MSKCC Risk Score Research Articles

Retrospective study assessing the role of theandrogen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading tothe question ofwhether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. AR-overexpression and its association with other genes could favor a transcriptomic signature set to aidin identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

Correlating HLA variants and the emergence of immune-related adverse events (irAEs) from ipilimumab/nivolumab (I/N) in patients (pts) treated on CheckMate 214.

659 Background: Combination therapy with I/N can achieve long-term benefit in a sizable proportion of RCC pts, but broad application has been challenged by a high incidence of irAEs. Host features affecting antigen presentation are candidate determinants of irAE pathogenesis, and isolated reports have linked Human Leukocyte Antigen (HLA) variations to organ- specific irAEs. We analyzed data for pts treated on a phase 3 trial to investigate association of class 1 HLA variants with development of irAEs from I/N and develop a tool to predict risk for toxicity. Methods: We analyzed germline HLA + clinical data for 472 pts receiving I/N vs sunitinib (SUT). Based on allelic variants for HLA-A and B pts were categorized into 12 established HLA "Super-Types" (ST), sets of HLA variants with largely overlapping peptide binding specificity. We conducted uni- and multivariate (UV; MV) Cox proportional hazards regression to correlate HLA-ST variables with time to treatment-related AEs (TTrAE, grade 2+) in I/N pts using the Kaplan Meier method. Several MV HLA-ST models were developed on a discovery set (DISC; 2/3 random sample of I/N pts without replacement ) and compared using model concordance (c-index) on a validation set (VAL; remaining 1/3). Model coefficients were used to create a “HLA-ST score” that could be computed for individual pts. Results: 235 pts and 237 pts received I/N vs SUT and had available HLA data, respectively. On UV analysis for I/N, HLA-B07 ST had protective association TTrAE (HR= 0.65, 95% CI: 0.46,0.90; p= 0.010), while B62 associated adversely (HR=1.64, 95% CI: 1.12, 2.40; p=0.014). Relevant to the development of our model we identified interactions between several pairs of HLA ST. The HLA ST model with best performance in DISC (c-index= 0.606) and VAL (c-index=0.595) integrates B07, B62, A01, B08, and two interactions: B07-B08 and B07-A01. The model-generated HLA-ST score was significantly associated with TTrAE after adjusting for race, BMI, region, PDL1 status, and MSKCC risk score (DISC p<0.001; VAL p=0.028). No association with TTrAE was seen in SUT treated pts (p=0.655), neither in UV nor MV model. I/N-treated patients with HLA-ST score dichotomized >= vs < median had significantly different TTrAE both in DISC (p=0.004) and VAL (p=0.009); again, no difference was observed in the SUT arm (p=0.5). The weighted HLA-ST score had no association with PFS or OS for I/N pts. Conclusions: In this large sample of I/N-treated patients, class I HLA variants were associated with the risk of developing irAEs. We developed a HLA ST based score that correlated with treatment toxicity independent of relevant clinical and demographic features. No association with TTrAE was seen in SUT-treated pts. These results highlight the potential of characterizing germline features to predict immune related toxicity upfront and deserves further study. Clinical trial information: NCT02231749 .

Prognostic value of the ratio of maximum to minimum diameter of primary tumor in metastatic clear cell renal cell carcinoma

BackgroundSeveral models and markers were developed and found to predict outcome of advanced renal cell carcinoma. This study aimed to evaluate the prognostic value of the ratio of maximum to minimum tumor diameter (ROD) in metastatic clear cell renal cell carcinoma (mccRCC).MethodsPatients with mccRCC (n = 213) treated with sunitinib from January 2008 to December 2018 were identified. Cutoff value for ROD was determined using receiver operating characteristic. Patients with different ROD scores were grouped and evaluated. Survival outcomes were estimated by Kaplan–Meier method.ResultsThe optimal ROD cutoff value of 1.34 was determined for progression free survival (PFS) and overall survival (OS). Patients in ROD ≥ 1.34 group had shorter PFS (9.6 versus 17.7 months, p < 0.001) and OS (25.5 versus 32.6 months, p < 0.001) than patients in ROD < 1.34 group. After adjustment for other factors, multivariate analysis showed ROD ≥ 1.34 was an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.006). Patients in ROD ≥ 1.34 group presented higher proportions of pT3/4 stage (89.2% versus 10.8%, p = 0.021), WHO/ISUP grade III/IV (72.0% versus 28.0%, p = 0.010), tumor necrosis (71.0% versus 29.0%, p = 0.039), sarcomatoid differentiation (79.1% versus 20.9%, p = 0.007), poor MSKCC risk score (78.4% versus 21.6%, p < 0.001) and poor IMDC risk score (74.4% versus 25.6%, p < 0.001) than ROD < 1.34 group.ConclusionPrimary tumor with higher ROD was an independently prognostic factor for both PFS and OS in patients with mccRCC who received targeted therapy. Higher ROD was also associated with high pT stage, high WHO/ISUP grade, sarcomatoid features, tumor necrosis, poor MSKCC and IMDC risk score.

