Jo-An Seah

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer

BACKGROUND Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This studys objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. PATIENTS AND METHODS All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. RESULTS A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. CONCLUSIONS A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.BACKGROUND Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This studys objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. PATIENTS AND METHODS All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. RESULTS A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. CONCLUSIONS A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.

Neoadjuvant chemotherapy (NC) should be administered to fit patients with newly diagnosed, potentially resectable muscle-invasive urothelial cancer (MIUC) of the bladder – A 2013 CAGMO Consensus Statement and Call for a Streamlined Referral Process

Neoadjuvant chemotherapy (NC) improves overall survival in patients with resectable muscle-invasive urothelial cancer of the bladder (MIBC). However uptake of NC in Canada is dis-appointingly low. Following a detailed literature review and in consultation with urologic oncology, the Canadian Association of Genitourinary Medical Oncologists (CAGMO) has developed a consensus statement for the use of NC in MIBC. Our primary goal is to increase the uptake of NC for MIBC in Canada and improve patient outcomes.

Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy

Purpose: Level I evidence supports the usefulness of neoadjuvant cisplatin based chemotherapy for muscle invasive bladder cancer. Since dose dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) has mostly replaced traditional MVAC, we compared pathological response and survival rates in patients with locally advanced bladder cancer who received neoadjuvant chemotherapy with dose dense MVAC vs gemcitabine and cisplatin. Materials and Methods: We retrospectively reviewed the records of patients with urothelial cancer who received neoadjuvant chemotherapy and underwent cystectomy at a total of 20 contributing institutions from 2000 to 2015. Patients with cT3‐4aN0M0 disease were selected for this analysis. The rates of ypT0N0 and ypT1N0 or less were compared between the gemcitabine and cisplatin, and dose dense MVAC regimens. Two multivariable Cox proportional hazards regression models of overall mortality were generated using preoperative and postoperative data. Results: Of the patients who underwent neoadjuvant chemotherapy and radical cystectomy during the study period 319 met our inclusion criteria. A significantly lower rate of ypT0N0 was observed in the gemcitabine and cisplatin arm than in the dose dense MVAC arm (14.6% vs 28.0%, p = 0.005). The rate of ypT1N0 or less was 30.1% for gemcitabine and cisplatin compared to 41.0% for dose dense MVAC (p = 0.07). The mean Kaplan‐Meier estimates of overall survival in the gemcitabine and cisplatin, and dose dense MVAC groups were 4.2 and 7.0 years, respectively (p = 0.001). On multivariable cox regression analysis based on preoperative data patients who received gemcitabine and cisplatin were at higher risk for death than patients who received dose dense MVAC (HR 2.07, 95% CI 1.25–3.42, p = 0.003). Lymph node invasion (HR 1.97, 95% CI 1.15–3.36, p = 0.01) and hydronephrosis (HR 2.18, 95% CI 1.43–3.30, p <0.001) were also associated with higher risk of death. Conclusions: In our retrospective cohort of patients with locally advanced bladder cancer dose dense MVAC was associated with higher complete pathological response and improved survival rates compared to gemcitabine and cisplatin. A clinical trial is warranted to validate these hypothesis generating results to test the superiority of neoadjuvant dose dense MVAC in patients with locally advanced bladder cancer.

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone.

Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate‐resistant prostate cancer (mCRPC).

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

BackgroundCisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy.Patients and methodsPatients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes.ResultsOf 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70).ConclusionIn this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

MP58-04 DENSE DOSE MVAC VERSUS GC IN PATIENTS WITH CT3-4A BLADDER CANCER TREATED WITH RADICAL CYSTECTOMY: A REAL WORLD EXPERIENCE

