Prognostic Risk Groups Research Articles

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives.The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.

External Validation of a Nomogram and Risk Grouping System for Predicting Individual Prognosis of Patients With Medulloblastoma

Background: Medulloblastoma (MB) is one of the most malignant neuroepithelial tumors in the central nervous system. This study aimed to establish an effective prognostic nomogram and risk grouping system for predicting overall survival (OS) of patients with MB. Materials and Methods: The nomogram was constructed based on data from the database of Surveillance, Epidemiology, and End Results (SEER). This database consisted of 2,824 patients with medulloblastoma and was used as the training cohort. The data of another additional 161 patients treated at the Sun Yat-sen University Cancer Center (SYSUCC) were used as the external validation cohort. Cox regression analysis was used to select independent prognostic factors. Concordance index (C-index) and calibration curve were used to predict the prognostic effect of the nomogram for overall survival. Results: In the training cohort, Cox regression analyses showed that the prognostic factors included histopathology, surgery, radiotherapy, chemotherapy, tumor size, dissemination, and age at diagnosis. The internal and external validated C-indexes were 0.681 and 0.644, respectively. Calibration curves showed that the nomogram was able to predict 1-, 3-, and 5-year OS for patients with MB precisely. Using the training cohort, a risk grouping system was built, which could perfectly classify patients into four risk nomogroups with a 5-year survival rate of 83.9%, 76.5%, 64.5%, and 46.8%, respectively. Conclusion: We built and validated a nomogram and risk grouping system that can provide individual prediction of OS and distinguish MB patients from different risk groups. This nomogram and risk grouping system could help clinicians making better treatment plan and prognostic assessment.

Next-Generation Sequencing Targeted Chronic Lymphocytic Leukemia Panel: A Pilot Study

Background: Rapid progress in next-generation sequencing (NGS) technologies make it possible to spell out the mutational status, the genetic and epigenetic variability of chronic lymphocytic leukemia (CLL). The identification of driver mutations allows us to expand understanding of the pathogenesis of CLL, to identify prognostic groups and to select potential targets for therapy, contributing to the development and implementation of new targeted drugs and its combinations. Nevertheless, the course of CLL does not always correspond to the existing prognostic risk groups, assessed by "standard" cytogenetic and molecular genetic methods. The NGS technology admits establishing markers of an unfavorable course of the disease. Aim: To assess the mutational status of patients (pts) with CLL using the developed Lymphoid Targeted NGS Panel and to study the possible correlation of the mutational status with the clinical characteristics of the disease. Method: In this prospective study were included 24 pts with CLL: treatment-naïve (n=8) and relapsed/refractory (n=16). The diagnosis of CLL was established according to iwCLL criteria (iwCLL, Hallek et al., 2018) and show only typical immunophenotype. The pts were divided into three prognostic groups according to cytogenetic assay: favorable (n=14), neutral (n=2), and unfavorable (n=8). Although, 20/24 pts were divided into two prognostic groups taking into account the data on the mutational status of the immunoglobulin heavy-chain variable (IGHV) region: favorable (n=8) and unfavorable (n=12). Four patients have no available data on IGHV mutational status. All patients had indications for starting treatment: FCR (n=7), RB (n=6), ibrutinib (n=3), venetoclax (n=1), acalabrutinib (n=5), combination of venetoclax and acalabrutinib (n=2). DNA samples were extracted from peripheral B-cell lymphocytes via the standard phenol-chloroform method. Average reading depth of 1000x is produced on a MiSeq platform (Illumina, USA). The 2% threshold of allele frequency (VAF) was used. The clinical significance of mutations was established using the following databases: COSMIC, ClinVar, gnomAD with application in silico analysis (Cscape, Cancer Genome Interpreter, SNPs&Go). The Lymphoid Panel includes 117 genes, part of which is involved in the main 8 cellular signaling pathways underlying the pathogenesis of CLL. We have completed a pilot NGS study using the developed Lymphoid Targeted Gene Panel on DNA samples of six treatment-naïve pts. Results: Genetic aberrations were identified in all DNA samples using NGS. Somatic mutations were detected in 82.9% of cases, in an amount from 15 to 37. In four pts (4/6) with an unfavorable prognosis (cytogenetics and unmutated IGHV), known pathogenic variants of mutations were identified: JAK3 V722L, NOTCH1 P2514fs*4, IDH2 T352P, TP53 Lys120Glu, BRAF D594G. The existing approach to the interpretation of the results does not allow making an unambiguous conclusion about the clinical significance of variants in the IDH2 and JAK3 genes, despite the known pathogenic effect of the variants. The detected variant of the mutation (Lys120Glu) in the TP53 gene is often associated with the presence of a 17p13 deletion, which was confirmed by the FISH assay and correlated with the unfavorable clinical course of the disease in patient CLL-024. Twenty-two mutations were identified, the pathogenicity of which has not yet been determined, in the amount of 2 to 5 (median=3.5) mutations per patient. It should be noted that two patients (CLL-023, CLL-024) with unfavorable prognosis had mutations both in BCR gene and in NOTCH2 gene of unknown significance. Conclusion: The data obtained from a pilot study demonstrate the possibility of using NGS technology in clinical practice. The assessment of the mutational status of pts with CLL using NGS correlates with the clinical parameters of pts. Considering that there is currently no information about prognostic significances of identified mutations, additional research is required. Disclosures Martynkevich: Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Shuvaev:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Voloshin:Novartis: Honoraria, Speakers Bureau.

