Faculty Bibliography

The heterogeneity of an individual patient's tumor has been linked to treatment resistance, but quantitative biomarkers to rapidly and reproducibly evaluate heterogeneity in a clinical setting are currently lacking. Using established tools available in a College of American Pathologists-accredited and Clinical Laboratory Improvement Amendments-certified clinical laboratory, we quantified digital pathology features on 9,225 individual circulating tumor cells (CTC) from 179 unique metastatic castration-resistant prostate cancer (mCRPC) patients to define phenotypically distinct cell types. Heterogeneity was quantified on the basis of the diversity of cell types in individual patient samples using the Shannon index and associated with overall survival (OS) in the 145 specimens collected prior to initiation of the second or later lines of therapy. Low CTC phenotypic heterogeneity was associated with better OS in patients treated with androgen receptor signaling inhibitors (ARSI), whereas high heterogeneity was associated with better OS in patients treated with taxane chemotherapy. Overall, the results show that quantifying CTC phenotypic heterogeneity can help inform the choice between ARSI and taxanes in mCRPC patients. Cancer Res; 77(20); 5687-98. ©2017 AACR.

PURPOSE/OBJECTIVE:A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in the disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic non-castrate, and metastatic castration-resistant prostate cancer (CRPC). METHODS:Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was employed to identify single nucleotide variations, small insertions and deletions, copy number alterations and structural rearrangements in over 300 cancer-related genes in tumors and matched normal blood. RESULTS:alterations were specifically enriched in CRPC. CONCLUSION/CONCLUSIONS:Through genomic profiling of prostate tumors representing the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis and castration-resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer, for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8⁺ and CD4⁺ T cells and exhibited oligoclonal expansion of specific T cell subsets. We also detected CD8⁺ T cell reactivity against predicted neoepitopes after isolation of cells from a blood sample taken almost 3 years after the tumors were resected. These findings suggest that multiple distinct tumor immune microenvironments co-exist within a single individual and may explain in part the heterogeneous fates of metastatic lesions often observed in the clinic post-therapy. VIDEO ABSTRACT.

PURPOSE/OBJECTIVE:The aim of this study was to assess the diagnostic performance of computed tomography (CT) for initial staging of non-endometrioid carcinomas of the uterine corpus. MATERIALS AND METHODS/METHODS:Waiving informed consent, the Institutional Review Board approved this Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study of 193 women with uterine papillary serous carcinomas, clear cell carcinomas, and carcinosarcomas, who underwent surgical staging between May 1998 and December 2011 and had preoperative CT within 6 weeks before surgery. Two radiologists (R1, R2) independently reviewed all CT images. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and area under the curve were calculated using operative notes and surgical pathology as the reference standard. RESULTS:The respective sensitivities and specificities achieved by R1/R2 were 0.79/0.64 and 0.87/0.75 for detecting deep myometrial invasion (MI) on CT; 0.56/0.63 and 0.93/0.79 for detecting cervical stromal invasion; 0.52/0.45 and 0.95/0.93 for detecting pelvic nodal metastases; and 0.45/0.30 and 0.98/0.98 for detecting para-aortic nodal metastases. Although CT had suboptimal sensitivity for the detection of omental disease, it had high PPV for omental seeding at surgical exploration (1.00 for R1 and 0.92 for R2). Inter-observer agreement ranged from moderate in the detection of deep MI (κ = 0.42 ± 0.06) to almost perfect in the detection of para-aortic nodal metastases (κ = 0.88 ± 0.08). CONCLUSION/CONCLUSIONS:In patients with uterine non-endometrioid carcinomas, CT is only moderately accurate for initial staging but may provide clinically valuable information by 'ruling-in' isolated para-aortic lymph node metastases and omental dissemination.

