Connections across the Cancer Continuum

The arc of science can be long, and we have seen cancer research progress from the biochemical experiments on metabolic enzymes and oncogenes performed decades ago to rapid, CRISPR-enabled genetic modeling, characterization of tumors and their microenvironments at unprecedented resolution, and sophisticated clinical trials investigating new targeted therapies, biologics, or dietary interventions. Broad population studies are providing new insights into the proportion of cancer cases that could be preventable by lifestyle changes and have uncovered the new puzzle of the increased incidence of early-onset cancers.A quarter century of the new millennium has already passed—as well as 25 years since the first draft of the human genome—and the arc of cancer research continues to bend, forging new and intriguing connections between discovery science and clinical implementation.We have noticed the field begin to pivot toward fundamental questions surrounding the true nature of “health.” What about the body’s metabolic or immunologic state is perturbed in the presence of cancer, and what is the ideal state a dietary or therapeutic intervention should be trying to maintain or restore? Is it appropriate to shift our attention away from the tumor to the host? Is it even possible to consider one without the other?Along those lines, what makes a normal cell state different from a malignant cell state? Recent analyses of “normal” tissues have indisputably shown that phenotypically normal cells harbor oncogenic mutations, so what shifts the equilibrium toward malignancy? Are there other nongenetic alterations that can be detected to ideally enable cancer interception? What distinguishes precancerous lesions that never progress from those that do? Are there tissue-specific differences in cancer evolution that hinder early detection and treatment of the most deadly cancers?If we can identify such distinguishing features, would there then be opportunities to predict risk of tumor formation or detect tumors at an early stage? How can we harness artificial intelligence for predictive modeling or early detection? For features that we already know are specific to tumors, what needs to be done to achieve suitable sensitivity and specificity for screening efforts?Of course, it is impossible to untangle these questions and avenues of research from current structural issues in the scientific enterprise that unfortunately contribute to health disparities and worse outcomes in certain patient populations: lack of diversity in preclinical and clinical samples, lack of inclusion in clinical trials, and unequal access to emerging technologies. How do we move beyond approaches that are currently only feasible in large academic research centers to those that can be applied globally and equitably?It is also impossible to untangle any of these questions from each other, and the work of all cancer researchers is interconnected. Which questions will we have answers to in the next 25 years? Which questions will remain unanswered? What questions do we not even know yet to ask? We look forward to finding out.L.A. Diaz reports membership on the board of directors of Quest Diagnostics and Epitope; being a compensated consultant to Innovatus CP, Seer, Absci, GSK, Delfi, Blackstone, and NeoPhore; and being an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy. Some of these licenses and relationships are associated with equity or royalty payments to the inventors. He holds equity in Quest Diagnostics, Epitope, Absci, Seer, Delfi, and Neophore. He divested his equity in Personal Genome Diagnostics to Labcorp in February 2022 and divested his equity in Thrive Earlier Detection to Exact Biosciences in January 2021. His spouse holds equity in Amgen. The terms of all these arrangements are being managed by Memorial Sloan Kettering in accordance with their conflict-of-interest policy. L.C. Cantley reports grants from the NIH during the conduct of the study. He is a founder of, stockholder in, and advisor to the following companies: Volastra, Faeth, Cell Signaling Technologies, Petra Pharmaceuticals and Larkspur. He is also a member of the board of directors of the Vallee Foundation.