Development of a Novel Prognostic Three-tier Risk Group Stratification in Men Receiving Post-Prostatectomy Radiation Therapy Without Androgen Deprivation Therapy

Development of a Novel Prognostic Three-tier Risk Group Stratification in Men Receiving Post-Prostatectomy Radiation Therapy Without Androgen Deprivation Therapy

Higher SBRT Dose Levels for Localized Prostate Cancer Are Associated with Improved Post-treatment Biopsy Outcomes

To investigate predictors associated with post-treatment biopsy outcomes after stereotactic body radiotherapy (SBRT) for localized prostate cancer. 231 patients treated with prostate SBRT to dose levels of 32.5 Gy to 42 Gy in five fractions (median dose 40Gy) underwent a post-treatment biopsy performed approximately two years after therapy to evaluate local control status. The majority of the patients had intermediate risk disease, 38.5% unfavorable, (n = 89) and 33.3% favorable (n = 77) and the remaining 18.6% (n = 43) and 9.5% (n = 22) had low and high-risk disease. 22.9% (n = 53) were treated with neoadjuvant and concurrent androgen deprivation therapy on conjunction with SBRT for a median duration of 4.6 months. Logistic regression analyses assessed relationships between factors and post-treatment biopsy outcomes (positive vs. negative/treatment effect). The median follow-up time was 46 months (range: 19-116 months). The incidence of positive, negative, and treatment-effect and biopsies were 16.0%, 56.3%, and 27.7%, respectively. The incidence of a positive biopsy according to dose was 33.3% (n = 8/24), 21.4% (n = 6/28), 19.4% (n = 6/31), 11.5% (n = 17/148) for 32.5 Gy, 35 Gy, 37.5 Gy and > = 40 Gy, respectively. The incidence of a positive biopsy was 7% (n = 3/43), 16.9% (n = 13/77), 21.3% (n = 19/89), and 9.1% (n = 2/22) for low, favorable intermediate, unfavorable intermediate and high risk respectively. Patients treated with SBRT doses of <40 Gy (OR: 2.59, 95%CI: 1.19-5.64, p = 0.016) and those with an unfavorable intermediate/high risk (OR: 2.31, 95%CI: 1.07-5.00, p = 0.034) had higher odds of a positive biopsy outcome. The use of neoadjuvant and concurrent ADT did not impact on post-treatment biopsy outcomes. In this cohort representing the largest number of post-treatment biopsies performed on patients treated with prostate SBRT, higher dose levels were associated with improved post-treatment biopsy outcomes independent of prognostic risk group.

457P 1st-line panitumumab plus FOLFIRI or FOLFOX for patients with RAS wildtype metastatic colorectal cancer in Germany: Interim results of the non-interventional study VALIDATE

The metastatic colorectal cancer (mCRC) prognostic score (mCCS) predicts overall survival (OS) of patients (pts) with mCRC at start of 1st-line therapy (Marschner N, et al. Colorectal Dis. 2019). Based on 5 clinical routine parameters, i.e. tumor stage, tumor grading and lymph node (LN) ratio (affected LNs / total number of resected LNs) at primary diagnosis, primary tumor resectability and number of metastatic sites at start of 1st-line treatment, pts were assigned to three prognostic risk groups with decreasing OS from low to intermediate and high risk group.

