Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study.

OBJECTIVE: To evaluate patient preference for short (gist) or detailed/extensive decision aids (DA) for genetic testing at ovarian cancer (OC) diagnosis. DESIGN: Cohort study set within recruitment to the Systematic Genetic Testing for Personalised Ovarian Cancer Therapy (SIGNPOST) study (ISRCTN: 16988857). SETTING: North-East London Cancer Network (NELCN) population. POPULATION/SAMPLE: Women with high-grade non-mucinous epithelial OC. METHODS: A more detailed DA was developed using patient and stakeholder input following the principles/methodology of IPDAS (International Patients Decision Aids Standards). Unselected patients attending oncology clinics evaluated both a pre-existing short and a new long DA version and then underwent mainstreaming genetic testing by a cancer clinician. Appropriate inferential descriptive and regression analyses were undertaken. MAIN OUTCOME MEASURES: Satisfaction, readability, understanding, emotional well-being and preference for long/short DA. RESULTS: The mean age of patients was 66 years (interquartile range 11), and 85% were White British ethnicity. Of the participants, 74% found DAs helpful/useful in decision-making. Women reported higher levels of satisfaction (86% versus 58%, p < 0.001), right amount of information provided (76.79% versus49.12%, p < 0.001) and improved understanding (p < 0.001) with the long DA compared with the short DA. There was no statistically significant difference in emotional outcomes (feeling worried/concerned/reassured/upset) between 'short' and 'long' DA; 74% of patients preferred the long DA and 24% the short DA. Patients undergoing treatment (correlation coefficient (coef) = 0.603; 95% CI 0.165-1.041, p = 0.007), those with recurrence (coef = 0.493; 95% CI 0.065-0.92, p = 0.024) and older women (coef = 0.042; 95% CI 0.017-0.066, p = 0.001) preferred the short DA. Ethnicity did not affect outcomes or overall preference for long/short DA. CONCLUSIONS: A longer DA in OC patients has higher satisfaction without increasing emotional distress. Older women and those undergoing treatment/recurrence prefer less extensive information, whereas those in remission preferred a longer DA.

p53-Abnormal "Fields of Dysplasia" in Human Papillomavirus-Independent Vulvar Squamous Cell Carcinoma Impacts Margins and Recurrence Risk.

Abnormal p53 (p53abn) immunohistochemical (IHC) staining patterns can be found in vulvar squamous cell carcinoma (VSCC) and differentiated vulvar intraepithelial neoplasia (dVIN). They can also be found in the adjacent skin that shows morphology that falls short of the traditional diagnostic threshold for dVIN. Vulvectomy specimens containing human papillomavirus-independent p53abn VSCC with margins originally reported as negative for invasive and in situ disease were identified. Sections showing the closest approach by invasive or in situ neoplasia to margins were stained with p53 IHC stains. We evaluated the following: (1) detection of morphologically occult p53abn in situ neoplasia, (2) rates of margin status change after p53 IHC staining, and (3) effect of p53abn IHC staining at margins on the 2-year local recurrence rates. Seventy-three human papillomavirus-independent p53abn VSCCs were included. Half (35/73, 48%) had documented an in situ lesion in the original report. The use of p53 IHC staining identified 21 additional cases (29%) with the p53abn in situ lesions that were originally unrecognized. The histology of in situ lesions in the p53abn "field" varied and became more subtle (morphologically occult) farther away from the VSCC. Fifteen (21%) cases had a morphologically occult and previously unrecognized p53abn in situ lesion present at a resection margin, which conferred an increased risk of local recurrence (5/7 [71.4%] vs 6/22 [27.3%], P = .036). The p53abn in situ lesions at a margin were confirmed to have TP53 mutations by sequencing. p53 IHC staining identified morphologically occult p53abn in situ lesions surrounding human papillomavirus-independent VSCC. p53abn IHC staining at a margin was associated with a 3-fold increased risk of local recurrence.

Concise Reporting of Benign Endometrial Biopsies is an Acceptable Alternative to Descriptive Reporting.

