Citations

140 Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach but patients with positive section margins (R1) disease have not always the same cancer-specific survival (CSS). The current study aims to analyze current postoperative pathological features in order to predict CSS of HRPC patients with R1, but with negative lymph nodes (pN0), treated with surgery. Methods: From a multi-institutional retrospective cohort of 5,876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1541 patients with pN0 and R1 were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT<3) and p-Gleason score (pGS≥8 and pGS<8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age at surgery was 66 years (42-89). Of all patients, 399 (25.9%) had GS≥8 and 999 (64.8%) had pT≥3 at definitive histopathology. Patients were classified as COMBO groups: C1 (423; 27.4%; GS<8,pT<3), C2 (674; 43.7%; GS<8, pT≥3), C3 (83; 5.4%; GS≥8, pT<3), C4 (362; 23.5%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 3%/5%, C2 15%/21%, C3 21%/20%, C4 28%/40%. Kaplan-Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97%, C2 93.8%, C3 85.1% and C4 77.3% (p<0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide margin-positive, pN0 HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]

114 Background: High-risk prostate cancer (HRPC) is a challenging disease and the role of surgery is often considered in the context of a multimodal approach. The indication for adjuvant therapy after surgery for HRPC patients who have specimen-confined disease (R0, pN0, <pT3b) is still difficult. The current study aims to analyze postoperative pathological features which help to predict CSS in specimen-confined HRPC and thus may aid in the decision to administer adjuvant EBRT or ADT. Methods: From a multi-institutional retrospective cohort of 5876 HRPC patients treated by radical prostatectomy and pelvic lymph node dissection, 1391 patients with specimen-confined disease were selected. Following surgery, adjuvant EBRT and/or ADT were delivered according to institutional protocols. Patients were subdivided into four groups according to pT stage (pT≥3 and pT<3) and final Gleason score (GS≥8 and GS<8). Kaplan-Meier plots with log-rank tests and a Cox proportional hazards model were applied to study CSS. All significance levels were set at 0.05. MedCalc was used for all statistical analyses. Results: Median age was 65 years (43-84). Of all patients, 346 (24.9%) had GS≥8 and 794 (57.1%) had pT≥3 at definitive histopathology. Patients were classified into COMBO groups: C1 (478; 34.4%; GS<8,pT<3), C2 (567; 40.8%; GS<8, pT≥3), C3 (119; 8.6%; GS≥8, pT<3), C4 (227; 16.3%; GS≥8, pT≥3). Adjuvant EBRT and ADT, respectively, were delivered in C1 2%/2%, C2 15%/22%, C3 3%/10%, C4 18%/25%. Kaplan Meier plots demonstrated statistically different 10-yr CSS between groups: C1 97.4%, C2 95.2%, C3 89.9% and C4 84.4% (p<0.0001). COMBO groups were also compared using a Cox model and results are shown in the Table. Conclusions: COMBO groups demonstrated to be able to subdivide specimen-confined HRPC into 4 demarcated groups with significantly different CSS. This subdivision could be considered an easy-to-use tool which can help for counseling patients for adjuvant treatment strategies. [Table: see text]

97 Background: Optimal management of chronic medications is uncertain in life-limiting illness. To inform shared decision making, we assessed patient perceptions in a trial on the safety of discontinuing statins in life-limiting illness. Methods: Eligible adults (life expectancy 1–12 months, on statin for ≥ 3 months for primary/secondary prevention, recent functional decline, no active cardiovascular disease) were randomized to discontinue or continue statins and were followed monthly for up to 1 year. Cognitively intact participants were asked 9 questions regarding discontinuing statins prior to randomization. We used Pearson chi-square to compare responses between study groups and between those with and without cancer. Of 381 participants, 297 (78%) were cognitively intact (138 discontinued, 159 continued statins). Mean age was 72 years (SD 11) and mean number of medications used was 11.5 (SD 5.0); 58% (N = 173) had cancer. Results: There were no statistically significant differences between the study groups in responses to the medication perception questions. Aggregate findings are presented (Table). Patients with cancer were less likely to think that they may be able to stop other medications (28% vs. 42%, p=0.007) and that statin discontinuation means that the doctor is giving up on them (1% vs. 7%, p=0.013). Conclusions: Few participants expressed concerns about discontinuing statins; many perceived potential benefits. Cancer patients may perceive less impact from stopping statins. Clinicians should inquire about patient concerns when engaging in shared decision making about discontinuing chronic medications in the setting of advanced cancer. Clinical trial information: NCT01415934. [Table: see text]

