Abstract
ABSTRACT Aim: The prospective identification of patients (pts) with tumors that are resistant to AR tx de novo (DN) reduces pt morbidity and enables the early exploration of alternative approaches. We examined CTCs, the incidence of specific CTC subpopulations, AR protein expression and AR localization from blood samples taken prior to AR Tx, inclusive of abiraterone acetate + prednisone (AA + P), enzalutamide (E) or taxanes (T) to determine if a prediction model could be developed for DN resistance. Methods: 40 blood samples were collected from mCRPC pts immediately prior to treatment with AR tx (15 AA + P, 9 E, & 16 T). Pts were treated with AR Tx and followed with outcomes classified as true response (TR) (n = 10), acquired resistance (AcR, initial response followed by progression within the first 6 months of treatment) (n = 13), or DN resistance (n = 17). Samples were processed utilizing the Epic Sciences platform. CTCs, defined as traditional (CK + , CD45-, intact nucleus, distinct morphology), cluster (≥ 2 attached CTCs), CK- (CK-, CD45-, distinct morphology, intact nucleus), and small (CK + , CD45-, small intact nucleus) were examined for AR. PSA, CellSearch®, and clinical history were recorded. Results: DN pt blood draws had higher numbers of all cell events and AR+ CTCs than AcR or TR. CTC Events per 7.5mL of Blood True Responders (n = 10) Acquired Resistors (n = 13) de novo Resistance (n = 17) Mean PSA (range) 13.36 (0.51–24.98) 307.76 (7.94–1774.5) 435.08 (0.71–2589.9) CellSearch® ≥ 5 CTC CellSearch® (Unfavorable) 20% 69% 65% Epic CTCs ≥ 5 Traditional CTCs 90% 100% 94% Mean total CTC events per patient 130 193 629 Mean AR+ CTCs per patient 20 51 266 Mean CK- CTCs per patient 22 29 52 Conclusions: Patients with DN resistance to AR tx have higher baseline CTC event frequency than responders (including traditional, CK-ve and AR expressing CTCs). Higher CTC event frequency was also observed in AcR as compared with TR responders. By analysing overall CTC counts (including subpopulations), DN resistant patients may be identified through analysis of a baseline blood draw. Analysis of baseline CTC heterogeneity in AcR may also provide insights to minor resistant subclonal populations. Further CTC analysis of AcR and DN baseline samples is warranted. Disclosure: J. Louw, R. Krupa, A. Jendrisak, D. Marrinucci and R. Dittamore: I am an employee and stockholder of Epic Sciences; H.I. Scher: Research funding from Janssen, Janssen Research, and Medivation Uncompensated advisor for Janssen, Janssen Research, and Medivation. All other authors have declared no conflicts of interest.
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