Citations

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 > 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 > 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 > 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 > 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 > 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 > 10 pk-yrs had favorable 3-yr PFS and OS rates that were not significantly worse than those with < 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]

Background: The American Heart Association recently published an updated algorithm for quantifying cardiovascular health (CVH)—the Life’s Essential 8 score. We quantified US levels of CVH using the new score. Methods: We included individuals ages 2 through 79 years (not pregnant or institutionalized) who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys in 2013 through 2018. For all participants, we calculated the overall CVH score (range, 0 [lowest] to 100 [highest]), as well as the score for each component of diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, using published American Heart Association definitions. Sample weights and design were incorporated in calculating prevalence estimates and standard errors using standard survey procedures. CVH scores were assessed across strata of age, sex, race and ethnicity, family income, and depression. Results: There were 23 409 participants, representing 201 728 000 adults and 74 435 000 children. The overall mean CVH score was 64.7 (95% CI, 63.9–65.6) among adults using all 8 metrics and 65.5 (95% CI, 64.4–66.6) for the 3 metrics available (diet, physical activity, and body mass index) among children and adolescents ages 2 through 19 years. For adults, there were significant differences in mean overall CVH scores by sex (women, 67.0; men, 62.5), age (range of mean values, 62.2–68.7), and racial and ethnic group (range, 59.7–68.5). Mean scores were lowest for diet, physical activity, and body mass index metrics. There were large differences in mean scores across demographic groups for diet (range, 23.8–47.7), nicotine exposure (range, 63.1–85.0), blood glucose (range, 65.7–88.1), and blood pressure (range, 49.5–84.0). In children, diet scores were low (mean 40.6) and were progressively lower in higher age groups (from 61.1 at ages 2 through 5 to 28.5 at ages 12 through 19); large differences were also noted in mean physical activity (range, 63.1–88.3) and body mass index (range, 74.4–89.4) scores by sociodemographic group. Conclusions: The new Life’s Essential 8 score helps identify large group and individual differences in CVH. Overall CVH in the US population remains well below optimal levels and there are both broad and targeted opportunities to monitor, preserve, and improve CVH across the life course in individuals and the population.

