Clinical Utilization Pattern of Liquid Biopsies (LB) to Detect Actionable Driver Mutations, Guide Treatment Decisions and Monitor Disease Burden During Treatment of 33 Metastatic Colorectal Cancer (mCRC) Patients (pts) at a Fox Chase Cancer Center GI Oncology Subspecialty Clinic

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 naïve 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-naïve 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.

Two‐point‐NGS analysis of cancer genes in cell‐free DNA of metastatic cancer patients

“…During anti‐cancer drug treatment, subclones survive and multiply, contributing to further evolution of metastases into diverse tumor cell phenotypes. Several studies demonstrated that at disease progression, expanding clones are different with respect to those identified at the beginning in tumor biopsy and that expanding clones may be selected by progresses therapies and have differential sensitivities to therapy . This was extensively shown for both hematological and solid tumors …”

“…2 This was extensively shown for both hematological [3][4][5] and solid tumors. 1 Large-scale studies demonstrated a limited usefulness of molecular profiling obtained from Formalin-Fixed and Paraffin-Embedded tumor specimen of primary tumor, relapse, or metastasis. 6 Tumor biopsies normally accomplish the sampling of only a part of the tumor and may only capture a fraction of its heterogeneity, consequently not being totally informative about the levels of genetic variability of a patient's cancer.…”

“…Among patients with distant metastatic disease, the visceral metastasis was the most common metastatic site (32.4%) followed by coexistence of both bone and visceral (19.1%) (Table 1). The median follow-up of OS for all patients was 3.2 months (range[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. At the time of survival analysis, death by tumor progression occurred in 12/68 (17.6%) patients.…”

PIK3CA-CDKN2A clonal evolution in metastatic breast cancer and multiple points cell-free DNA analysis

“…3 European Institute of Oncology, Milan, Italy. 4 Oncology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.…”

“…Classically, haematological malignancies have taught us that, within the dynamic clonal evolution, a subclonal expansion of a pre-existing mutated clone leads often to relapse [2,3]. Expanding clones may be selected by treatment acquiring drug resistance and patients who relapse after an effective therapy usually have a poor prognosis [4,5]. While at the beginning of tumor expansion there is a consistent, although variable, mutational burden from ten to hundred clones, at relapse the leading clone is usually only one [5].…”