Abstract IA14: Linking heterogeneous data to enable knowledge discovery in health care

Abstract The vision of precision medicine relies on the linkage of large-scale clinical, molecular, environmental, and patient-generated datasets. Traditionally, diverse data streams have been analyzed independently, including the wealth of information captured in electronic health records (EHRs). However, to successfully leverage the volumes of data that can be used in health care, cross-modality integration is necessary. We have developed a clinical data warehouse for prostate cancer that integrates multiple data streams, from structured EHR data to imaging, state registries to patient-generated data, as well as the rich granular information contained in unstructured clinical narrative text. This rich, longitudinal dataset facilitates secondary data use and enhances observational research in oncology. We have developed advanced machine learning approaches to analyze these data. Our methods can accurately classify patients into clinical and pathologic stage groups and prognostic risk groups. These classifications can be used at point of care to guide optimal treatment pathways based on evidence-based guidelines (e.g., identify high-risk patients for whom a radionuclide bone scan is recommended). Furthermore, linking routinely collected patient surveys to EHRs reveals important differences in global physical and mental health between demographic and clinical subgroups. Giving clinicians visibility into these patient-reported outcomes can help personalize treatment pathways and may inform population health initiatives to support vulnerable groups. The granular health data we collect and link also provide population-based views into changes in treatment patterns and effects from policy changes, e.g., changes to PSA screening guidelines. The integration of diverse data streams presents unique technical, semantic, and ethical challenges; however, our work suggests that multimodal clinical data can significantly improve the performance of prediction algorithms and guide treatment decisions, powering knowledge discovery at the patient and population level. Citation Format: Tina Hernandez-Boussard. Linking heterogeneous data to enable knowledge discovery in health care [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr IA14.

Histopathological re-evaluations of biopsies in prostate cancer: a nationwide observational study

Background Grading prostate biopsies has an important role in determining treatment strategy. Histopathological evaluations suffer from interobserver variability and therefore biopsies may be re-evaluated. Objective To provide insight into the extent of, characteristics associated with and clinical implications of prostate biopsy re-evaluations in daily clinical practice. Methods Patients diagnosed with prostate cancer (PCa) by biopsy between October 2015 and April 2016 identified through the Netherlands Cancer Registry were included. The proportion of re-evaluations was assessed and characteristics were compared between patients with and without biopsy re-evaluation. Interobserver concordance of ISUP grade and EAU prognostic risk classification was determined by calculating Cohen’s kappa. Results Biopsy re-evaluation was performed in 172 (3.3%) of 5214 patients. Primary reason for re-evaluation in patients treated with curative intent was referral to another hospital. Most referred patients treated with curative intent (n = 1856) had no re-evaluation (93.0%, n = 1727). Patients with biopsy re-evaluation were younger and underwent more often prostatectomy compared to patients without re-evaluation. The disagreement rate for ISUP grade was 26.1% and interobserver concordance was substantial (κ-weighted = 0.74). Re-evaluation resulted in 21.1% (n = 14) of patients with localised PCa in a different prognostic risk group. More tumours were downgraded (57.1%) than upgraded (42.9%). Interobserver concordance was very good (κ weighted = 0.85). Conclusion Pathology review of prostate biopsies is infrequently requested by clinicians in the Netherlands but in a non-negligible minority of patients with localised PCa the pathology review led to a change in prognostic risk group which might impact their treatment.

Prognostic Role of Early Interim Fluorodeoxyglucose Positron Emission Tomography in Patients With Advanced Seminoma Undergoing Standard Treatment.

Patients with advanced seminoma have an exceedingly favorable prognosis. Studies aiming to reduce the total treatment burden and side effects in patients with well-defined disease and very good prognosis are warranted. In a prospective observational study, patients with advanced stage seminoma were treated with bleomycin, etoposide, and cisplatin (BEP) or EP according to guidelines. Fluorodeoxyglucose with positron emission tomography and computed tomography (FDG-PET/CT) examinations were performed at baseline, after 2 cycles (PET/CT2) in all patients, and after chemotherapy at the physician's discretion. Disease response to treatment assessed by PET/CT was qualitatively evaluated by 2 independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to guidelines (at baseline, after treatment, during follow-up). The study's primary endpoint was to evaluate the association between PET/CT2 findings and relapse-free survival. From January 2009 to January 2017, a total of 75 consecutive patients were enrolled, of whom 70 were included for analysis. The clinical disease stage was IIA-B and IIC-III in 40% and 60%, respectively. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these patients had stage IIC-III disease. Five-year relapse-free survival of PET/CT2-positive patients was 75% (95% confidence interval, 60-95) compared to 97.8% (95% confidence interval, 93.7-100) of PET/CT2-negative patients (P= .002). In univariate analyses, PET/CT2 was significantly associated with relapse-free survival (P= .02). No residual FDG uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, but it may be useful to optimize the standard prognostic risk groups and may be tested within larger prospective clinical trials of chemotherapy deescalation.