Prospective observational study on Pazopanib in patients treated for advanced or metastatic renal cell carcinoma in countries in Asia Pacific, North Africa, and Middle East regions: PARACHUTE study

BackgroundClinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking.MethodsPARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI).ResultsOverall, 190 patients with a median age of 61 years (range: 22.0–96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving < 85%. Of the 145 evaluable patients, 56 (39%) remained progression free at 12 months, and the median PFS was 10 months (95% CI: 8.48–11.83). 19% of patients (21/109) were long-term responders (on pazopanib for ≥18 months). The best response per RECIST 1.1 was CR/PR in 24%, stable disease in 44%, and PD in 31%. Most frequent (> 10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%).ConclusionsResults of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies.

Diagnosis-to-Treatment Interval Is an Important Prognostic Factor with a Time-Dependent Effect Predicting Event-Free Survival after 12 Months from First-Line Treatment in Newly Diagnosed Diffuse Large B-Cell Primary CNS Lymphoma

Diagnosis-to-Treatment Interval Is an Important Prognostic Factor with a Time-Dependent Effect Predicting Event-Free Survival after 12 Months from First-Line Treatment in Newly Diagnosed Diffuse Large B-Cell Primary CNS Lymphoma

PD39-03 HYPOXIA-INDUCIBLE FACTOR (HIF) PATHWAY GENES PREDICT OVERALL SURVIVAL FOR METASTATIC CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II (PD39)1 Apr 2020PD39-03 HYPOXIA-INDUCIBLE FACTOR (HIF) PATHWAY GENES PREDICT OVERALL SURVIVAL FOR METASTATIC CLEAR CELL RENAL CELL CARCINOMA Paige K Kuhlmann*, MD Shengchen Su, Sungyong You, PhD Devin Patel, MD Brian Rini, MD Susan Halabi, Eric J Small, andMD Hyung L KimMD Paige K Kuhlmann*Paige K Kuhlmann* More articles by this author , Shengchen SuShengchen Su More articles by this author , Sungyong YouSungyong You More articles by this author , Devin PatelDevin Patel More articles by this author , Brian RiniBrian Rini More articles by this author , Susan HalabiSusan Halabi More articles by this author , Eric J SmallEric J Small More articles by this author , and Hyung L KimHyung L Kim More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000918.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prognosis for metastatic RCC (mRCC) is variable. Aberrant HIF signaling is associated with progression of RCC. Using primary tumor tissue from Cancer and Leukemia Group B (CALGB) 90206, we assessed HIF pathway genes as predictors of overall survival (OS) in mRCC. METHODS: Gene expression was determined from 324 archival pretreatment nephrectomy specimens available from a phase III trial of 732 patients treated with interferon alpha (INF) vs. INF plus bevacizumab. TaqMan RT-qPCR was performed on the OpenArray platform using RNA extracted from tumor tissue macrodissected based on review of H&E staining by a genitourinary pathologist. Normalized gene expressions were centered and scaled across samples with means set at 0 and standard deviations set at 1 (z-score). HIF pathway genes were assessed in univariable and multivariable cox proportional hazard models as predictors of OS. The Cancer Genome Atlas (TCGA) RCC dataset was used for validation of the multivariable prognostic model. RESULTS: A total of 17 HIF pathway genes were assessed in univariable analysis, and 5 of these genes were associated with OS. Expression of VHL predicted OS (p=0.006). HIF2a (p=0.044) but not HIF1a (p=0.716) predicted OS. VEGF-D (p=0.026), but not VEGF-A (p=0.425), VEGF-B (p=0.440), or VEGF-C (p=0.135), was associated with OS. TGFA (p=0.014) and CCND1 (p=0.039) also exhibit significant association with OS. For illustration, patients were dichotomized into high and low risk groups based on mean gene expression score, and Kaplan-Meier plots were generated (Figure). In multivariable analysis, VEGF-D, TGFA and VHL were significant predictors of OS with HR of 1.49 [95% CI 1.16-1.94] between high and low risk groups (p=0.002). The model had a 5-year c-index of 0.62. When MSKCC clinical risk factors were added to this model, the 5-year c-index remained unchanged at 0.62, with HR=1.77 [95% CI 1.36-2.29] between high and low risk groups (p<0.0001). TCGA data does not allow MSKCC risk score to be calculated. Our multimarker model had a 5-year c-index of 0.56 when applied to the TCGA RCC dataset with HR=1.48 [95% CI 1.06-2.06] between high and low risk groups (p=0.022). CONCLUSIONS: The HIF pathway genes associated with OS include CCND1, VEGF-D, HIF2a, TGFA, and VHL. In a multivariable model, VEGF-D, TGFA and VHL were independent predictors of OS. Future studies should consider HIF pathway genes and multivariable models based on these genes as predictors of response to treatments targeting the hypoxia pathway and angiogenesis. Source of Funding: Supported by Award Numbers R01CA133072, Homer and Gloria Harvey Family Endowed Chair, and Lauhlere Family Fund © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e808-e809 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Paige K Kuhlmann* More articles by this author Shengchen Su More articles by this author Sungyong You More articles by this author Devin Patel More articles by this author Brian Rini More articles by this author Susan Halabi More articles by this author Eric J Small More articles by this author Hyung L Kim More articles by this author Expand All Advertisement PDF downloadLoading ...

