Kohli, Manish

Abstract Background and Aims: Progastrin is a tumor promoting peptide which is detectable in the blood of patients with different cancers. Progastrin gene is a direct target of the WNT/ß-catenin oncogenic pathway involved in tumorigenesis and possibly tumor progression/ treatment efficacy. Since WNT/ß-catenin oncogenic pathway is dysregulated in advanced prostate cancer we evaluated plasma progastrin in metastatic prostate cancer as a predictive and prognostic biomarker. Methods: Metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castration resistant prostate cancer (mCRPC) states were enrolled in a cohort study of blood sample collection and follow-up for outcomes between 9/2009 and 11/2013. Patients were enrolled in mHSPC unique sub-cohorts before initiating androgen deprivation therapy (ADT); during ADT; at the time of failure of ADT and before starting chemotherapy. Plasma progastrin was measured using the ELISA cancerREAD®. Progastrin concentrations in the cancer patients (test set) was assessed against 213 samples from asymptomatic volunteers from the French blood establishment (control set) and prograstin levels were also compared for each of the above four mHSPC and mCRPC cohorts as well as for association with time to failure on AA for the mHSPC cohort and overall survival for both mHSPC and mCRPC subcohorts. We also determined progastrin levels in patients with two serial samples to evaluate if changes were predictive for overall survival. Results: Of the 523 mHSPC+mCRPC patients 96 were in mHSPC state enrolled before starting ADT; 101 mHSPC patients were enrolled while receiving ADT; 143 mHSPC patients were enrolled at the time of ADT failure and 143 were clinically progressive mCRPC. All cohorts were unique and 246/523 patients had two serial samples collected and analyzed across all subcohorts. The median time of follow up of the whole cohort was 8.34 years (IQR: 4.53-12.97) and 371/523 had died at the time of the analysis. Plasma progastrin levels was detected in 87.6% of all the patients (cut-off value 1 pM, range 0 to 311 pM, median value of 4.7 pM) compared to the control set (median value=0.61 pM; IQR 0.00-1.58). The Receiver Operating Characteristic analysis indicated an area under the curve of 0.84 (p<0.0001; 95% CI 0.81 to 0.87). Of these, 106 patients had a decrease and 140 patients an increase of progastrin levels. Patients with a serial increase of progastrin had a worst overall survival compare to the other group (p=0.019). Conclusion: Progastrin is a blood based biomarker elevated in advanced prostate cancer patients serial increases in progastrin levels during treatment are predictive of poor survival. Progastrin assay might be useful for monitoring therapeutic interventions like androgen deprivation therapy effects as well for advanced prostate cancer patients. Citation Format: Manish Kohli, Winston Tan, Lea Payen, Carole Langlois-Jacques, Pierre Liaud, Delphine Maucort-Boulch, Dominique Joubert, Alexandre Prieur. Plasma progastrin level as a predictive and prognostic biomarker in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2294.

Abstract Background and Aims: Progastrin is a tumor promoting peptide which is detectable in the blood of patients with different cancers (Prieur et al. AACR 2017, Prieur et al. ASCO 2017). Progastrin gene is a direct target of the WNT/ß-catenin oncogenic pathway involved in tumorigenesis of many organs, but it is unknown if it has any prognostic significance in metastatic renal cell cancer (mRCC) patients. We evaluated progastrin as a prognosis marker along with known markers of prognosis in mRCCC. Methods: 145 patients with mRCCC were enrolled in this study and blood samples were drawn after consent. Progastrin was measured using the ELISA cancerREAD®. Progastrin concentrations in the 145 mRCCC patients (test set) was assessed against 213 samples from asymptomatic volunteers from the French blood establishment (control set). The prognostic impact of progastrin levels was determined with overall survival (OS) using Cox proportional hazards and also compared to MSKCC based clinical prognosis (good;intermediate; poor). Statistical significance was considered at P≤0.05. Results: The median follow-up of the cohort was 5.45 years (IQR: 1.87-9.95) and at the time of analysis 98/145 patients had died from disease progression. Plasma progastrin was detected in 95% of the patients (cut-off value 1 pM, range 0 to 272 pM, median value of 7.2 pM; IQR 3.20-19.71) compared to the control set (median value=0.61 pM; IQR 0.00-1.58). The Receiver Operating Characteristic analysis indicated an area under the curve of 0.92 (p<0.0001; 95% CI 0.89 to 0.94). At the univariate level, MSKCC scores (good; intermediate; poor categories) in this cohort was associated with OS and was prognostic (p<0.0001). We detected progastrin levels were higher with MSKCC score poor prognostic (p<0.0002) (median 30.39 pM; IQR 9.31-57.20). Elevated progastrin was also independently associated with poor survival (p<0.0001) and a multivariate model of MSKCC taken with progastrin levels remained significantly associated with poor survival (p<0.0001). Conclusion: Elevated progastrin levels in mRCCC is correlated with poor survival and further refines clinically used MSKCC prognostic scores. Progastrin assay is a simple and inexpensive blood test that might define subsets of mRCCC patients with poor survival who need to be identified for aggressive treatments. Citation Format: Manish Kohli, Winston Tan, Lea Payen, Carole Langlois-Jacques, Pierre Liaud, Delphine Maucort-Boulch, Dominique Joubert, Alexandre Prieur. Prognostic impact of progastrin levels in blood compared to MSKCC based clinical prognosis in metastatic renal cell cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2289.

