ECOG-ACRIN Cancer Research Group Research Articles

A Pro-Inflammatory Gene Signature Characterizes a Better Risk Aged AML Patient Group in ECOG-ACRIN Cancer Research Group's Clinical Trial E3999

Background: Acute myeloid leukemia in patients over the age of 60 (aAML) is associated with poor prognosis. aAML patients are the majority diagnosed but are underrepresented in large molecular studies. We have identified two clinical subgroups of aAML patients with distinct survival outcomes (low-risk and high-risk) in ECOG-ACRIN Cancer Research Group's clinical trial E3999 (NCT00046930). We hypothesize that these two groups are characterized by distinct biological mechanisms that contribute to leukemogenesis. We also hypothesize that the low-risk group harbor molecular and phenotypic signatures characteristic of known better-risk AMLs. Methods: Diagnostic specimens were obtained from patients enrolled in NCT00046930. Disease enriched cells were isolated by negative selection of lymphocytes (magnetic beads). Flow cytometry was used to characterize the blast population. Bulk RNA-sequencing was performed on 220 blast enriched samples and 10 age matched normal controls (CD34+ bone marrow cells). Transcriptional differences were determined using DESeq2. Differentially expressed genes (DEGs) were identified as those with an absolute log2 fold change greater than 1 and q less than 0.05. Gene set enrichment analysis (GSEA) was performed against the MSigDB databases. Upstream regulators associated with gene expression changes were identified using Ingenuity Pathway Analysis (IPA). DESeq2 was used to identify genes that were differentially associated with overall survival times between the risk groups. Enrichment for transcription factor gene targets was calculated using EnrichR based on the CHEA Transcription Factor Target Dataset. Cytokines were quantified in a subset of patient serum samples using a Luminex assay. Results: We identified 2314 DEGs between the low-risk and high-risk aAMLs with high-risk as the baseline. The upregulated genes in the low-risk aAMLs were positively enriched for gene signatures derived from: 1. Favorable risk AML ( NPM1 mutated), 2. M4 and M5 AML patients, 3. Differentiated hematopoietic cells and 4. Inflammatory response pathways. On the contrary, upregulated genes in the high-risk aAMLs were enriched for gene signatures identified in hematopoietic and leukemic stem cells and known poor-risk AMLs (for example: EVI1 fusion). Accordingly, immunophenotypic data from flow cytometry results gated on the blast populations validated differences in the surface expression of hematopoietic cell markers between the two groups. Next, we sought to determine upstream regulators associated with the DEGs using IPA. We identified 107 potential upstream regulators that associated with the changes in gene expression observed between the low- and high-risk groups (87 activated and 20 inhibited). The results suggested that several pro-inflammatory cytokines (ex. tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ)) were predicted activators in the low-risk aAML group. Accordingly, we detected significantly higher levels of TNFα and IFNγ in the serum levels of a subset of low-risk aAML patients. Finally, we assessed for genes whose expression significantly associated with overall survival. Interestingly, in agreement with a previously proposed inflammation score (iScore), we identified higher iScore associated with the high-risk group. Of note, the upstream regulators identified do not overlap with those contributing to the calculation of iScore. Additionally, longer overall survival times were associated with higher levels of expression of genes associated with heme metabolism and erythroblast differentiation in the low-risk aAML patient group. Conclusions: Our results suggest that the low-risk aAML patients were characterized by a more mature hematopoietic cell gene expression signature and cell surface markers as well as a pro-inflammatory state. Our study supports the possibility that pro-inflammatory cytokines and/or signaling could mediate AML cell survival in the low-risk aAML patient group. The high-risk aAML patients were characterized by a more primitive hematopoietic and leukemic stem cell gene expression signature. Collectively, we propose that differences in the underlying molecular and/or immune-based mechanisms could contribute to leukemogenesis in the two risk groups. These findings suggest that distinct therapeutic approaches may need to be considered to improve clinical outcomes in the two aAML risk groups.

The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.

Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer. A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression. A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR],3.57; 95% CI, 1.69-7.54; p=.0009), and more likely to report being asked about smoking (OR,4.24; 95% CI, 1.64-10.98; p=.0029), but less likely to report receiving counseling (OR,0.11; 95% CI, 0.02-0.58; p=.0086) versus those in the least disadvantaged neighborhoods. Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Outcomes by time to adjuvant therapy in E3311, a phase II trial of transoral surgery (TOS) followed by pathology-based adjuvant treatment in HPV-associated (HPV+) oropharynx cancer (OPC): A trial of the ECOG-ACRIN Cancer Research Group.

6036 Background: E3311 is a phase II randomized study of intermediate risk HPV+ OPC patients who underwent TOS by credentialed surgeons and were then treated by pathology-guided, deintensified post-operative treatment. Recent retrospective population data suggest that time to post-operative radiotherapy (PORT) > 6 weeks is associated with worse progression-free survival (PFS). Methods: We retrospectively analyzed demographics, pathologic characteristics, and oncologic outcomes in E3311 by time to initiation of PORT (short vs long, exploring both 6 and 7 weeks postop as the cutpoint). Binary and categorical variables were compared using a chi-square test (or a Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. PFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test, which was stratified by intermediate- (Arms B/C) vs high-risk (Arm D). Results: Among 321 evaluable patients, the median time to initiation of PORT was 5.1 weeks (range 0.7-15.7); 5.0 (0.7-15.7) for Arm B, 5.1 (2.4-7.0) for Arm C, 5.6 (3.6-7.9) for Arm D. No significant difference in PFS or OS was observed whether PORT commenced by 6 or 7 weeks postoperatively, compared with longer time to initiation of PORT (p = 0.62 and 0.65, p = 0.30 and p = 0.41, respectively). 3-yr PFS rates were 93.5% (95% CI: 89.4%, 96.0%) among those treated ≤6 weeks, and 91.2% (95% CI: 81.4%, 95.9%) among those treated > 6 weeks; 3-yr OS rates were 96.1% (95% CI: 92.7%, 98.0%) among those treated ≤6 weeks, and 94.1% (95% CI: 84.9%, 97.8%) among those treated > 6 weeks. No significant differences in outcomes were observed between intermediate risk treatment arms (deintensified (50Gy) or standard dose (60Gy) RT). Additional demographic and pathologic characteristics, including primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between those with short vs long time to PORT, whether 6 or 7 weeks was used as the cutpoint. There were more T2 tumors in those treated > 7 weeks postop (84% vs. 49%, p = 0.007). PS = 1 patients were more numerous among those with shorter time to PORT (10% vs 0%, with the 7 week cutpoint). Conclusions: In contrast to retrospective NCDB data, intermediate- and high-risk HPV+ OPC patients enrolled on E3311 had favorable 3-yr PFS and OS rates that were not significantly worse when adjuvant therapy was started > 6 wks or > 7wks. These results argue against a survival advantage for initiation of PORT within 6 or 7 weeks for early-stage HPV+ OPC managed with high-quality transoral resection. The optimal time window to initiate PORT in HPV+ OPC patients remains to be determined. Clinical trial information: NCT01898494 .

