances upon biochemichal and genetic assessment can repercute not only on individual therapeutic modalities in cancer subtypes, but rather on a myriad of diseases converging to a similar genetic profile. For me, particularly, it highlights that the so pursued widespread "cancer cure" is no longer a medical reverie, and is actually translating itself in accurate description and profiling of biochemical features in tumor types. With the advent of machine learning and big data, the possibility for correlation and therapeutic combination goes sky-high, and the practical upgrades in cancer management may startle even the most skeptical scientist.
Today, it is already possible to find excellent rates of response to cancer in specialized centers, with cure rates ranging from 60 to 65%. With the advances we are witnessing in studies of oncogenesis and molecular biology we will certainly achieve higher cure rates over time, making cancer a less impactful diagnosis from a physical and emotional point of view and providing a better quality of life for those who receive that diagnosis.
Molecular medicine is an important factor related to almost all diseases, unfortunately this knowlegde isn’t part of daily practice in the majority of specialties yet. In oncology, however, the genetics already is a clinical practice reality and plays an important role on daily decisions of an oncologist. It seems that physicians have a general trend to expect always cure their patients, and so must deal with some frustration when it isn’t possible. But researches like RECIST come to show us that even though patients can’t be cured it is possible to increasing months overall survive rate, what is outstanding.
Cancer is a genetic disease and as medicine advance with molecular biology more the understanding of its mechanisms come to light. Knowing exactly which are the mutations that cause cells to behavior in a harmful way and being able to escape the immune system will permit researchers to counter attack the disease healing or prolongating the life of patients. I hope that in the future studies like RECIST will make possible that witch patient with a dangerous cancer receive a treatment that can attack every important mutation/protein in the tumor.
The development of new therapeutic strategies should therefore be triggered by the understanding of the underlying biology through sophisticated clinical trials. Targeting specific pathways has open the hope of a more focused and personalized medicine which has the potential to bring more efficient and tailored treatments to patients. Nevertheless, a number of innovative solutions to address biological challenges across histologies have been initiated and the question of whether histology agnostic trials could be conceived is a logical next question. So, the hope remains in the attempt of using a treatment that can prevent and attack the mutations e proteins of each tumor.
With the advance of the molecular diagnosis and the personalized treatment of the tumors, the medical science is going to a new level of specificity, and this will require multidisciplinary teams to be able to provide an evidence-based treatment. The use anti-PD-1 in patients with MMR-d / MSI-H tumors is just another example of the complexity of the cancer treatment.
It is very exciting to know that we live in a new era in cancer treatment and diagnostic, in which molecular biology has allowed us to know more about the genetic e microenvironmental characteristics of several tumors. Although a long path needs to be taken to make the high microsatellite instability (MSI-H) / mismatch repair-deficiency (MMR-d) and high tumor mutational burden (TMB-H) are predictive markers for immunotherapy in a wide variety of tumors used in everyday medical practice and widely available to the patients.
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