Citations

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.

Abstract Chemotherapy resistant breast cancer is a major health challenge, resulting in high relapse rates and poor survival. Neoadjuvant chemotherapy (NACT) is a standard treatment for women with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. A completed course of NACT results in two possible outcomes: pathologic complete response (pCR) or residual disease. While pCR is a reliable clinical prognostic biomarker associated with excellent outcomes and prolonged survival, especially for TNBC and HER2+ cancers, patients with residual disease have a higher risk of recurrence. Patients with residual disease can be further stratified clinically using the Residual Cancer Burden (RCB) classification; however, patients with similar RCB classes may experience dramatically different clinical outcomes. Thus, additional precision biomarkers to stratify patients with residual disease after NACT are needed to identify patients at highest risk of recurrence, and to develop new therapeutic strategies to eradicate multidrug-resistant tumors. Supported by strong evidence in developmental, evolutionary and cancer biology, we found that K-RAS-SIAH pathway activation is a major tumor driver, and SIAH represents a key tumor vulnerability in breast cancer. Normal K-RAS/SIAH signaling pathway activation is indispensable for proper cell-cell communication, cell proliferation and tissue homeostasis in multicellular organisms. However, abnormal K-RAS/SIAH pathway activation is highly prevalent in high-risk and locally advanced breast cancer, and may confer chemo-resistance to these high-risk mammary tumors. Based on its evolutionary conservation and significance as the most downstream signaling module indispensable for K-RAS signal transduction, SIAHON/OFF expression is a reliable readout of K-RAS/EGFR/HER2 pathway activation/inactivation. We showed that SIAHON/OFF expression is a binary code in residual mammary tumors that can be used to stratify patients, augment RCB classification, forecast tumor relapse, and predict patient survival after 1st line NACT in a pilot retrospective study. Multidrug-resistant high-grade breast cancer is a genetically diverse, highly heterogeneous disease that challenges our ability to individualize and optimize precision therapy. Persistent K-RAS-SIAH-EGFR pathway activation endows TNBC with therapy resistance, and increases the risk of metastasis and early relapse. As such, we developed a K-RAS/SIAH-centered biomarker discovery program and a new anti-SIAH research initiative with the intended goal of designing novel and potentially life-saving anti-K-RAS targeted strategies to control and eradicate multidrug-resistant and intractable mammary tumors. Citation Format: Amy H. Tang, Lauren L. Siewertsz van Reesema, Vasilena P. Zheleva, Janet S. Winston, Rick J. Jansen, Emanuel F. Petricoin, Matthew P. Goetz, Matthew P. Goetz, Harry D. Bear, Richard A. Hoefer. Detect early tumor relapse in high-risk breast 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 2145.

Abstract Background Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. Methods We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. Results The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Conclusion EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.

In observational studies, left ventricular mass (LVM) and structure are strong predictors of mortality and cardiovascular events. However, the effect of hypertension treatment on LVM reduction and its relation to subsequent outcomes is unclear, particularly at lower blood pressure (BP) targets. In an ancillary study of SPRINT (Systolic Blood Pressure Intervention Trial), where participants were randomly assigned to intensive BP control (target systolic BP target <120 mm Hg) versus standard BP control (<140 mm Hg), cardiac magnetic resonance imaging was performed at baseline and 18-month follow-up to measure: LVM, volumes, ejection fraction, and native T1 mapping for myocardial fibrosis. At baseline, 337 participants were examined (age: 64±9 years, 45% women); 300 completed the 18-month exam (153 intensive control and 147 standard control). In the intensive versus standard BP control group at 18 months, there was no difference in change in LVM (mean±SE =−2.7±0.5 g versus −2.3±0.7 g; P =0.368), ejection fraction, or native T1 ( P =0.79), but there was a larger decrease in LVM/end-diastolic volume ratio (−0.04±0.01 versus −0.01±0.01; P =0.002) a measure of concentric LV remodeling. There were fewer cardiovascular events in the intensive control group, but no significant association between the reduced events and change in LVM or any other cardiac magnetic resonance imaging measure. In SPRINT-HEART, contrary to our hypothesis, there were no significant between-group differences in LVM, function, or myocardial T1 at 18-month follow-up. These results suggests that mediators other than these LV measures contribute to the improved cardiovascular outcomes with intensive BP control.

Intraoperative Transesophageal Echocardiography (TEE) during orthotopic liver transplant (OLT) is used to gather real-time information on cardiovascular function and intravascular volume status. We report a case where nonstandard TEE views were used to inspect the hepatic vasculature after allograft implantation. A 29-year-old male with secondary biliary cirrhosis with a MELD score of 20 underwent OLT using a liver from a 21-year-old brain-dead donor. Postreperfusion TEE, using the modified hepatic vein views, confirmed the presence of an inferior vena cava (IVC) suprahepatic anastomotic stenosis and hepatic vein and IVC thrombus resulting in hepatic venous outflow obstruction, allograft congestion, and hemodynamic instability. These nonstandard TEE images established the extent of suprahepatic caval outflow obstruction, in which intraoperative ultrasound was unable to definitively demonstrate. This guided real-time surgical decision-making in the postimplantation phase of the operation—ultimately leading to hepatic vein and IVC thrombectomy and revision of suprahepatic caval anastomosis.

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]

5063 Background: The systemic therapies available to patients with metastatic prostate cancer (mPC) have improved dramatically over the past decade. Prior to 2010, the only agents with a proven survival benefit for patients with metastatic disease were androgen deprivation therapy and docetaxel. Since then, five new agents have been FDA approved and have proven survival benefit in phase III trials. Anecdotal experience suggests that the increased available lines of therapy have changed the profile of mPC to include a higher prevalence of visceral metastases. Methods: A retrospective review of 474 patients with prostate cancer who died in 2009 and in 2016 was performed. Patients with metastatic disease who had imaging within 6 months of death were included. A total of 164 patients were eligible for analysis. Results: Mean age at death overall was 77.4 years (SD 9.5) and did not differ signifiantly by cohort. Overall rates of visceral and distant metastases to include lung, liver, adrenal, brain, renal, spleen, and thyroid, were higher in patients who died in 2016 as compared to those who died in 2009 (40.0% and 26.1%, respectively, p = 0.07). Lung metastases were more prevalent in patients who died in 2016 versus in 2009 at 26.3% and 13.0%, respectively (p = 0.05). Patients who died in 2009 received a median of 3 (range 1-10) systemic treatments versus 4 (range 0-13) in those who died in 2016 (p = 0.005). Forty-four percent of patients who died in 2016 used five or more lines of systemic treatments compared to 26.1% of patients in 2009. Conclusions: The emergence of new systemic therapies for mPC is changing the natural history of the disease. Forty percent of patients now develop visceral metastases compared to 26% in the past. These changes will drive the need for new treatment approaches targeting visceral metastases. [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]