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178 Abstracts

  • Introduction & Objectives

    Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is widely recommended for muscle-invasive bladder cancer (MIBC). There is no clear survival benefit for AC. Atezolizumab (atezo; MPDL3280A) is an anti-PDL1 antibody that inhibits the binding of PD-L1 to PD-1 and B7-1. Atezo demonstrated a 50% unconfirmed response rate and manageable safety profile in patients (pts) with metastatic BC with higher levels of PD-L1 expression on tumor-infiltrating immune cells (IC; Petrylak, ASCO 2015, abstract 4501). Therefore, there is a strong rationale to test atezo in the adjuvant setting. IMvigor 010 (NCT02450331) is a Phase III open-label, multicenter, randomized, controlled study to evaluate the efficacy and safety of atezo adjuvant treatment compared with observation in pts with PD-L1−selected MIBC who are at high risk for recurrence following cystectomy.

    Material & Methods

    Pts will be randomized 1:1 to receive atezo (1200 mg intravenously every 3 weeks) or undergo observation as adjuvant treatment for up to 1 year. Pts will be stratified by number of lymph nodes resected, nodal status, tumor stage after cystectomy, age-adjusted Charlson Comorbidity Index and prior NAC. Inclusion criteria include histologically or cytologically confirmed MIBC, cystectomy with lymph node dissection and Eastern Cooperative Oncology Group performance status ≤ 2. Pts with prior NAC must have tumour staging of ypT2−T4a or ypN+; pts without prior NAC must be ineligible for or have declined cisplatin-based AC and have tumour staging of pT3−T4a or pN+. PD-L1 expression on IC in cystectomy tumour specimens will be centrally assessed using the SP142 immunohistochemistry (IHC) assay. Pts with a PD-L1 IHC score of IC2/3 (IC ≥ 5% PD-L1+) are eligible. The primary efficacy endpoint is disease-free survival. Secondary efficacy endpoints are overall survival, disease-specific survival and distant metastasis–free survival. The safety objective is to evaluate the safety and tolerability of atezo in the adjuvant setting. The exploratory objective is to assess predictive, prognostic and pharmacodynamic biomarkers. Disease recurrence will be determined by the investigator based on radiographic evidence with the support of available biopsy results. Approximately 440 pts will be enrolled globally. This trial is currently enrolling. For more information on this trial and other ongoing atezo clinical trials, please visit www.ClinicalTrials.gov.

  • Introduction & Objectives

    Skeletal metastasis is observed in the majority of men with advanced prostate cancer and is a frequent source of morbidity. In these patients, the homeostatic balance between bone formation and resorption is frequently disrupted, with predominance of osteoblastic activity manifesting as sclerotic bony disease. This disruption is clinically assessable with circulating serum markers of bone metabolism. We previously reported in men with bone-metastatic CRPC as part of SWOG 0421, a phase III trial of docetaxel +/- atrasentan, that these blood-based biomarkers have significant independent prognostic value and that a small group of CRPC patients with highly elevated markers preferentially benefit from bone-targeted therapy (Lara, et al. JNCI 2014). Here, we report our analysis of the contribution of these markers individually or collectively as prognostic factors for overall survival (OS) adjusted for known clinical covariates in the S0421 dataset.

    Material & Methods

    Markers for bone resorption (N-telopeptide [NTx] and pyridinoline [PYD]) and formation (C-terminal collagen propeptide [CICP] and bone alkaline phosphatase [BAP]) were measured in pre-treatment sera collected from men in the SWOG 0421 trial. Log-transformed levels of the markers and clinical covariates (including age, baseline PSA, performance status, and pain score, among others) were individually assessed for association with OS by univariate Cox regression. Significant risk factors were included in a multivariate Cox regression model for OS; bone markers were added individually and collectively to this model in a stepwise selection process. Receiver operating characteristic (ROC) curves were constructed for risk factor models +/- bone markers. The contribution of bone markers to prognostic risk groupings was also assessed.