Prognostic value of risk stratification using blood biochemical parameters in Japanese patients with metastatic renal cell carcinoma treated by nivolumab.

724 Background: Nivolumab is a standard treatment for previously treated advanced renal-cell carcinoma (RCC). However, nivolumab is effective in only a limited number of patients; therefore, we evaluated the prognostic value of several biomarkers, including inflammation-based prognostic scores and changes in these scores following nivolumab treatment in Japanese patients with metastatic RCC. Methods: We retrospectively reviewed the medical records of 65 patients with previously treated metastatic RCC and who received nivolumab. MSKCC and IMDC risk, inflammation-based prognostic scores, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and Glasgow prognostic score before and 6 weeks after the treatment were recorded. Categorical variables influencing disease-specific and overall survival were compared using Cox proportional-hazards regression models. Results: Univariate analysis showed that MSKCC risk score ( P = 0.0052), lactate dehydrogenase (LDH) ( P = 0.0266), LMR ( P = 0.0113), and PLR ( P = 0.0017) had a significant effect on disease-specific survival. Multivariate analyses showed that PLR and LDH were found to be independent prognostic factors for disease-specific survival ( P = 0.0008, RR = 7.95, 95% CI, 2.16–51.64 and P = 0.0123, RR = 3.92, 95% CI, 1.37–10.80, respectively). The combination of PLR and LDH was the most significant prognostic biomarker in metastatic RCC for disease-specific ( P &lt; 0.0001) and overall ( P &lt; 0.0001) survival. Changes in LMR and PLR in response to nivolumab were significant prognostic factors for disease-specific survival ( P &lt; 0.0001 and P = 0.0477, respectively). Conclusions: The combination of PLR and LDH may be a potential biomarker for estimating disease-specific and overall survival in Japanese patients with metastatic RCC treated by nivolumab. If changes of inflammation-based prognostic scores in response to nivolumab treatment might be improved, nivolumab treatment should be continued.

792P - Clinical significance of early circulating tumor cells (CTC) changes, analyzed by AdnaTest, in patients (pts) receiving first-line methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy (CT) for metastatic urothelial cancer (UC)

The therapeutic paradigm of metastatic UC is rapidly shifting due to the advent of new promising targeted therapies or immunotherapies. Liquid biopsies and the early identification of reliable predictive and prognostic factors in the treatment course may be a key to optimize the available standard therapies. 5 mL of whole blood from pts receiving first-line MVAC were collected at baseline (t0) and after 2 cycles (t2). Samples were processed by immunomagnetic beads (AdnaTest ProstateCancerSelect kit) and the expression of EPCAM, MUC1 and ERBB2 was studied using multiplex-PCR. CTC positivity and cutoffs, obtained by ROC curve analysis in healthy donors, were: ≥1 positive marker among EPCAM (≥0.40 ng/µl), MUC1 (≥0.10 ng/µl) and ERBB2 (≥0.20 ng/µl). CTC variation (t0/t2) was split in favorable (+/-, -/-, -/+) and unfavorable group (+/+) due to small numbers. Univariable analyses were undertaken for progression-free (PFS) and overall survival (OS). Multivariable analyses with bivariable associations with clinical factors were also done to improve understanding of effects. Among the 31 analyzed pts, 17 (54.8%) were CTC+ at t0 and no association was found with any baseline pt and tumor characteristic, as well as with CTC status and objective response to MVAC. Unfavorable CTC trend was observed in 10/26 (38.5%) cases. CTC dynamic changes better predicted for 3-year (3y) PFS and OS probability compared to CTC status assessed at single time points. Unfavorable trend was univariably detrimental on both 3y PFS probability (10% vs 49.2%, p = 0.006) and 3y OS probability (20% vs 63.5%, p = 0.017). Significance was maintained after adjusting for liver metastases (p = 0.031 and p = 0.025 for PFS and OS) and MSKCC risk score (p = 0.014 and 0.025). We proposed a novel technique to early assess CTC status in metastatic UC receiving MVAC CT. Early CTC changes may be useful to improve our prognostic ability. Pending validation, these results may lead to improved trial designs and to refine the sequence of conventional CT options in the clinical setting.

Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer.