In the United Kingdom, endometrial biopsy reports traditionally consist of a morphologic description followed by a conclusion. Recently published consensus guidelines for reporting benign endometrial biopsies advocate the use of standardized terminology. In this project we aimed to assess the acceptability and benefits of this simplified "diagnosis only" format for reporting non-neoplastic endometrial biopsies. Two consultants reported consecutive endometrial biopsies using 1 of 3 possible formats: (i) diagnosis only, (ii) diagnosis plus an accompanying comment, and (iii) the traditional descriptive format. Service users were asked to provide feedback on this approach via an anonymized online survey. The reproducibility of this system was assessed on a set of 53 endometrial biopsies among consultants and senior histopathology trainees. Of 370 consecutive benign endometrial biopsies, 245 (66%) were reported as diagnosis only, 101 (27%) as diagnosis plus a brief comment, and 24 (7%) as diagnosis following a morphologic description. Of the 43 survey respondents (28 gynecologists, 11 pathologists, and 4 clinical nurse specialists), 40 (93%) preferred a diagnosis only, with 3 (7%) being against/uncertain about a diagnosis only report. Among 3 histopathology consultants and 4 senior trainees there was majority agreement on the reporting format in 53/53 (100%) and 52/53 (98%) biopsies. In summary, we found that reporting benign specimens within standardized, well-understood diagnostic categories is an acceptable alternative to traditional descriptive reporting, with the latter reserved for the minority of cases that do not fit into specific categories. This revised approach has the potential to improve reporting uniformity and reproducibility.

Significance of p53 and presence of differentiated vulvar intra-epithelial neoplasia (dVIN) at resection margin in early stage human papillomavirus-independent vulvar squamous cell carcinoma.

OBJECTIVE: Vulvar squamous cell carcinoma and in situ lesions can be stratified by human papillomavirus (HPV) and TP53 status into prognostic risk groups using p16 and p53 immunohistochemistry. We assessed the significance of vulvar squamous cell carcinoma resection margin positivity for either differentiated vulvar intra-epithelial neoplasia (dVIN) or abnormal p53 immunohistochemistry, and other pathologic variables, in a cohort of patients with HPV-independent (HPV-I) p53 abnormal (p53abn) vulvar squamous cell carcinomas. METHODS: Patients with stage I-II HPV-I p53abn vulvar squamous cell carcinoma with negative invasive margins who did not receive adjuvant radiation from a single institution were included. Tumors underwent margin reassessment using p53 immunohistochemistry. Cases were segregated into (1) morphologic dVIN at margin; or (2) abnormal p53 immunohistochemistry staining at margin without morphologic dVIN (p53abn immunohistochemistry); or (3) margins negative by morphology and p53 immunohistochemistry. Clinicopathologic/outcome data were collected. RESULTS: A total of 51 patients were evaluated: (1) 12 with dVIN on margin; (2) 12 with p53abn immunohistochemistry on margin without morphologic dVIN; and (3) 27 with margins negative for morphologic dVIN and p53abn immunohistochemistry. The recurrence rate for patients with dVIN or p53abn immunohistochemistry on the margin was equally high at 75% each, compared with 33% with margins negative for morphologic dVIN and p53abn immunohistochemistry (p=0.009). On multivariate analysis, positive in situ margins maintained an association with disease recurrence (p=0.03) whereas invasive margin distance (radial and deep), lymphovascular invasion, and tumor size did not. CONCLUSIONS: Patients with stage I-II HPV-I vulvar squamous cell carcinoma with margins positive for either dVIN or p53abn immunohistochemistry without morphologic dVIN showed increased disease recurrence, regardless of invasive margin distance. These findings show that p53 immunohistochemistry is a useful adjunct for evaluating margin status in HPV-I vulvar squamous cell carcinoma and may support repeat excision for positive in situ margins (dVIN or p53abn immunohistochemistry).

PNL2: A Useful Adjunct Biomarker to HMB45 in the Diagnosis of Uterine Perivascular Epithelioid Cell Tumor (PEComa).

Perivascular epithelioid cell tumors (PEComa) are rare neoplasms characterized by co-expression of melanocytic and muscle markers. HMB45 and Melan-A are used to confirm a PEComa diagnosis; however, both are often focally expressed and sensitivity for Melan-A is low. PNL2 is a reliable biomarker for epithelioid melanoma and renal angiomyolipoma/PEComa. The objective of this study was to determine PNL2 utility in diagnosing uterine PEComas as well as distinguishing PEComas from uterine smooth muscle tumors (SMTs). Twenty-one uterine PEComas and 45 SMTs were analyzed for PNL2; a subset was also stained for HMB45, Melan-A, Cathepsin-K, Desmin, and h-Caldesmon. Cases were scored as negative (0), focal (<10% of tumor cells), or patchy to diffusely positive (>10% of tumor cells). PEComas were positive for PNL2, HMB45, and Melan-A in 86%, 100%, and 57% of cases, respectively. In PEComas, PNL2 was patchy to diffusely positive more frequently (10/18, 56%) than Melan-A (4/12, 33%). In contrast, 2 of 45 (4%) SMTs were focally PNL2 positive; HMB45 was focally positive in 4 SMTs (11%) and all were negative for Melan-A. Desmin and h-Caldesmon were positive in 90% and 57% of PEComas, and 91% and 82% of SMTs. Cathepsin-K was positive in 100% of PEComas and 93% of SMTs. PNL2 is a useful biomarker for the diagnosis of uterine PEComa, with comparable sensitivity and specificity to HMB45. In contrast, PNL2 stains more PEComas when compared with Melan-A. Cathepsin-K, Desmin, and h-Caldesmon are of little utility for distinguishing PEComas and SMTs; however, lack of Cathepsin-K argues against PEComa. These results suggest that PNL2 should be used in conjunction with HMB45 in the diagnosis of PEComa of the uterine corpus.

