Expanded Genomic and Early-Detection Testing Define Next Level of Precision Oncology Screening and Management

The field of oncology is heading toward widespread genetic testing and implementation of screening methods with multi-cancer early detection, explained N. Jewel Samadder, MD, MSc, FACG, AGAF, adding that increased access and prospective research are key to both endeavors.

“Eventually every patient will be offered genomics and multi-omics to guide their disease risk stratification and personalized disease management, including somatic, germline, circulating tumor DNA, whole-exome to whole-genome sequencing, polygenic risk scores, and multi-omics like transcriptome, RNA and metabolomics,” Samadder said in a presentation during the Advances and Innovations in Endoscopic Oncology and Multidisciplinary Gastrointestinal Cancer Care meeting. Samadder is a professor of medicine at Mayo Clinic Arizona in Phoenix.¹

Multi-cancer early detection represents the holy grail of cancer medicine, Samadder explained.

Multi-cancer early detection uses a targeted methylation, next-generation–based assay to detect and analyze cell free DNA in the bloodstream and protein biomarkers before deploying machine learning to detect a cancer signal and predict the tissue of origin.

“Can we identify microscopic amounts of tumor DNA in the blood, lead[ing] to detection of early asymptomatic disease that improves survival and cure?” he asked.

Samadder noted that only 5 cancers––breast, colon, cervical, lung, and prostate––have screening methods available, leaving the remaining 75% of cancers devoid of early detection. Optimal multi-cancer early detection should have high aggregate sensitivity, with current-generation platforms covering more than 20 cancers. Additionally, multi-cancer early detection has a very low false positive rate below 1%, preventing unnecessary imaging and invasive procedures, Samadder said.

Only one multi-cancer early detection test is currently available for commercial use, but over 15 are in development. However, Samadder cautioned, “All of these tests are coming to market without true prospective, high-quality data. They are running case control studies on either biospecimens or retrospective studies and utilizing that to say their test works, which is not adequate.”

The PATHFINDER study (NCT04241796), however, is a prospective trial evaluating multi-cancer early detection in 6,662 patients across 7 centers in the United States. In findings presented at the 2022 ESMO Congress,² investigators showed that 1.4% (n = 92) of patients had a positive signal, leading to 33 true positives and 57 false positives. A total of 36 solid tumor and hematologic cancers were diagnosed (early stage, n = 14), with a specificity rate of 99.1%. The tissue of origin was predicted accurately in 85.3% of cases, with positive and negative predictive values of 38% and 98.6%, respectively.

Ongoing large-scale trials seeking to build on these data include NHS-Galleri, Pathfinder2, SOAR, and Vanguard, Samadder said.

In addition to creating appropriately designed prospective trials, investigators will have to overcome several other barriers before multi-cancer early detection is widely accepted in practice, Samadder said. He noted that these challenges include identifying which cancers to target. “As we start seeing more and more data, it’s becoming very apparent that estrogen receptor–positive breast cancer, prostate, renal, and uterine cancers do not seem to be picked up well with multi-cancer early detection testing—[along with] brain cancers, for sure, because of the blood-brain barrier—so there are certain tumors that this test will miss.”

Additional potential restraints include the limited expectation of pre-cancer detection, questions regarding whether the test will replace or add to standard-of-care screening and surveillance methods, and how it will be used alongside artificial intelligence and imaging modalities.

“What we don’t want to see from a population point of view is that people radiate toward this blood-based testing instead of colonoscopy or colorectal cancer screening with stool DNA and FIT, [or] instead of breast mammograms and breast examinations, where we have decades of good quality data that work. We don’t want to change that curve away from high-quality, evidenced-based cancer screening,” Samadder said.

Samadder also discussed the role of cancer genetic assessment, specifically for young- or early-onset colorectal cancer. “[Approximately] 70% of colorectal cancers are sporadic, meaning there’s no one single genetic, environmental cause. Familial is about a quarter. [There may be] a strong family history in first- and second-degree relatives, but no one genetic cause can be elucidated. And then about 10%, maybe up to around 20%, of the time we can now identify a single gene in the patient that is inherited through generations through their mom’s or their dad’s side, that is predisposing them to the development of colon or other cancers.”

Considerations for genetic evaluation for colorectal neoplasia are broken down into 4 subcategories, Samadder explained: the type of tumor or germline testing; who to test; the determination of whether germline genetic testing is necessary; and the risks, benefits, and alternatives to testing.

“In today’s oncology world, [pathology] routinely looks at the patient’s tumor through immunohistochemical staining for mismatch repair deficiency or microsatellite instability before they hit your door, or the oncologist has already ordered it depending on the sequence of being seen,” Samadder said.

Tumor somatic or circulating tumor DNA testing should be discussed with the patient because results may indicate the presence of a germline mutation, specifically if the variant allele fraction is above 25% to 30%, Samadder added.

Deciding who to test, be it the individual in front of you or an affected family member, is less of a concern today than in the past, Samadder said, because the price of testing has come down. Moreover, blood- and saliva-based testing methods can even be done locally so that patients do not have to travel long distances to understand their risk.

“We pull genomic DNA out of that tube, and we send it off for testing for up to 100 different cancer genes. These include all the genes associated with colorectal, pancreas, melanoma, breast, and ovarian cancer, and the cost of this genetic testing is down to less than $300 from several labs. I often tell our patients for less than the cost of your Netflix subscription, I can screen you for a multitude of cancer risk,” Samadder said.

Prior indications for genetic testing have been updated in revisions to the January 2022 National Comprehensive Cancer Network guidelines. “Now the guidelines state that anybody with colorectal adenocarcinoma, regardless of age, should be offered genetic testing. This joins the guidelines for ovarian and pancreatic cancer, where all patients should be offered genetic testing. We’re waiting on breast and prostate to go that direction as well,” Samadder said.

Findings from a phase 2 trial (NCT04165772) further underscore the importance and implications of testing, Samadder stated, explaining that of 14 patients with locally advanced rectal cancer enrolled on the trial, 11 with Lynch syndrome experienced endoscopic and radiographic response with the PD-1 inhibitor dostarlimab-gxly (Jemperli), preventing the need for surgery.³

“I don’t think this is a cure all, but in a select group of patients, this could have marked effect. You have to pick out that patient either by biomarker or, in this case, genetic predisposition,” Samadder said.

“We’re going to move away completely from germline testing on panels and referral to genetics––the traditional model––to one where every patient walking in the door of a practice is going to have a saliva or blood sample, and we’re going to run exome and eventually whole-genome sequencing, where we can sequence all 19,000 genes in the body, identify the variants that will cause heart disease, early Alzheimer’s, and cancers, and return them actively in the patient’s electronic medical record to guide treatment decision making for their entire life,” Samadder concluded.

Disclosures: Dr Samadder reported final relationships with Janssen Research and Development, Cancer Prevention Pharmaceuticals, and Recursion Pharmaceuticals. 

References

1. Samadder NJ. Precision oncology: decoding genomics in cancer practice. Presented at: Advances and Innovations in Endoscopic Oncology and Multidisciplinary Gastrointestinal Cancer Care. April 15, 2023. Scottsdale, Arizona. Accessed April 16, 2023.
2. Schrag D, McDonnell CH, Nadauld L, et al. A prospective study of a multi-cancer early detection blood test. Ann Oncol. 2022;33(suppl 7):S961. doi:10.1016/j.annonc.2022.07.1029
3. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair–deficient, locally advance rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445