CRA9003 Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012). Methods: We conducted a 16 center randomized phase II study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m2 daily for 5 days in 28-day cycles (or DTIC 1000 mg/m2 q21 days) for patients (pts) with metastatic UM with a Q209 Gq/11 mut who have not received prior TMZ/DTIC. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS) and response rate (RR). Select pts underwent tumor biopsies at baseline and after 14 (+/- 3 days) of sel. Our statistical plan required ≥80 pts randomized and ≥68 events to detect a PFS hazard ratio of 0.6 (p=0.1). Randomization was stratified by mut (Gq vs G11), M stage and number of prior therapies (tx). Tumor assessment occurred every 4 weeks (wks) for 8 wks and then every 8 wks using RECIST 1.1. Pts receiving TMZ who progressed could receive sel (TMZ→sel). Results: 80 pts were randomized. Sel (n=39): median age 66 (range 32-86), 54% male, 54% G11 mut, median ECOG PS 0 (range 0-1), 97% M1c, median prior tx 0 (range 0-2). TMZ (n=41): median age 60 (range 34-81), 63% male, 58% G11 mut, median ECOG PS 0 (range 0-1), 93% M1c, median prior tx 0 (range 0-2). 11/39 (28%) pts on sel experienced grade (gr) 3 toxicity (tox) manageable with dose modification (5 CPK elevation, 3 LFT elevation, 1 rash, 1 lymphopenia, 1 edema). 1/41 (2%) pt on TMZ experienced gr 3 tox (neutropenia). No gr 4/5 tox occurred. 28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14. At interim analysis (9/25/12), 55 pts were evaluable with 45 progression events and 16 deaths. Sel (n=27): median PFS 16 wks (95% CI 8-30.9), RR 11%, median OS 11.8 months (95% CI 4.8-not reached). TMZ (n=28): median PFS 4 wks (95% CI 3.7-15), RR 0%, median OS 4.7 months (95% CI 4.3-14.3). TMZ→sel (n=25): median PFS 8.1 wks (95% CI 7-15), RR 0%. Conclusions: Sel is the first drug to ever show improved clinical activity in UM relative to TMZ. Sustained target inhibition is observed with sel. Final results will be presented. Clinical trial information: NCT01143402.

603 Background: Anal squamous cell carcinoma (Anal SCC) is a rare, HPV-associated malignancy accounting for 2.4% of digestive system cancers. In most cases, these malignancies are detected in the early stages and successfully managed with chemoradiation therapy. Uncommonly, these cancers recur or present with metastases. In this setting, cisplatin and 5-fluorouracil represent the only endorsed regimen. Once beyond standard therapy, few therapeutic options exist for those patients with aggressive disease. The purpose of this study is to identify other novel, potential targets and therapeutic options for this disease, utilizing a multiplatform approach. Methods: 206 anal SCC specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). 6 cases were documented as positive for HPV or HIV; status was not provided on the remaining 200. Results: Key results are shown in the table below, shown as percent change/total cases. Conclusions: Multiplatform tumor profiling identified a low incidence of gene mutations. Protein expression aberrations identified potential treatment options not routinely considered, such as topoisomerase inhibitors and taxanes. Mutations in PIK3CA, Akt1, and FBXW7 as well as PTEN loss indicate potential for targeting the PI3 kinase pathway. Additionally, immunomodulatory agents may be a therapeutic option, based on PD-1 expression levels. Targeting the ErbB-family receptors, namely with anti-EGFR agents or newer generation pan-HER - inhibitors, may represent another option, given EGFR and HER2 amplification as well as EGFR overexpression. It should be mentioned that differences in anal carcinomas whose etiology is of viral origin may present different treatment options based on the driver mutations. [Table: see text]

249 Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.

