Abstract 613P
Background
Large scale transitions (LSTs) are chromosomal breakages that generate gains or losses ≥10 Mb. As an indicator of CIN, we previously validated a single-cell phenotypic classifier for identification of CTCs with at least 9 LSTs per cell (pLST-high). High CIN, defined as 3 or more pLST-high CTCs in a sample at baseline, was associated with shorter overall survival. Here, we explored high CIN as a predictive marker of drug sensitivity for patients (pts) with mCRPC.
Methods
CTC samples were collected from pts with mCRPC prior to taxane based chemotherapy (T) or an androgen receptor signaling inhibitor (ARSi). CTCs were identified on the Epic Sciences platform [Cytokeratin, CD45, DAPI, and AR staining] and CIN status classified as high (+) or low (-) using the phenotypic classifier (PMID 32816908). Radiographic progression was defined as new or increasing lesions on treatment per retrospectively reviewed clinical radiology reports.
Results
212 pre-treatment blood samples from 179 unique mCRPC pts were collected from 2012 to 2017. CTCs were detected in 191/212 (90%) samples, of which 47 (22%) were identified as CIN high (19/121 in ARSi cohort; 28/91 in taxane cohort). Outcomes of a multivariable Cox proportional hazards model for CTC CIN status with rPFS and overall survival (OS) adjusted for known prognostic variables are presented in the table. Table: 613P
| rPFS | OS | |
| Median time to event (mo) CIN+ vs CIN-* | 3.3 v 9.6 (ARSi) 4.2 v 4.6 (T) | 8.8 v 30.8 (ARSi) 9.4 v 13.5 (T) |
| HR (95% CI) CIN+ vs CIN-* | 2.3 (1.1 – 4.6) | 5.4 (2.9 – 10.0) |
| HR (95% CI) CIN continuous fold change** | 1.3 (1.1 – 1.5) | 1.4 (1.2 – 1.6) |
| CIN Interaction with Therapy (P) | P = 0.01 | P= 0.04 |
*dichotomized (≥3 vs < 3 CIN CTC/mL), **log2+1 transformed HR’s adjusted for line of therapy, visceral metastases, Hgb, ALK, LDH and PSA with 162 rPFS events + 156 deaths observed as of December 31 st , 2020. ARSi (enzalutamide = 72; abiraterone =49); Taxane (docetaxel = 55, cabazitaxel = 34, paclitaxel = 2).
Conclusions
In this study, CIN+ CTC number as a continuous variable or dichotomized as high or low was predictive for a shorter rPFS and OS, and a significant statistical interaction was observed between CIN and therapy. CIN high CTCs may predict for a poorer response to ARSi therapy versus taxane that warrants further prospective validation.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Study carried out under IRB protocol.
Funding
Has not received any funding.
Disclosure
J. Schonhoft: Financial Interests, Full or part-time Employment: Epic Sciences; Financial Interests, Stocks/Shares: Epic Sciences A. Anderson: Financial Interests, Full or part-time Employment: Epic Sciences; Financial Interests, Stocks/Shares: Epic Sciences. R. Wenstrup: Financial Interests, Full or part-time Employment: Epic Sciences; Financial Interests, Stocks/Shares: Epic Sciences. H.I. Scher: Financial Interests, Member of the Board of Directors, compensated consultant/advisor: Asterias Biotherapeutics; Financial Interests, Advisory Role, compensated consultant/advisor: Ambry Genetics Corp; Financial Interests, Advisory Role, compensated consultant/advisor: Konica Minolta Inc; Financial Interests, Advisory Role, compensated consultant/advisor: Bayer; Financial Interests, Advisory Role, compensated consultant/advisor: Pfizer Inc; Financial Interests, Advisory Role, compensated consultant/advisor: Sun Pharmaceuticals; Financial Interests, Advisory Role, compensated consultant/advisor: WCG Oncology; Non-Financial Interests, Advisory Role, uncompensated consultant/advisor: Amgen; Non-Financial Interests, Advisory Role, uncompensated consultant/advisory: ESSA Pharma Inc; Non-Financial Interests, Advisory Role, uncompensated consultant/advisory: Janssen Research & Development, LLC; Non-Financial Interests, Advisory Role, uncompensated consultant/advisory: Janssen Biotech, Inc; Financial Interests, Invited Speaker, uncompensated consultant/advisory: Sanofi Aventis; Financial Interests, Research Grant, To institution: Epic Sciences; Financial Interests, Research Grant, To institution: Illumina; Financial Interests, Research Grant, To institution: Janssen; Financial Interests, Research Grant, To institution: Menarini Silicon Biosystems; Financial Interests, Research Grant, To institution: Prostate Cancer Foundation; Financial Interests, Research Grant, To institution: ThermoFisher; Financial Interests, Other, Intellectual Property Rights: BioNTech; Financial Interests, Other, Intellectual Property rights: Elucida Oncology; Financial Interests, Other, Intellectual Property Rights: MaBVAX; Financial Interests, Other, Intellectual Property Rights: Y-mAbs Therapeutics, Inc; Non-Financial Interests, Other: Amgen; Non-Financial Interests, Other: Asterias Biotherapeutics; Non-Financial Interests, Other: Bayer; Non-Financial Interests, Other: ESSA Pharma Inc; Non-Financial Interests, Other: Menarini Silicon Biosystems; Non-Financial Interests, Other: Phosplatin; Non-Financial Interests, Other: Pfizer Inc; Non-Financial Interests, Other: Prostate Cancer Foundation; Non-Financial Interests, Other: WCG Oncology. All other authors have declared no conflicts of interest.