ctDNA Tumor Fraction May Be Prognostic Independent Biomarker in Several Advanced Cancers

Elevated circulating tumor fraction was associated with worsened overall survival across 4 advanced cancer types, according to data from an observational study.

Elevated circulating tumor fraction (TF), determined through ctDNA analysis, appears to be an independent and tumor-agnostic prognostic biomarker of outcomes in several solid malignancies, including metastatic breast cancer, colorectal cancer (CRC), castration-resistant prostate cancer (mCRPC), and advanced non-small cell lung cancer (NSCLC), according to data from a real-world outcomes study published in Annals of Oncology.

Data from univariable analyses demonstrated a strong correlation between elevated TF of at least 10% and worsened overall survival (OS) across all 4 cancer types: mCRPC (hazard ratio [HR] 3.3; 95% CI, 2.04-5.34; P <.001), metastatic breast cancer (HR 2.4; 95% CI, 1.71-3.37; P <.001), advanced NSCLC (HR 1.68; 95% CI, 1.34-2.10; P <.001), and metastatic CRC (HR 2.11; 95% CI, 1.39-3.20; P <.001). Multivariable analysis suggested that TF is an independent and consistent prognostic tool associated with survival due to similar point estimates and confidence intervals.

“In this analysis, we find that a single widely available blood-based biomarker (ctDNA TF) exhibits prognostic characteristics across cancer types in a US-based real-world dataset,” the investigators wrote. “The prognostic impact of TF is independent of most clinical features on multivariable analyses, thus offering orthogonal information.”

Investigators evaluated liquid biopsies from 1725 total patients, including 198 samples from patients with mCRPC, 402 with metastatic breast cancer, 902 with advanced NSCLC, and 223 with metastatic CRC. Across all 4 groups, patient characteristics reflected the expected disease traits. The study population contained a mix of molecular subgroups, with 16% of those in the NSCLC group having EGFR-positive disease and 48% of those in the mCRC group having RAS-positive disease. No variable assessed in the analysis had missingness of greater than 20% before imputation.

The HR for death across each patient group was 2.30 for mCRPC (95% CI, 1.28-4.13; P = .005), 2.02 for breast cancer (95% CI, 1.41-2.91; P <.001), 1.55 for NSCLC (95% CI, 1.21-2.00; P <.001), and 2.32 for CRC (95% CI, 1.45-3.70; P <.001).

In addition to the main findings, the large population of patients with NSCLC allowed for further analysis showing elevated TF of at least 10% to be directionally less prognostic for OS in patients with EGFR-positive tumors by next-generation sequencing (HR 1.46; 95% CI, 0.78- 2.71) vs EGFR-negative tumors (HR 1.94; 95% CI, 1.52-2.46). Moreover, elevated TF did not correlate with OS in patients with NSCLC and brain metastases (HR 1.10; 95% CI, 0.71-1.70), although it did in those without (HR 1.89; 95% CI, 1.46-2.45).

“Interestingly, some dominant prognostic features dilute the impact of TF such as the presence of brain metastases in aNSCLC—brain metastases may not shed ctDNA and the morbidity of a small amount of brain disease can be catastrophic on its own. The reason that TF had less prognostic effect in EGFR+ aNSCLC could be due to the availability of highly effective systemic therapy for this patient cohort.,” the investigators wrote.

The generalizability of these data are limited principally by the fact that the population receiving liquid biopsy may not closely resemble the broader population in the 4 cancer types examined. For example, health care providers might order the liquid biopsy test only on patients with certain traits or certain expected outcomes, or only on those at a specific line of therapy. More comprehensive future analyses are necessary to verify these findings.


Reichert ZR, Morgan TM, Li G, et al. Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study. Ann Oncol. Published online October 5, 2022. doi:10.1016/j.annonc.2022.09.163