    Results

    750 patients with evaluable bone marker and clinical data were included. Median age was 69 years with median PSA of 77 ng/dL; 417 (56%) had performance status >= 2; 304 (41%) had pain score >= 4; and 457 (61%) were on bisphosphonate therapy. Each of bone markers significantly contributed to the final Cox model, with higher levels associated with worse OS.  A Cox stepwise selection model adjusted for clinical covariates showed that the best combination was with BAP (Hazard Ratio [HR]=1.15, p=0.008), CICP (HR=1.27, p=0.0007), and PYD (HR=1.21, p=0.047). In ROC analysis, the AUC of clinical covariates for OS prognostication was 0.73; this significantly improved with the addition of CICP (AUC=0.76, p=0.003) or BAP (AUC 0.75, p=0.004) or combination BAP/CICP/PYD (AUC=0.76, p=0.001). Prognostic groups based on risk of death at 2 years (low: <35% probability; medium: 35-70%; high > 70%] were identified. 82 men were upstaged to a higher risk group while 98 were down-staged when bone markers were added to the model.

    Conclusions

    Baseline circulating markers of bone metabolism are independently associated with worse OS in bone-metastatic CRPC. ROC analysis showed that bone markers add to clinical covariates in significantly improving prognostic accuracy. Prognostic subgroups of CRPC patients with differential OS outcomes were identified, with risk reclassification seen in a substantial proportion when bone markers were considered. These results have critical implications for CRPC clinical trial design and bedside patient prognostication.

    Session: Oral presentations of the best abstracts

    Location: Saturday, 14 November 2015, 08:50 - 09:30, Auditorium

  • Introduction & Objectives

    Heat shock protein 27 (Hsp27) is over-expressed in bladder cancer (BC) and postulated to increase tumour growth, metastasis, and chemotherapy resistance. Apatorsen (A; OGX-427), a novel antisense oligonucleotide, inhibits Hsp27 production and can potentially enhance the efficacy of chemotherapy. This trial was designed to evaluate efficacy and safety of A in combination with gemcitabine and cisplatin (GC) in patients with advanced BC.

    Material & Methods

    Chemotherapy naïve patients with advanced BC were randomized to GC+A 600 mg, GC+A 1000 mg, or GC + placebo. Patients were stratified by Karnofsky performance status (KPS) and visceral disease. The primary endpoint was overall survival (OS). Prognostic sub-groups were retrospectively evaluated using multiple variable modelling and hierarchical step down. A post hoc analysis was performed to explore the hypothesis that Hsp27 inhibition might be relevant to OS in poor prognosis disease.

    Results

    A total of 179 patients were randomized/treated. Median OS was 15.2 months (m). When compared to GC + placebo, GC+A 600 demonstrated improved OS and PFS (OS HR = 0.856 and PFS HR = 0.830) versus GC+A 1000 (OS HR = 0.898; PFS HR = 0.927). Results from the post hoc model revealed that KPS, liver metastasis, alkaline phosphatase, and hemoglobin were prognostic. A median prognostic score dichotomized patients into poor and good prognosis groups (50% each group). Patients with poor prognosis treated with GC+A 600 had a greater reduction in risk of death (HR = 0.717) than patients with good prognosis (HR = 1.44). The most significant prognostic factor was KPS ≤80% (35% pts in GC+A 600 vs GC) resulting in HR = 0.50 in favour of GC+A 600. Overall treatment was well tolerated. Most common Grade ≥3 adverse events (AEs) were neutropenia, anemia, thrombocytopenia and hypertension. Frequency of ≥3 Grade toxicities were: 89% (GC), 93% (GC+A 600) and 95% (GC+A 1000). GC+A 1000 had a higher treatment discontinuation rate due to AEs.

    Conclusions

    Advanced BC patients with poor prognosis benefited from apatorsen 600mg combined with first line GC. Apatorsen may be impacting the intrinsic biology of patients with poor risk factors. Further evaluation is warranted in this patient population.

    Session: Oral presentations of the best abstracts

    Location: Saturday, 14 November 2015, 08:50 - 09:30, Auditorium

  • Introduction & Objectives

    Hematologic toxicity (HT) is an important side-effect of whole pelvis radiotherapy (WPRT). The aim of this study was to evaluate the incidence, severity and predictors of acute and late HT after prophylactic irradiation of the pelvic lymphnodes for prostate cancer (PCa) in postoperative chemo-naïve patients (pts).