Treatment results of pediatric acute myeloid leukemia with epigenetic drugs addition

Background. Currently, overall survival rate for pediatric patients with acute myeloid leukemia (AML) do not exceed 70 %. The intensity of modern AML chemotherapeutic programs has reached its limit, and further chemotherapy dose escalation for treatment results improvement is impossible, because it fraught with life-threatening complications. It is investigating a new ways of tumor treatment for improvement of AML patient’s survival level: therapeutic efficacy of targeted and epigenetic drugs.Objective: to evaluate the efficacy of epigenetic drugs (azacitidine, decitabine, all-trans-retinoid acid and valproic acid) in combination with AML-BFM 2004 protocol for treatment of pediatric AML.Materials and methods. 80 patients with primary AML diagnosis were enrolled the study. Age was ranged from 8 months to 17 years (median 6.7 ± 0.6 years). From June 2012 to January 2018 all patients were subdivided in two treatment groups. 1st group included 34 patients treated with NII POH AML 2012 protocol, 2nd group – 46 patients treated by AML-BFM 2004 protocol.Results. 3-year relapse-free survival in 1st group, regardless of prognostic risk group, was 66.7 ± 11.7 %, 2nd group – 68.9 ± 9.9 %. Eventfree survival (EFS) for patients from 1st group was 66.7 ± 11.7 %, form 2nd group – 50.4 ± 10.2 %. Overall survival in 1st group was 66.7 ± 14.3 %, 2nd group – 66.9 ± 7.5 %. For patients with unfavorable risk from 1st treatment group 3-year relapse-free survival was 69.1 ± 11.9 %, 2nd – 64.9 ± 11.3 % (p = 0,8). EFS – 69.1 ± 11.9 and 44.8 ± 11.3 % respectively (p = 0,13). 3-year overall survival for patients with unfavorable risk group was 69.4 ± 14.6 and 64.4 ± 7.9 % in 1st and 2nd treatment groups respectively.Conclusion. The efficacy of decitabine in “window” regimen was higher in contrast to azacitidine; epigenetic therapy with AML-BFM 2004 protocol allow us to achieve a higher EFS, because of induction mortality and infection-related death decrease – EFS in 1st group was 16 % higher than in 2nd. Besides, EFS in unfavorable risk group, who treated with epigenetic drugs, was 25 % higher – 69.1 ± 11.9 % and 44.8 ± 11.3 % in 1st and 2nd groups respectively (p = 0.13). Nevertheless, overall survival in both groups was the same – 66 % (1st – 66.7 ± 14.3 % and 2nd – 66.9 ± 7.5 %).

Maximal cardiopulmonary exercise testing in childhood acute lymphoblastic leukemia survivors exposed to chemotherapy.

The purpose of this study was to demonstrate if childhood acute lymphoblastic leukemia (ALL) survivors exposed to chemotherapy (i.e., doxorubicin) are able to achieve a safe maximal cardiopulmonary exercise test (CPET). A total of 250 childhood ALL survivors were eligible to undergo a CPET on ergocycle. Analyses were performed in 216 survivors and stratified in regard to their prognostic risk groups: 99 survivors (55 males and 44 females) at standard risk and 117 survivors (56 males and 61 females) at high risk. Results showed that 100% (n = 216) of survivors completed a maximal CPET confirmed by the achievement of two out of three of the following criteria: 197 survivors (91.2%) reached a peak RER value of ≥ 1.15, 197 survivors (91.2%) reached a RPE score > 7, and 210 survivors (97.2%) reached a maximal heart rate ≥ 85% of the predicted value. Linear regression analysis showed a significant association between the survivors' cumulative dose of doxorubicin and their VO2 peak measured. Two non-fatal adverse events were observed and reported at the end of the maximal CPET, while non-fatal adverse events were reported in 5 survivors during the recovery period. None of these events resulted in a long-term complication. Childhood ALL survivors with prior exposure to chemotherapy can achieve a safe maximal CPET. They were able of achieving a maximal exercise test without being limited by symptoms, potential overprotection, or musculoskeletal issues. Thus, it should be the norm to realize a CPET prior a physical activity program to propose an optimal prescription. This study provides important information regarding the maximal physiological parameters that childhood ALL survivors are able to reach and have important clinical implications in the exercise and oncology field for this population of survivors.

