From Premalignant Biology to Precision Interception: Connecting the Dots with a Curated Collection of Invited Articles

The vast majority of cancers (both solid tumors and hematologic malignancies) have identifiable histologically defined precursors better known as precancers that, if promptly addressed by early detection tools and interception strategies, offer a tremendous opportunity to substantially improve cancer survival beyond traditional oncologic approaches. However, capitalizing on this opportunity requires understanding the sequence of the key molecular events occurring in precancers and the microenvironmental pressures shaping them, including how the host immune response interacts with the early neoplastic process. Developing the critical data to understand the biology, particularly the immunobiology, of precancers will facilitate the rational design of novel strategies for their early detection, risk prediction, and interception for prevention of invasive cancers.

Nearly a decade ago, calls for a national PreCancer Atlas (PCA) initiative, analogous to The Cancer Genome Atlas (TCGA) for advanced cancers, was championed by various groups (1–3) spurred by technological advances enabling single-cell and spatial technologies, coupled with new computational tools. Because these new methods had significantly increased resolution over bulk profiling methods used in TCGA, they were ideally suited to interrogating precancers, which often contain limited numbers of cells with molecular alterations, or even subsets of cells more likely to progress to malignancy. These new methods promised a far more nuanced understanding of early cancer evolution and biology than any previously used methods could hope to approach, thus paving the way for the study of premalignant biology. And just as TCGA revealed hundreds of new driver genes and pathways to be exploited for therapeutic development, a national PCA effort based on the organized and systematic application of these new methods could hold similar potential to reveal or confirm hundreds of new targets to be exploited for risk prediction, early detection, and interception, with the ultimate goal of prevention of invasive disease.

In 2018, as part of the Beau Biden National Cancer Moonshot, the NCI launched the Human Tumor Atlas Network (HTAN) with the goal of “construct[ing] three-dimensional atlases of the dynamic cellular, morphologic, and molecular features of human cancers as they evolve from precancerous lesions to advanced disease” (4). Over the last 5 years, five funded HTAN groups have focused their efforts on profiling precancers from breast, colon, skin (melanoma), and lung. In this time, what progress has been made? What is next for HTAN and the field of premalignant biology? What lessons can individual investigators working in atlas construction and the larger prevention field take away from this initial effort and how might we apply those lessons to accelerate the development of novel early detection methods, risk prediction biomarkers, and interception agents? With the ongoing commercialization of multi-cancer early detection blood tests (5, 6), there has never been a more urgent need for more precise risk stratification tools and effective early interception approaches.

This special collection of articles is designed to curate: (i) the latest research on the transition of normal, at-risk tissue into precancers; (ii) the most recent findings from the HTAN PCA effort and the application of state-of-the-art technologies to the study of precancerous lesions; and (iii) the latest findings on topics critical to advancing the field of premalignant biology and the development of effective interception agents. The collection consists of a series of reviews and mini-reviews authored by leading experts in the fields of cancer evolution, systems biology, immunology, cancer genetics, and preventive agent development, among others. In its entirety, we hope this collection provides the readers of Cancer Prevention Research with an overview of the rapidly evolving areas of premalignant biology and cancer interception and will facilitate a better understanding across the prevention field of needed near-term next steps and long-term future directions to fully realize the opportunities presented by precancers.

The first review/mini-review of the series, by Rane and colleagues, explores the mutational landscape of healthy and premalignant tissues and its implications for early cancer interception strategies (7). Srivastava and colleagues summarize the research and findings of the five groups funded as part of HTAN to profile precancers across a range of organs and offer some future directions for the initiative (8). In a review/mini-review addressing the use of high-risk cohorts to study precancers, Monahan and colleagues offer lessons learned from colorectal cancer susceptibility syndromes (9). Chen and colleagues summarize the various molecular and spatial profiling technologies used in various PCA studies, emphasizing the themes emerging from across precancer types and the key opportunities and challenges facing the profiling of these lesions across space and time (10). Tosti and colleagues provide a review/mini-review highlighting the use of genetic models of preneoplasia and their contribution to the field (11). Haldar and colleagues offer a comprehensive overview of clinical trials of cancer immunoprevention agents, emphasizing emerging vaccine targets and delivery platforms and describing translational challenges and future directions (12). In a forthcoming review, Bowen and colleagues will briefly review the immune regulation of precancers, given that the interaction between immunity and neoplasia is now established as a fundamental principle of cancer development and progression (1, 13).

A. Maitra reports other support from Cosmos Wisdom Biotechnology, Freenome, and Tezcat Biotechnology outside the submitted work; in addition, A. Maitra has a patent for Thrive Earlier Detection, an Exact Sciences Company issued to Johns Hopkins University. A. Maitra is supported by the MD Anderson Pancreatic Cancer Moon Shot Program, P50CA221707, and U54CA274371. A. Maitra is also supported by the Sheikh Khalifa Bin Zayed Al-Nahyan Foundation. E.T. Hawk reports grants from 5P30CA016672-47 NCI Cancer Center Support Grant and other support from T. Boone Pickens Distinguished Chair for Early Cancer Prevention - endowed faculty position outside the submitted work. E. Vilar reports other support from Janssen Research and Development outside the submitted work; and consulting or advisory role with Janssen Research and Development, Recursion Pharma, Guardant Health, and Tornado/Cambrian. No disclosures were reported by the other author.

This work was supported by MD Anderson's Strategic Research Initiative Development (STRIDE) program; and CA016672 (U.S. NIH/NCI) to The University of Texas MD Anderson Cancer Center, Core Support Grant.