Plasma circulating tumor DNA (ctDNA) fraction and real-world overall survival (rwOS) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Stover Daniel G. , Morgan Todd Matthew , Graf Ryon , Li Gerald , Castellanos Emily , Snow Tamara , Swaminathan Akshay , Madison Russell , Schrock Alexa Betzig , Huang Richard S.P. , Oxnard Geoffrey R. , Venstrom Jeffrey Michael , Reichert Zachery R 
Published: June 2021

e17035

Background: Assessment of disease burden and severity influences numerous decisions in cancer care yet is not always straightforward. In mCRPC, most patients (pts) have bone-only metastases, for which disease burden quantification by imaging is challenging. Using commercially available assays for comprehensive genomic profiling (CGP), we hypothesized higher levels of ctDNA would associate with worse rwOS in mCRPC. Methods: Pts with mCRPC who received care within Flatiron Health (FH) network between 1/1/2011-6/30/2020 were assessed. Pts had to have FoundationOne Liquid performed ≤60 days prior to initiation of at least one line of therapy (LOT). Clinical characteristics and treatment history were obtained from deidentified, EHR data and linked to genomic data in the FH-Foundation Medicine Clinico-Genomic Database. Univariable and multivariable Cox proportional hazard models were utilized for rwOS comparisons indexed to LOT start, adjusted for LOT, age, and PSA, hemoglobin, alkaline phosphatase, albumin, and recent ECOG status when available. For one pt with two samples, the earlier one was used. Plasma ctDNA levels were quantified using a composite tumor fraction (cTF) measure based on aneuploidy and variant allele fraction (VAF), dichotomized at a previously reported threshold of 10% (Stover et al, JCO, 2018). Association of cTF with rwOS across common solid tumors was then explored in the FH-FMI CGDB for advanced breast cancer (BC), metastatic colorectal cancer (mCRC) and advanced non-small cell lung cancer (aNSCLC). Results: 78 mCRPC pts met criteria with 36 deaths to date. 15 (19%), 19 (24%), 17 (22%) and 27 (35%) samples were respectively obtained prior to first, second, third, or fourth mCRPC LOT, and median PSA was 85.1 ng/mL (IQR: 23.2 – 177). 69/78 (88%) were from community sites. cTF was ≥ 10% in 46/78 samples (60%) and was significantly associated with median PSA (115 vs. 27 ng/mL, p = 0.006) and elevated alk phos (52.2% vs. 12.5%, p < 0.001). Pts with ≥ 10% cTF had significantly worse rwOS (median 6.2 mo vs. not reached, HR: 9.9, 95% CI: 3.0 – 32.4, p < 0.001), which persisted in the multivariable Cox regression (HR: 9.4, 95% CI: 2.4 – 36.4, p = 0.001, n = 65, 13 missing clinical data). Preliminary results in other cancers, adjusted for LOT number only, were consistent with mCRPC; cTF ≥ 10% was associated with a worse rwOS in mBC (n=245, HR: 1.8 CI: 1.1 – 3.0), mCRC (n=107, HR: 2.1 CI: 1.1 – 4.3) and aNSCLC (n=432, HR: 1.8 CI: 1.3 – 2.5). Conclusions: Pretreatment ctDNA level is a prognostic factor in mCRPC in a real-world setting. With prospective validation, cTF may permit identification of high risk pts requiring more aggressive or investigational therapies. This phenomenon may not be unique to mCRPC and could offer similar insights in other cancer types.