Homayoun Zargar*, Vancouver, Canada; Jay B Shah, Houston, TX; Elisabeth E Fransen van de Putte, Amsterdam, Netherlands; Kylea R. Potvin, London, Canada; Kamran Zargar-Shoshtari, Tampa, FL; Bas W van Rhijn, Amsterdam, Netherlands; Siamak Daneshmand, LA, CA; Jeff M Holzbeierlein, Kansas City, KS; Philippe E Spiess, Tampa, FL; Eric Winquist, London, Canada; Simon Horenblas, Amsterdam, Netherlands; Colin Dinney, Houston, TX; Peter C Black, Vancouver, Canada; Wassim Kassouf, Montreal, Canada; Homayoun Zargar, Vancouver, Canada

Baseline neutrophil to lymphocyte ratio as a prognostic marker for patients with muscle-invasive bladder cancer being treated with neoadjuvant chemotherapy.

468 Background: The neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker, has been associated with a poor prognosis in several solid malignancies. In muscle-invasive bladder cancer (MIBC), an elevated pre-cystectomy NLR has been shown to predict for poor survival; however, its role in prognostication for patients being treated with neoadjuvant chemotherapy (NAC) is unknown. We evaluated the baseline NLR as an independent prognostic factor in patients with MIBC treated with NAC. Methods: Patients with MIBC treated with NAC in Alberta from 2005 to 2015, and at the Princess Margaret Hospital in Ontario from 2005 to 2013 were evaluated. All 290 patients treated with NAC were included; 272 were evaluable for NLR and outcomes. Patient, disease, and treatment-related factors were evaluated. NLR was examined prior to initiation of preoperative chemotherapy. The prognostic role of NLR on overall survival (OS) and progression-free survival (PFS) was determined using Cox proportional hazard regression analys...

735 Nomogram predicting cancer specific mortality (CSM) after neoadjuvant chemotherapy and radical cystectomy for muscle-invasive bladder cancer (BC): Results of an international consortium

INTRODUCTION AND OBJECTIVES: Long non-coding RNAs (lncRNAs) are emerging as important drivers of disease progression, and have been shown to modulate gene expression at several levels. Unfortunately, the molecular functions of a majority of lncRNAs identified are still poorly understood. While recent studies have identified subtypes of muscle-invasive bladder cancer (MIBC) at the mRNA level, the overall goal of this study is to obtain a deeper understanding of the lncRNAs that contribute to the molecular mechanisms that underlie the intrinsic subtypes of MIBC. METHODS: In this study, we utilized TCGA’s RNA-sequencing data to extract whole genome lncRNA expression from 211 MIBCs. Unsupervised consensus clustering was utilized to identify subtypes based on lncRNA expression profiles, and differential expression analysis was performed in the R statistical programming environment. To further study the lncRNAs associated with the luminal subtype, cell lines were exposed to rosiglitazone, a PPARg agonist, and RNA-sequencing was performed. PPARg associated lncRNA candidates were validated in an independent cohort using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Consensus clustering of lncRNA expression identified two intrinsic subtypes of MIBCs, which were synonymous with the intrinsic basal and luminal subtypes recently discovered through mRNA expression profiling. Previous work has shown that PPARg is amplified in approximately 15% of luminal MIBCs, and luminal MIBCs are enriched with an activePPARgmRNAexpression signature. In this study, lncRNAs up-regulated after exposure to rosiglitazone were highly expressed in luminal MIBCs, as confirmed by gene set enrichment analysis (GSEA). Differential expression analysis revealed SNHG18 to be up-regulated after PPARg activation, and to be highly expressed in luminal MIBCs. RNA immunoprecipitation studies confirmed that SNHG18 is directly bound by PPARg, and subsequent knockdown of SNHG18 resulted in decreased expression of several luminal PPARg target genes including uroplakins and fibroblast growth factor receptor-3 (FGFR3). CONCLUSIONS: Currently, FGFR3 is an important therapeutic target in MIBCs with activating mutations occurring in approximately 17% of cases. Overall, we have identified a novel lncRNA, SNHG18, to be a co-activator of PPARg that controls downstream expression of FGFR3. The results suggest that SNHG18 could potentially serve as a predictive biomarker, or as a possible drug target to increase the efficiency of FGFR3 targeted therapies.

