Presentation by Dr Michael Berger, Memorial Sloan Kettering Cancer Center
Patient’s cancers, and their plan of treatment are often as unique and individualized as the patients that have them are. As such, the use of what is known as ‘precision medicine’ in the setting of oncology is generally based on the identification of specific molecular alterations in a patient’s tumor that allow for uncontrolled growth and proliferation. Accordingly, the targeted inhibition of this molecular alteration can shut down the tumor’s growth pathway in a very specific manner, and often with limited toxicity. Moreover, the study of gene alterations in cancer at the larger, population-based level, can lead to better diagnostic methods and a greater understanding of cancers in general. At the 2022 OneOncology conference held in Nashville, Tennessee, Dr Michael Berger from the Memorial Sloan-Kettering Cancer Center (MSKCC) highlighted the evolution of precision medicine approaches at his center, and the promise it holds for the future.
The fundamental principle of precision medicine in oncology relies on an understanding of the changes in gene expression between the tumor (T), and the corresponding normal tissue (N), for example, breast cancer as compared with normal breast tissue. Dr Berger noted the example of testing in lung cancer, for which many molecular alterations have been identified and targeted for drug therapy. Over the last decade, testing in a newly diagnosed lung cancer patient has evolved from the use of many different tests (with differing technologies and efficiencies) on a very limited lung biopsy sample, to the use of advanced technologies such as next-generation sequencing (NGS) that allows for a much more efficient, simultaneous assessment of a wide range of genetic markers using the same sample, with a single test. The program at MSKCC (termed MSK-IMPACT), for example, now has accumulated a matched tumor/normal (T/N) profile for some 505 cancer-related genes. MSK-IMPACT has also accumulated a vast database of information from over 86,000 tumors across more than 68,000 patients, and 88 cancer types.
Dr Berger outlined the many benefits of applying this type of T/N testing on a population-scale, which can allow for precision diagnosis and therapy selection for an individual patient’s cancer. He highlighted the program at MSKCC, called OncoKB, which is an FDA-recognized clinical knowledge database that entails a comprehensive diagnostic assessment for every cancer patient. The program thus far has enabled the detection of at least one “targetable” genetic alteration in between 34% and 69% of patients. Targetable refers to the potential for a given genetic alteration (and therefore the tumor) to be specifically inhibited by an available drug or class of drugs.
Patients at Dr Berger’s center thus receive a personalized MSK-IMPACT report that describes alterations such as mutations (changes in a specific gene), gene amplifications (increased copies of a gene), and gene deletions (loss of a specific gene), among other alterations. The information is also “annotated” or linked in the OncoKB system to the patient’s specific clinical data and tumor type, as well as any clinical trials or approved drug therapies that may apply. One of the many advantages of compiling this type of information and having it readily available is that it can facilitate patient enrollment in clinical trials specific to the patient’s cancer type and associated molecular alterations. A new and more efficient type of clinical trial which has emerged using this type of data is the so called “basket trial” which enrolls all patients with a specific genetic alteration in their tumor, regardless of what type of tumor it is. For example, if both a breast cancer and a lung cancer patient have the same type of genetic alteration (e.g., alteration Y) in their tumor, both can be treated with drug X, which specifically targets alteration Y. This allows for a more rapid detection of an efficacy signal for drug X within a specific cancer type, as opposed to waiting until sufficient number of patients with alteration Y have been accumulated for a specific cancer type (e.g., patients with alteration Y that have lung cancer) to test drug X. The program also allows for automated eligibility monitoring for trials of targeted therapy and can greatly facilitate trial enrollment by sending updates and notifications to the treating physician.
Genomic and clinical information within the database can also be used for “data mining” to identify measurable tumor markers (“biomarkers”) related to a specific cancer type relative to all tumor types (“pan-cancer” markers). The MSK-IMPACT program has been extensively involved in data sharing through the international cBioPortal for cancer genomics, which has compiled information from over 150,000 solid tumors across over 137,000 patients, and MSK-IMPACT is also a leading contributor to the national database on cancer, known as AACR-GENIE.
Dr Berger noted that, at the present time, information reported with the MSKCC program includes gene mutations, copy number alterations (increase or decrease in the number of copies for a specific gene), gene fusions (one gene becoming abnormally attached to another gene), and other relevant tumor characteristics such as tumor mutational burden (TMB), and microsatellite instability (MSI). TMB refers to the overall number of gene alterations found in the tumor and can be informative when determining treatment. MSI, which refers to a high propensity for mutations or gene alterations in the tumor, is another characteristic of tumor cells that can help to inform on type of cancer treatment. He also briefly outlined a wide range of other, as-yet investigational aspects of T/N changes that will be assessed in the future, all of which can greatly enhance our understanding of specific cancers, including how they arise, how they spread, and what kind of treatments may be most appropriate.
Dr Berger also highlighted an expansion of the MSKCC program to include an opt-in secondary analysis of germline alterations in cancer patients, which refers to changes that are already present in the patient’s normal DNA (as opposed to their tumor’s DNA). He noted that this analysis has now been completed in more than 25,000 cancer cases, and 17% of the changes that have been identified are pathogenic or likely to be pathogenic. In addition, 5% of the patients examined thus far exhibit alterations that are considered highly penetrant, meaning that if such an alteration is present the patient is very likely to have a condition that is associated with that genetic alteration. This type of germline testing in combination with tumor genetic analysis can also allow for assessment of cancer risk through T/N sequencing. For example, a process known as clonal hematopoiesis of indeterminate potential (CHIP) is a common occurrence with age and in some cases can be a precursor to hematologic malignancies, or blood cancers. CHIP is detected in some 25 to 30% of patients with solid tumors, and as such these patients may have an increased risk of blood cancer and can be candidates for enhanced screening or surveillance.
Dr Berger noted that, although originally developed for use in patients with advanced or metastatic cancers, data from MSK-IMPACT is also likely to provide useful information for additional populations, such as those with early-stage cancers, those with rare cancer subtypes, as well as Black, Asian, and minority populations which are often underrepresented in clinical trials. Other MSKCC initiatives underway include the development of novel, blood-based diagnostic tests, such as the MSK-ACCESS panel which screens for 129 of the most clinically relevant genes from MSK-IMPACT, using cell free DNA (cfDNA) that is detectable in blood samples. The testing, which can be used to assess such variables as response to cancer treatment or the presence of residual cancer cells in the body, was approved for use in New York State in 2019 and has thus far been performed for some 7,200 cfDNAs across 5,200 cancer patients.
The initiatives underway at MSKCC, as described by Dr Berger, provide an elegant example of how a vast cancer genetics database, improved diagnostic methods, and more efficient clinical trial design can be integrated to further advance the use of precision medicines in cancer, and to enhance our overall molecular understanding of the disease.
See more from the 2022 OneOncology Conference here.
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