Extrauterine high-grade serous carcinomas with bilateral adnexal involvement as the only two disease sites are clonal based on tp53 sequencing results: implications for biology, classification, and staging.

A previous multicenter study of 67 cases of Stage I/II tubo-ovarian high-grade serous carcinoma with complete tubal sampling identified 7 cases in which there were only two disease sites, comprising tumor involving opposite adnexa with no extra-adnexal involvement. This study aimed to determine whether such low-stage extrauterine high-grade serous carcinomas with only two sites of involvement, located on opposite adnexa, have identical or different TP53 mutations in order to investigate their clonal relationship. DNA extracted from both sites of involvement was subjected to TP53 sequencing (n=6) or sequencing of one site and mutation confirmation by droplet digital PCR for the other site (n=1). Of the 7 cases analyzed, 1 case had unilateral serous tubal intraepithelial carcinoma with contralateral ovarian high-grade serous carcinoma, 3 had tubal high-grade serous carcinomas (±serous tubal intraepithelial carcinoma) with contralateral ovarian high-grade serous carcinoma, 2 had bilateral ovarian high-grade serous carcinomas with normal tubes, and 1 had bilateral fallopian tube high-grade serous carcinoma with normal ovaries. All 7 cases showed identical TP53 mutations in tumor from both disease sites. Therefore, these rare cases of high-grade serous carcinoma confined to opposite adnexa all show clonal identity between the two sites of involvement, suggesting unifocal origin and metastasis rather than multifocal origin. Our results suggest that serous tubal intraepithelial carcinoma or adnexal high-grade serous carcinoma can metastasize to the contralateral adnexa without peritoneal involvement. Given the clonal relationship between the two sites, such cases should be considered stage II, with stage I reserved for cases with unilateral and unifocal adnexal involvement. Furthermore, serous tubal intraepithelial carcinoma without invasion should be taken to constitute a disease site for staging purposes.

Disease Distribution in Low-stage Tubo-ovarian High-grade Serous Carcinoma (HGSC): Implications for Assigning Primary Site and FIGO Stage.

The latest FIGO and TNM (eighth edition) staging systems for ovarian, tubal, and peritoneal neoplasms require primary site assignment as tubal/ovarian/peritoneal, but provide no guidance or criteria. Fewer than 10% of extrauterine high-grade serous carcinoma (HGSC) cases present at low stage (stage I/II). Low-stage cases offer a unique opportunity to understand the pattern of disease early in its evolution prior to wide dissemination and provide valuable evidence for guiding specimen handling and tumor staging. This study aimed to examine disease distribution in low-stage tubo-ovarian HGSC. Anonymized pathology reports of 152 stage I/II extrauterine HGSCs from 6 teaching hospitals were analyzed: group 1 (n=67) comprised cases with complete tubal examination by Sectioning and Extensively Examining the FIMbriated end of the tube (SEE-FIM) and group 2 (n=85) consisted of cases without documentation of both tubes being fully examined by the SEE-FIM or a SEE-FIM-like protocol. The stage, site/pattern of involvement, site/size of largest tumor focus and laterality of tubal and ovarian involvement were recorded. Tubal mucosal involvement was present in 95% of optimally examined cases and many factors influenced detection of tubal disease. Bilateral involvement, suggestive of metastasis, was significantly more frequent in the ovaries (35%) than the tubes (9%) (P<0.0001, Fisher exact test). No case showed a complete absence of tubal/ovarian involvement, questioning the biological existence of primary peritoneal HGSC. Disease distribution in low-stage cases supports a tubal origin for most HGSCs. Detailed tubal sampling upstages some apparent stage I cases through detection of microscopic tubal involvement.

The Chemotherapy Response Score (CRS): Interobserver Reproducibility in a Simple and Prognostically Relevant System for Reporting the Histologic Response to Neoadjuvant Chemotherapy in Tuboovarian High-grade Serous Carcinoma.