Screening for extranodal extension in HPV-associated oropharyngeal carcinoma: evaluation of a CT-based deep learning algorithm in patient data from a multicentre, randomised de-escalation trial

Pretreatment identification of pathological extranodal extension (ENE) would guide therapy de-escalation strategies for in human papillomavirus (HPV)-associated oropharyngeal carcinoma but is diagnostically challenging. ECOG-ACRIN Cancer Research Group E3311 was a multicentre trial wherein patients with HPV-associated oropharyngeal carcinoma were treated surgically and assigned to a pathological risk-based adjuvant strategy of observation, radiation, or concurrent chemoradiation. Despite protocol exclusion of patients with overt radiographic ENE, more than 30% had pathological ENE and required postoperative chemoradiation. We aimed to evaluate a CT-based deep learning algorithm for prediction of ENE in E3311, a diagnostically challenging cohort wherein algorithm use would be impactful in guiding decision-making. For this retrospective evaluation of deep learning algorithm performance, we obtained pretreatment CTs and corresponding surgical pathology reports from the multicentre, randomised de-escalation trial E3311. All enrolled patients on E3311 required pretreatment and diagnostic head and neck imaging; patients with radiographically overt ENE were excluded per study protocol. The lymph node with largest short-axis diameter and up to two additional nodes were segmented on each scan and annotated for ENE per pathology reports. Deep learning algorithm performance for ENE prediction was compared with four board-certified head and neck radiologists. The primary endpoint was the area under the curve (AUC) of the receiver operating characteristic. From 178 collected scans, 313 nodes were annotated: 71 (23%) with ENE in general, 39 (13%) with ENE larger than 1 mm ENE. The deep learning algorithm AUC for ENE classification was 0·86 (95% CI 0·82-0·90), outperforming all readers (p<0·0001 for each). Among radiologists, there was high variability in specificity (43-86%) and sensitivity (45-96%) with poor inter-reader agreement (κ 0·32). Matching the algorithm specificity to that of the reader with highest AUC (R2, false positive rate 22%) yielded improved sensitivity to 75% (+ 13%). Setting the algorithm false positive rate to 30% yielded 90% sensitivity. The algorithm showed improved performance compared with radiologists for ENE larger than 1 mm (p<0·0001) and in nodes with short-axis diameter 1 cm or larger. The deep learning algorithm outperformed experts in predicting pathological ENE on a challenging cohort of patients with HPV-associated oropharyngeal carcinoma from a randomised clinical trial. Deep learning algorithms should be evaluated prospectively as a treatment selection tool. ECOG-ACRIN Cancer Research Group and the National Cancer Institute of the US National Institutes of Health.

Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292)

BackgroundStudies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer.Patients and Methods This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes’ B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes’ B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes’ B2 colon cancer with no additional chemotherapy.ResultsFrom August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03–20.3 years). Among patients with Dukes’ B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes’ B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

Screening for Extranodal Extension with Deep Learning: Evaluation in ECOG-ACRIN E3311, a Randomized De-Escalation Trial for HPV-Associated Oropharyngeal Carcinoma

<h3>Purpose/Objective(s)</h3> Treatment for HPV-associated oropharyngeal carcinoma (HPV-OPC) is associated with excellent disease control, but high treatment-related morbidity, leading to interest in de-escalation strategies. ECOG-ACRIN Cancer Research Group E3311 is a Phase II trial wherein HPV-OPC patients were treated with transoral robotic surgery and randomized postoperatively to de-escalated radiotherapy, so long as they lacked high-risk pathologic criteria, including macroscopic (>1 mm) extranodal extension (ENE). The protocol excluded patients with radiographic or clinically matted nodes, yet >30% of enrollees demonstrated ENE and required adjuvant chemoradiation. In prior work, we developed and validated a deep learning algorithm (DLA) to predict pathologic ENE based on diagnostic computed tomography (CT). We hypothesized that DLA could generalize to the HPV-OPC E3311 patient population, a diagnostically challenging cohort where use could be particularly impactful. <h3>Materials/Methods</h3> We obtained pretreatment CTs and corresponding surgical pathology reports from E3311 as available. The lymph node with largest short-axis diameter (SAD) and up to two additional nodes were segmented on each scan and annotated for ENE based on pathology reports. DLA performance for ENE prediction was compared directly to four board-certified head and neck radiologists (R1-4) who were provided with a validated educational tool to help diagnose ENE. Primary endpoint was area under the receiver operating characteristic curve (AUC), compared via the Delong method. Secondary measures were sensitivity (1 - false negative rate) and specificity (1 - false positive rate (FPR)). Interrater agreement was evaluated with Fleiss Kappa. <h3>Results</h3> From 177 collected scans, 311 lymph nodes were annotated: 71 (23%) with ENE, 39 (13%) with >1 mm ENE. Of nodes, 202 (65%) had SAD ≥1 cm. DLA AUC for ENE classification was .85 [95%CI: .80 - .89], outperforming R1-4 (Table, P<.001 for each). Reader specificity and sensitivity showed high variability with poor interrater agreement (Table, Kappa: 0.28). Matching DLA specificity to that of the reader with highest AUC (R2) (FPR<22%) yielded improved sensitivity to 75% (+13%). Setting DLA FPR to <30% yielded sensitivity of 87% (Table). DLA also showed improved performance versus R1-4 for >1 mm ENE (AUC: .85 [95%CI: .80 - .89] vs mean 0.68 [95%CI: .62 - .74], P<.001) and for nodes with SAD ≥1 cm (AUC: .74 [95%CI: .67 - .81]) vs mean AUC: .58 [95%CI: .55 - .62], P<.001). <h3>Conclusion</h3> DLA showed high performance in predicting pathologic microscopic and macroscopic ENE on a challenging cohort of patients with HPV-OPC from a prospective clinical trial, substantially outperforming expert head and neck radiologists from tertiary care centers. DLA should be evaluated in a clinical trial with the goal of reducing trimodality therapy.

Reduced Aspiration Rates for 50 Gy Postoperative Radiation in HPV-Associated Oropharynx Cancer in E3311: A Trial of the ECOG-ACRIN Cancer Research Group

<h3>Purpose/Objective(s)</h3> E3311 was a Phase II randomized trial that demonstrated excellent disease control (95% PFS) after primary transoral surgery (TOS) with de-escalated postoperative radiotherapy (RT) for intermediate risk HPV associated oropharyngeal cancer (OPC). De-escalation of postoperative RT to 50 Gy was largely motivated by the need to improve functional outcomes. Our objective was to explore over time and across arms: 1) aspiration rates per modified barium swallow (MBS) studies as reported by site clinicians, and 2) accuracy of site reporting against central review of MBS images. <h3>Materials/Methods</h3> 495 patients underwent TOS. MBS was included as an optional procedure in 316 patients from 50 of 59 sites at baseline, post-TOS, 6- and 24-months. Aspiration by site clinicians' MBS reading was logged in the trial database. MBS images were also centrally reviewed at MD Anderson Cancer Center using Penetration-Aspiration Scale criteria. Exploratory post hoc analyses compared aspiration rates baseline to post-TOS in all patients using McNemar's test, and between all arms at the post-TOS time point and between the two randomized arms at 6 and 24 months using Fisher's exact test. Kappa assessed agreement of site clinicians and central review. <h3>Results</h3> Pooling all arms, aspiration was reported at baseline in 2.4% of MBS studies increasing to 13.3% after TOS (p < 0.01), then decreasing to 10.8% and 9.0% at 6-months and 24-months, respectively. Post-TOS aspiration rates did not significantly differ between all arms (p = 0.97). After RT, aspiration rates were significantly different at 6 months (p=0.04) but not at 24 months between randomized arms. In a subset of 62 MBS, site clinicians demonstrated substantial reliability grading aspiration on MBS in comparison to central review (92% exact agreement; <i>k</i> = 0.62, 95% CI: 0.32-0.92). <h3>Conclusion</h3> Using a standardized MBS protocol, site clinicians reported aspiration with high accuracy relative to central image review. Aspiration rates were low overall, increasing significantly after TOS. De-escalated radiotherapy was associated with significantly lower aspiration rates at 6 months, not maintained at 24 months.

