Citations

3502 Background: DFS with 3 years median follow-up (3yDFS) was validated as a surrogate for OS with 5 years median follow-up (5yOS) in adjuvant chemotherapy CC trials prior. Recent data showed improved survival after recurrence and OS, over time, in pts who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS, as well as the optimal follow-up of OS to aid its utility in future adjuvant trials is needed. Methods: Individual patient data from 8 randomized adjuvant studies conducted from 1998-2009 were included; 3 trials tested anti-VEGF or anti-EGFR agents. Trial-level surrogacy examining the correlation of treatment effect estimates (i.e. hazard ratios) of 3yDFS and 5y to 8yOS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models. For the R2, a value closer to 1 indicates a stronger correlation. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% Confidence Interval (CI) > 0.60. The rank correlation coefficient (ρ) quantified the individual-level surrogacy. Results: Total of 18,886 pts were analyzed, with median age 60, 54% male, 83% stage III, 59% > 12 nodes examined. Median follow-up for survival ranged from 5 to 10 years across trials. Trial level correlation between 3yDFS and OS remained strong (R2WLS ≥0.74; R2Copula ≥ 0.89) and increased as the median follow-up of OS extended longer (see table). Analyses limited to stage III pts and/or trials tested biologics showed consistent results. Conclusions: 3yDFS remains a validated surrogate endpoint for 5yOS in adjuvant trials in CC pts per prespecified criteria. The correlation was strengthened with more than 6 years of follow-up for OS. [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]

PURPOSE To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with resected biliary tract cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of the literature on adjuvant therapy for resected biliary tract cancer and provide recommended care options for this patient population. RESULTS Three phase III randomized controlled trials, one phase II trial, and 16 retrospective studies met the inclusion criteria. RECOMMENDATIONS Based on evidence from a phase III randomized controlled trial, patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months. The dosing used in this trial is described in the qualifying statements, while it should be noted that the dose of capecitabine may also be determined by institutional and regional practices. Patients with extrahepatic cholangiocarcinoma or gallbladder cancer and a microscopically positive surgical resection margin (R1 resection) may be offered chemoradiation therapy. A shared decision-making approach is recommended, considering the risk of harm and potential for benefit associated with radiation therapy for patients with extrahepatic cholangiocarcinoma or gallbladder cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Background: Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN -encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy. Methods: We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap. Results: Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation > 480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events. Conclusion: TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.

AbstractObjectiveTo determine the antenatal sonographic lung area measurement method in left congenital diaphragmatic hernia (CDH) with the highest interrater agreement among North American Fetal Therapy Network (NAFTNet) centers within and outside the fetoscopic tracheal occlusion (FETO) consortium and in comparison with a European “expert” reviewer (ER).MethodsNineteen members from nine FETO consortium centers and 29 reviewers from 17 non‐FETO centers reviewed ultrasound clips of the chest from 13 fetuses with isolated left CDH and were asked to select a static plane for lung area measurement using anteroposterior (AP), longest, and trace methods. Interrater agreement in lung area measurements was determined using intraclass correlation coefficient (ICC). Bland‐Altman analysis was used to evaluate mean difference (bias) between NAFTNet reviewers and ER.ResultsAmong FETO centers, agreement was highest using trace (ICC 0.94; 95% CI, 0.83‐0.98), followed by longest (ICC 0.89; 95% CI, 0.75‐0.97) and lowest for A‐P (ICC 0.83; 95% CI, 0.67‐0.94). Similar trends were noted in non‐FETO centers. When compared with ER, bias was lowest for trace: 14 ± 38 mm2 and 19 ± 36 mm2 for FETO and non‐FETO centers, respectively.ConclusionThe trace method demonstrated the highest interrater agreement and lowest bias for lung area estimation in left CDH across NAFTNet.

728 Background: Adjuvant FOLFOX therapy for stage II patients remains controversial, and selection criteria are imprecise. We examined the trend of disease-free survival (DFS: time to recurrence or death, whichever occurs first); time to recurrence (TTR: time to recurrence, censored at death without recurrence); survival after recurrence (SAR); and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of pts with stage II colon cancer enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated using adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by multivariate Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T stage, number of lymph nodes (LNs) examined, tumor side, and histologic grade. Results: In total, 1,122 pts with stage II were identified; 71% and 29% were treated in the old and new era, respectively. Pts enrolled in the new era were significantly younger and more likely to have higher tumor-grade and right-sided tumors compared to old era. More pts in the new era (71%) had ≥12 LNs examined compared to the old era (53%). After adjusting for potential confounding effects, no difference in DFS, TTR, SAR or OS between old and new eras was found (Table). Although median SAR increased from 13.6 to 26 months over time, this was not statistically significant, likely due to lack of power. An increased TTR over time (HRadj. 0.41, padj.= 0.002) was observed in pts with ≥12 LNs examined (3-yr TTR: 92% in old era vs. 96% in new era), but not pts with <12 LNs examined (pinteraction = 0.04). Conclusions: In stage II colon cancer pts who received adjuvant FOLFOX, no significant increase of DFS or OS was observed over time. However TTR was longer only in pts with ≥12 LNs examined. [Table: see text]

724 Background: Adjuvant FOLFOX is the standard of care for pts with stage III colon cancer and a platform to test new agents. Improvements in supportive care and development of newer treatments for metastatic disease impact the overall outcome of pts treated with adjuvant therapy. We examined the trend of disease-free survival (DFS), survival after recurrence (SAR), and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of colon cancer pts enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated by adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T/N stage, tumor sidedness and histologic grade. Results: In total, 7,230 pts (stage II [n = 1122]; stage III [n = 6,108]) were identified; 32% and 68% were treated in the old and new era, respectively. Stage III pts enrolled in the new era were significantly younger, more likely to have T4/N2 disease, higher tumor grade, and left-sided tumors. After adjusting for pt characteristics, no difference in DFS was seen over time. However prolonged SAR and OS were observed in pts treated in the new era (Table). 5yr OS increased from 76% to 80% over time. Median SAR improved from 14.8 to 26.4 months. Conclusions: Stage III colon cancer pts who received adjuvant FOLFOX experienced significant improvements in SAR and OS—but not DFS—over time. In view of the improvements in OS and nearly doubled SAR, the optimal duration of OS follow-up to evaluate the benefits of adjuvant therapy (currently 5 years) should be reassessed, and ACCENT investigators are planning to conduct these additional analyses using their large pooled-trial database. [Table: see text]

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).