Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response

Abstract

Purpose: For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT. Patients and Methods: Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response. Results: Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology. Conclusions: Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.

Nascent prostate cancer heterogeneity drives evolution and resistance to intense hormonal therapy

“…In the present study, we attempt to subdivide otherwise high-risk tumors based on their evolutionary state at the time of treatment. The finding that larger tumors were more likely to resist therapy 18 fit well with the model that they had undergone more cell divisions since originating, with more opportunities for diversity and punctuated evolutionary events. Meanwhile smaller and more homogenous tumors were thus more sensitive, despite harboring features of advanced cancers such as higher Gleason grades and cribriform glandular architecture.…”

“…By definition, an ER case meant that all MRI-visible lesions responded exceptionally well. At the patient level, a subset of INR tumors demonstrated objective heterogeneity because they included lesions that responded as well as lesions that persisted 18 , with the intrinsic variability associated with intrapatient response characteristics. At the extreme end of this phenomenon was a patient in our study who harbored two completely independent tumors that exhibited differential responses to therapy 20 .…”

“…The fact that PSA levels tended to be uniformly high yet were heterogeneously reduced in INR cases is consistent with the hypothesis that AR-high tumors are more likely to respond to AR-directed therapy 39,40 , and that lower PSA staining is representative of an AR-low subpopulation. Indeed, in situ PSA levels were reduced by treatment 18 , with poor responders a priori less dependent upon AR. This finding is further supported by the observation that baseline GR histologic intensity increased with RCB post-treatment.…”

“…The RP specimen was grossed and sectioned in the same plane as the mpMRI, using a customized 3-D printed mold designed using the most recent post-treatment mpMRI 19 . Surgical specimens were stained with H&E and additional immunostains to verify the presence of residual tumor, including anti-NKX 3.1, PIN-4 cocktail, CAM5.2, and anti-p63 18,20 . Determination of residual disease was performed by three genitourinary pathologists (M.J.M., H.Y., and R.T.L.).…”

“…We thus hypothesized that evolutionary principles relating diversity and heterogeneity to clinical outcome could explain in part why larger tumors at baseline could result in diverse resistance mechanisms post-treatment. In this study, we present the integrated histologic and genomic analysis of 141 laser capture microdissected tumor exomes representing 110 baseline biopsy tissues from 37 patients with intermediate-to-high risk prostate cancer who were enrolled in a phase 2, single-arm clinical trial of neoadjuvant androgen deprivation therapy intensified by the addition of enzalutamide 18 . Using both tissue- and DNA-based analyses, we observe that the volume of residual disease at the end of therapy increases proportionally with tumoral diversity at baseline.…”