A 3-tier histopathologic scoring system, the chemotherapy response score (CRS), was previously devised for reporting the histologic response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIc/IV tuboovarian high-grade serous carcinoma. This has been shown to predict the outcome and offer additional information to other methods of assessing the treatment response. In the present study, the reproducibility of this scoring system was assessed by determining the interobserver agreement among reporting pathologists. A total of 5 groups each comprising 3 pathologists with different levels of expertise were selected. The participants underwent an online tutorial on how to apply the CRS system. 40 cases (38 cases in 2 appraiser groups) were scored individually by each of the 15 pathologists. The interobserver reproducibility was calculated using Fleiss' κ, Kendall's coefficient of concordance, and the absolute agreement between (a) individual pathologists within 1 group, (b) with the majority score agreement between all groups, and (c) with all individual scores. The CRS system was found to be highly reproducible among all the pathologists' groups (κ=0.761). The agreement in identifying the group of patients with the best response to chemotherapy was exceptionally high (κ=0.926). We conclude that CRS has a high interobserver reproducibility, especially in identifying the subgroup of patients with the best chemotherapy response, justifying its inclusion in clinical trials and reporting practice.

INNOVATE: A prospective cohort study combining serum and urinary biomarkers with novel diffusion-weighted magnetic resonance imaging for the prediction and characterization of prostate cancer.

BACKGROUND: Whilst multi-parametric magnetic resonance imaging (mp-MRI) has been a significant advance in the diagnosis of prostate cancer, scanning all patients with elevated prostate specific antigen (PSA) levels is considered too costly for widespread National Health Service (NHS) use, as the predictive value of PSA levels for significant disease is poor. Despite the fact that novel blood and urine tests are available which may predict aggressive disease better than PSA, they are not routinely employed due to a lack of clinical validity studies. Furthermore approximately 40 % of mp-MRI studies are reported as indeterminate, which can lead to repeat examinations or unnecessary biopsy with associated patient anxiety, discomfort, risk and additional costs. METHODS/DESIGN: We aim to clinically validate a panel of minimally invasive promising blood and urine biomarkers, to better select patients that will benefit from a multiparametric prostate MRI. We will then test whether the performance of the mp-MRI can be improved by the addition of an advanced diffusion-weighted MRI technique, which uses a biophysical model to characterise tissue microstructure called VERDICT; Vascular and Extracellular Restricted Diffusion for Cytometry in Tumours. INNOVATE is a prospective single centre cohort study in 365 patients. mp-MRI will act as the reference standard for the biomarker panel. A clinical outcome based reference standard based on biopsy, mp-MRI and follow-up will be used for VERDICT MRI. DISCUSSION: We expect the combined effect of biomarkers and VERDICT MRI will improve care by better detecting aggressive prostate cancer early and make mp-MRI before biopsy economically viable for universal NHS adoption. TRIAL REGISTRATION: INNOVATE is registered on ClinicalTrials.gov, with reference NCT02689271 .

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51-62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51-71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.

Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway.

OBJECTIVES: To determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain is common and could prove a useful marker for the activation status of the PI3K-AKT-mTOR pathway in penile squamous cell carcinoma (PSCC). METHODS: Fresh frozen tissue and archival blocks were collected from 24 PSCC patients with 15 matched normal penile epithelium (NPE) tissue from St George's Hospital. PIK3CA mutational and copy number status (CNS) was assessed via Sanger sequencing and fluorescence in-situ hybridisation, respectively. PIK3CA RNA expression was quantified using TaqMan gene expression assay. HPV DNA was detected with INNO-LiPA assay. p-AKT and p-mTOR protein expression were assessed using western blot and immunohistochemistry. RESULTS: PIK3CA copy number gain was found in 11/23 (48%) patients, with mutations present in only 2/24 (8%) patients. In comparison to NPE, PSCC showed significantly lower PIK3CA RNA expression (p=0.0007), p-AKT (Ser473) nuclear immunoexpression (p=0.026) and protein expression of p-AKT (Thr308) (p=0.0247) and p-mTOR (Ser2448) (p=0.0041). No association was found between PIK3CA CNS and p-AKT and p-mTOR protein expression. CONCLUSION: Based on our results the PI3K-AKT-mTOR pathway is not a key driver in PSCC carcinogenesis and the therapeutic targeting of this pathway is unlikely to produce significant clinical benefit.

PIK3CA copy number aberration and activation of the PI3K-AKT-mTOR pathway in varied disease states of penile cancer.