Population-based incidence of gastrointestinal stromal tumors in Puglia.

This study presents the incidence of gastrointestinal stromal tumors (GISTs) in an Italian region of over 4 million inhabitants monitored for 10 years and is the largest incidence study of this type of cancer conducted so far in Italy. In order to ensure the registration of all GISTs, including those with nonmalignant behavior, a cancer list was integrated with the cases found through an ad hoc data mining process that covered all the pathologic reports of Puglia. Case distributions by sex, age groups, site, and prognostic groups according to Miettinem and Lasota classification and crude and age-standardized incidence rates were produced. In the 10-year period 2006 to 2015, 708 cases of GIST were recorded in Puglia. The average crude incidence rate was 1.7 per 100,000 person-years and the age-standardized incidence rate, using 2013 European standard population, was 1.8 per 100,000 person-years (95% confidence interval [CI], 1.6-1.9). Incidence was higher in men than in women: crude incidence rate was 2.0 per 100,000 person-years and age-standardized incidence rate 2.2 per 100,000 person-years (95% CI, 2.0-2.4) in men and 1.5 per 100,000 person-years and 1.4 per 100,000 person-years (95% CI, 1.2-1.6) in women. Our incidence rates are comparable with those of other international studies and they are located in the medium to high end of the range. The comparisons are affected by a different capacity of the cancer registries to intercept and record GISTs with nonmalignant behavior. Distribution of cases for sex, age groups, sites, and prognostic risk groups are consistent with previous results.

Abstract C061: Molecular landscape of acute myeloid leukemia in Mexico

Abstract The understanding of the somatic driver mutations and genetic abnormalities in acute myeloid leukemia (AML) has enabled the discovery of actionable mutations and improved risk stratification; however, it is unclear how the distribution of molecular defined subsets varies within different populations. The median age of AML diagnosis in Mexico is younger than for other international cohorts; however, no mutational analysis has been performed to date. We thus sought to ascertain differences in somatic mutations in this population. Methods: We created a collaborative research initiative to evaluate the frequency of recurrently mutated genes in 48 Mexican AML patients using a combination of whole-exome and targeted next-generation sequencing. We compared the prevalence to other reported Hispanic cohorts in the US and large international cohorts. Results: The median age of diagnosis was 38 year (15-86). Somatic mutations were detected in 96% of patients, with a median of 2 mutated genes per patient (range 0-6). The most prevalent mutations in the cohort were FLT3 (29%) (with FLT3-TKD over-represented in 21% of the total cohort vs. 10% for FLT3-ITD and 6% harboring simultaneous ITD and TKD mutations), followed by CEBPA (21%), TET2 (19%), DNMT3A (19%), RUNX1 (15%) and NPM1 (12%). Fusion genes were detected in 21% of patients, with t(8;21)(AML-ETO) being the most commonly found (13%), followed by MLL rearrangements (4%) and inv(16)(CBFB-MYH11) (2%). When compared to international cohorts, CEBPA, RUNX1 GATA2, TET2, AML1-ETO, U2AF1, ASXL1 and KIT were found to be enriched in our cohort. In contrast, mutations in FLT3-ITD, DNMT3A, NPM1 and IDH2 were under-represented in the Mexican cohort. There was an over-representation of CEBPA mutated AML, with a characteristic mutational distribution and variant allele frequencies (VAF) in the 50% range that could be indicative of a greater incidence of germline predisposition in this population. The median overall survival for the cohort was 9 months. Adjustment for prognostic variables that tend to have better prognosis, such as lower age, higher prevalence of CEBPA and lower FLT3-ITD prevalence, did not attenuate the disparities in disease outcomes. Conclusion: Mexican AML patients show a distinct genetic repertoire compared with other international cohorts that point to differences in host genetic susceptibility and environmental factors. Interestingly, some of the detected variants are targetable mutations that could influence management decisions. Despite some better prognostic risk groups such as younger age, lower FLT3-ITD and higher CEBPA, the outcomes for the cohort were overall poor, which correlates to reports of Hispanic minorities in the SEER database. Based on these findings, it is important to further investigate the true incidence of germline mutations in Mexican patients and other Hispanic patients and determine if there is a genetic susceptibility to develop AML that could explain some of the difference in age of onset and molecular findings. Citation Format: Alexandra Gomez-Arteaga, Nuria Mencia-Trinchant, Adolfo Martinez Tovar, Irma Olarte Carrillo, Anel Garcia Laguna, Etta Rozen Fuller, Christian Ramos Penafiel, Monica L. Guzman, Duane C. Hassane. Molecular landscape of acute myeloid leukemia in Mexico [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C061.