190 Background: It is not known if biopsy of CRPC stage metastases alters CTC results. We evaluated pre & post biopsy CTC counts in a prospective cohort undergoing pre-chemotherapy abiraterone acetate/prednisone (AA/P). Methods: CTC enumeration was performed on 7.5mL blood using the FDA cleared immunomagnetic/immunofluorescence assay (CellSearch). Time of blood draw for CTC counts pre/post biopsy was recorded for each biopsy. Biopsies were performed using 11/13 gauge core biopsy device for bone lesions and 18 gauge core needle biopsy device for soft tissue/nodal metastases. All patients (pts) underwent two serial biopsies 3 months apart. Change in CTC counts pre/post biopsy for visits 1 and 2 were evaluated using Wilcoxon signed rank test (significance at p<0.05). Differences in CTC count change (visit1) pre/post biopsy based on metastatic site (skeletal vs. non-skeletal) was compared using Wilcoxon rank-sum test. Results: Median age of the cohort was 74 years (IQR: 68-78); median PSA at V1 was 16.4 ng/ml (IQR: 6.4-87.6); at V2 was 11.5 ng/ml (IQR: 1.8-23.7). Of 59 pts undergoing biopsies 42 were in bone and 17 in nodal/soft tissue masses. At V1, pre/post biopsy CTC counts were measured on 50 and 49 pts, respectively; at V2, pre/post CTC counts were measured on 43 and 36 pts. High volume metastatic disease at V1 was observed in 67.8 % of all pts. Table lists CTC counts and time of collection pre/post biopsy for both visits. Mean change in pre/post biopsy CTC counts for skeletal sites was 0.7 (range: -12 to 64) compared to 12.1 (range: -21 to 13) for non-skeletal sites (p=0.23). Conclusions: An increase in mean CTC counts after biopsy of CRPC metastases was observed. No significant differences in change of CTC counts based on site biopsied (skeletal versus non-skeletal) was noted. Correlation with clinical outcomes is on-going. Clinical trial information: NCT# 01953640. [Table: see text]

174 Background: AA/P is an FDA approved treatment for mCRPC. Since markers of early resistance to AA/P are unknown, we report initial findings of androgen receptor (AR) based associations with short term (12 week) progression on AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemotherapy AA/P underwent metastatic site biopsies at baseline (pre AA/P) and after 12 weeks. Baseline somatic whole exome DNA, tumor gene expression for AR full length (ARFL), AR splice variant 7 (ARV7) and ARV7/ARFL ratios were compared in progessors versus non-progressors. Progression at or within 12 weeks of AA/P therapy was defined as death or disease progression by PCWG2 “composite progression (CP)” and/or “radiographic progression” endpoints. Wilcoxon rank-sum tests were used to test for differences in the two groups for comparing ARFL, ARV7 expressions and ARV7/ARFL ratios and chi square tests were used for differences in copy number variation. Results: Between 1/2013 and 6/2014, 59 pts were enrolled of which 44 have disease assessment data at the12-week time point. CP was observed in 17/44 patients. DNA seq and clinical data was available for 42/44 pts. Using radiographic progression at 12 weeks, AR Amplification/Gain was observed in 20/26 non-progressors (13 with Amplification) and in 9/16 progressors (P-value = 0.19; OR 2.5). ARFL and ARV7 gene expressions in both groups is provided in table. Conclusions: A trend towards higher ARV7/ARFL gene expression ratio in metastases was observed with early progression on AA/P. AR gain/amplification is observed less often in pts with early progression. Validation of these findings is on-going in this prospective trial. Clinical trial information: NCT# 01953640. [Table: see text]

