Original from: GenomeWeb

New research suggests a combination of molecular profiling on tumor tissue and corresponding circulating tumor DNA (ctDNA) samples can provide clinically actionable clues that may be missed using either approach alone, particularly for individuals with breast cancer or non-small cell lung cancer (NSCLC).

"Our findings emphasize the complementary nature of these testing modalities, especially for NSCLC and breast cancer," Justin Guinney, senior VP of cancer genomics at Tempus said in an email, explaining that "our study underscores how dual testing can improve the detection of actionable variants in the solid tumors examined," which may be subject to "intratumoral and inter-site heterogeneity."

As they reported in JAMA Network Open on Monday, Guinney and colleagues from Tempus, Vanderbilt University Medical Center, and other centers analyzed biopsy-based tumor tissue sequences and blood-based ctDNA profiles for 3,209 de-identified individuals with advanced breast cancer, NSCLC, prostate cancer, or colorectal cancer (CRC) who had available molecular and clinical data in the Tempus database.

The team noted that the liquid biopsies were performed using the Tempus xF next-generation sequencing-based gene panel test, while the Tempus xT NGS approach was used to assess matched tumor-normal tissue samples. The tissue and ctDNA samples were collected from each patient within the same 30-day stretch.

Based on criteria set forth by the National Comprehensive Cancer Network (NCCN), the combined tissue-ctDNA testing approach uncovered targetable variants in 1,448 of the cancer cases, the team reported, noting that 351 patients had targetable variants found solely by solid tumor sample testing and another 135 patients had clinically actionable variants that turned up in the ctDNA profiling arm of the study alone.

"Findings from our study — using a large, clinically heterogeneous cohort — support the claim that concurrent testing is feasible and clinically beneficial for detecting more actionable variants among patients with advanced cancer," the authors wrote.

The actionable variants unearthed with each approach varied by cancer type, gene, actionable variant considered, and the amount of ctDNA available, the investigators reported. 

"Although the benefits associated with concurrent testing varied in magnitude by cancer type, higher detection persisted across all four cancer types and was most pronounced in breast cancer and NSCLC," they explained, "reaffirming NCCN guideline support for ctDNA testing in these populations."

In the advanced breast cancer patients, for example, roughly one-fifth of the actionable variants found came from the ctDNA test side. More than half of those ctDNA-specific actionable variants fell in the ESR1 gene, which the authors called a "common cause of acquired resistance to aromatase inhibitor endocrine therapy."

Such actionable alterations are known to be a biomarker for response to anti-estrogen drug elacestrant (the Menarini Group's Orserdu) in women with advanced hormone receptor-positive breast cancer, Guinney wrote, noting ctDNA offers a window for tracking the allele fraction of ESR1 alterations prior to treatment and over the course of the therapy.

In patients with NSCLC, meanwhile, the researchers uncovered 513 actionable variants, including 337 variants that were concordant by tissue and ctDNA testing. Another 149 variants turned up in the tissue biopsy alone, including actionable EGFR variants, while 27 variants in KRAS and other genes were picked up in ctDNA alone.

"In NSCLC, clinical guidelines currently recommend ctDNA testing to help overcome logistical complications in molecular testing," Guinney said, adding that the current study "strengthens the rationale for dual testing in NSCLC by increasing the total number of detected, actionable alterations."

He and his coauthors noted that further research will be needed to dig into the anticipated treatment selection improvements associated with concurrent tissue and ctDNA testing, along with their effects on patient outcomes.

Source: Cancer Study Sees Actionable Variants Boost with Concurrent Tissue, Circulating Tumor DNA Testing