Prognostic role of early interim [18F] fluoro-deoxy-glucose positron emission tomography in patients with advanced seminoma undergoing standard treatment.

5055 Background: In patients (pts) with advanced seminoma, efforts are underway to tailor a risk-adapted treatment strategy to the individual pt. Our main objective was to prospectively determine the prognostic value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT2) after two cycles of bleomycin, etoposide and cisplatin (BEP) or EP chemotherapy under standardized treatment and PET evaluation criteria. Methods: Pts with advanced-stage seminoma were treated with BEP or EP according to guidelines. PET/CT examinations were performed at baseline, after two cycles in all pts and after chemotherapy at physician’s choice. PET/CT response was qualitatively evaluated by two independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to the guidelines (at baseline, after treatment, during follow-up). The primary endpoint was the relapse-free survival (RFS). Results: From 01/2009 to 01/2017, 75 consecutive pts were enrolled, of whom 70 were evaluable. The clinical stage was IIA-B and IIC-III in 40% and 60% of the pts, respectively. Eight pts (11.4%) received consolidation radiotherapy. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these pts presented with stage IIC-III. The median follow-up was 79 months. Five-year RFS of PET/CT2-positive pts was 75% (95%CI: 60-95%) compared with 97.8% (95%CI: 93.7-100%) of PET/CT2-negative pts (p = .002). This significant improvement in RFS was maintained when analyzing only pts with clinical stage IIC-III (p = 0.04) and by excluding those who received consolidation RT (p = 0.02). An increasing linear association was found between the maximum diameter of retroperitoneal lymph nodes and the rate of PET/CT2+. In univariable Cox regression analyses, PET/CT2+ (HR: 12.9, 95%CI: 1.5-106.9, p = 0.02) and elevated HCG levels (HR: 6.3, 95%CI: 1.2-32.3, p = 0.03) were significantly associated with RFS, whereas IGCCCG risk group was not (p = 0.1). PET/CT2 result was also associated with the tumor shrinkage post-BEP (p = 0.009), whereas complete response at CT did not predict the RFS (p = 0.3). Conclusions: No residual FDG-uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, may outperform the utility of standard prognostic risk groups and may be more accurate to predict the RFS compared to standard response criteria. Benchmark RFS estimates for the design of the next clinical trials of chemotherapy de-escalation are offered.

Modern immunological criteria for a stratification of risk groups for precursor B cell acute lymphoblastic leukemia in children

Background. Modern therapy programs allow achieving high survival rates in children with acute lymphoblastic leukemia (ALL). However, there is a group of patients in whom a relapse occurs, which makes it necessary to search for optimal tools for monitoring remission and the earliest detection of ALL relapse. According to clinical and immunological studies, assessment of minimal residual disease (MRD) levels is one of the leading criteria for response to treatment and can be the basis for risk-stratified therapy.&#x0D; Aim. Assessment of MRD levels on the 15th day of induction as the main parameter for stratification of patients into prognostic risk groups and the impact of MOB levels on patient survival.&#x0D; Materials and methods. The study included 117 children with a newly diagnosed precursor B-cell ALL. All patients were given an induction course according to the BFM ALL IC 2009 protocol.&#x0D; MRD levels were determined by flow cytometry.&#x0D; Results. Given the MRD based stratification, a truly standard risk group was identified, the survival rate of which reached 100%.&#x0D; Conclusions. The use of MRD as the main tool for the risk of adapted therapy made it possible to improve survival in patients of the standard risk group, as well as to optimize therapy for high and medium risk groups in the future.

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Introduction: The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Methods: Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan–Meier curve, and both univariate and multivariate Cox proportional models. Results: BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively (p < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129–1.754, p = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10–1.82; p = 0.006) were identified as independent prognostic factors. Conclusion: Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.

