Precancer is a lesion containing abnormal cells that have not invaded neighboring tissues even though epidemiological, experimental, or clinical evidence for an increased risk of developing cancer exists. As such, precancer is an alluring clinical option.

“We want to stop cancer before it develops,” said Catriona H. M. Jamieson, MD, PhD, UCSD Moores Cancer Center, who opened an AACR Annual Meeting 2022 plenary session dedicated to the science of precancer on Saturday, April 9.

The session, Precancer Discovery Science, can be viewed on the virtual platform by registered meeting participants through July 13, 2022.

Jamieson discussed some of the new techniques and technologies being used to characterize the alterations that lead to precancers. The eventual goal is to identify, then eradicate stems cells likely to progress to cancer before tumors can develop, she said.

Hematopoietic stem cells are self-renewing and self-regulated, Jamieson explained. But a variety of oncogenic lesions can transform them into cancer progenitor cells protected from apoptosis and tumor suppression, with longevity, assurance, and shielded from adaptive and innate immune responses.

The progenitors that are derived from hematopoietic stem cells turn on the capacity to clone themselves and the difference between cancer progenitor cells and stem cells is that progenitor cells don’t know how to turn it off, Jamieson said. “Clonal changes, even those triggered by chemotherapy, are associated with adverse clinical changes throughout the body,” she added.

In humans, periodic bursts of the cytidine deaminase APOBEC3 drive precancerous stem cell initiation. APOBEC drives RNA rewriting, recoding, and rewiring by ADAR, part of an innate antiviral immune mechanism activated by cytokines. The result is a loop that drives malignant generation and survival. The APOBEC/ADAR loop can also drive therapeutic resistance across multiple cancer types, Jamieson said.

An investigational agent, rebecsinib, shows potential to interrupt that malignant loop and block leukemia development.

Three key barriers to intercepting cancer are identifying individuals with precancerous lesions, assessing individual risk of progression, and discovering targets to intercept progression.

“We need prevention, not treatment, just as cardiology has done over recent decades,” said Avrum E. Spira, MD, MSc, Boston University School of Medicine. “We have to prevent cancer, not treat it. And to prevent cancer, we have to get to the root causes of premalignant lesion progression to invasive cancer.”

The Pre-Cancer Atlas (PCA), a temporal and spatial atlas of cellular and molecular changes associated with the progression of premalignant lesions to invasive cancer, is already helping. The PCA is designed to identify patients with premalignant lesions, develop molecular biomarkers that predict progression, and identify novel targets to intercept cancer development, Spira said.

At least five consortia across 28 medical centers are developing PCAs covering more than nine organ types with longitudinal biopsies from over 2,000 patients using multiple molecular profiling technologies.

A squamous cell lung cancer PCA using transcriptomic profiling of premalignant lesions has identified specific immune alterations associated with progression of premalignant bronchial lesions. MicroRNA miR-149-5p, which regulates the NLRC5 gene, appears to downregulate CD8+ T cell activity, leading to early immune evasion and progression.

“We are now testing this hypothesis in preclinical models,” Spira said. “Other PCAs are similarly identifying the immune microenvironment as a determinant of malignant progression in other organs. We need to translate these insights into interventions.”

Barrett’s esophagus is a good model for that translation. The slow progression from Barrett’s to esophageal adenocarcinoma offers a wide window for intervention, but the current model of endoscopic screening and resection is not practical on a population basis.

Rebecca Fitzgerald, MD, FMedSci, EMBO, University of Cambridge, Cambridge, United Kingdom, is developing an alternative screening, biomarker, and treatment program based on a novel cell collection device, Cytosponge. Other groups have developed their own non-endoscopic devices to collect esophageal cell samples for molecular screening.

A phase IV trial of Cytosponge showed a 10-fold increase in Barrett’s detection compared to usual care, and a randomized biomarker screening trial of 120,000 individuals has been funded, Fitzgerald reported.

“Current data show that 66 percent of Barrett’s patients have low risk and only need surveillance,” she said. “Another 17 percent are at moderate risk for progression and need more frequent surveillance or endoscopy. The remaining 17 percent are high risk and referred for endoscopy. This is a new era where we can identify people at risk for progression to esophageal adenocarcinoma and intervene early.”

Oncogenic drivers offer yet another approach to stopping cancer early. Somatic mosaicism arises from a single cell mutation during fetal development and shares features with inherited genetic diseases and somatic oncogenic drivers.

“Timing of the mutation dictates the extent of disease and organ involvement,” said Veronica Kinsler, MD, PhD, Great Ormond St. Hospital for Children and the Francis Crick Institute, London, United Kingdom. “The result is a mixture of phenotypes in a single individual.”

Most of the causative mutations in mosaic disease occur in classic oncogenic drivers such as BRAF, KRAS, NRAS, HRAS, and others. Many of these conditions have a predisposition to malignancy, Kinsler said.

About a third of patients have a family history of mosaic disease, though the genetic factors are largely unknown, she noted.

One factor that has been identified is overexpression of transcription factor PPP2R3B, which induces pigment cell proliferation and predisposes to mosaic disease with large and multiple nevi. PPP2R3B overexpression leads to a significant and sustained increase in the expression of the novel gene C21orf91. Knocking down C21orf91 rescues pigment cell phenotype switching induced by PPP2R3B.

GNAQ/GNA11 mosaicism is associated with chronic serum calcium depletion with age, Kinsler said. The mechanism is aberrant constitutive and ligand-induced calcium signaling. This aberrant calcium signaling can be restored by inhibiting the calcium release-activated channel. A clinical trial is planned.

Trials are already underway to intercept cancers associated with BRCA variants.

Risk-reducing surgery can reduce mortality from BRCA-associated cancers, noted Susan M. Domchek, MD, Basser Center for BRCA and the University of Pennsylvania. But the quality-of-life impact can be devastating, she said, so other approaches are needed.

BRCA1 and BRCA2 variants are associated with increased risk for pancreas, ovary, breast, and prostate cancers. But conventional drug development starts with metastatic disease.

“We should be thinking about this another way—cancer interception,” Domchek said. “This is where we could have maximal impact.”

After the RANK ligand emerged as a target for breast cancer prevention, researchers realized the U.S. Food and Drug Administration had already approved denosumab, which targets the RANK ligand, for osteoporosis. A 10-year trial in breast cancer prevention is underway with more than 2,918 women who have germline BRCA1 mutations.

PARP inhibitors are another possibility. Multiple PARP inhibitors have been approved to treat multiple tumors associated with BRCA1/2 mutations.

“Can we go to prevention with PARP inhibitors?” Domchek asked. “We don’t know, but the early signals are positive.”

Cancer vaccines are another approach with multiple immuno-interception trials currently in progress. One of the more promising targets is hTERT, a nearly universal tumor antigen. A recent phase I study using an hTERT DNA-based vaccine proved to be both safe and immunogenic. An immuno-interception trial in healthy women with BRCA1/2 mutations is underway.

“We have considered cancer interception for years, now we have the tools to translate it. We want to intercept cancer and change people’s lives,” Domchek said.

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