238 (PB118) - Phase II study of sunitinib in tumors with c-KIT mutations: results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocol V

Background: KIT mutations are common in gastrointestinal stromal tumors (GISTs) but are also found to a lesser degree in other tumor types such as mucosal melanomas, testicular seminomas or dysgerminomas. The NCI-MATCH study is a tumor agnostic platform trial enrolling patients to targeted therapies based on genomic alterations. Subprotocol V of the NCI-MATCH platform trial investigated sunitinib in patients with tumors harboring c-KIT mutations. Material & Methods: EAY131-V, is an open-label, single arm, phase 2 study. Eligible patients were those with a somatic c-KIT mutation on exons 9, 11, 13, and 14. Exclusions were mutations on exons 17, 18 which are reported to have resistance to sunitinib. Excluded tumor types were GIST, renal cell carcinoma, and pancreatic neuroendocrine tumors which have a known response to sunitinib. Patients received sunitinib 50 mg orally daily for 4 weeks with 2-week rest, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival (PFS) at 6 months, PFS, and toxicities. Results: Between November 1, 2016, and May 21, 2020, 10 patients were enrolled, 9 were analyzable. Median age was 62 years (range 30–76), 77.8% received 2 lines of systemic therapy, while 22.2% received >3 lines. The most common tumor type was melanoma (44%), followed by squamous cell carcinoma of the lung or thymus (33%). There were 2 partial responses (PRs), both in squamous cell carcinomas, with an ORR of 22.2% (90% CI 4.1%–55%) and stable disease in 44%. Estimated 6-month PFS was 33.3% (90% CI 15.4%–72.4%). The 2 PRs had a PFS of 8 months and 10.8 months, respectively. Grade 3–4 toxicities at least possibly related to treatment occurred in 5 patients and included a thromboembolic event (n = 1), skin infections (n = 2), and lymphopenia (n = 2). This arm of the study was closed in 2022 based on low accrual, despite an amendment for additional actionable mutations. Prevalence of eligible c-KIT mutations after screening 5540 patients was estimated at 0.13%. Conclusions: In this study, sunitinib monotherapy for c-KIT mutations did not meet the primary endpoint for response, but in this small sample size a potential signal cannot be ruled out. Estimated rates of c-KIT mutations was lower than expected, impacting accrual to this arm. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180820, U10CA180794, UG1CA233302, UG1CA233180, UG1CA233341, and UG1CA189869. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. No conflict of interest.

Outcomes by tobacco history in E3311, a phase II trial of transoral surgery (TOS) followed by pathology-based adjuvant treatment in HPV-associated (HPV+) oropharynx cancer (OPC): A trial of the ECOG-ACRIN Cancer Research Group.

6077 Background: E3311 is a phase II randomized study which showed favorable outcomes among intermediate (INT) risk HPV+ OPC patients (pts) who underwent TOS followed by pathology-guided or adapted, deintensified adjuvant treatment. Among HPV+ pts treated with definitive chemoradiation, survival outcomes are worse among those who smoked &gt; 10 pack years (pk-yrs). Methods: We retrospectively analyzed demographics, pathologic results, and efficacy outcomes from E3311 by smoking group (current (C) vs. former (F) and &gt; 10 vs. ≤10 pk-yrs – the latter a pre-specified stratification factor for INT patients). Binary and categorical variables were compared using a chi-square test (or Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test. Results: Among 359 evaluable pts, performance status (PS) was significantly worse for pts with &gt; 10 pk-yrs vs. ≤10 pk-yrs (15.4% vs. 7.9% with PS of 1, p = 0.034). Primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between the groups of &gt; 10 vs. ≤10 pk-yrs. Smoking status (F vs. C) was available for 182 pts with a history of smoking. Slightly more C vs. F smokers had tonsil as primary site (79.5% vs. 65.0%, p = 0.09). Positive margins were significantly more frequent among C smokers (10.3% vs. 2.1%; p = 0.029). Overall, there were no significant differences in PFS (p = 0.55) or OS (p = 0.94), comparing those with &gt; 10 vs. ≤10 pk-yrs, or comparing C vs. F smokers (p = 0.76, p = 0.82, respectively). Similarly, no significant differences were observed within the treatment arms. (Table 1) Conclusions: In this analysis of smoking status in E3311, INT risk HPV+ OPC pts who are C smokers or have a history of &gt; 10 pk-yrs had favorable 3-yr PFS and OS rates that were not significantly worse than those with &lt; 10 pk-yrs history. This data represents the first treatment approach for HPV+ OPC in which outcomes were not influenced by smoking status. Clinical trial information: NCT01898494. [Table: see text]

Association between state Medicaid policies and accrual of Black participants to cancer clinical trials.

1501 Background: Black individuals remain underrepresented in U.S. cancer clinical trials, partly due to financial barriers to participation. While coverage of the routine costs of trial participation has long been mandatory for Medicare and the commercially insured, only 16 states have enacted similar mandates for Medicaid enrollees. Given the disproportionate representation of Black individuals in state Medicaid programs, we hypothesized that such mandates may have led to improved accrual of Black participants to cancer clinical trials. Methods: We conducted a retrospective, quasi-experimental study using de-identified data from the ECOG-ACRIN Cancer Research Group to evaluate changes in the accrual of Black participants to cancer clinical trials associated with state-mandated Medicaid coverage of routine trial costs. The study population included non-elderly adults enrolled in therapeutic clinical trials for breast, colorectal, lung, or prostate cancer from 2000-2019. We employed a difference-in-differences approach with event-study specification to compare outcomes in states that mandated Medicaid coverage of routine trial costs relative to states that did not, before and after mandates were enacted. Outcomes included the proportion of trial participants who had Medicaid insurance (vs. non-Medicaid) and the proportion who were Black (vs. non-Black). Models adjusted for age, sex, cancer type, cancer stage, study phase, and study site (community vs. academic). Results: Among 24,321 trial participants (mean age 52.0 [SD 8.2] years, 82.8% female), 7.2% had Medicaid coverage and 10.5% were Black. Compared to states without Medicaid coverage mandates, states with mandates had a statistically significant increase in the proportion of Black trial participants in the first year following the mandate (+6.4 percentage points [95%CI 1.8% to 11.0%]) but not in subsequent years. There was no association between state mandates and the proportion of trial participants enrolled in Medicaid (effects ranged from -0.7 percentage points [95%CI -4.6% to 3.3%] in the first year after mandates to -3.9% [95%CI -8.6% to 0.8%] in the third year). Conclusions: State-mandated Medicaid coverage of the routine costs of trial participation was associated with a short-term increase in the proportion of Black trial participants. These findings suggest that Medicaid policies have the potential to improve representation of racial minority groups in cancer clinical trials, and support recent federal legislation mandating state Medicaid programs to cover trial participation costs as of January 2022. Our study was limited by use of data from only one large cancer research group, focus on only four common cancers, and limited power to analyze the policy impact for other racial and ethnic minority groups. Additional work is needed to replicate these findings in larger cohorts of trial participants.