A Clinico-Genotypic Prognostic Index for De Novo Composite Diffuse Large B-Cell Lymphoma Arising from Follicular Lymphoma in Asian patients treated in the Rituximab Era

Composite follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL) is uncommonly found on lymph node biopsy and represents a rare haematological malignancy. We aim to examine clinico-pathological features of patients with FL/DLBCL and investigate predictors of survival outcome. We included in our retrospective study patients with histologically-proven FL/DLBCL at diagnosis (n = 106) and who were subsequently treated with rituximab-based chemoimmunotherapy from 2002–2017 at the National Cancer Centre. The cohort consisted of 34 women and 72 men with a median age of 59 years (range, 24–82). In a multivariate model inclusive of known clinico-pathological parameters at diagnosis, advanced stage (p = 0.0136), presence of MYC and/or BCL6 rearrangement (p = 0.0376) and presence of B symptoms (p = 0.0405) were independently prognostic for worse overall survival (OS). The only remaining independent prognostic variables for worse OS after including first-line treatment data in the model were use of chemotherapy regimens other than R-CHOP (p = 0.0360) and lack of complete response to chemotherapy (p < 0.0001) besides the presence of B symptoms (p = 0.0022). We generated a Clinico-Genotypic Index by point-wise addition of all five adverse parameters (score of 0–1, 2, 3, 4–5) which revealed four prognostic risk groups with a predicted 5-year OS of 100%, 62%, 40% and 0% (p < 0.0001) accounting for 50.0%, 24.5%, 18.9% and 6.6% of the cohort respectively. We propose that R-CHOP should be the recommended first-line regimen for composite FL/DLBCL.

Prognostic factors in advanced seminoma: An analysis from the IGCCCG Update Consortium.

386 Background: Extrapulmonary visceral metastases were the only adverse prognostic factor among 660 advanced seminomas in the original classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) treated between 1975 and 1990 and published 1997. Outcomes may have improved with current era management and additional prognostic factors may exist. Methods: To update the original IGCCCG classification, an international consortium (30 centers/groups) provided data on 2458 advanced seminoma patients treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2015 in prospective cohorts or clinical trials. Progression-free (PFS) and overall survival (OS) probabilities were calculated. CART analysis was used to identify prognostic factors inside original IGCCCG good risk group to further refine the classification. Among eligible 2302 patients with full data, a training set of 1509 patients (1437 good risk and 72 intermediate risk) was used for model building. An independent set of 793 patients was set aside for validation. Primary endpoints were PFS and OS at 5 years. Results: Compared with the 1997 IGCCCG benchmarks, the 5-year PFS rates increased to 88.7% (87.2 - 89.9%) and 78.4% (69.6 - 84.9%) in good and intermediate IGCCCG patients. The corresponding 5-year OS rates were 95.4% (94.4 - 96.2%) and 87.2% (79.2 - 92.2%). CART analysis identified LDH with a cut-point of 2.5 x ULN as the single most significant prognostic factor in good risk patients with 5-y PFS rates of 92.1% (90.3 - 93.6%) and 79.2% (74.2 - 83.4%) in low and high LDH subgroups. (HR = 2.90, P &lt; .0001). Good risk patients with LDH above 2.5 x ULN (313 of 1411 patients) performed similarly to the intermediate IGCCCG patients; hCG was not independently prognostic. Conclusions: In this modern era series, the original IGCCCG still significantly discriminates between "good” and "intermediate" risk metastatic seminoma, but with significantly improved PFS and OS in both risk groups. LDH at a cut-off point of 2.5 x ULN further refines this classification and identifies men with intermediate risk seminoma in the absence of extrapulmonary visceral metastases. This refinement will be relevant to improve future seminoma care.

Abiraterone acetate (AA) with or without cabazitaxel (CBZ) in treatment of chemotherapy naive metastatic castration-resistant prostate cancer (mCRPC).

84 Background: Loss of retinoblastoma tumor suppressor (RB) function has been shown to lead to CRPC and is strongly associated with poor outcome. RB functions as a transcriptional repressor; as such, loss of RB causes de-repression of pro-tumorigenic gene networks, including deregulation of the androgen receptor (AR) locus, excessive AR production, and castration-resistant (ligand independent) AR activity that can bypass hormone therapy. Our hypothesis is that leveraging RB status can direct treatment decisions. The primary objective of the trial (NCT02218606) was to determine the radiographic progression free survival (rPFS) of AA/prednisone (AAP) with and without CBZ in mCRPC patients (pts) that have progressed on primary androgen deprivation therapy and no prior AR directed therapy or chemotherapy. Methods: This is a multicenter non-comparative randomized phase 2 trial. Pts were randomized 1:1 to AAP with crossover to CBZ upon AAP failure (Arm 1), or the combination of AAP + CBZ (Arm 2). Randomization was stratified by the CALGB 90401 prognostic risk groups. The primary endpoint was rPFS (time from randomization to radiographic progression or death, whichever occurs first). Arms were analyzed separately. Results: Between October 2014 and March 2019, 93 pts were accrued; 81 were randomized. Median age was 68 years and ECOG performance status was 0 or 1. Endpoints are shown in Table. Therapies were well tolerated. Conclusions: Results of AAP + CBZ (Arm 2) in chemotherapy naïve pts suggest that men may derive benefit from the earlier use of CBZ with acceptable toxicity, supporting further study of this combination in mCRPC pts. Circulating Tumor Cells are being analyzed for changes in RB/AR expression. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Sanofi US; Support: Prostate Cancer Foundation. Clinical trial information: NCT02218606. [Table: see text]