457 Background: Curative therapy for PDAC is currently achievable through resection only, but ≤ 15% of patients are candidates for surgery. FG-3019, a recombinant human mAb to connective tissue growth factor (CTGF), plus gemcitabine (G) significantly reduced tumor growth, increased apoptosis and improved survival vs G alone in the KPC mouse model. Higher FG-3019 exposure and lower baseline (BL) CTGF were independently and significantly associated with improved overall median and 1-year survival (OS) in a Ph2a trial with G and erlotinib in stage 3 or 4 PDAC. Neoadjuvant treatment of LAPC with FG-3019 combined with multidrug therapy may change the fibrotic character of LAPC and thus may make it amenable to surgical resection and potentially improve OS. Methods: Patients with unresectable LAPC (confirmed by laparoscopy) are randomized to G/NP ±FG-3019 for 6-cycle/24-week treatment. Safety, efficacy, PK and changes in CT, PET, & CA19.9 from BL through end of treatment (EOT) are assessed. Up to 4 endoscopic ultrasound (EUS) guided core biopsies are collected at BL. Protein microarrays of pre- and post-treatment biopsies are prepared from tumor and stromal cells isolated by laser capture microdissection. Surgical exploration is performed in subjects who achieved the protocol-defined criteria for possible resection. Results: To date, 11 subjects were enrolled with 5 randomized to +FG-3019 arm. There were no complications from laparoscopy or EUS core biopsies that were clinically significant or delayed dosing. Per investigator assessment, no FG-3019-related SAEs were reported, nor any identified toxicity suspected from combination of FG-3019 with chemotherapy. Overall, CA19.9 mean change from BL was −62.7% at Week 8 (n = 8), and target lesions were reduced by 20.6% (n = 6) at Week 16. Three out of 4 subjects had PET SUVmax reductions of ≥ 30% at EOT. Additional data from protein microarrays will be presented. Conclusions: Based on the limited data collected so far, this trial design is feasible and the G/NP +FG-3019 combination is well-tolerated and appears to be active. Summary results on surgical exploration of subjects will be provided later. Clinical trial information: NCT02210559.

237 Background: AA/P is an approved treatment for mCRPC but there are no known predictive markers of response or resistance. We conducted a prospective trial to evaluate if Androgen Receptor (AR) & AR-variant (ARV) expression in tissue metastases can predict resistance to AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemo AA/P underwent metastatic site biopsies prior to (pre-AA/P) and after 12 weeks of treatment. Composite progression at 12 weeks, (primary endpoint) was evaluated with PSA, RECIST, bone scan and symptoms (per PCWG2). mRNA expressions of pre-AA/P ARFL, ARV3, ARV7, ARV9, ARV23, ARV45, four cell cycle division genes, Chromogranin-A (CHGA) together with PSA/testosterone levels, Gleason Score (GS) at initial diagnosis; high versus low volume disease; time from starting hormone therapy to mCRPC stage and serum CHGA levels were evaluated using a logistic regression model for predicting resistance at 12 weeks of therapy. A final multivariate model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.3 in univariate analysis. Results: Between 6/2013 & 3/2015, 82 pts were enrolled of which 52 had complete mRNA expression & disease assessment data at the12-week time point for analysis. Median age of the cohort was 72.5 yrs (IQR: 68.5-78); median pre-AA/P PSA was 18 ng/ml (IQR: 8.1- 46.6); GS distribution at initial diagnosis for GS 2-6; 7; 8-10 was 11; 14; 27 respectively. Progression was observed in 21/52 pts after 12 weeks. At the univariate level elevated pre-AA/P expression of ARV3 (p = 0.08), ARV7 (p = 0.26), ARV9 (p = 0.04), and cell division cycle gene CDC45 (p = 0.19) along with GS at diagnosis (p = 0.29) met the threshold for inclusion into multivariate analysis. Elevated expression of pre-therapy ARV9 in metastases alone was associated with progression at 12 weeks (OR: 3.9; CI 1.07 – 14.16; C-Index: 0.63). The 12-week biopsy of pts with progression had increased ARV9 mRNA expression compared to pts responding at 12 weeks (p = 0.14). Conclusions: Increased ARV9 mRNA expression in metastases is associated with early resistance to AA/P. This observation will need further validation in comparable datasets. Clinical trial information: NCT #0195364.