Breast-Specific Epigenetic Regulation of DeltaNp73 and Its Role in DNA-Damage-Response of BRCA1-Mutated Human Mammary Epithelial Cells.

The function of BRCA1/2 proteins is essential for maintaining genomic integrity in all cell types. However, why women who carry deleterious germline mutations in BRCA face an extremely high risk of developing breast and ovarian cancers specifically has remained an enigma. We propose that breast-specific epigenetic modifications, which regulate tissue differentiation, could team up with BRCA deficiency and affect tissue susceptibility to cancer. In earlier work, we compared genome-wide methylation profiles of various normal epithelial tissues and identified breast-specific methylated gene promoter regions. Here, we focused on deltaNp73, the truncated isoform of p73, which possesses antiapoptotic and pro-oncogenic functions. We showed that the promoter of deltaNp73 is unmethylated in normal human breast epithelium and methylated in various other normal epithelial tissues and cell types. Accordingly, deltaNp73 was markedly induced by DNA damage in human mammary epithelial cells (HMECs) but not in other epithelial cell types. Moreover, the induction of deltaNp73 protected HMECs from DNA damage-induced cell death, and this effect was more substantial in HMECs from BRCA1 mutation carriers. Notably, when BRCA1 was knocked down in MCF10A, a non-malignant breast epithelial cell line, both deltaNp73 induction and its protective effect from cell death were augmented upon DNA damage. Interestingly, deltaNp73 induction also resulted in inhibition of BRCA1 and BRCA2 expression following DNA damage. In conclusion, breast-specific induction of deltaNp73 promotes survival of BRCA1-deficient mammary epithelial cells upon DNA damage. This might result in the accumulation of genomic alterations and allow the outgrowth of breast cancers. These findings indicate deltaNp73 as a potential modifier of breast cancer susceptibility in BRCA1 mutation carriers and may stimulate novel strategies of prevention and treatment for these high-risk women.

Survival Outcomes From a Cumulative Analysis of Worldwide Observational Studies on Sequential Use of New Agents in Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION: The sequential use of a number of new agents (NAs) have improved the overall survival (OS) of patients with metastatic castration-resistant prostate cancer whose disease progresses after docetaxel (DOC) treatment. The aim of this study was to assess the cumulative survival outcomes of different sequencing strategies by evaluating the individual data from published studies of patients treated with a post-DOC treatment sequence of 2 NAs. PATIENTS AND METHODS: The patients' individual data were analyzed to investigate whether different sequencing strategies lead to differences in OS. RESULTS: We analyzed the data of 1099 evaluable patients. Among the patients treated with a second-line new hormone agent (NHA), median OS from the start of third-line treatment was significantly longer in the patients treated with cabazitaxel (CABA) than in those treated with abiraterone acetate or enzalutamide. Median cumulative OS (cumOS) from the start of second-line treatment was 21.1 months in the patients who received NHA then NHA, 22.1 months in those who received NHA then CABA, and 21.0 months in those who received CABA then NHA. Among the patients with a second-line progression-free survival of ≥6 months, median cumOS was significantly longer in patients who received CABA-including sequences than in those treated with NHA then NHA sequences (29.5 vs. 24.8 months; P = .03). CONCLUSION: Our findings suggest that the sequential use of NAs with different mechanisms of action improves cumOS regardless of the order in which they are administered, thus supporting the hypothesis of cross-resistance between the 2 NHAs.

Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database.

AIM OF THE STUDY: Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry. METHODS: The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence. RESULTS: Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes. CONCLUSIONS: Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.

Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial.

BACKGROUND: Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting. PATIENTS AND METHODS: AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors. RESULTS: Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments. CONCLUSION: In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.

Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017.

BACKGROUND: In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. OBJECTIVE: To present the report of APCCC 2017. DESIGN, SETTING, AND PARTICIPANTS: Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; "oligometastatic" prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. RESULTS AND LIMITATIONS: Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. CONCLUSIONS: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. PATIENT SUMMARY: The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.

Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database.

BACKGROUND: The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown. OBJECTIVE: To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences. DESIGN, SETTING, AND PARTICIPANTS: Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity. RESULTS AND LIMITATIONS: A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3. CONCLUSIONS: In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs. PATIENT SUMMARY: The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma.

