Transforming Cancer Prevention through Precision Medicine and Immune-oncology

Abstract

We have entered a transformative period in cancer prevention (including early detection). Remarkable progress in precision medicine and immune-oncology, driven by extraordinary recent advances in genome-wide sequencing, big-data analytics, blood-based technologies, and deep understanding of the tumor immune microenvironment (TME), has provided unprecedented possibilities to study the biology of premalignancy. The pace of research and discovery in precision medicine and immunoprevention has been astonishing and includes the following clinical firsts reported in 2015: driver mutations detected in circulating cell-free DNA in patients with premalignant lesions (lung); clonal hematopoiesis shown to be a premalignant state; molecular selection in chemoprevention randomized controlled trial (RCT; oral); striking efficacy in RCT of combination chemoprevention targeting signaling pathway alterations mechanistically linked to germline mutation (duodenum); molecular markers for early detection validated for lung cancer and showing promise for pancreatic, liver, and ovarian cancer. Identification of HPV as the essential cause of a major global cancer burden, including HPV16 as the single driver of an epidemic of oropharyngeal cancer in men, provides unique opportunities for the dissemination and implementation of public health interventions. Important to immunoprevention beyond viral vaccines, genetic drivers of premalignant progression were associated with increasing immunosuppressive TME; and Kras vaccine efficacy in pancreas genetically engineered mouse (GEM) model required an inhibitory adjuvant (Treg depletion). In addition to developing new (e.g., epigenetic) TME regulators, recent mechanistic studies of repurposed drugs (aspirin, metformin, and tamoxifen) have identified potent immune activity. Just as precision medicine and immune-oncology are revolutionizing cancer therapy, these approaches are transforming cancer prevention. Here, we set out a brief agenda for the immediate future of cancer prevention research (including a "Pre-Cancer Genome Atlas" or "PCGA"), which will involve the inter-related fields of precision medicine and immunoprevention - pivotal elements of a broader domain of personalized public health.

Figure 1

The molecular alterations associated with earliest pathological steps preceding the development of invasive carcinoma have not been well characterized. A Premalignant Cancer Genome Atlas (PCGA) is needed to both support the collection and molecular profiling (circus plot) of premalignant lesions (purple cells) to identify the sequence of initial driver events that cause normal cells (orange cells) to acquire cancer hallmarks such as uncontrolled growth that enable lesions (purple cells) to progress to fully invasive carcinoma, including the critical “additional genomic events” (e.g., checkpoint/tumor suppressor loss or other co-activating event) that transform a premalignant lesions (purple cells in the 4^th circle to the right) to frank cancer (far right). In addition to the sequence of driving events, characterizing the premalignant microenvironment, including the contribution of the stroma and the immune system particularly T-cell (blue cells) regulation that will allow for a better understanding of the selective forces that determine which molecular drivers give an evolutionary advantage to drive premalignant lesions to become invasive cancer. This figure is modified in part from Campbell et al. (21).