Association Between Surgery Preference and Receipt in Ductal Carcinoma In Situ After Breast Magnetic Resonance Imaging

Guiding treatment decisions for women with ductal carcinoma in situ (DCIS) requires understanding patient preferences and the influence of preoperative magnetic resonance imaging (MRI) and surgeon recommendation. To identify factors associated with surgery preference and surgery receipt among a prospective cohort of women with newly diagnosed DCIS. A prospective cohort study was conducted at 75 participating institutions, including community practices and academic centers, across the US between March 25, 2015, and April 27, 2016. Data were analyzed from August 2 to September 24, 2021. This was an ancillary study of the ECOG-ACRIN Cancer Research Group (E4112). Women with recently diagnosed unilateral DCIS who were eligible for wide local excision and had a diagnostic mammogram within 3 months of study registration were included. Participants who had documented surgery and completed the baseline patient-reported outcome questionnaires were included in this substudy. Women received preoperative MRI and surgeon consultation and then underwent wide local excision or mastectomy. Participants will be followed up for recurrence and overall survival for 10 years from the date of surgery. Patient-reported outcome questionnaires assessed treatment goals and concerns and surgery preference before MRI and after MRI and surgeon consultation. Of the 368 participants enrolled 316 (86%) were included in this substudy (median [range] age, 59.5 [34-87] years; 45 women [14%] were Black; 245 [78%] were White; and 26 [8%] were of other race). Pre-MRI, age (odds ratio [OR] per 5-year increment, 0.45; 95% CI, 0.26-0.80; P = .007) and the importance of keeping one's breast (OR, 0.48; 95% CI, 0.31-0.72; P < .001) vs removal of the breast for peace of mind (OR, 1.35; 95% CI, 1.04-1.76; P = .03) were associated with surgery preference for mastectomy. After MRI and surgeon consultation, MRI upstaging (48 of 316 [15%]) was associated with patient preference for mastectomy (OR, 8.09; 95% CI, 2.51-26.06; P < .001). The 2 variables with the highest ORs for initial receipt of mastectomy were MRI upstaging (OR, 12.08; 95% CI, 4.34-33.61; P < .001) and surgeon recommendation (OR, 4.85; 95% CI, 1.99-11.83; P < .001). In this cohort study, change in patient preference for DCIS surgery and surgery received were responsive to MRI results and surgeon recommendation. These data highlight the importance of ensuring adequate information and ongoing communication about the clinical significance of MRI findings and the benefits and risks of available treatment options.

Quality of Life in Patients

Background: The ECOG-ACRIN randomized phase 3 clinical trial E1912 established ibrutinib-rituximab (IR) as the standard of care for CLL patients <= 70 years in the frontline setting by improving the progression free (PFS) and overall survival (OS) compared to previous standard chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) (Shanafelt et al. NEJM 2019). Quality of life (QOL) was an important secondary endpoint on this trial comparing continuous (IR) vs time-limited (FCR) therapy due to the differing profile of treatment-related toxicities over the short and long-term. E1912 patient-reported outcomes (PROs) results are presented here.Methods: Patients enrolled on E1912 completed the Functional Assessment of Cancer Therapy-General (FACT-G) and Leukemia subscale at randomization (baseline), 3, 6, and 12 months post-randomization, and every 6 months for 2 years regardless of disease status. The primary outcome was the 31-item FACT-Leukemia Trial Outcome Index (FACT-Leu TOI), calculated by summing items from the FACT-G physical wellbeing (PWB), functional well-being (FWB), and leukemia subscales (score range: 0-124). The primary endpoint was defined as the difference in FACT-Leu TOI change scores from randomization to 12 months (at response evaluation) between patients treated with continuous therapy Arm A (IR) vs time-limited therapy Arm B (FCR). Mean change scores from baseline to each time point were calculated using all cases with data at baseline and the corresponding time point. Comparisons between treatment arms were performed using two-sample t tests. Linear mixed effects models were used to estimate the trajectories of PRO scores.Results: PRO data was extracted on 3/8/2021. PRO data was provided at baseline and 12 months for 233/354 (65.8%) patients on the IR arm and 118/175 (67.4%) patients on the FCR arm. At enrollment, there were no significant differences in the baseline FACT-Leu TOI scores (mean ± SE) between the two arms: IR (93.27 ± 1.03) vs FCR (92.68 ± 1.38; p=0.73). The FACT-Leu TOI score improved from baseline to 12 months in both arms (Table 1 and Figure 1). The change scores from baseline to 12 months, the primary outcome, were not significantly different between IR (7.59 ± 1.09) vs FCR (8.22 ± 1.44; p=0.73). Change in FACT-Leu TOI from baseline to 3 months was 5.77 ± 0.77 and 4.06 ± 1.18 (p=0.22); and from baseline to 6 months was 6.87 ± 0.87 and 8.01 ± 1.44 (p=0.50) in the IR and FCR arms, respectively.After the first 6 months of treatment, the improvement in FACT-Leu TOI scores was maintained in both treatment arms. There was no significant difference in total FACT-Leu TOI score in the continuous therapy (IR) vs time-limited therapy (FCR) arms over the first 36 months post registration.Analysis of FACT subscales showed PWB improved in the IR arm (0.37 ± 0.22) and declined in the FCR arm (-0.92 ± 0.39) from baseline to 3 months (p=0.004 for difference in PWB change between arms) but there was no significant difference between the two arms for change in PWB scores from baseline to 6 and 12 months. There were no significant differences between the two arms for change in FWB and FACT-Leu subscales from baseline to 3, 6 and 12 months.Conclusions: QOL improves in CLL patients age 70 and younger when treated in the frontline setting with IR or FCR. The improvement in QOL is maintained during continuous therapy with ibrutinib and there is no significant decline in QOL over time. Given the improvement in PFS and OS with IR over FCR seen in E1912, the results of this QOL analysis support the use of frontline ibrutinib in previously untreated younger CLL patients.Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180794, U10CA180820, UG1CA189863, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233230, UG1CA233253, UG1CA233277, UG1CA233290, UG1CA233339, UG1CA189859, UG1CA233332. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. [Display omitted] DisclosuresKay: Oncotracker: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Coutre: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Other: Data Safety Monitoring Committee, Research Funding. Barr: AstraZeneca: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Abbvie/Pharmacyclics: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Mato: Adaptive Biotechnologies: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; Janssen: Consultancy, Research Funding; Genmab: Research Funding. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau. Stone: Onconova: Consultancy; AbbVie: Consultancy; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Takeda: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Innate: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Litzow: Actinium: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Tallman: NYU Grand Rounds: Honoraria; Kura: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Shanafelt: Genentech, Pharmacyclics: Research Funding. Wagner: Eli Lilly, Johnson & Johnson: Other: Spouse, previously held individual stocks;; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Athenex Inc: Consultancy.