BACKGROUND: Cabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types. PATIENTS AND METHODS: Patients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment. RESULTS: Seventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks. CONCLUSION: Cabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions. REGISTRATION: This trial is registered at ClinicalTrial.gov (NCT00940225).

Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib.

BACKGROUND: The Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models categorize patients with 1 or 2 risk factors as intermediate prognosis (INTMP). This category encompasses 15 and 19 permutations of the MSKCC and IMDC risk factors, respectively. The purpose of the present retrospective analysis of data from INTMP patients in 6 clinical trials was to determine whether this heterogeneity influences the response to sunitinib. PATIENTS AND METHODS: Patients with INTMP metastatic renal cell carcinoma (mRCC) were identified using the MSKCC and IMDC classifications. The statistical data were analyzed using Cox regression analysis, Kaplan-Meier methods, and Pearson χ2 tests. RESULTS: The patient characteristics and risk factors were similar in the MSKCC (n = 548) and IMDC (n = 517) groups. Overall, 59% had 1 risk factor and 41% had 2 risk factors. The most common was low hemoglobin alone or with an interval of < 1 year since diagnosis. In both groups, patients with 1 risk factor had longer overall survival (OS) and progression-free survival (PFS) than did those with 2 risk factors (P < .001 for both outcomes). Patients in the IMDC group with 1 risk factor had a greater objective response rate (ORR; P = .023). In both groups, OS was longer for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 than for those with ECOG PS 1 or 2 (P < .001). An ECOG PS of 0 was also associated with superior PFS and ORR in the MSKCC group (P < .05). CONCLUSION: INTMP comprises a heterogeneous group of mRCC patients in whom the number of risk factors and ECOG PS might predict the outcome with sunitinib.

Outcome of Patients With Metastatic Chromophobe Renal Cell Carcinoma Treated With Sunitinib.

BACKGROUND: Sunitinib is a standard treatment for metastatic clear cell renal cell carcinoma (mccRCC). Data on its activity in the rare variant of metastatic chromophobe renal cell carcinoma (mchRCC), are limited. We aimed to analyze the activity of sunitinib in a relatively large and homogenous international cohort of mchRCC patients in terms of outcome and comparison with mccRCC. METHODS: Records from mchRCC patients treated with first-line sunitinib in 10 centers across 4 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and outcome were performed. Subsequently, mchRCC patients were individually matched to mccRCC patients. We compared the clinical benefit rate, progression-free survival (PFS), and overall survival (OS) between the groups. RESULTS: Between 2004 and 2014, 36 patients (median age, 64 years; 47% male) with mchRCC were treated with first-line sunitinib. Seventy-eight percent achieved a clinical benefit (partial response + stable disease). Median PFS and OS were 10 and 26 months, respectively. Factors associated with PFS were the Heng risk (hazard ratio [HR], 3.3; p = .03) and pretreatment neutrophil-to-lymphocyte ratio (NLR) >3 (HR, 0.63; p = .02). Factors associated with OS were the Heng risk (HR, 4.1; p = .04), liver metastases (HR, 3.8; p = .03), and pretreatment NLR <3 (HR, 0.55; p = .03). Treatment outcome was not significantly different between mchRCC patients and individually matched mccRCC patients. In mccRCC patients (p value versus mchRCC), 72% achieved a clinical benefit (p = .4) and median PFS and OS were 9 (p = .6) and 25 (p = .7) months, respectively. CONCLUSION: In metastatic chromophobe renal cell carcinoma, sunitinib therapy may be associated with similar outcome and toxicities as in metastatic clear cell renal cell carcinoma. The Heng risk and pretreatment NLR may be associated with PFS and OS. IMPLICATIONS FOR PRACTICE: Data on the activity of sunitinib in metastatic chromophobe renal cell carcinoma (mchRCC) are limited. This study analyzed the activity of sunitinib in a cohort of mchRCC patients. Of 36 patients with mchRCC who were treated with first-line sunitinib, 78% achieved a clinical benefit. Median PFS and OS were 10 and 26 months, respectively. Treatment outcome was not significantly different between mchRCC patients and individually matched metastatic clear cell RCC patients.