OBJECTIVES/OBJECTIVE:To evaluate the recommendations for multiparametric prostate MRI (mp-MRI) interpretation introduced in the recently updated Prostate Imaging Reporting and Data System version 2 (PI-RADSv2), and investigate the impact of pathologic tumour volume on prostate cancer (PCa) detectability on mpMRI. METHODS:This was an institutional review board (IRB)-approved, retrospective study of 150 PCa patients who underwent mp-MRI before prostatectomy; 169 tumours ≥0.5-mL (any Gleason Score [GS]) and 37 tumours <0.5-mL (GS ≥4+3) identified on whole-mount pathology maps were located on mp-MRI consisting of T2-weighted imaging (T2WI), diffusion-weighted (DW)-MRI, and dynamic contrast-enhanced (DCE)-MRI. Corresponding PI-RADSv2 scores were assigned on each sequence and combined as recommended by PI-RADSv2. We calculated the proportion of PCa foci on whole-mount pathology correctly identified with PI-RADSv2 (dichotomized scores 1-3 vs. 4-5), stratified by pathologic tumour volume. RESULTS:PI-RADSv2 allowed correct identification of 118/125 (94 %; 95 %CI: 90-99 %) peripheral zone (PZ) and 42/44 (95 %; 95 %CI: 89-100 %) transition zone (TZ) tumours ≥0.5 mL, but only 7/27 (26 %; 95 %CI: 10-42 %) PZ and 2/10 (20 %; 95 %CI: 0-52 %) TZ tumours with a GS ≥4+3, but <0.5 mL. DCE-MRI aided detection of 4/125 PZ tumours ≥0.5 mL and 0/27 PZ tumours <0.5 mL. CONCLUSIONS:PI-RADSv2 correctly identified 94-95 % of PCa foci ≥0.5 mL, but was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL. DCE-MRI offered limited added value to T2WI+DW-MRI. KEY POINTS/CONCLUSIONS:• PI-RADSv2 correctly identified 95 % of PCa foci ≥0.5 mL • PI-RADSv2 was limited for the assessment of GS ≥4+3 tumours ≤0.5 mL • DCE-MRI offered limited added value to T2WI+DW-MRI.

PURPOSE/OBJECTIVE:To determine if second-opinion review of gynaecologic oncologic (GynOnc) magnetic resonance imaging (MRI) by sub-specialized radiologists impacts patient care. METHODS:469 second-opinion MRI interpretations rendered by GynOnc radiologists were retrospectively compared to the initial outside reports. Two gynaecologic surgeons, blinded to the reports' origins, reviewed all cases with discrepancies between initial and second-opinion MRI reports and recorded whether these discrepancies would have led to a change in patient management defined as a change in treatment approach, counselling, or referral. Histopathology or minimum 6-month imaging follow-up were used to establish the diagnosis. RESULTS:Second-opinion review of GynOnc MRIs would theoretically have affected management in 94/469 (20 %) and 101/469 (21.5 %) patients for surgeons 1 and 2, respectively. Specifically, second-opinion review would have theoretically altered treatment approach in 71/469 (15.1 %) and 60/469 (12.8 %) patients for surgeons 1 and 2, respectively. According to surgeons 1 and 2, these treatment changes would have prevented unnecessary surgery in 35 (7.5 %) and 31 (6.6 %) patients, respectively, and changed surgical procedure type/extent in 19 (4.1 %) and 12 (2.5 %) patients, respectively. Second-opinion interpretations were correct in 103 (83 %) of 124 cases with clinically relevant discrepancies between initial and second-opinion reports. CONCLUSIONS:Expert second-opinion review of GynOnc MRI influences patient care. KEY POINTS/CONCLUSIONS:• Outside gynaecologic oncologic MRI examinations are often submitted for a second-opinion review. • One-fifth of MRIs had important discrepancies between initial and second-opinion interpretations. • Second-opinion review of gynaecologic oncologic MRI is a valuable clinical service.

PURPOSE/OBJECTIVE:To examine the mode of relapse detection and subsequent treatment after partial or radical nephrectomy in patients with low-risk (pT1, N0, Nx) kidney cancer. METHODS:Retrospective study on 1404 patients treated with partial or radical nephrectomy for low-risk kidney cancer from the years 2000-2012. Scans for chest imaging (X-ray or CT) and abdominal imaging (CT, MRI, or ultrasound) are tabulated. For those patients with relapse, the site, mode of detection, and symptoms were recorded. RESULTS:Twenty-one patients relapsed with a median follow-up of 4.1 years for patients who did not relapse. In 17 (81 %) patients, relapse was detected by imaging alone, while 4 (19 %) patients presented with symptoms. Of the patients who relapsed by imaging, 13 (76 %) were treated immediately, while 4 (24 %) continued observation. During the first 3 years of follow-up, 5762 imaging studies were performed to detect 8 relapses, with 6 patients receiving immediate treatment. The median number of imaging studies per patient per year for the first 3 years was 1.7 (interquartile range 1.0, 2.3) including 30 % CT, 3 % MRI, 36 % X-ray, and 31 % ultrasounds. CONCLUSION/CONCLUSIONS:We found a low yield of surveillance imaging in the first 3 years for pT1 kidney cancer. Nearly 1000 imaging studies were performed to detect one relapse that required treatment. Further studies are needed to evaluate the clinical impact of imaging surveillance according to recent guidelines.