Myopodin is a cytoskeleton protein that shuttles to the nucleus depending on the cellular differentiation and stress. It has shown tumor suppressor functions. Myopodin methylation status was useful for staging bladder and colon tumors and predicting clinical outcome. To our knowledge, myopodin has not been tested in kidney cancer to date. The purpose of this study was to evaluate whether myopodin methylation status could be clinically useful in renal cancer (1) as a prognostic biomarker and 2) as a predictive factor of response to antiangiogenic therapy in patients with metastatic disease. Methylation-specific polymerase chain reactions (MS-PCR) were used to evaluate myopodin methylation in 88 kidney tumors. These belonged to patients with localized disease and no evidence of disease during follow-up (n=25) (group 1), and 63 patients under antiangiogenic therapy (sunitinib, sorafenib, pazopanib, and temsirolimus), from which group 2 had non-metastatic disease at diagnosis (n=32), and group 3 showed metastatic disease at diagnosis (n=31). Univariate and multivariate Cox analyses were utilized to assess outcome and response to antiangiogenic agents taking progression, disease-specific survival, and overall survival as clinical endpoints. Myopodin was methylated in 50 out of the 88 kidney tumors (56.8%). Among the 88 cases analyzed, 10 of them recurred (11.4%), 51 progressed (57.9%), and 40 died of disease (45.4%). Myopodin methylation status correlated to MSKCC Risk score (p=0.050) and the presence of distant metastasis (p=0.039). Taking all patients, an unmethylated myopodin identified patients with shorter progression-free survival, disease-specific survival, and overall survival. Using also in univariate and multivariate models, an unmethylated myopodin predicted response to antiangiogenic therapy (groups 2 and 3) using progression-free survival, disease-specific, and overall survival as clinical endpoints. Myopodin was revealed hypermethylated in kidney cancer. Myopodin methylation status identified which patients showed a more aggressive clinical behavior and predicted antiangiogenic response. These observations support the clinical utility of an unmethylated myopodin as a prognostic and predictive biomarker in kidney cancer.

Comparison of simultaneous high dose stereotactic radiotherapy with normofractionated radiotherapy in patients with metastatic renal cell carcinoma under systemic therapy.

467 Background: Conventional radiation therapy (RT) is considered ineffective in metastatic renal cell carcinoma (mRCC). There are data suggesting that this might be related to low doses per fraction and that higher doses could be more effective. We introduced hypofracationated high-dose radiation therapy in patients with an indication for radiotherapy an retrospectively compared the results to patients with a conventional radiation therapy. Methods: We identified 97 pts with mRCC and an indication for radiotherapy of metastatic lesions between 2007 and 2013. All pts underwent simultaneous systemic therapy based on targeted agents and systemic therapy. 83 pts had a hypofractionated high dose stereotactic radiation (HDRT) (5 Gy per fraction, 3 fractions per week, total 45 Gy) while 14 pts underwent conventional normo-fractionated radiotherapy (NDR) (1.8 Gy per fraction) as described elsewhere. Results: Median age was 64.1 years (27-86). 189 metastatic lesions were irradiated. 64% of the pts had clear cell histology, with 14% harboring papillary RCC type II and 11% other subentities. Median overall survival was significantly longer for pts after HDRT was 9.4 months (+/-9.4 months) and 4.5 months (+/- 3.4 months) after NDR (p=0.01). The multivariate cox regression analysis revealed the MSKCC risk score, HDR therapy and the disease free survival as positive predictors for survival. No grade III toxicities were found, with 24% of the patients experiencing grade 1 or 2 side effects, mainly diarrhea and fatigue. Conclusions: In mRCC HDRT with simultaneous systemic therapy is related to a better overall survival than NRT. HDRT in combination with targeted therapy should be regarded the standard of care if RT is indicated.

Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy.

We aimed to assess the prognostic role of pretreatment neutrophilia, lymphocytopenia, and neutrophil to lymphocyte ratio (NLR) in patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKIs) for late relapsing (>5 years) metastatic renal cell carcinoma (mRCC). Data were collected from 13 Italian centers involved in the treatment of metastatic RCC. Late relapse was defined as >5 years after initial radical nephrectomy. One hundred fifty-one patients were included in this analysis. Among them, MSKCC risk score was favorable in 68 %, intermediate in 29 %, and poor in 3 %. Fifty-six patients (37 %) had NLR ≥3 at the start of VEGFR-TKI therapy (group A), while 95 had lower NLR (63 %, group B). The median overall survival (OS) was 28.8 months in group A and 68.7 months (95 % confidence interval (CI) 45.3-NA) in group B (p < 0.001). The median progression-free survival (PFS) was 15.8 months in group A and 25.1 months in group B (p = 0.03). At multivariate analysis, MSKCC risk group and NLR were independent prognostic factors for both OS and PFS. Pretreatment NLR is an independent prognostic factor for patients with late relapsing mRCC treated with first-line VEGFR-TKIs. A better characterization of baseline immunological impairment may optimize the management of this RCC subpopulation.

