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Translating an explosion of knowledge in molecular oncology
Editor’s note: In this issue, HemOnc Today launches a new column that will provide updates about and perspective into molecular oncology. To contribute to this column or share topics, email Wafik El-Deiry, MD, PhD, FACP, at wafik.eldeiry@gmail.com or Alexandra Todak at stodak@healio.com.
There have been many advances in the molecular analysis of cancer in recent years, with an explosion of knowledge that can be daunting and rapid.
Progress in our understanding has been coming from genomics, analysis of responders in clinical trials, new biomarkers, an appreciation of the complexities of the tumor microenvironment, host genetics, single cell technologies, targeted therapeutics and immunotherapy, to name a few.
It is time for a regular column that can provide updates in key areas to help us keep up and also ensure we have an ongoing way to gain perspective.
The overriding goal and theme of this column — Molecular Oncology — will be to describe the current or expected future impact of basic science on clinical practice.
While describing the basic science or technological advances, we will attempt to keep a balance between the scientific progress and how far in the future the clinical impact is expected.
Areas of interest for this column over the coming year will include:
- Actionable risk factors from hosts genetics — This topic covers how specific mutations uncovered by host genomics will affect clinical care in terms of altered surveillance, eligibility for prevention studies, or influence either on surgical technique or choice of systemic therapy.
Examples might include what to do with an inherited CHK2, ATM, BRCA2, TP53,APC or MSH2 mutation as far as added surveillance, whether national prevention studies are available, and how planned surgery or systemic therapy might be altered if these inherited susceptibilities are identified.
- Small vs. large genomic panels — In the era of precision oncology and therapeutics, an important question on the mind of every clinician who treats cancer is what molecular test is appropriate and when.
The question is pertinent to what tests may be appropriate for early- vs. late-stage disease; whether limited small panel testing would suffice at particular points in a patient’s clinical course; and when, how often and using what platform — tissue biopsy, liquid biopsy, etc — might follow-up testing be reasonable. Should the OS data for the population at large be compared, or is it important to compare the effect of large panel testing on those who have actionable alterations that would not have been discovered without testing?
This topic will need to regularly evaluate the level of available evidence while keeping in mind the challenges due to the vast heterogeneity of cancer.
- Molecular targets that await new drugs — One of the major challenges in molecular oncology is that, in some respects, genomics and new technologies have outpaced the clinical translation and applications. One of the areas where this is palpable is in the lack of available therapeutics for various cancer drivers. It is a common experience in 2018 to receive a report after extensive molecular profiling and realize immediately that some of the major drivers of cancer still have no developed or approved drugs.
Examples include mutant p53, mutant Ras and deregulated beta-catenin from APC mutation, among many others. This topic will add perspective because, as a community — and this community includes industry — there needs to be consistent effort to get to where we need to be. The path of orphan drug approval for limited indications does not address a major unmet need in the oncology clinic, with ongoing high mortality with advanced therapy-resistant disease.
- New molecular oncology advances in the field — As clinicians or scientists, we are bombarded every week by incredible scientific advances with the promise of a new way to detect cancer, a new way to potentially prevent it or a new way to treat it. This column will try to bring some of the promising advances from the scientific literature that may be of interest to the readers.
Some examples include an unexpected immune-stimulatory effect of cyclin-dependent kinase inhibitory small molecule drugs, MAPK-independent effects of RAF kinase inhibition, “double-negative prostate cancers” that overexpress fibroblast growth factor and have increased MAPK activity that bypasses androgen receptor dependence, the clinical impact of the four new consensus molecular subtypes in colorectal cancer, or the discovery of ZHX2 as a VHL substrate and oncogenic driver in clear cell renal cell cancer.
A lot of the advances are mentioned in the lay press, as well as social media, so much so that over several weeks there are often dozens of noteworthy advances that also then get forgotten fairly quickly. The column will provide a way to take another look at the most exciting advances with some effort to prioritize what may be promising or of great interest.
- New technologies and resources — It is important to appreciate new technologies and resources, and to understand how they affect clinical practice. Some notable examples include ongoing efforts to establish patient-derived xenograft, or PDX, models and patient-derived organoid models. These continue to be promising. But, how impactful in the clinic are they, and what will it take to get there?
Ways of characterizing the tumor microenvironment to understand cancer biology, metastasis and drug resistance represent some of the most exciting areas of research.
Efforts through the Cancer Moonshot to develop a Human Tumor Atlas Network to understand cancer development, therapy response or resistance are ongoing. It is important for clinicians to know about these efforts that are using single cell profiling, imaging and data analysis to learn about cancer and how to treat it better.
In fact, we now have the technology to profile the dynamic expression of every single gene in a single cell, the so-called “RNA velocity of single cells.” Comparisons of normal and tumor cells — including the effects of the hypoxic, low pH immunosuppressive tumor microenvironment — await us as potential areas of therapy development.
- Controversies in molecular oncology — This column will cover ongoing controversies in precision oncology, including topics such as whether all patients’ tumors should be profiled, at what stage of disease and for what reason, including whether it makes sense as far as cost and expected benefit.
There will be discussion of trial design to get the needed level of evidence to justify recommendations. An ongoing area of controversy revolves around the clinical utility of liquid biopsy and potential confounders to interpretation, such as clonal hematopoiesis, not to mention keeping up with the increasing number of testing platforms and the issue of discordant results between blood and tumor.
- Understanding resistance mechanisms — This topic, which is fundamentally important to basic and translational work in oncology, has ongoing clinical relevance.
We gain insights from patients who respond or are resistant to chemotherapy, radiotherapy, targeted therapy or immunotherapy. Effort will be made to think about where the field may need to go to overcome the resistance, as this is what oncologists want and patients deserve. There is lots to be learned as far as patient and tumor heterogeneity.
There is much to keep up with and a need for greater expertise in molecular oncology — or, as George W. Sledge Jr., MD, described it a few years ago in his ASCO Annual Meeting presidential address, “clinical cancer biology.”
For more information:
Wafik S. El-Deiry, MD, PhD, FACP, is deputy director of Fox Chase Cancer Center and HemOnc Today’s Associate Editor for Molecular Oncology. He can be reached at wafik.eldeiry@gmail.com.
Disclosure: El-Deiry reports no relevant financial disclosures.