Abstract P3-08-03: Breast cancer index and prognostic performance in invasive lobular breast cancer

Abstract Background: Invasive lobular carcinoma (ILC) has distinct clinical, histologic, molecular, and biological characteristics. Dyscohesive cells infiltrating the mammary stroma, lack of E-cadherin expression, mutations in the PIK3CA pathway and lower incidence of GATA3 mutations are hallmarks of these tumors. As a result of these molecular features, tumor biology is of key importance in determining prognosis and treatment approaches for ILC. The Breast Cancer Index (BCI) is a gene expression signature validated as a significant and independent prognostic factor both for risk of overall (0-10 years) and late (5-10 years post-diagnosis) distant recurrence, and is predictive of extended endocrine benefit in patients with early-stage, HR+ breast cancer. The objective of the current study is to examine BCI prognostic risk stratification and potential clinical utility specifically in ILC. Methods: In this multi-institutional, prospectively defined retrospective study, FFPE tumor samples from 356 HR+ stage I-III N0 and N+ ILC patients diagnosed between 1997-2011 were collected. Genomic risk stratification was performed using BCI-prognostic models (N0: gene expression alone; N+: gene expression plus tumor size and grade) using previously validated assay cut-points. Prognostic performance for 10-year and late DR risk was estimated using Kaplan-Meier analysis and the difference was evaluated by log-rank test and Cox proportional hazards regression. Results: Results were generated on 311 evaluable patients (99% ER+, T1 52%, 42% N+, 66% grade II) with 10 years of median follow-up. BCI significantly stratified ILC patients into three prognostic risk groups based on 10-year risk of DR (p &amp;lt; 0.0001). Notably, BCI low and intermediate risk patients demonstrated similar patterns and rates of distant recurrence, with limited risk in early DR (0-5 years) and increasing risk of late DR (5-10 years), constituting a single risk group in lobular cancer. Analysis combining the low and intermediate risk groups resulted in 53% and 47% of patients classified as BCI low/int and high risk, respectively. In well and moderately differentiated N0 tumors, 18% of patients were classified by BCI as high risk. The overall 10-year risk of DR was significantly different (hazard ratio [HR] =4.67, 95% confidence interval [CI]: 2.24 - 9.74; p &amp;lt; 0.0001) between BCI low/int (6.9%, 95% CI: 2.4% - 11.2%) and high (27.9%, 95% CI: 19.3% - 35.5%). The risk was also significantly different for both early (0-5 years; p = 0.001) and late DR (5-10 years; p = 0.02). For early DR, the risk was 1.4% (0.0% - 3.3%) and 11.8 (6.2% - 17.1%) for the low/int and high risk groups, respectively; while for late DR, the risk was 5.6% (1.4% - 9.5%) and 18.2% (10.1% - 25.6%), respectively. Conclusion: BCI was a significant prognostic factor in risk stratification of ILC and identified a substantial proportion of ILC, which is generally associated with indolent characteristics, that were associated with a high 10-year risk of DR and late DR. In addition, BCI reclassified a considerable proportion of clinically low and moderate grade tumors as high genomic risk. These results support a role for genomic classification with BCI to define distinct prognostic subtypes based on tumor biology towards more individualized treatment strategies for patients with ILC. Citation Format: Tal Sella, Raquel Nunes, Kai Treuner, Jennifer Atkinson, Jenna Wong, Yi Zhang, Pedro Exman, David Dabbs, Andrea Richardson, Catherine Schnabel, Dennis Sgroi, Steffi Oesterreich, Ashley Cimino-Mathews, Otto Metzger. Breast cancer index and prognostic performance in invasive lobular breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-03.