841P - Metastatic Renal Cell Carcinoma (Mrcc) Treated with Targeted Therapies (Tt) in the Community Setting: an Italian Survey on 1238 Pts

ABSTRACT Aim: This survey verified reproducibility in the real world of the survival data reported in the literature. Methods: This study reviewed individual data of 1238 pts treated with TT from mid 2007 to December 2012 in 35 Italian Institutions. Results: Median age was 66 yrs (range 24-91). Histology was clear cell (CC) (84%), with sarcomatoid component (7%), others (9%); nephrectomy was performed in 88% of the pts and 36.5% of the pts presented with ≥3 metastatic sites. PS (ECOG) was 0 in 53%, 1 in 34%, ≥2 in 9%, ne in 4% of the pts. Median OS (mOS) was 24 mo. Sunitinib (su) was the 1stline (ln) therapy (tx) in 964 pts (78%), sorafenib (so) in 152 (12%), temsirolimus (tem) in 51 (4%), others in 71 (5%). Response rate to 1st ln tx was: CR 4%, PR 31%, SD 30%, PD 28%, ne 7%. In 918 evaluable pts, MSKCC risk score was poor (10%), intermediate (46%) and good (18%). Dose reduction was required in 46%; 39% of the pts had a duration of 1st ln tx 6 mo, no tx interruption, no dose reduction were statistically related to execution of 2nd line tx. Cox multivariate analysis showed that execution of 2nd line tx, no dose reduction, type of drug, 1st ln duration >6 mo, CC histology, no tx interruption, MSKCC risk score, PS, type of response were statistically related to OS. mOS (all p Nephrectomy vs not 28 / 6.5 Metastatic sites ≤2 vs ≥3 31 / 18 PS 0 vs 1 vs ≥2 38.5 /18.6 / 6 CR vs PR vs SD vs PD 62.5 /39 / 29 / 7.8 Poor vs intermediate vs good MSKCC risk score 6.4 / 26 /46 Dose reduction: yes vs not 19.8 / 33.6 1st ln duration 6 mo 9.1 / 36.5 Conclusions: This large survey: i) confirmed survival data for the individual drugs ii) identified predictive and prognostic factors iii) showed similar OS between the principal sequences of tx. Disclosure: All authors have declared no conflicts of interest.

The role of prognostic factors in metastatic renal cell carcinoma (mRCC) treated with targeted therapies (TT): Data from an Italian retrospective multicentric study.

e15512 Background: Several prognostic factors in mRCC have been largely described in the literature. This study was aimed to verify whether some of these factors maintain their prognostic role in a cohort of pts treated in the community setting outside clinical trials. Methods: 902 pts with mRCC treated with TT from 2007 to December 2012 in 28 Italian centres were included in the analysis. Various potential prognostic factors were correlated with overall survival (OS). Results: Median age was 60 (range 25-89), 75% of pts were males; median OS (mOS) was 24 mo. Histology was clear cell (CC), CC with sarcomatoid component, papillary, NOS, not available in 82%, 6%, 4%, 4% and 4 %, respectively. mOS in the CC subgroup was 28 vs 12.5 mo of the non CC subset (p&lt;0.001). Nephrectomy was performed in 88% of the cases. mOS of these pts was 28 mo vs 6.5 in those without surgery (p&lt;0.001). The number of metastatic sites was &gt;2 in 43% of the pts. mOS of this group was 18 mo vs 31 mo of pts with ≤2 metastatic sites (p=0.0001). MSKCC risk was good in 32%, intermediate in 53% and poor in 15% of the pts. According to MSKCC risk score, mOS was 6.4, 24 and 49 mo in poor, intermediate and good subsets, respectively (p&lt;0.001). The small subset of pts (2%) with both thrombophilia and neutrophilia had a dismal mOS of 3 mo. PS (ECOG) was 0-1 in 90% of the pts; mOS of pts with PS ≥2 was 6 mo (p=0.0001). The findings of multivariate analysis are showed in the Table. Conclusions: The results of our survey confirm that clear cell histology, prior nephrectomy, number of metastatic sites, PS, MSKCC risk, platelets, and neutrophils count maintain their prognostic value also in mRCC pts treated with TT in the everyday clinical practice. [Table: see text]

Genetic polymorphisms’ influence in outcome of metastatic renal cell cancer patients treated with VEGF-targeted agents.