    Material & Methods

    From October 2012, a prospective observational study designed to evaluate the intestinal, hematological and urinary toxicities from WPRT was activated. 125 pts treated with ADV (n=73) or SALV (n=52) intent (static field IMRT:19; VMAT:61; Tomotherapy (TT):45), with conventional (CF, 1.80 Gy/fr, n=39) or HYPO fractionation (median 2.35 Gy/fr, n=86) were considered. Dose to the prostatic bed ranged: 72-75.6 Gy (CF) and 65.8-72.8 Gy (HYPO); dose to nodes: 50.4 Gy (CF) and 51.8 Gy (HYPO). HT was obtained for a blood count pre-RT, at middle and end of RT, at 3-6-12 months and every 6 months from the end of RT.
    Clinical and dosimetric data were collected. Contours of pelvic bones, used as a surrogate for pelvic bone marrow (BM), were delineated: Ilium (IL), lumbosacral spine (LS), lower pelvis (LP) and whole pelvis (WP). HT was scored according to CTCAE and as % variation from baseline for white blood cells (WBC), absolute neutrophil (ANC) and lymphocyte (ALC) counts, red blood cells (RBC), hemoglobin (Hb) and platelets (PLT).

    Results

    A significant and persisting decline in total WBC and, even more markedly, of ALC, while the reduction of ANC, RBC, Hb and PLT was less severe (Fig 1a). All patients who developed acute lymphopenia G1+, of which 89% and 37% G2+ and G3+ but, surprisingly, without any significant infection. Acute G3 lymphopenia was 31%, 45% and 33%, and late G2 at 1 year from RT end 8%, 23% and 19% for pts that underwent TT, VMAT and IMRT, respectively.
    At multivariate analyzes, two robust predictive models of lymphopenia were developed: ALC at baseline (ALCbase) and WP-V40 (AUC=0.73) were associated to acute G3 lymphopenia; ALCbase, IL-V40 and smoking (AUC=0.90) to late G2 lymphopenia (Fig 1b). Best cut-off values (assessed by ROC) discriminating pts with/without lymphopenia were: ALCbase≤1830/µL  and WP-V40>599.4 cc (acute); ALCbase ≤1780/µL and IL-V40>94.6 cc (late).

    Conclusions

    HT after WPRT can be severe and prolonged, but it might be reduced by the application of specific dose-volume constraints to pelvic BM.
    Supported by AIRC Investigational Grant#14603

  • Introduction & Objectives

    Prostate cancer (PC) is the most common malignancy in the male population however; molecular diagnostic/prognostic markers that better define this pathology are very limited and frequently found to be unspecific (i.e. PSA). Therefore, it is necessary to provide new clues for novel diagnostic/prognostic/therapeutic targets in this pathology. Some Genes belong to a family of homeodomain-containing transcription factors that determine cell/tissue identity during normal embryonic development which, have been shown to be re-expressed by different tumoral cell-types. Interestingly, some studies have indicated that the engrailed variants (EN1andEN2) might be used as a potential diagnostic markers of early PC however; these few studies are conflicting and incomplete and, to date, limited information is available concerning the presence of these variants in PC-cells. Therefore, the main goals of this study were to analyse the expression levels of EN1- and EN2-variants in PC-tissues and cell lines and, to determine urinary levels of EN2-variant in patients with and without PC.

    Material & Methods

    To that end, we implemented a triple strategy by using: 1) paraffin-embedded PC-tissues obtained from radical prostatectomies and its adjacent normal-control tissues; 2) normal and androgen-dependent (LnCaP/VCaP/22Rv1) and androgen-independent (DU145/PC3) PC-cell lines and; 3) Urinary fluids from patients with PC and control-patients.

    Results

    Expression of EN2-variant, but not EN1-variant, was up-regulated in PC-tissues compared to normal-adjacent tissues (p<0.05). Moreover, EN1/EN2-variants were not expressed in a normal-prostate cell-line while, EN2-variant was over-expressed in all PC cells-lines analyzed (LnCaP>>DU145>VCaP>PC3>22Rv1). Interestingly, only DU145 cells expressed EN1-variant. Median urinary levels of EN2-variant collected from PC and controls-patients without prostate massage were similar (~0.8ng/ml).

    Conclusions

    Altogether, our ongoing studies suggest a potential role of EN-variants, especially EN2, in PC cells. Therefore, additional experiments are planned to determine the functional role of these EN-variants in PC-cells as wells as, additional measures of urinary and plasma EN2 levels in PC and control patients following a prostate massage.

    Funding: PI13-00651, PI-0639-2012, BIO-0139, CTS-1406, BFU2013-43282-R, CD11/00276 and CIBERobn
    Keywords: Prostate Cancer, Engrailed-1 y -2 variants, diagnostic/therapeutic markers

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