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AACR Speakers Make Case for Pre-Cancer Genome Atlas as Early Detection Technologies Loom


NEW YORK (GenomeWeb) – Speakers at this week's annual meeting of the American Association for Cancer Research made a strong case for the comprehensive study of the genomics and other features of pre-cancerous states, which could yield new strategies to predict ahead of time which patients with these lesions will actually progress to cancer and which will not.

Such understanding is still woefully underdeveloped, meeting participants argued, posing problems for clinicians as genomic and other technologies advance that could pick up early mutation events or incipient cancers in greater numbers of otherwise healthy people.

Though early detection has the potential to drastically reduce cancer morbidity and mortality, it also brings with it increases in false positives, overdetection, and overdiagnosis, which already pose problems for clinicians even without the availability of the blood-based genomic screening tools now being advanced.

The AACR meeting was thick with reports on technologies for detecting cancer-associated mutations in the blood with increasing sensitivity. Liquid biopsy poster presentations stretched over more than five sessions, and dominated several symposia and other events.

But as investigators perfect these tools, the clinical field is still grappling with how it could or should use such information, as well as how it can serve patients with pre-cancers identified with current technologies like radiologic imaging, and standard clinical screening methods.

In one of the first sessions of the meeting, several researchers discussed the need for what they called a pre-cancer genome atlas — a broad profile of patients with pre-cancerous lesions and other types of dysplasia, in order to understand the factors that drive some of these patients to develop full, clinically manifest malignancy, and others not.

Investigators proposed this idea early last year in Cancer Prevention Research. "A proper PCGA will require multicenter coordinated efforts to comprehensively profile premalignant lesions collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types," authors wrote.

At the meeting, speakers highlighted results from some smaller efforts already going on, which speak to the potential of a much broader, coordinated program.

Boston University's Avrum Spira described he and his colleagues' work to sequence bronchoscopy samples from individuals with pre-cancerous lesions in their airways in order to molecularly map the progression of squamous cell lung cancer.

Because standard clinical practice with squamous tumors is to follow pre-cancerous lesions with repeat biopsies, this offers a perfect experimental platform for longitudinal genomic analyses.

Spira and colleagues have been using RNA-seq and whole-exome sequencing, and also looking at microRNA in these patients, and shared some findings from a cohort of 50 examined so far.

For example, the investigators have identified gene-expression-based molecular subtypes among premalignant lesions, independent of clinical pathological features.

"Most high-grade lesions cluster in one group but it's not a perfect correlation, so the molecular data is telling us something beyond what the pathologist is seeing under the microscope," Spira said.

Moreover, it appears that there are molecular features that distinguish subtypes that go on to progress versus those that regress away from malignancy, he added.

Meanwhile, from exome sequencing, Spira and his collaborators are also starting to see patterns of mutations that occur only in pre-malignancies, only in malignancies, or that occur in common in both, suggesting new candidate driver events that may explain the mutational progression from pre-cancer to cancer.

The hope in this, and other contexts, according to Brian Reid from the Fred Hutchinson Cancer Center, is to provide better diagnoses without increasing the overdiagnosis that can result from increased or enhanced screening.

Reid and colleagues have been looking for biomarkers that can help distinguish high-risk cases of Barrett's esophagus, which are likely to progress to esophageal cancer, from those that are indolent and unlikely to progress.

With increased screening, he said, the clinical field has seen overdiagnosis increase without corresponding success in diagnosing cases that go on to cause malignant disease and death.

Finally, Rafael Bejar of the University of California, San Diego shared another effort in which he and colleagues are investigating molecular features of premalignant states in the hematologic cancer space.

Clonal hematopoiesis has recently come under increasing attention as researchers have discovered that somatic mutation events and clonal expansions can occur that share features with known blood cancers. While some of these cases progress to symptomatic disease, others do not, spurring efforts to identify markers that can distinguish which of these indeterminate clonal expansions are dangerous and which are not.

But while there is a baseline of pathologic knowledge about the progression of precancerous lesions in some areas — like hematopoietic disorders, or in tumors like lung, esophageal, and colon cancers — clinicians are now facing a future of sensitive blood-based genomic testing that could pick up evidence of occult pre-cancer that is even less understood: in patients without visible tumors, lesions, or other classic pathologic features.

During a separate session on liquid biopsy, Dana Farber's Geoffrey Oxnard raised an example of a patient — an 80-year old woman with EGFR mutant lung cancer who showed a great clinical response to an EGFR inhibitor.

Tested using a droplet digital PCR method Oxnard developed and has implemented into his clinical practice at Dana Farber, this patient showed a complete clearance of this EGFR mutation from her blood. However, liquid biopsy also picked up a KRAS mutation in her circulating cell-free DNA. Patients with KRAS-mutant lung cancer should not respond to EGFR inhibition.  

"We looked for an occult finding … maybe she has colon cancer," Oxnard said. But investigators found nothing. Eventually the team was able to figure out that the KRAS mutation was being shed from the patient's white cells, more specifically T cells.

"There are still things we don't understand … We are still learning," he argued. "So before we start using this to screen for cancer I need to understand what it means when an 80-year old has a KRAS mutation in her T cells."

Interestingly, although liquid biopsy early detection tests have the potential to further complicate cancer medicine by increasing the detection of individuals with pre-cancerous states of one kind or another, the also offer a promising tool for further efforts toward a PCGA because they make serial analyses much easier.

While pre-cancers in the squamous cell space are easy to biopsy repeatedly because they occur in the upper airway, Spira said, pre-malignant lesions low in the lungs can't receive the same treatment.

So for other types of cancer like lung adenocarcinoma – liquid biopsy techniques might offer a way to track patients in order to glean the same types of molecular harbingers of pre-cancer progression or regression.

According to Spira, the idea of a PCGA was included among the ideas proposed for investment under the US Cancer Moonshot initiative and has been under discussion by the National Cancer Institute.

An important consideration moving forward will not only be expanding from some of these individual efforts to more systematic studies but also deciding what genomic or other molecular tools should be prioritized.

"We have to decide as a field which platforms to bring to bear," Spira said. "[My group,] we are doing RNA-seq, but epigenetics would be very valuable, proteomics, metabolomics, microbiome … there is a laundry list of things one could do. So I would argue this is one of the challenges for the NCI as it plans a national initiative, to prioritize."