e16559 Background: ARVs that develop early during treatment with abiraterone acetate/ prednisone (AA/P) may play a role in treatment resistance. We evaluated metastatic site and whole blood mRNA expression of full-length AR (AR-FL) and ARVs to characterize treatment-emergent ARVs (TE-ARVs) from men with mCRPC pre- and post- 12 weeks of AA/P collected in a prospective clinical trial (NCT#01953640). Methods: RNAseq performed on paired metastatic site biopsy (n = 40) and whole blood (n = 25) passed quality control. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. AR-FL or ARVs were detected if ≥ 2 splice reads aligned to unique splice junctions for AR-FL, AR-8, AR-45, AR-23, AR-V3, AR-V5V6, AR-V7, AR-V8, AR-V9, AR-V10, AR-V12, AR-V13, and AR-V14, and normalized to splice reads per million (SRPM). Cox proportional hazard regression analysis was performed on AR-FL and AR-Vs with ≥1 SRPM for association with time to treatment change (TTTC). Results: In metastatic site biopsies post-AA/P, the average number of splice reads was 27,376,541 (range 7,753,998 to 62,456,773). The median number of ARVs detected was 2 (range 0-8), with a total of total of 110 ARVs identified (Table). Dynamic shifts in ARV profiles were observed post-AAP, with 41 TE-ARVs identified in 17 unique patients. The most common TE-ARV was AR-8 (n = 8), followed by AR-45 (n = 5), AR-23 (n = 5), and AR-V7 (n = 4). The presence of AR-V7 post-AAP was adversely associated with TTTC (hazard ratio 2.46, p = 0.013). The identification of early TE- ARV was not associated with TTTC. In whole blood samples, post-AA/P detection of AR-FL was low (n = 3) and no ARVs were detected. Conclusions: No specific patterns were observed in ARV profiles obtained in the metastatic biopsies after 12 weeks of treatment with AA/P. Clinical trial information: 01953640. [Table: see text]

5047 Background: We identified plasma cell free DNA (cfDNA) based copy number variations (CNV); single nucleotide variants (SNVs) & TMPRSS-ERG fusion in four sub states of metastatic prostate cancer (mPCa) and determined the impact on survival. Two mHSPC cohorts included treatment naïve, gp-1 and mHSPC patients (pts) responding to chronic androgen ablation (AA) (gp-2). Two mCRPC cohorts included mHSPC pts with PSA relapse on chronic AA (gp-3) and a clinically progressive mCRPC cohort post AA (gp-4). Methods: Enrollment of mPCa pts was performed from 2009-14 who were followed until 2018. Plasma from collected blood was used for extracting cfDNA. NGS was performed using Illumina HiSeq X for a preselected target panel of 129 genes including DNA damage repair genes. Statistical analyses of genomic aberrations were performed in R 3.5.1 and Cox proportional-hazard models were used for survival analyses. Results: A total of 255 pts were enrolled with 215 having adequate cfDNA that passed NGS QC. Median study follow up was 90.2 (Range:73;99) months. The table highlights pts in each gp with CNV, SNV, fusion events. ARamplification was higher in mCRPC gps3&4 (20/103 pts) compared to 3/106 pts in mHSPC gps1&2 (p < 0.001) and was prognostic for poor survival in mCRPC (p < 0.001;HR:3.34; 95%CI: 1.9-5.76). 54/103 pts in gp3&4 had SNVs in TP53 compared to 34/106 pts in mHSPC gps1&2 (P < 0.01). SNVs in APC, AR, CDK12 and BRIP1 were also increased in gps3&4 (p < 0.01). Gp1 mHSPC pts with SNVs in ATM/ CHEK2 had shorter response to AA (p < 0.001; HR:3.66; 95%: CI:1.81-7.39). Conclusions: Plasma cfDNA based somatic aberrations are detected with increased prevalence in mHSPC to mCRPC states. The ease of specimen collection and the need for molecular profiling in mPCa increases its potential for clinical applications in pt care. [Table: see text]