4635 Background: Single nucleotide polymorphisms (SNP) in critical signaling pathways may impact the outcome of metastatic renal cell cancer (mRCC) patients (pts) treated with VEGF targeted agents. Methods: Germline DNA was extracted from 263 pts of European-American ancestry enrolled in a prospective protocol with full baseline and follow up clinical data. A total of 113 common SNPs within select genes involved in RCC pathogenesis, angiogenesis and drugs metabolism were genotyped and associations sought with clinical outcome. The primary endpoint was progression free survival (PFS), defined as time from VEGF targeted therapy to progression or death. Cox model tested for the association between SNPs with PFS in univariate and multivariate model that adjusted for age, gender, type of VEGF inhibitor and MSKCC risk score. The false discovery rate (pFDR) was used to control for the number of tests performed. Results: The median follow-up time was 51.6 months (mo), 81% of pts had progression or death events. All patients were treated with an approved VEGF targeted agent (bevacizumab, sunitinib, sorafenib or pazopanib). Fifty three percent (140/263) of pts were treated with sunitinib. Two SNPs, one in HIF2α and one in VEGFR2, showed a significant association with the risk of progression. Compared to the dominant genotype (frequency 83%, median PFS 10.1mo), the VEGFR2 rs2305948 variant genotype (frequency 17%) showed a superior PFS (median 19.2mo) corresponded to an adjusted hazard ratio (HR) of 0.56 (95%CI: 0.37-0.84; p=0.005). Similarly and compared to the dominant genotype (frequency 94%, median PFS 10.6mo), the HIF2α rs11687512 variant genotype (frequency 6%) had a superior PFS (median 26.5mo) with an adjusted HR of 0.33 (95%CI 0.16-0.68; p=0.002). The analysis adjusted for age, gender, type of VEGF targeted therapy (Sunitinib vs. others) and MSKCC risk score. False discovery rate was &lt;20% with both SNPs. Conclusions: Inherited variants may influence the PFS of pts with mRCC treated with VEGF targeted agents. Validation of these findings in an independent cohort is required. If validated, these results could help identifying subset of pts that are more likely to remain progression free on treatment.

Effect of combination of systemic therapy and local therapy with cryoablation on outcome in metastatic renal cell cancer (mRCC): An extended follow-up report.

e15081 Background: Resection of metastasis in renal cancer (mRCC) yields 5-year survival rates of 20% to 30%. Yet most patients (pts) poor surgical candidates or have unresectable disease. Percutaneous cryoablation is a minimally invasive procedure employed for local therapy of metastatic foci, but its role in inducing long term remissions in combination with systemic therapy is unknown. Methods: Following IRB approval and HIPAA compliance, a retrospective review of records for pts receiving cryotherapy and systemic targeted therapy from 2004-2007 at Karmanos Cancer Institute was performed to enable a minimum follow up of 3 years. OS was estimated using the Kaplan-Meier methodology. Results: Of the 27 patients identified 85% were male, 88% Caucasian, and 77% had clear cell histology. 2 pts had sarcomatoid mRCC. All patients had prior nephrectomy. 24 patients had multiple metastatic sites: 9 with 2 sites, 8 with 3 sites and 7 with ≥ 4 sites. 15%, 52%, 11%, and 22% had favorable, intermediate, poor, and indeterminate MSKCC risk score, respectively. Systemic therapy was interrupted for at least 1 week prior to and after cryotherapy and resumed after complete healing. One major complication of nerve paresis was noted from lumbar paravertebral mass cryotherapy. Median number of ablations was 2 (range 1-4). Of the 60 total ablations 13%, 28%, 27%, 17%, and 15% were renal bed, visceral, soft tissue, bone, and lymph nodes respectively. The median OS from diagnosis of metastatic disease was 49.6 months (95% confidence interval: 21.2- 54.9 months).The 2 yr OS rate is 90% (95% CI: 78-100%) and 5 yr OS rate is 68% (49-87%). 8 patients (30%) are alive to date. Conclusions: The strategy of combining systemic therapy and local control of metastasis with cryoablation had favorable impact on OS in mRCC even after longer follow up. Cryoabalation is a minimally invasive, well tolerated technique, applicable to the majority of mRCC patients. Prospective investigation or case-control studies to evaluate the incorporation of cryoabalation with targeted systemic therapy in advanced RCC is warranted.

Tumor burden as an independent prognostic factor in metastatic renal cell carcinoma (mRCC).