A 3-Arm Randomized Phase II Trial with Bendamustine/Rituximab Therapy in Untreated High Risk (HR) Follicular Lymphoma (FL): Bortezomib Induction or Novel IMiD® Continuation (BIONIC) Study from the ECOG-ACRIN Cancer Research Group

Background: The BIONIC study tested whether bortezomib (V) improved the complete remission (CR) rate when added to standard bendamustine/rituximab (BR) induction in untreated high risk (HR) FL and whether lenalidomide (Len) integrated as “continuation” treatment (Tx) given concurrently with maintenance rituximab (MR) enhanced remission duration vs MR alone.Methods: Study eligibility included: ages ≥18 years; untreated; HR disease; and grade I/II or IIIa FL with the latter determined by central pathologic review (NCT01685008). HR disease was defined as high tumor burden by GELF and/or FLIPI score 3-5. Pts were randomized to 1 of 3 arms in a 1:2:2 ratio (stratified by FLIPI & GELF): a) BR induction x 6 followed by MR q 2 months x 2 years (BR-R) vs b) BVR induction x 6 (V: 1.3 mg/m2 IV/SQ days 1, 4, 8, 11) followed by MR q 2 months x 2 years (BVR-R) vs c) BR x 6 followed by q 2 months MR x 2 years + Len 20 mg/day (21/28 days) continuation x 1 year (BR-LR). Initial plans were to enroll 250 pts; due to a high non-enrollment rate to the continuation/maintenance phase of Tx (ie, 10% BR-R arm, 22% of BVR-R, and 26% BR-LR arm), an additional 36 pts were randomized to the BR+R vs BR+LR arms to preserve study power. In these study arms, 54, 66, and 83 FL pts, respectively, received post-induction Tx. Response was assessed by 2007 IWG criteria with PET/CT. The 1st primary objective was previously presented (ie, CR rate BVR 74% vs 59% two BR induction arms combined, P=0.008, Evens et al ASCO 2016). We report here on all study endpoints, including the 2nd primary objective of 1-year disease-free survival (DFS) with Len continuation Tx (ie, BR-LR vs standard BR-R) as well as progression-free survival (PFS), overall survival (OS), and safety/tolerability across all Tx arms & phases of Tx.Results: The study enrolled from 1/2011 to 5/2015 with a final accrual of 289 pts. 30 pts were excluded for never starting study Tx (n=9), ineligibility (n=5), and central pathology review (n=16), yielding 257 evaluable pts (ie, BR-R n=60; BVR-R n=85; BR-LR n=112). Among all pts, median age was 61 years (24-89); GELF was high in 91%; FLIPI 3-5 in 57%; ECOG PS: 0=56%, 1=42%, and 2=2%; B symptoms present 28%; marrow involvement 59%; >1 extranodal site 27%; and stages IIB 7%, III 27% and IV 66%. For induction Tx received, 88%, 87%, and 78%, respectively, of pts randomized to the BR-R vs BVR-R vs BR-LR arms received all 6 planned cycles. CR rates for induction Tx by were 71%, 74%, and 55%, respectively. Collectively, the 1-year DFS results suggested no added benefit from lenalidomide (details to be presented at meeting). With a median follow-up of 3.95 years, the median PFS has not been reached in any arm. Among the first 250 pts enrolled, 3-year PFS rates for BR-R vs BVR-R vs BR-LR Tx arms were 76% vs 81% vs 74%, respectively, P=0.49 (see Figure 1A); the 3-year PFS rates including the additional 36 enrolled pts were nearly identical. The most common grade 3/4 AEs among pts randomized to Len-R continuation vs MR were: neutropenia 66% vs 20% (P <0.0001); febrile neutropenia 10% vs 2% (P=0.05); anemia 6% vs 0 (P=0.08); fatigue 6% vs 2% (P=0.40); and pneumonia 6% vs 2% (P=0.40). Of patients assigned to Len-R, 59% had dose reductions of Len, most due to an adverse event (AE). When comparing Len-R continuation vs MR, 17% vs 6% of pts (P=0.06), respectively, came off continuation/maintenance Tx due to AE/toxicity. By study arm, rates of all 2nd cancers (including skin) were 6%, 9%, and 8% for BR-R, BVR-R and BR-LR, respectively (P=0.45); non-melanoma skin cancer rates were 2% on each arm. Overall, there were 34 deaths on study, including 7 grade 5 lethal events (2.7%). Of the latter, 4 (1.4%) were possibly related to Tx with 1 occurring during induction, 2 during maintenance, and 1 post-maintenance off study. The corresponding 3-year OS rates for all pts treated in the BR-R vs BVR-R vs BR-LR arms were 87% vs 90% vs 84%, respectively, P=0.37 (see Figure 1B).Conclusions: The BIONIC study showed that Tx with standard BR induction followed by MR was safe in HR FL. The addition of V to BR induction enhanced the CR rate, but did not translate into improved PFS. Additionally, Len continuation Tx as prescribed in this study was associated with increased toxicity vs MR, while yielding similar PFS and OS vs BR-R treated pts. Based upon these results, neither V added to BR induction nor Len added to MR following BR induction can be recommended in FL. Quality of life analyses as well as detailed imaging and correlative biomarker studies are underway. [Display omitted] DisclosuresEvens:AbbVie: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Kite Pharma: Consultancy; Affimed: Consultancy; Seattle Genetics: Consultancy; Amgen: Consultancy; • Spectrum Pharmaceuticals: Consultancy. Advani:Bayer Healthcare Pharmaceuticals: Research Funding; Sutro: Consultancy; Nanostring: Consultancy; Infinity: Research Funding; Regeneron: Research Funding; Merck: Research Funding; Juno Therapeutics: Consultancy; Janssen: Research Funding; Kura: Research Funding; Millennium: Research Funding; Spectrum: Consultancy; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Research Funding; Pharmacyclics: Consultancy; Gilead: Consultancy; Agensys: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; FortySeven: Research Funding; Cell Medica: Research Funding. Witzig:Kura: Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Winter:Glaxo-Smith-Kline: Research Funding; Merck: Research Funding. Kahl:Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy; Genentech: Consultancy.

