Faculty Bibliography

Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m² on day 1 and cisplatin 35 mg/m² on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.

OBJECTIVE:The objective of our study was to investigate whether the CT features of serous borderline tumors (SBTs) differ from those of low-grade serous carcinomas (LGSCs) and to evaluate if mutation status is associated with distinct CT phenotypes. MATERIALS AND METHODS/METHODS:This retrospective study included 59 women, 37 with SBT and 22 with LGSC, who underwent CT before primary surgical resection. Thirty of 59 patients were genetically profiled. Two radiologists (readers 1 and 2) independently and retrospectively reviewed CT examinations for qualitative features and quantified total tumor volumes (TTVs), solid tumor volumes (STVs), and solid proportion of ovarian masses. Univariate and multivariate associations of the CT features with histopathologic diagnoses and mutations were evaluated, and interreader agreement was determined. RESULTS:At multivariate analysis, the presence of bilateral ovarian masses (p = 0.03), the presence of peritoneal disease (PD) (p = 0.002), and higher STV of ovarian masses (p = 0.002) were associated with LGSC. The presence of nodular PD pattern (p < 0.001 each reader) and the presence of PD calcifications (reader 1, p = 0.02; reader 2, p = 0.003) were associated with invasive peritoneal lesions (i.e., LGSC). The presence of bilateral ovarian masses (p = 0.04 each reader), PD (reader 1, p = 0.01; reader 2, p = 0.004), and higher STV (p = 0.03 for each reader) were associated with the absence of BRAF mutation (i.e., wild type [wt]-BRAF). CONCLUSION/CONCLUSIONS:The CT features of LGSCs were distinct from those of SBTs. The CT manifestations of LGSC and the wt-BRAF phenotype were similar.

The unprecedented progress in the treatment of metastatic castration-resistant prostate cancer is only beginning to be realized in patients with noncastrate disease. This slow progress in part reflects the use of trial objectives focused on time-to-event end points, such as time to metastasis and overall survival, which require long follow-up durations and large sample sizes, and has been further delayed by the use of approved therapies that are effective at the time of progression. Our central hypotheses are that progress can be accelerated, and that outcomes can be improved by shifting trial objectives to response measures occurring early that solely reflect the effects of the treatment. To test these hypotheses, a continuously enrolling multi-arm, multi-stage randomized trial design, analogous to that used in the STAMPEDE trial, has been developed. Eligibility is focused on patients with incurable disease or those with a high risk of death with any form of monotherapy alone. The primary objective is to eliminate all disease using a multimodality treatment strategy. End points include pathological complete response and an undetectable level of serum prostate-specific antigen, with recovery of serum testosterone levels. Both are binary, objective, and provide an early, quantitative indication of efficacy.

This corrects the article DOI: 10.1038/nrclinonc.2017.160.