Metformin Use and Outcome of Sunitinib Treatment in Patients With Diabetes and Metastatic Renal Cell Carcinoma.

BACKGROUND: Although studies in several cancer types suggest that metformin has antitumor activity, its effect on the outcome of targeted therapies in metastatic renal cell carcinoma (mRCC) is poorly defined. We aimed to analyze the effect of metformin use on the outcome of sunitinib treatment in diabetic patients with mRCC. PATIENTS AND METHODS: We performed a retrospective study of diabetic patients with mRCC, who were treated with sunitinib in 8 centers across 2 countries. Patients were divided into metformin users and nonusers. The effect of metformin use on response rate, progression-free survival (PFS), and overall survival (OS), was tested. Furthermore, univariate and multivariate analyses of the association between clinicopathologic factors and metformin use, and outcome were performed using the entire patient cohort. RESULTS: Between 2004 and 2014, 108 diabetic patients with mRCC were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The groups were balanced regarding clinicopathologic factors. Clinical benefit (partial response + stable disease) in group 1 versus 2 was 96% versus 84% (P = .054). Median PFS was 15 versus 11.5 months (P = .1). Median OS was 32 versus 21 months (P = .001). In multivariate analyses of the entire patient cohort (n = 108), factors associated with PFS were active smoking and pretreatment neutrophil to lymphocyte ratio > 3. Factors associated with OS were metformin use (hazard ratio, 0.21; P < .0001), Heng risk, active smoking, liver metastases, and pretreatment neutrophil to lymphocyte ratio > 3. CONCLUSION: Metformin might improve the OS of diabetic patients with mRCC who are treated with sunitinib.

The Evolution of Nephrectomy and Patient Characteristics in Metastatic Renal Cell Carcinoma Patients Enrolled Into First-Line Tyrosine Kinase Inhibitors Clinical Trials.

INTRODUCTION: The objective of this study was to compare rates of nephrectomy (Nx) in, and characteristics of, patients with metastatic renal cell carcinoma (mRCC) enrolled in prospective clinical trials of tyrosine kinase inhibitors (TKIs) that were completed through (Group 1) versus after (Group 2) 2007. PATIENTS AND METHODS: Searching online databases, we retrospectively identified phase I to III trials with ≥ 15 patients with mRCC treated with first-line TKIs, alone or in combination with other agent(s). RESULTS: Of 70 trials identified, 42 were included in the analysis (n = 6074 patients). Compared with Group 1, Group 2 patients had significantly less Nx (85.7% vs. 93.7%; P < .001) and prior cytokine therapy (11.1% vs. 46.8%; P < .001). Group 2 also had significantly fewer patients with good prognostic risk (based on Memorial Sloan-Kettering Cancer Center criteria) or performance status (both P < .001). Group 2 patients had a significantly greater objective response rate than Group 1 patients (intent-to-treat analysis: 28.6% vs. 23.1%, respectively; P < .001), whereas Group 1 patients had significantly more stable disease. Clinical benefit was similar in both groups (P = .157), and the means of median progression-free survival were comparable (8.2 and 9.0 months in Groups 1 and 2, respectively; P = .2528). CONCLUSIONS: Use of Nx in mRCC patients participating in clinical trials has declined in the TKI era. More patients with worse prognostic risk profiles are participating in first-line TKI trials after 2007, but objective response rates are higher. Despite patient characteristics that favor the earlier group, progression-free survival is similar as TKIs have replaced cytokines as first-line therapy.

Is there a "Trial Effect" on Outcome of Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib?