Genomic Landscapes in Elderly AML

Acute Myeloid Leukemia (AML) in patients over the age of 60 (elderly AML) remains a clinical challenge. Despite advances in the field, outcomes for elderly AML patients remains poor regardless of treatment administered. We hypothesize that elderly AML is characterized by the acquisition of somatic mutations that enhance leukemogenic potential and associate with worse clinical outcomes. To test this hypothesis, we determined the landscape of somatic mutations in de novo AML patient samples from the phase III prospective ECOG-ACRIN Cancer Research Group clinical trial 3999 (E3999; NCT00046930; ages 60-93). DNA was isolated from patient specimens processed to isolate blast-enriched cells (CD3 and CD19 depletion using Miltenyi magnetic beads) and patient-matched CD3-positive cells (flow cytometry) as germline controls. Exome capture was performed in paired disease and germline samples from 210 patients. Samples were sequenced on a HiSeq 2500 obtaining a median coverage of 150x bases per position. Low-coverage whole genome sequencing was used to identify copy number alterations (CNAs) in 202 of the samples. Indexed Illumina libraries were sequenced to a coverage of approximately 3 million reads per sample.The Cancer Genome Project pipeline guidelines were utilized to determine somatic mutation events in the whole exome data. We aligned the reads with BWA mem, determined somatic copy number aberrations using CNVKit, short insertions and deletions (including FLT3 Internal Tandem Duplication) using Pindel, and substitutions using CaVEMan. We then used classical heuristics including strand bias, mapping quality and high rate of presence in the ExAC database to remove artifacts and non-somatic variants. Finally, we used COSMIC and published data in the literature to triage events into known oncogenic events, unknown but likely oncogenic events and variants of unknown significance. CNAs were determined from the whole genome sequencing data by partitioning the human genome into 60 thousands bins (i.e. resolution of 50kb) and counting uniquely mapped reads within the genomic bins/intervals. Read counts within bins were subsequently processed and transformed into integer copy number states.We found a range of 1 to 37 mutational events per sample (median of 15), including 0 to 7 oncogenic or likely oncogenic events (median of 2). Most commonly mutated genes were NPM1 (25.7%); epigenetic modifier genes: TET2 (24.7%), DNMT3A (20.5%), ASXL1 (12.9%), and IDH2 (11.4%); FLT3 (20%); spliceosome complex genes: SRSF2 (19.5%), U2AF1 (10%) and STAG2 (10%); RUNX1 (15.7%); TP53 (12.4%), and NRAS (11.9%). Comparing our AML cohort to the mutation landscape reported by Papaemmanuil et. al., NEJM 2016 (age range: 18 to 84 years), we found that the elderly group was enriched in oncogenic mutations in the SRSF2, TET2, U2AF1 and ASXL1 and depleted for IDH1 and FLT3 (Fisher exact test adjusted p-value <0.05) genes. Furthermore, the elderly AML patient cohort was enriched in spliceosome/cohesin modifier and TP53-complex karyotype subtypes (Fisher exact test: p<2.8*10^-8 and p<10^-5 respectively).Detailed analyses of the mutational spectra in the E3999 clinical trial suggests enrichment for mutations in epigenetic modifiers, spliceosome factors, and cytogenetic events associated with poor prognosis in AML. These may be underlying the aggressive phenotype in this age range and contribute to disease pathogenesis.Authors contributed equally: Ari Melnick and Ross LevineCo-corresponding authors: Maria Kleppe and Francine E. Garrett-Bakelman DisclosuresLowe:Mirimus Inc.: Consultancy. Neuberg:Synta Pharmaceuticals: Other: Stock shares. Levine:Roche: Research Funding; Roche: Research Funding; Qiagen: Equity Ownership; Celgene: Research Funding; Celgene: Research Funding; Qiagen: Equity Ownership.

Targeted Deep Sequencing in Untreated Progressive CLL Helps to Better Dissect the Genomic Landscape and Shows Novel Associations between Mutations, Prognostic and Clinical Parameters: Data from E1912, a Randomized Phase III Study of the ECOG-ACRIN Cancer Research Group

Next-generation sequencing studies have significantly improved our understanding of the chronic lymphocytic leukemia (CLL) genetic landscape, tumor architecture and allowed the identification of associations between specific mutations and clinical outcome. Hence, mutations in TP53, NOTCH1, SF3B1, BIRC3, EGR2 and MYD88 are known to be associated with differential prognosis. Despite the work performed on these genes, several additional putative tumor-driver genes are recurrently mutated in CLL, but their clinical impact remains unclear.In order to gain further understanding, we performed targeted deep sequencing in baseline samples of a large CLL cohort (n=436) participating in the North American Intergroup study (NAIG) designated as E1912 and led by ECOG. This trial is a randomized Phase III of Ibrutinib (Ibr) and Rituximab (R) vs FCR in previously untreated CLL. We screened 25 putative driver genes recurrently mutated in CLL, and 2 genes (BTK and PLCG2) associated with Ibr resistance. The CD5+/CD19+ B lymphocyte population was flow-sorted. All coding regions were amplified using customized oligos. Samples were run on an IonTorrent sequencer. Variants were called using IonTorrent Somatic VariantCaller. VCF files were annotated using BioR. Somatic variants with a Mapping Quality <20 or read depth <10X were removed. Variants of interest were inspected using IGV. The mutational status was analyzed for association with FISH, IGHV mutation status, expression of CD38, CD49d and ZAP70 (all 3 determined at entry to the trial). We were not able to evaluate associations to clinical responses for the different arms as this trial remains blinded for clinical outcome until 2018.Deep sequencing allowed us to analyze the CLL genomics landscape in more detail. An average coverage of 970X depth was obtained, detecting 35% of mutations in minor subclones (<10% of reads). Therefore, mutation rates for most genes were higher than previous published whole exome and whole genome sequencing studies. Overall, 350 (80%) patients (pts) carried at least one putative driver gene mutated, 205 (47%) carried 2 or more and 89 (20%) 3 or more mutated genes (range 0-7). The most commonly mutated gene was NOTCH1 (22%), followed by SF3B1 (20%), ATM (18%), BIRC3 (11%), XPO1 (10%) and POT1 (9%). Mutations in the RAS pathway were found in 13% of cases (KRAS 7%, BRAF 6%, NRAS 2%). Overall, 25% of cases with activating mutations in the RAS pathway (BRAF, KRAS, NRAS), showed >1 mutation affecting one or more genes of this pathway (range 2-5 mutations). Multiple mutations affecting the same gene (>2 mutations in tumor suppressor genes or >1 mutation in activating genes) were also recurrently found in BIRC3, ATM, TP53, MED12, SF3B1, XPO1, EGR2, DDX3X, and NOTCH1. Overall, the existence of genetic subclones showing convergent evolution was observed in 15% of CLL pts. Even using deep sequencing, no BTK or PLCG2 mutations were found in progressive but untreated CLLs. We found multiple associations between mutations and known prognostic and clinical parameters. Mutations in NOTCH1 (p=0.002), BIRC3 (p<0.001), MED12 (p<0.001), KRAS (p<0.001), and BRAF (p=0.001) were enriched in patients with trisomy 12; ATM (p<0.001) and EGR2 (p=0.002) in cases with deletion 11q and MYD88 (p=0.008) with deletion 13q. Mutations in SF3B1, NOTCH1, XPO1, MED12, BRAF were associated with ZAP70 expression (p<0.05). CD38 expression was significantly higher (p<0.05) in pts with mutations in SF3B1, NOTCH1, BIRC3, EGR2, KRAS, BRAF and CD49d expression in cases with mutations in NOTCH1, BIRC3, EGR2, KRAS, and BRAF .This study, performed on a large cohort of untreated but progressive CLL, provides novel data about the mutation status of driver genes and their associations with clinical and prognostic parameters. By using deep sequencing we found that mutation rates were higher than previous studies for most genes, including key cancer-related pathways (i.e. RAS). We previously described the existence of convergent evolution in CLL (Blood 125:492-8). In this study we showed that this evolutionary mechanism is a common event in CLL, found in 15% of these trial pts and involving most driver genes. Additionally, our data reinforces that BTK and PLCG2 mutations are not found in Ibr-naive pts. Finally, this study provides the genetic groundwork for subsequent prospective comparative analyses of the clinical outcome for CLL treated with Ibr-R vs FCR in this phase 3 NAIG trial. DisclosuresBarrientos:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. O'Brien:Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; GSK: Consultancy; Alexion: Consultancy; Janssen: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; Sunesis: Consultancy; Aptose Biosciences, Inc.: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Celgene: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; ProNAI: Other: Research Support: Honorarium, Research Funding; Vaniam Group LLC: Consultancy. Fonseca:Merck: Consultancy; Takeda: Consultancy; Pharmacyclics: Consultancy; AMGEN: Consultancy; Jansen: Consultancy; Celgene Corporation: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Mayo Clinic & Dr Fonseca: Patents & Royalties: Prognostication of myeloma via FISH, ~$2000/year; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Kay:Tolero Corporation: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Pharmacyclics: Research Funding. Shanafelt:Genentech, Celgene, Pharamacyclics, Jansen, GlaxoSmithKline, AbbVie, Hospira, and Cephalon: Research Funding.