397 Background: During the last ten years, several classifications have been used to assess the prognosis in mRCC. In none of them, tumor burden (TB) has been considered. This study investigates the prognostic role of baseline TB in terms of progression free survival (PFS) and overall survival (OS), in patients with mRCC. Methods: All patients with clear cell mRCC enrolled in our center, in 2 second-line trials, post cytokine, with sunitinib and sorafenib or placebo (Escudier JCO 2009, Escudier NEJM 2007), were selected for this analysis. TB was defined as the sum of the longest unidimensional diameter of each target lesions assessed using RECIST criteria. PFS and OS were estimated using Kaplan-Meier method and compared using the log-rank test. Association between TB and PFS or OS was evaluated using the Cox proportional hazards model. Multivariable analyses were adjusted for modified MSKCC risk class and treatment. Non-parametric Spearman rank test (rs) was used to assess the correlations between TB and MSKCC risk groups or ECOG Performance Status (PS). Results: Final population included 124 patients: 66% received sorafenib or sunitinib and 34% received placebo; median follow up was 80.1 months (IQR: 68.8 – 88.0). Baseline TB was divided into 3 tertiles (1.3 - 9.4 cm; 9.5 - 19.0 cm; 19.1 - 47.3 cm). TB was related to PFS and OS and, when adjusting for modified MSKCC risk class and treatment, these associations remained significant: each 1 cm increase in TB increased the progression risk by 5% (HR: 1.05; 95%CI, 1.02 – 1.07; p &lt; 0.0001) and the death risk by 5% (HR: 1.05; 95%CI, 1.03 – 1.08; p &lt; 0.0001). OS decreased with TB: the median tertiles OS values were: 42.1 months (95%CI: 24.0 – 60.2), 20.1 months (95%CI: 14.5 – 25.7), and 11.2 months (95%CI: 4.8 – 17.6), respectively (p &lt; 0.0001, figure 2). The TB was positively related to ECOG PS (rs = 0.357; p &lt; 0.0001) and to MSKCC risk score (rs = 0.478; p &lt; 0.0001). Patients with higher TB had shorter PFS, shorter OS, poorer MSKCC score and increased ECOG PS. Conclusions: TB is easy to calculate with standard CT and significantly relates to OS and PFS in patients with mRCC. We report for the first time the independent prognostic role of baseline TB in mRCC.

Second-line treatment for renal cell cancer

Second-line treatment for renal cell cancer

Correlation of Circulating Angiogenic Factors with Circulating Tumor Cells and Disease Recurrence in Patients Undergoing Curative Resection for Colorectal Liver Metastases

Circulating angiogenic factors (CAF) have been shown as therapeutic targets and prognostic biomarkers in metastatic colorectal cancer. However, their correlation with circulating tumor cells (CTC) is unknown, as is their role as prognostic biomarkers in patients amenable for curative resection. Preoperative blood samples were collected in patients undergoing potentially curative resection of colorectal liver metastases. Serum levels of eight CAF and CTC were analyzed by using ELISA and CK20 RT-PCR, respectively. Prognostic factors were identified by a Cox proportional hazards model. A total of 107 patients were eligible for final analyses. Circulating levels of PlGF, EGF, and bFGF were increased, whereas PDGF-A and Ang-1 levels were decreased in patients compared with healthy control subjects. CTC were detected in 36 of 63 patients (57%) and were associated with significantly lower levels of EGF and bFGF. On univariate analyses, multiple metastases (p = 0.04), a MSKCC risk score >2 (p = 0.004), and detection of CTC (p = 0.05) were associated with disease recurrence. Multivariate analysis, including the panel of eight CAF, revealed a MSKCC score >2 [hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.11-3.82; p = 0.02] and low levels of circulating PlGF (HR, 0.26; 95% CI, 0.08-0.81; p = 0.02) as independent predictors of poor recurrence-free survival. CAF may indicate patients who are at high risk for disease recurrence. The notion that CAF may identify patients who benefit from adjuvant therapy or antiangiogenic agents warrants further investigation.