Neoadjuvant gemcitabine-cisplatin (GC) for muscle-invasive bladder cancer (MIBC): Does midway CT staging predict for pathologic complete response (pCR)?

306 Background: Neoadjuvant cisplatin-based chemotherapy (NC) improves overall survival in MIBC, with pCR post radical cystectomy (RC) linked to better outcomes. NC is underutilized in part due to concerns over disease progression during NC. Midway radiological CT (post 2 NC cycles) may identify patients (pts) progressing on NC who should proceed to definitive therapy (DT). Methods: We reviewed 39 MIBC pts planned to receive 4 cycles of NC (GC) between Jan2005-April2013. Most pts (70%) had midway CT staging. A radiological response was defined as clear improvement in tumour +/- nodal status on CT compared to baseline, taking into account prior trans-urethral resection of bladder tumour; any other result was considered no response. DT consisted of RC, concurrent chemoradiation (CCR), or radiation alone (R). Descriptive statistics and Fisher’s exact test examined associations between disease characteristics and outcomes. Results: Overall, 28 pts (72%) completed planned NC; 7 pts (18%) stopped early due to n...

Abstract 909: Defining molecular and laboratory predictive biomarkers of response to cisplatin-based neoadjuvant chemotherapy (NC) in muscle-invasive bladder cancer (MIBC) - preliminary results and future plans

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: MIBC is common, yet there has been little progress in its research, with no new therapeutic agents approved in years. The optimal therapeutic modalities and treatment sequence are not entirely well-defined. Cisplatin-based NC prior to definitive radical cystectomy (RC) increases overall survival (OS), yet is only active in a proportion of patients (pts). A pathological complete response (pCR) at RC is associated with improved OS, but there are currently no molecular biomarkers predicting which pts are likely to achieve pCR, and thus treatment decisions are currently based solely on clinical parameters. Methods: Since micro-RNAs (miRNAs) are known to be key-players in cancer, we chose to study the differences in miRNA expression patterns between 7 pts who achieved pCR and 9 pts who did not respond (‘responders’ and ‘non-responders’, respectively), using commercial micro-arrays (Agilent ®) and quantitative RT-PCR. In a different cohort, we performed a retrospective chart review of 29 pts with MIBC receiving NC to find associations between clinical, biochemical or radiological characteristics and pCR. As the peripheral blood neutrophil-to-lymphocyte ratio (NLR) is thought to non-specifically correlate with systemic inflammatory burden, we analyzed its levels before and during NC as well as prior to RC. Results: The trend of change in NLR was significantly different between responders and non-responders (p=0.039), the former exhibiting a sustained decrease in NLR throughout chemotherapy up until RC, and the latter exhibiting a transient decrease in NLR by mid-NC, followed by an increase to above baseline. One miRNA was significantly lower in responders than in non-responders (q value=0.048, corrected for multiple comparisons), and five miRNAs with the identical seed sequence (thus potentially targeting the same mRNAs) were also all lower in responders, one with borderline significance (q value=0.1, corrected). Conclusions: These findings suggest that chemo-sensitivity of MIBC is determined by both inherent molecular characteristics as well as the immune/inflammatory system, and raises the question whether the response to NC could be enhanced by decreasing the systemic inflammatory burden. We will corroborate these results in larger pts cohorts and search for potential targets of these miRNAs. We also plan to initiate a prospective multi-center clinical trial in which both intra-tumoral and circulating miRNAs, as well as micro-environment/systemic inflammatory markers, will be monitored and assessed in order to establish predictive factors for pCR with NC. Citation Format: Raya Leibowitz-Amit, Jo-An Seah, Raanan Berger, Srikala S. Sridhar. Defining molecular and laboratory predictive biomarkers of response to cisplatin-based neoadjuvant chemotherapy (NC) in muscle-invasive bladder cancer (MIBC) - preliminary results and future plans. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 909. doi:10.1158/1538-7445.AM2014-909