Predictors of surgery preference and quality of life in DCIS after breast MRI: A trial of the ECOG-ACRIN Cancer Research Group (E4112).

6564 Background: Management of ductal carcinoma in situ (DCIS) remains variable, requiring an understanding of patient preferences and concerns to enhance the treatment decision-making process. Pre-operative MRI and surgeon recommendation can further inform surgery choice. Quality of life (QoL) is also an important consideration in treatment decision-making. The aims of this study were to assess patients’ treatment preferences before and after MRI and surgeon consultation, concordance between treatment preference and surgery received, and trends in health-related QoL (HRQL) among a prospective cohort of women newly diagnosed with DCIS. Methods: A prospective nonrandomized clinical trial by the ECOG-ACRIN Cancer Research Group (E4112) enrolled women diagnosed with unilateral DCIS from 75 institutions between March 2015 and April 2016. Participants underwent either wide local excision (WLE) or mastectomy. Surveys queried patient-reported outcomes (PRO) including treatment preference and concerns, and HRQL before and after surgery. Logistic regression models were used to associate surgery preference and actual surgery received with demographic, clinical and PRO data. Change from baseline in HRQL was assessed using linear regression. Results: At study entry, age (OR 0.39, per 5-year increment, 95%CI, 0.21-0.75; p = 0.005) and treatment goals related to the importance of keeping one’s breast (OR 0.51, 95%CI 0.34-0.76; p = 0.001) and removal of the breast for peace of mind (OR 1.46, 95%CI 1.09-1.95; p = 0.01) drove surgery preference for mastectomy vs. WLE. After receipt of MRI and surgeon consultation, surgery preference was primarily mediated by MRI upstaging (OR 11.18, 95%CI 3.19-39.16; p &lt; 0.001). Only 4% of women received a type of surgery that did not match their final treatment preference. The strongest predictors of actual surgery received were MRI upstaging (OR 15.80, 95%CI 4.85-51.46) and surgeon recommendation of mastectomy (OR 4.60, 95%CI 1.52-13.94). Receipt of a single surgery was associated with significantly improved mental health from baseline to one year after definitive surgery (p = 0.02 for mastectomy; p = 0.003 for single WLE). Self-reported Black race was an independent predictor of worsened mental (p = 0.001) and physical (p = 0.04) health at one year after definitive surgery, despite no significant racial differences in baseline HRQL. Conclusions: Our findings highlight the importance of communication between providers and patients regarding treatment preferences and goals, the clinical significance of MRI findings, and the benefits/risks of available treatment options. Future research to identify modifiable factors associated with declining mental and physical health is needed to inform targeted interventions to mitigate racial disparities and enhance HRQL in patients with DCIS.

Comparing the clinical impact of pancreatic cyst surveillance programs: A trial of the ECOG-ACRIN cancer research group (EA2185).

TPS10608 Background: The optimal surveillance strategy for pancreatic cysts, which occur in up to 20% of the adult population, is ill defined. Although risk of malignant degeneration of these cysts is low, pancreatic cancer mortality remains high. Two cyst surveillance guidelines, one proposed by an international consensus group (Fukuoka) and the other by the American Gastroenterological Association (AGA), are accepted standards. Both rely on radiographic and endoscopic ultrasonographic imaging. They differ in indications for, and intervals between, imaging tests, with the Fukuoka guideline advocating more intensive imaging. Clinical guidelines that provide discordant recommendations may undercut the quality and/or value of care, and have implications for societal health care costs. The primary objective of this prospective trial is to compare the clinical effectiveness and associated resource utilization of the Fukuoka and AGA guidelines for pancreatic cyst surveillance. Secondary objectives include a comparison of resource utilization and patient reported outcomes. We are also collecting and banking radiomics data and biospecimens to identify novel methods that might improve cancer risk stratification. Methods: 4606 asymptomatic patients with newly identified pancreatic cysts ≥1cm in diameter are being randomized 1:1 to high intensity (Fukuoka) or low intensity (AGA) surveillance. The primary endpoint is a composite of any pancreatic cancer without surgery, unresectable pancreatic cancer or cancer &gt; T1a, N0 at surgery, and benign disease at surgery. This sample size will provide 90% power to identify a 30% relative difference in the primary outcome at 5 years between the two study arms. Study duration is 8 years in total, allowing for 2 years of cohort enrollment, 5 years of prospective follow-up, and six months reserved for study initiation and close out. Study participants must be ≥ 50 years and ≤ 75 years with an ECOG Performance Status 0-1 at baseline. Participants must have received a CT or MRI within 6 months of registration that identifies a new ≥1 cm pancreatic cyst. Patients with a prior diagnosis of a pancreatic cyst, pancreatic malignancy or a history of pancreatic resection are not eligible. Additional exclusion criteria include a history of acute or chronic pancreatitis, a family history of pancreatic adenocarcinoma in 1 or more first degree relatives, imaging findings or clinical signs that would prompt immediate surgical consideration (enhancing mural nodule, solid component in cyst, pancreatic duct &gt; 10mm, cyst causing obstructive jaundice), a comorbid illness that precludes pancreatic cyst resection, pregnancy or current participation in an established surveillance program. As of February 4, 2021, thirty three (33) participants have been enrolled from two hundred (200) potential sites. Clinical trial information: NCT04239573 .

A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naive metastatic anal cancer patients: A trial of the ECOG-ACRIN cancer research group (EA2176).

