Abstract
Background: Liquid biopsy (LB) captures dynamic genomic alterations (alts) across metastatic colorectal cancer (mCRC) therapy and may complement tissue biopsy (TB). We sought to describe the utility of LB and better understand mCRC biology during therapy.Methods: Thirty-three patients (pts) with mCRC underwent LB. We used permutation-based t-tests to assess associations between alts, and clinical variables and used Kendall's tau to measure correlations.Results: Of 33 pts, 15 were women; 22 had colon, and the rest rectal cancer. Pts received a median of two lines of therapy before LB. Nineteen pts had limited testing on TB (RAS/RAF/TP53/APC), 11 extended NGS, and 3 no TB. Maxpct and alts correlated with CEA (p < 0.001, respectively). In 3/5 pts with serial LB, CEA correlated with maxpct trend, and CT tumor burden. In 6 pts, mutant RAS was seen in LB and not TB; 5/6 had received anti-EGFR therapy prior to LB, suggesting RAS alts developed post-therapy. In two pts RAS-mutated by TB, no RAS alts were detected on LB; these pts had low disease burden on CT at time of LB that also did not reveal APC or TP53 alts. In six patients who were KRAS wt based on TB, post anti-EGFR LB revealed subclonal KRAS mutations, likely a treatment effect. The median number of alts was higher post anti-EGFR LB (n = 12) vs. anti-EGFR nave LB (n = 22) (9.5 vs. 5.5, p = 0.059) but not statistically significant. More alts were also noted in post anti-EGFR therapy LB vs. KRAS wt anti-EGFR-nave LB (n = 6) (9.5 vs. 5) among patients with KRAS wild-type tumors, although the difference was not significant (p = 0.182).Conclusions: LB across mCRC therapy detects driver mutations, monitors disease burden, and identifies sub-clonal alts that reflect drug resistance, tumor evolution, and heterogeneity. Interpretation of LB results is impacted by clinical context.
Highlights
A key factor contributing to the lethal outcome of cancer, therapeutic failure, and drug resistance is intra-tumoral heterogeneity and clonal evolution of tumors caused by accumulation of somatic mutations [1,2,3]
Multiple validation studies have been published utilizing this assay, including analytical studies and clinical validations in patients with advanced non-small cell lung cancer, colorectal cancer, and other solid tumors; such studies demonstrate high concordance between clinical plasma- and tissue-based genotyping methods which supports the clinical accuracy of the Guardant360 Liquid biopsy (LB) assay [3, 14, 15]
In 3/5 pts with serial LBs, CEA correlated with maxpct trend and CT tumor burden (Figure 3)
Summary
A key factor contributing to the lethal outcome of cancer, therapeutic failure, and drug resistance is intra-tumoral heterogeneity and clonal evolution of tumors caused by accumulation of somatic mutations [1,2,3]. In patients with advanced colorectal cancer who receive multiple lines of therapy during the course of treatment, understanding the evolution of genetic alts during treatment can inform clinical management, and clinical trial design [6,7,8,9]. This is becoming important in the era of precision oncology where acquired mutations may suggest novel options for therapy or resistance to targeted agents [10,11,12]. We sought to describe the utility of LB and better understand mCRC biology during therapy
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