IMPORTANCE/OBJECTIVE:Androgen receptor-signaling inhibitor (ARSi) drugs prolong life in metastatic castration-resistant prostate cancer (mCRPC), but such tumors eventually become resistant and progress. Comprehensive positron emission tomography/computed tomography (PET/CT) imaging using fluoro-2-D-deoxyglucose F 18 ([18F]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([18F]-FDHT) for androgen receptor (AR) expression determine heterogeneity of imaging phenotypes, which may be useful in distinguishing patients who will benefit from ARSi drugs from those who need alternative treatments. OBJECTIVE:To test the hypothesis that PET/CT-based assessments of AR expression and glycolytic activity would reveal heterogeneity affecting prognosis. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Between April 6, 2007, and October 4, 2012, patients with mCRPC underwent imaging with both [18F]-FDG and [18F]-FDHT at Memorial Sloan Kettering Cancer Center. The patients were naive to ARSi treatment with enzalutamide or abiraterone acetate and were referred during documented disease progression. Image-directed biopsy determined the presence or absence of prostate cancer at positive imaging sites. INTERVENTIONS/METHODS:PET/CT imaging was performed with [18F]-FDHT and [18F]-FDG; select individual lesions were biopsied to correlate imaging phenotype with histologic findings. MAIN OUTCOMES AND MEASURES/METHODS:All metabolically active lesions were interpreted as [18F]-FDHT-positive (AR1) or [18F]-FDHT-negative (AR0) and as [18F]-FDG-positive (Glyc1) or [18F]-FDG-negative (Glyc0). Correlation was performed with overall survival for both individual lesion imaging phenotype as well as patient-specific imaging phenotype. RESULTS:The mean (SD) age of the 133 patients was 68 (8.6) years. Imaging phenotypes of 2405 PET/CT-positive lesions (median, 12.0 per patient) included 1713 (71.2%) AR1Glyc1, 386 (16.0%) AR1Glyc0, and 306 (12.7%) AR0Glyc1. On multivariate analysis, each phenotype had an independent negative impact effect on survival, most pronounced for AR0Glyc1 lesions (hazard ratio [HR], 1.11; 95% CI, 1.05-1.16; P < .001), followed by AR1Glyc1 lesions (HR, 1.05; 95% CI, 1.03-1.06; P < .001) and AR1Glyc0 lesions (HR, 1.03; 95% CI, 1.00-1.05; P = .048). When sorted by lesion type, 4 patient-specific groups emerged: (1) concordant, with all AR1Glyc1 (34 patients [25.6%]); (2) AR predominant, with AR1Glyc1 and varying numbers of AR1Glyc0 (33 [24.8%]); (3) Glyc predominant, with AR1Glyc1 and varying numbers of AR0Glyc1 (40 [30.1%]); and (4) mixed, with AR1Glyc1 plus a mixture of varying numbers of AR1Glyc0 and AR0Glyc1 (26 [19.5%]). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Heterogeneity of PET/CT imaging phenotype has clinical relevance on a lesion and individual patient level. With regard to mCRPC lesions, most express ARs, consistent with initial benefit of ARSi drugs. On a patient basis, 49% (groups 3 and 4) had at least 1 AR0Glyc1 lesion-the imaging phenotype with the most negative effect on survival, possibly due to ARSi resistance.

In the past year, the results of three studies in the field of prostate cancer imaging — the prostate MR imaging study (PROMIS), an analysis of the cost-effectiveness of various diagnostic strategies based on PROMIS data, and a retrospective analysis of a prostate-specific membrane antigen (PSMA)-directed PET radiopharmaceutical — have been published that could have lasting effects on clinical practice.

The original version of this article unfortunately contained mistakes. The figures 7D, 7E and 7F were missing in the article and arrows were missing in the figures 6C, 8B and 11C. The year of publication and volume number for references 19, 79 and 87 have been updated. Also, the Table 2 layout has been improved for better readability. The Publisher apologizes for the mistakes and the inconvenience caused.

Purpose To investigate the associations between BRCA mutation status and computed tomography (CT) phenotypes of high-grade serous ovarian cancer (HGSOC) and to evaluate CT indicators of cytoreductive outcome and survival in patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 108 patients (33 with BRCA mutant and 75 with BRCA wild-type HGSOC) who underwent CT before primary debulking. Two radiologists independently reviewed the CT findings for various qualitative CT features. Associations between CT features, BRCA mutation status, cytoreductive outcome, and progression-free survival (PFS) were evaluated by using logistic regression and Cox proportional hazards regression, respectively. Results Peritoneal disease (PD) pattern, presence of PD in gastrohepatic ligament, mesenteric involvement, and supradiaphragmatic lymphadenopathy at CT were associated with BRCA mutation status (multiple regression: P < .001 for each CT feature). While clinical and CT features were not associated with cytoreductive outcome for patients with BRCA-mutant HGSOC, presence of PD in lesser sac (odds ratio [OR] = 2.40) and left upper quadrant (OR = 1.19), mesenteric involvement (OR = 7.10), and lymphadenopathy in supradiaphragmatic (OR = 2.83) and suprarenal para-aortic (OR = 4.79) regions were associated with higher odds of incomplete cytoreduction in BRCA wild-type HGSOC (multiple regression: P < .001 each CT feature). Mesenteric involvement at CT was associated with significantly shorter PFS for both patients with BRCA-mutant HGSOC (multiple regression: hazard ratio [HR] = 26.7 P < .001) and those with BRCA wild-type HGSOC (univariate analysis: reader 1, HR = 2.42, P < .001; reader 2, HR = 2.61; P < .001). Conclusion Qualitative CT features differed between patients with BRCA-mutant HGSOC and patients with BRCA wild-type HGSOC. CT indicators of cytoreductive outcome varied according to BRCA mutation status. Mesenteric involvement at CT was an indicator of significantly shorter PFS for both patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. ^© RSNA, 2017 Online supplemental material is available for this article.