TPS3614 Background: Anal cancer is growing in annual incidence globally and human papillomavirus (HPV) remains the predominant risk factor underlying its development. Due to its relative rarity, clinical trials in anal cancer have historically been difficult to conduct and treatment options for metastatic disease remain limited. Carboplatin/paclitaxel (CP) was compared to cisplatin/5-fluorouracil (historical standard of care) in a recent randomized phase II clinical trial (InterAACT; EA2133) in treatment-naïve metastatic anal cancer, finding that response rates were equivocal, but that overall survival (OS) was significantly longer in the CP arm (20 months vs 12.3 months, p = 0.014). Additionally, reduced grade 3/4 toxicities were seen in the CP arm. NCI9673, a single-arm phase II study, established safety and efficacy of nivolumab in previously-treated metastatic anal cancer. Progression-free survival (PFS) was 4.1 months (95% CI 3.0-7.9) and OS was 11.5 months (95% CI 7.1-not estimable). Multiple randomized trials in lung cancer have demonstrated efficacy of platinum-based chemotherapy combined with checkpoint inhibitors. Together these studies form the rationale behind combining CP and nivolumab in treatment-naïve metastatic anal cancer. Methods: EA2176 (NCT04444921) is the first NCTN phase III randomized clinical trial in treatment-naïve metastatic anal cancer. Stratification factors include HIV status and history of chemoradiation for curative intent. Patients will be randomized to carboplatin (AUC = 5, Day 1) plus paclitaxel (80mg/m2, Days 1, 8, 15) +/- nivolumab 240mg IV (Cycle 1 = Days 1, 15; Cycle ≥2 = Day 1, 480mg) q 28-days until disease progression or treatment intolerance. CP will be given for up to 6 cycles, while nivolumab will be continued as maintenance for up to 2 years. The primary endpoint is PFS. Secondary objectives include OS, response rate, and toxicity. Goal enrollment is 205 patients and the study continues accrual. This sample size will provide 80% power at a two-sided α of 0.05 to detect a 4.8-month improvement in PFS assuming 8 months in the control arm. Novel correlative studies include sequential quantitative tumor-derived cell-free HPV ctDNA levels (serotypes 16 and 18; Sysmex-Inostics SafeSEQ NGS assay). Correlative funding provided in part by the Farrah Fawcett Foundation and Sysmex Inostics, Inc. Clinical trial information: NCT04444921.

Biomarker testing in non-small cell lung cancer (NSCLC): An assessment of current practices in precision oncology in the community setting—A trial of the ECOG-ACRIN cancer research group (EAQ161CD).

e18649 Background: Molecular biomarker testing is integral to NSCLC cancer care, but adoption and testing practices in the community are varied and often suboptimal. Testing practices, such as standard testing protocols and results turnaround time (TAT), impact timely treatment decisions. We examined adoption and testing practices for guideline recommended NSCLC biomarkers among National Cancer Institute Community Research Program (NCORP) sites. The study was conducted in collaboration with Wake Forest NCORP Research Base. Methods: An online survey was administered to onsite labs affiliated with NCORP sites April 2019 – June 2020. We assessed testing practices for 7 NCCN recommended biomarkers, including 3 with category 1 recommendation (EGFR, ALK, PD-L1) and 4 with category 2 recommendations (BRAF, ROS1, MET, RET). Guideline concordant result TAT was defined as return of EGFR and ALK results in ≤ 10 days (Lindeman 2018) (see Table for other outcomes). We used proportions, including two-sided Fischer exact tests, to compare outcomes by site characteristics (safety net, practice size). Results: The survey response rate was 69% (58/85). All responding labs offered testing for category 1 biomarkers (EGFR, ALK and PD-L1); only 10% conducted these tests in-house (Table). The majority of labs also tested for category 2 biomarkers (67%). TAT varied, with most labs returning results in ≤ 10 days for EGFR and ALK (69%, but only a minority meet this TAT for all biomarkers. Larger practice size (&gt; 1400 new cancer cases a year) was associated with in-house testing of EGFR, ALK, PD-L1 (p=0.03) and having standard testing protocols (p&lt;0.001). Safety net affiliation did not significantly impact practices. Conclusions: We found universal adoption of NCCN category 1 biomarkers among the labs affiliated with NCORP sites, with the majority meeting guideline concordant results TAT. There is opportunity for improvement in adoption of category 2 biomarkers and result TAT, for example, by using standard testing protocols. Reassuringly, no difference in testing practices was detected by safety net affiliation.[Table: see text]

A phase II/III study of perioperative nivolumab and ipilimumab in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of a safety run-in—A trial of the ECOG-ACRIN Cancer Research Group (EA2174).

4064 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent therapy. The use of immune checkpoint inhibition is beneficial for treatment of this cancer in the metastatic and adjuvant settings but the role of these agents in the perioperative setting remains unclear. Here we report the results of an initial safety run-in of nivolumab when given in combination with neoadjuvant chemoradiation. Methods: Pts with a localized T1N1-3M0 or T2-3N0-2M0 E/GEJ adenocarcinoma with an ECOG PS of 0-1 and whom were deemed surgical candidates for an esophagectomy by a qualified surgeon were eligible. In step 1, pts were randomized to neoadjuvant therapy with carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously (IV) weekly x 5 along with 41.4-50.4 Gy radiation without (Arm A) or with (Arm B) nivolumab 240 mg IV during weeks 1 and 3 of treatment, followed by esophagectomy. Pts underwent a second randomization (step 2) to adjuvant nivolumab 240 mg IV every 2 weeks x 12 cycles with or without ipilimumab 1 mg/kg IV every 6 weeks during cycles 1, 4, 7 and 10. For the safety run-in, 30 pts were planned for accrual to allow for 12 evaluable pts per arm. Pts were followed for safety during neoadjuvant therapy through surgery and toxicities monitored per CTCAEv5. Pre-specified early stopping rules were defined to allow halting of the trial if deemed unsafe. Planned study accrual is 278 pts. Neoadjuvant primary endpoint is pathologic complete response rate, adjuvant primary endpoint is disease-free survival. Results: A total of 31 pts were enrolled to the safety run-in element of the study (Arm A, n = 16; Arm B n = 15). Male, 94%; White, 100%; median age, 62; esophageal adenocarcinoma, 52%; GEJ, 48%. Grade (G) 3 events occurring in more than one pt on Arm A—decreased lymphocytes (n = 5). G4 events occurring on Arm A—decreased lymphocytes (n = 1). G3 events occurring in more than one pt on Arm B—decreased lymphocytes (n = 2); anemia (n = 2); leukopenia (n = 4); hypotension (n = 2). G4 events occurring on Arm B—decreased lymphocytes (n = 3); cardiac tamponade and pericardial effusion (n = 1). Cardiac events were thought to be secondary to tumor location, not neoadjuvant treatment. On Arm B, notable G3 events seen in one pt each included colonic obstruction, wound infection and esophageal anastomotic leak. Of pts who have reached the time for surgery, 12/14 pts on Arm A and 13/13 pts on Arm B have proceeded to surgery. Of pts who have completed step 1, 7/14 pts on Arm A and 8/11 pts on Arm B have registered to step 2. Conclusions: The addition of nivolumab to carboplatin, paclitaxel and radiation in the neoadjuvant setting appears to be safe with no disproportionate level of toxicity observed between the two treatment arms. Accrual to the remainder of the trial continues with 43/278 patients accrued. Clinical trial information: NCT03604991.