3037 Background: The successes of recent publications on “multi-tumor” circulating markers highlight the relevance of novel universal diagnostic cancer serum biomarkers. Since the Wnt/ß-catenin/Tcf4 pathway, activated in many tumors, induces the GAST Gene encoding progastrin synthesis, we hypothesized that progastrin, easily measurable in the blood, might be a “multi-tumor” diagnostic biomarker. Methods: Progastrin levels were measured in the blood samples of 1319 patients with 12 different cancer origins, and compared to those of 557 asymptomatic 18-75 years old blood donors. Moreover the longitudinal kinetics of progastrin concentrations were serially assessed during treatments in 168 patients with ovarian cancers enrolled in the randomized CHIVA trial (NCT01583322, GINECO), 191 patients with peritoneal involvement from gastro-intestinal cancers enrolled in BIG-RENAPE trial (NCT03787056), and in 95 HCC patients. The progastrin was measured using an ELISA test developed by ECS Progastrin (Prilly, Switzerland). Results: Compared to healthy blood donors, progastrin was found at higher concentrations in the plasma of cancer patients: median 4.47 vs 0.20 pM, P < 0.0001; diagnostic discriminative power, ROC analysis AUC = 0.86 (95% CI, 0.83-0.89; P < 0.0001). Progastrin levels were found elevated in all cancer groups, regardless of disease stages, and of pathology origins: ROC AUCs ranged from 0.71 to 0.93, all P < 0.0001 (Table). The longitudinal progastrin changes during treatments, suggest relationships to tumor burden, and potential monitoring value. Conclusions: Progastrin is a novel ubiquitous cancer biomarker, easily detectable in the blood using an affordable ELISA test (CancerRead Lab test(R)). It may change the future paradigms about screening (in particular for populations at higher or lower risks of cancer), cancer diagnostic & monitoring. [Table: see text]

Background: Four large RCTs (ASSURE, S-TARC, PROTECT, ATLAS) tested adjuvant VEGF-TKI therapy in high risk RCC. The results were variable for efficacy and there were concerns for increased toxicity and decline in quality of life (QoL). We performed an updated meta-analysis including results of ATLAS trial to asses a risk-benefit for adjuvant post-operative treatments in high risk RCC patients by assessing reported disease-free survival (DFS), overall survival (OS), and toxicity endpoints. Methods: Literature search was done using Medline, CENTRAL, and Embase. The DerSimonian and Laird random effects model was used to pool estimates for DFS, OS, and common side effects across the 4 trials. A subgroup analysis was performed for sunitinib alone because of its FDA approval. Heterogeneity was assessed with Cochrane Q statistic and was quantified with I2 test. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: The 4 RCTs included 4,820 patients. Adjuvant therapy with TKIs yielded no significant improvement in DFS or OS as compared to placebo (DFS HR=0.916; 95% CI, 0.832–1.009 and OS HR=1.09; 95% CI, 0.886–1.150). Separate analysis of DFS in sunitinib vs placebo did not show any benefit (2 studies, N=1,909; HR=0.90; 95% CI, 0.67–1.19). Use of TKIs was associated with significantly increased risk of drug toxicity. Increased risk of grade 3 or 4 adverse events (RR=5.110; 95% CI, 3.765–6.935), diarrhea (RR=10.725; 95% CI, 4.672–24.622), fatigue (RR=3.310; 95% CI, 1.879–5.829), hypertension (RR=4.274; 95% CI, 3.452–5.292) and palmar/plantar dysesthesia (RR=20.53; 95% CI, 9.006–46.801) was observed. There was no statistically significant heterogeneity amongst included trials. QoL endpoints were inconsistently reported. Risk of bias was low. Conclusions: This pooled analysis provides further evidence that there is no OS or DFS benefit associated with adjuvant TKI treatment. There was a significantly increased risk of grade 3 or 4 toxicity in greater than half of the patient population leading to decline in QoL during TKI therapy. Carefully selected very high-risk patients who can tolerate these agents without dose modifications may benefit from adjuvant TKI approach.

263 Background: In non-metastatic CRPC with short PSA doubling time, APA or ENZA with ADT have shown to slow development of metastasis. We performed an indirect comparison of APA and ENZA clinical effectiveness (efficacy and side effects) using network meta-analysis. Methods: A search of Medline, Embase, Cochrane Library, and Cochrane Central Register of Controlled Trials was performed to identify relevant RCTs. Collected data included hazard ratio (HR) and confidence interval (CI) for primary outcome of median time to metastasis free survival (MFS) and secondary outcomes of median time to overall survival (OS), PSA progression, initiation of cytotoxic therapy and number of adverse events (AE) in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. We used a fixed effects model using Bayesian approach to generate pooled estimates. Results: Two randomized trials (n=2608) were analyzed. SPARTAN trial compared APA plus ADT to ADT alone and PROSPER compared ENZA plus ADT to ADT alone. Risk of bias was low. There were no statistically significant differences between APA and ENZA in MFS, OS, median time to PSA progression and initiation of cytotoxic therapy. The MFS endpoint hazard ratio (HR) was 0.97 (95% CI 0.73-1.28) for comparing the two drugs. APA had fewer reports of hypertension (HR 0.54, 95% CI 0.31–0.91) compared to enzalutamide. However, no significant differences were observed in other AEs including grade 3 or higher AE, serious AE, AE leading to death or trial discontinuation. Common AEs (nausea, diarrhea, fall, dizziness, arthralgia, weight loss) and AEs of special interests (mental impairment disorders, seizures) were also comparable between APA and ENZA. Conclusions: In non-metastatic CRPC with short PSA doubling time, APA and ENZA showed similar time to metastasis free survival. APA was associated with lower incidence of hypertension than ENZA; otherwise, side effect profile was similar. Given similar efficacy and risk profile demonstrated in this study, clinical decision making should depend on other factors such as cost and availability.