PURPOSE: Studies suggested the existence of a 'trial effect', in which for a given treatment, participation in a clinical trial is associated with a better outcome. Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). We aimed to study the effect of clinical trial participation on the outcome of mRCC patients treated with sunitinib, which at present, is poorly defined. MATERIALS AND METHODS: The records of mRCC patients treated with sunitinib between 2004-2013 in 7 centers across 2 countries were reviewed. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS), between clinical trial participants (n=49) and a matched cohort of non-participants (n=49) who received standard therapy. Each clinical trial participant was individually matched with a non-participant by clinicopathologic factors. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 25%, intermediate 59%, poor 16%), prior nephrectomy (92%), RCC histology (clear cell 86%), pre-treatment NLR (>3 in 55%, n=27), sunitinib induced hypertension (45%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non-participants, RR was partial response/stable disease 80% (n=39) versus 74% (n=36), and progressive disease 20% (n=10) versus 26% (n=13) (p=0.63, OR 1.2). The median PFS was 10 versus 11 months (HR=0.96, p=0.84), and the median OS 23 versus 24 months (HR=0.97, p=0.89). CONCLUSIONS: In mRCC patients treated with sunitinib, the outcome of clinical trial participants was similar to that of non-participants who received standard therapy.

Bisphosphonates in patients with renal cell carcinoma and bone metastases: a sunitinib global expanded-access trial subanalysis.

AIM: To investigate retrospectively the effects of bone metastases and bisphosphonates in sunitinib-treated metastatic renal cell carcinoma patients. PATIENTS & METHODS: Patients in Groups (Gp) 1 and 2, but not Gp3, had bone metastases. Gp2 received bisphosphonates following standard practice. RESULTS: Gp2 had less favorable prognosis than Gp1. Gp3 had fewer metastases and the best prognosis. More serious adverse events occurred in Gp2 versus Gp1. The difference in overall survival between Gp1 and Gp2 was not significant after adjusting for covariates. Significantly shorter overall survival in Gp1 versus Gp3 persisted after adjusting for covariates. CONCLUSION: Bone metastases may have a negative prognostic impact in metastatic renal cell carcinoma. Bisphosphonates may have delayed early disease progression for prognostically worse sunitinib/bisphosphonate-treated patients.

Activity of cabazitaxel after docetaxel and abiraterone acetate therapy in patients with castration-resistant prostate cancer.

BACKGROUND: Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC. PATIENTS AND METHODS: One hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods. RESULTS: Twenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69). CONCLUSION: A limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.

Experience with sunitinib treatment for metastatic renal cell carcinoma in a large cohort of Israeli patients: outcome and associated factors.

BACKGROUND: The VEGFR/PDGFR inhibitor sunitinib was approved in Israel in 2008 for the treatment of metastatic renal cell carcinoma (mRCC), based on an international trial. However, the efficacy of sunitinib treatment in Israeli mRCC patients has not been previously reported. OBJECTIVES: To report the outcome and associated factors of sunitinib treatment in a large cohort of Israeli mRCC patients. METHODS: We conducted a retrospective study of an unselected cohort of mRCC patients who were treated with sunitinib during the period 2006-2013 in six Israeli hospitals. Univariate and multivariate analyses were performed to determine the association between treatment outcome and clinicopathologic factors. RESULTS: We identified 145 patients; the median age was 65 years, 63% were male, 80% had a nephrectomy, and 28% had prior systemic treatment. Seventy-nine percent (n = 115) had clinical benefit (complete response 5%, n = 7; partial response 33%, n = 48; stable disease 41%, n = 60); 21% (n = 30) were refractory to treatment. Median progression-free survival (PFS) was 12 months and median overall survival 21 months. Factors associated with clinical benefit were sunitinib-induced hypertension: [odds ratio (OR) 3.6, P = 0.042] and sunitinib dose reduction or treatment interruption (OR 2.4, P = 0.049). Factors associated with PFS were female gender [hazard ratio (HR) 2, P = 0.0041, pre-sunitinib treatment neutrophil-to-lymphocyte ratio < or = 3 (HR 2.19, P = 0.002), and active smoking (HR 0.19, P < 0.0001). Factors associated with overall survival were active smoking (HR 0.25, P < 0.0001) and sunitinib-induced hypertension (HR 0.48, P = 0.005). To minimize toxicity, the dose was reduced or the treatment interrupted in 39% (n = 57). CONCLUSIONS: The efficacy of sunitinib treatment for mRCC among Israeli patients is similar to that in international data.

Tissue specific DNA methylation in normal human breast epithelium and in breast cancer.

Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer.

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS: An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS: Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION: Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.