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. 2023 Jan;34(1):111-120.
doi: 10.1016/j.annonc.2022.09.163. Epub 2022 Oct 5.

Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study

Z R Reichert  1 , T M Morgan  1 , G Li  2 , E Castellanos  3 , T Snow  3 , F G Dall'Olio  4 , R W Madison  2 , A D Fine  2 , G R Oxnard  2 , R P Graf  2 , D G Stover  5
Affiliations

Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study

Z R Reichert et al. Ann Oncol. 2023 Jan.

Abstract

Background: Genomic analysis of circulating tumor DNA (ctDNA) is increasingly incorporated into the clinical management of patients with advanced cancer. Beyond tumor profiling, ctDNA analysis also can enable calculation of circulating tumor fraction (TF), which has previously been found to be prognostic. While most prognostic models in metastatic cancer are tumor type specific and require significant patient-level data, quantification of TF in ctDNA has the potential to serve as a pragmatic, tumor-agnostic prognostic tool.

Patients and methods: This study utilized a cohort of patients in a nationwide de-identified clinico-genomic database with metastatic castration-resistant prostate cancer (mCRPC), metastatic breast cancer (mBC), advanced non-small-cell lung cancer (aNSCLC), or metastatic colorectal cancer (mCRC) undergoing liquid biopsy testing as part of routine care. TF was calculated based on single-nucleotide polymorphism aneuploidy across the genome. Clinical, disease, laboratory, and treatment data were captured from the electronic health record. Overall survival (OS) was evaluated by TF level while controlling for relevant covariables.

Results: A total of 1725 patients were included: 198 mCRPC, 402 mBC, 902 aNSCLC, and 223 mCRC. TF ≥10% was highly correlated with OS in univariable analyses for all cancer types: mCRPC [hazard ratio (HR) 3.3, 95% confidence interval (CI) 2.04-5.34, P < 0.001], mBC (HR 2.4, 95% CI 1.71-3.37, P < 0.001), aNSCLC (HR 1.68, 95% CI 1.34-2.1, P < 0.001), and mCRC (HR 2.11, 95% CI 1.39-3.2, P < 0.001). Multivariable assessments of TF had similar point estimates and CIs, suggesting a consistent and independent association with survival. Exploratory analysis showed that TF remained consistently prognostic across a wide range of cutpoints.

Conclusions: Plasma ctDNA TF is a pragmatic, independent prognostic biomarker across four advanced cancers with potential to guide clinical conversations around expected treatment outcomes. With further prospective validation, ctDNA TF could be incorporated into care paradigms to enable precision escalation and de-escalation of cancer therapy based on patient-level tumor biology.

Keywords: breast cancer; colorectal cancer; non-small-cell lung cancer; prognosis; prostate cancer; tumor fraction.

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Conflict of interest statement

Disclosure Financial disclosures: GL, RWM, ADF, GRO, and RPG are employees of Foundation Medicine, a wholly owned subsidiary of Roche, and have equity interest in Roche. EC and TS are employees of Flatiron Health, a wholly owned subsidiary of Roche, and have equity interest in Roche. DGS has participated on an advisory board with Novartis. ZRR has received consulting fees and institutional funding from AstraZeneca. TMM has participated in an advisory board for Myovant Sciences. FGD has declared no conflicts of interest.

Figures

Figure 1.
Figure 1.. Consolidated Standards of Reporting Trials (CONSORT) diagram showing cohort attrition after applying inclusion and exclusion criteria to the four datasets in the tumor types of interest.
aNSCLC, advanced non-small-cell lung cancer; CGDB, clinico-genomic database; CRC, colorectal cancer; mBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; mCRPC, metastatic castration-resistant prostate cancer; NSCLC, non-small-cell lung cancer.
Figure 2.
Figure 2.. Elevated TF is prognostic for worse overall survival in the four tumor histologies studied.
Kaplan–Meier plots of real-world overall survival from therapy start, stratified by tumor fraction at a cut-off of 10% as measured within 60 days prior, in (a) mCRPC, (b) mBC, (c) aNSCLC, and (d) mCRC. aNSCLC, advanced non-small-cell lung cancer; CI, confidence interval; HR, hazard ratio; mBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; mCRPC, metastatic castration-resistant prostate cancer; NR, not reached; TF, tumor fraction.
Figure 3.
Figure 3.. Multivariable modeling shows elevated TF remains highly prognostic for worse overall survival across tumor types even after adjusting for established disease-specific prognostic markers.
Forest plots showing hazard ratios for each variable used in multivariable Cox proportional hazards modeling for (a) mCRPC, (b) mBC, (c) aNSCLC, and (d) mCRC. aNSCLC, advanced non-small-cell lung cancer; ECOG, Eastern Cooperative Oncology Group; LLN, lower limit of normal; mBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; mCRPC, metastatic castration-resistant prostate cancer; TF, tumor fraction; ULN, upper limit of normal; WNL, within normal limits.
Figure 4.
Figure 4.. Exploratory analysis of varying the tumor fraction cutpoint shows tumor fraction remains prognostic for real-world overall survival across tumor types regardless of the cutpoint.
Exploratory analysis of the effect of varying the cTF cutpoint on the hazard ratio for the TF high versus TF low groups in univariable Cox proportional hazards models. Cutpoints between 1% and 20% are tested in increments of 1% in (a) mCRPC, (b) mBC, (c) aNSCLC, and (d) mCRC. The dotted line shows a hazard ratio of 1. Behind each plot of hazard ratios is a histogram of TF values between 1% and 20%, expressed as a percentage of all patients per disease. The full histogram is presented in Supplementary Figure S2, available at https://doi.org/10.1016/j.annonc.2022.09.163. aNSCLC, advanced non-small-cell lung cancer; mBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; mCRPC, metastatic castration-resistant prostate cancer.
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