BACKGROUND: Therapeutic targeting of the PI3K-AKT-mTOR pathway may benefit patients with advanced penile squamous cell carcinoma (PSCC). OBJECTIVES: To determine the prevalence of PIK3CA copy number gain and correlate this with the activity status of PI3K-AKT-mTOR pathway in pre-malignant penile intraepithelial neoplasia (PeIN) and invasive PSCC. MATERIALS AND METHODS: Archival tissue blocks were obtained from 58 PeIN and 244 primary PSCC patients treated at St George's Hospital. PIK3CA copy number status (CNS) was assessed by fluorescence in-situ hybridisation. High-risk HPV DNA was detected with INNO-LiPA assay. p16INK4A, p-AKT and p-mTOR protein expression were assessed using immunohistochemistry (IHC). RESULTS: Increased prevalence of PIK3CA copy number gain was seen in PSCC in comparison to PeIN (84/199 (42%) vs. 10/58 (17%); p = 0.0009). Analysis of the p-AKT and p-mTOR revealed a tendency to a more common expression of cytoplasmic p-AKT (p = 0.1318), nuclear p-AKT (p<0.0001) and cytoplasmic mTOR (p = 0.0006) in PeIN than PSCC. A significant association between p-AKT cytoplasmic immunoexpression and PIK3CA CNS (p = 0.0404) was found in PeIN. CONCLUSION: Overall, PIK3CA copy number gain correlated with activation of the PI3K-AKT-mTOR pathway in PeIN and activation of this pathway is primarily involved in early penile carcinogenesis. Based on these results therapeutic targeting of this pathway in advanced PSCC is unlikely to produce significant clinical benefit. Future studies will need to focus on alternative therapeutic targets.

Clinical Use of Programmed Cell Death-1 and Its Ligand Expression as Discriminatory and Predictive Markers in Ovarian Cancer.

Purpose: We aimed to establish whether programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, in ovarian cancer tumor tissue and blood, could be used as biomarkers for discrimination of tumor histology and prognosis of ovarian cancer.Experimental Design: Immune cells were separated from blood, ascites, and tumor tissue obtained from women with suspected ovarian cancer and studied for the differential expression of possible immune biomarkers using flow cytometry. PD-L1 expression on tumor-associated inflammatory cells was assessed by immunohistochemistry and tissue microarray. Plasma soluble PD-L1 was measured using sandwich ELISA. The relationships among immune markers were explored using hierarchical cluster analyses.Results: Biomarkers from the discovery cohort that associated with PD-L1+ cells were found. PD-L1+ CD14+ cells and PD-L1+ CD11c+ cells in the monocyte gate showed a distinct expression pattern when comparing benign tumors and epithelial ovarian cancers (EOCs)-confirmed in the validation cohort. Receiver operating characteristic curves showed PD-L1+ and PD-L1+ CD14+ cells in the monocyte gate performed better than the well-established tumor marker CA-125 alone. Plasma soluble PD-L1 was elevated in patients with EOC compared with healthy women and patients with benign ovarian tumors. Low total PD-1+ expression on lymphocytes was associated with improved survival.Conclusions: Differential expression of immunological markers relating to the PD-1/PD-L1 pathway in blood can be used as potential diagnostic and prognostic markers in EOC. These data have implications for the development and trial of anti-PD-1/PD-L1 therapy in ovarian cancer. Clin Cancer Res; 23(13); 3453-60. ©2016 AACR.

Necrotizing granulomatous inflammation of the glans penis.

We describe the case of a 73-year-old man who presented with a 10-month history of an ulcerating lesion on the glans penis. Initially this was thought to be an invasive squamous cell carcinoma but a biopsy showed histological features consistent with necrotizing granulomatous inflammation. Extensive serological, immunological and microbiological tests only showed a positive antinuclear and perinuclear antineutrophil cytoplasmic antibodies indicating a possible autoimmune aetiology but an underlying systemic cause was not identified. Treatment with oral corticosteroids limited the inflammatory process but due to the gross destruction of the glans penis, he still required a glansectomy and split-skin graft reconstruction from which he recovered well. Although this patient ultimately required surgery for this rare presentation, this case highlights the differential diagnosis of penile ulceration (that transcends neoplasia) and the importance of performing and interpreting penile biopsies before undertaking potentially mutilating definitive surgery.

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer.

IMPORTANCE: The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain. OBJECTIVE: To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months. INTERVENTIONS: Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression. MAIN OUTCOMES AND MEASURES: The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis. RESULTS: Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response. CONCLUSIONS AND RELEVANCE: Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.