1997 NATURAL HISTORY OF PATIENTS WITH DISEASE RECURRENCE AFTER NEPHRECTOMY FOR LOCALIZED RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Advanced1 Apr 20111997 NATURAL HISTORY OF PATIENTS WITH DISEASE RECURRENCE AFTER NEPHRECTOMY FOR LOCALIZED RENAL CELL CARCINOMA Ari Adamy, Shahrokh F. Shariat, Kian Tai Chong, Grace Russo, James Costaras, Melanie Bernstein, and Paul Russo Ari AdamyAri Adamy New York, NY More articles by this author , Shahrokh F. ShariatShahrokh F. Shariat New York, NY More articles by this author , Kian Tai ChongKian Tai Chong New York, NY More articles by this author , Grace RussoGrace Russo New York, NY More articles by this author , James CostarasJames Costaras New York, NY More articles by this author , Melanie BernsteinMelanie Bernstein New York, NY More articles by this author , and Paul RussoPaul Russo New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2224AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We investigated the natural history of patients who experienced disease recurrence in a large single center series of patients treated with nephrectomy for a clinically localized RCC. METHODS We identified 2,368 patients with unilateral, clinically localized RCC treated with either partial or radical nephrectomy between January 1989 and October 2008. Overall, 256 patients who experienced disease recurrence were included in the analysis. The previously published MSKCC prognostic scoring system was used to categorize patients at the time of recurrence. Univariate and multivariable Cox regression models were used to evaluate predictors of cancer-specific survival. The predictors included in the model were those present at the time of nephrectomy and those at the time of disease recurrence. RESULTS The median time from nephrectomy to disease recurrence was 19.5 months. Overall, 146 patients died from RCC and 6 patients died from other causes. The median follow-up from time of disease recurrence for those patients alive at the last follow-up was 28 months. The 2- and 5-year survival probabilities from time of disease recurrence for the entire cohort were 64% (95% CI 58% – 70%) and 36% (29% – 43%). On univariate analyses, T4 stage at nephrectomy (HR 3.63; 95%CI 1.78–7.40; p<0.001), presence of symptoms at recurrence (HR 2.23; 95% CI 1.56–3.17; p<0.001), lack of metastasectomy (HR 2.02; 95%CI 1.39–2.94; p<0.001), intermediate (HR 2.98; 95%CI 1.86 – 4.78; p<0.001) and poor risk score (HR 18.1; 95%CI 9.25 – 35.3; p<0.001), and shorter time from nephrectomy to recurrence (HR 0.99; 95%CI 0.98 – 0.99; p=0.001) were significantly associated with worse cancer-specific survival. Age, gender, tumor size, T2 and T3 stage, N stage, and tumor histology were not associated with cancer-specific survival. On multivariable analysis, T4 stage (HR 4.03; 95%CI 1.49 – 10.8; p=0.006), presence of symptoms at recurrence (HR 2.55; 95%CI 1.66 – 3.91; p<0.001), lack of metastasectomy (HR 1.77; 95%CI 1.14 – 2.77; p=0.011) and intermediate (HR 2.52; 95%CI 1.50 – 4.24; p<0.001) and poor risk (HR 13.4; 95%CI 6.25 – 28.8; p<0.001) remained independent predictors of cancer-specific survival. CONCLUSIONS We confirmed that intermediate and poor MSKCC risk score and the absence of metastasectomy are independently associated with a higher risk of cancer-specific death. In addition, patients diagnosed with recurrence due to symptoms related to metastatic disease have also worst outcomes. Factors related to the primary tumor were not associated with survival after the development of metastatic disease. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e799 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ari Adamy New York, NY More articles by this author Shahrokh F. Shariat New York, NY More articles by this author Kian Tai Chong New York, NY More articles by this author Grace Russo New York, NY More articles by this author James Costaras New York, NY More articles by this author Melanie Bernstein New York, NY More articles by this author Paul Russo New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Demographics, response, and overall survival of patients with advanced renal cell cancer to sunitinib in a cohort of minority patient population

e16164 Background: Sunitinib is a tyrosine kinase inhibitor active in renal cell cancer (RCC). There is scanty literature of its efficacy in minority population. Methods: 21 patients (pts) with RCC who received sunitinib between February 2006-September 2007 were identified and studied as a retrospective cohort. Clinical and survival data were analyzed using fisher's test, chi square test, Kaplan Meier analyses. Results: Of the 21 patients, 11 (52%) were female and 10 (47%) male, 7 (33.3%) African American, 7 (33.3%) Hispanic, and 5 (23.8%) Caucasian. Median age at diagnosis was 59 years (32–74). 7 (33.3%) had clear cell and 3 (14.3%) sarcomatoid pathology. Mixed, poorly differentiated, papillary and unknown histology were 2 (9.5%) each. 12 (57%) pts had stage 4 disease at diagnosis, stage 3 in 3 (14.3%), stage 2 in 1 (4.8%) and 5 (23%) had missing data. 14(66.7%) pts underwent nephrectomy while 7 (33.3%) did not. 6 (28.6%) pts has good MSKCC risk score, 11 (52.4%) intermediate risk and 3 (14.3%) poor risk. Sunitinib was given at a dose of 50 mg daily for 4 wks followed by 2 wks off. Median duration of treatment was 2.5 months (0–9 mts) and median follow up was 13 mts (1–21 mts). Common grade 3–4 toxicities observed were hand foot syndrome (n = 2), hypertension (n = 2) and thrombocytopenia (n = 1). 4 pts discontinued therapy due to adverse events. 5 (23.8%) has stable disease and 13 (61.9%) had progressive disease. Response to sunitinib was not influenced by sex, race, performance status, MSKCC Score, serum calcium level, LDH and hemoglobin level. Median survival of the group was 4 mts with no difference based on gender (p = 0.8), ethnicity (p = 0.8) or histologic type (p = 0.7). Survival of pts with ECOG performance status (PS) 1 was 8 mts, PS 2 was 4 mts, PS 3 was 2 mts (p = 0.001), MSKCC good risk was 9.4 mts, intermediate score was 9.4 mts and poor risk was 2 mts (p = 0.18). Hemoglobin (p = 0.6), LDH (p = 0.6), calcium (p = 0.2) did not affect the survival. Conclusions: In this minority cohort of pts with RCC treated with sunitinib, response and median survival is much lower than the historical controls. Tolerability and side effect profile are similar to reported literature. Prospective studies are warranted in the treatment of RCC with sunitinib in ethnic minority population. No significant financial relationships to disclose.