Abstract Chronic inflammation is a well-established carcinogenic pathway for colorectal cancer (CRC), but the role of inflammation in CRC prognosis is not well understood. Since cytokines are central in extensive biological networks to regulate inflammation, it is of great importance to investigate inflammatory cytokines and CRC survival. Among an NCI-sponsored adjuvant chemotherapy trial for patients with stage III colon cancer conducted between 2010 and 2015 (CALGB/SWOG 80702), we collected serum samples from 1,498 participants at a median of 1.6 months (interquartile [IQR]: 1.3-1.9 months) after surgery. IL-6, TNFR2, and hsCRP were assayed as biomarkers of chronic inflammation and were categorized into quintiles. The primary outcome was disease-free survival, defined as time from randomization to recurrence or death from any cause. Secondary outcomes included overall survival and time to recurrence. We estimated the associations of inflammatory biomarkers with survival using multivariable Cox proportional hazards regression. Of 1,498 participants (median follow-up: 5.9 years), mean age was 61.3 years, 82.2% were White, 55.5% were male, and 387 experienced recurrence or death. Medians (IQRs) of biomarkers were 2.6mg/L (1.2-5.6mg/L) for IL-6, 2.9×103pg/mL (2.3-3.6×103pg/mL) for TNFR2, and 2.6mg/L (1.2-5.6mg/L) for hsCRP. Compared to the lowest quintile (Q1), the highest quintile (Q5) in inflammatory biomarkers was significantly associated with worse disease-free survival (hazard ratios were 1.52 [95% CI, 1.08-2.15] for IL-6, 1.76 [95% CI, 1.22-2.54] for TNFR2, and 1.66 [95% CI, 1.17-2.35] for hsCRP). Similar patterns were observed for overall survival and time to recurrence. Our findings suggest that higher levels of inflammation after diagnosis were significantly associated with worse survival among those with stage III colon cancer, and reducing inflammation may be considered as a potential intervention to improve CRC survival. ‬‬ Associations of Inflammatory Biomarkers with Survival after Adjustment for Clinicopathologic Factors Q1 Q2 Q3 Q4 Q5 P for Trend Disease-free survival IL-6 1.00 1.14 (0.80-1.62) 1.37 (0.97-1.94) 1.44 (1.02-2.03) 1.52 (1.08-2.15) 0.02 TNFR2 1.00 1.21 (0.84-1.74) 1.43 (0.99-2.05) 1.56 (1.09-2.25) 1.76 (1.22-2.54) 0.002 hsCRP 1.00 1.34 (0.95-1.90) 1.62 (1.15-2.29) 1.26 (0.88-1.80) 1.66 (1.17-2.35) 0.04 Overall survival IL-6 1.00 1.44 (0.91-2.29) 1.56 (0.98-2.48) 1.48 (0.93-2.34) 1.68 (1.07-2.65) 0.09 TNFR2 1.00 1.57 (0.94-2.63) 1.88 (1.13-3.13) 1.92 (1.15-3.20) 2.31 (1.39-3.84) 0.003 hsCRP 1.00 1.27 (0.81-2.00) 1.72 (1.11-2.65) 1.22 (0.77-1.92) 1.73 (1.12-2.69) 0.06 Time to recurrence IL-6 1.00 1.34 (0.92-1.95) 1.48 (1.01-2.16) 1.55 (1.06-2.27) 1.54 (1.05-2.26) 0.07 TNFR2 1.00 1.14 (0.78-1.67) 1.28 (0.87-1.87) 1.48 (1.01-2.16) 1.54 (1.04-2.27) 0.02 hsCRP 1.00 1.27 (0.87-1.83) 1.64 (1.14-2.36) 1.21 (0.82-1.77) 1.55 (1.07-2.26) 0.12 Citation Format: En Cheng, Shi Qian, Anthony F. Shields, Elizabeth M. Cespedes Feliciano, Andrew B. Nixon, Ardaman P. Shergill, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Dequincy Lewis, Benjamin Tan, Eileen M. O'Reilly, Justin C. Brown, Philip A. Philip, Bette J. Caan, Jeffrey A. Meyerhardt. Associations of inflammatory biomarkers with survival among patients with stage III colon cancer (CALGB/SWOG 80702 [Alliance]) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 682.

Abstract Background: While most EGFR-mutant NSCLC tumors are resistant to checkpoint inhibitors, a small subset has durable responses. Certain molecular subtypes of EGFR may be more responsive. There is a lack of clarity on the genomic and immune profiles of EGFR subtypes, and further elucidation of this may assist in optimally identifying those likely to respond to immune-based therapies. Methods: Profiles of 5,510 lung adenocarcinoma specimens were obtained utilizing next-generation sequencing of 592 genes (Caris Life Sciences) and categorized by EGFR subtype. PD-L1 expression (Ab: 22c3), tumor mutational burden (TMB), immune cell type fractions, and co-mutations in TP53 were assessed by EGFR subtype and compared to wild-type (WT) tumors. Results: Of the total cohort, 791 (14.4%) were EGFR-mutant (Table). Among EGFR-mutant tumors, exon 19 deletions were most common (49.7%), followed by L858R, (32.9%), exon 20 insertions (13.0%), L861Q (2.9%), and G719X (1.5%). PD-L1 positivity of each EGFR subtype as compared to WT did not vary, except for L858R tumors which had a significantly lower percentage of PD-L1 positive cases. Exon 19 deletion, L858R, and exon 20 insertion tumors were significantly less likely to have high PD-L1 or high TMB compared to WT. Among the EGFR subtypes, L861Q and G719X tumors had the greatest percentage with high TMB. TP53 co-mutations were frequent in EGFR tumors, especially among L861Q and G719X tumors. Exon 19 deletion and L858R tumors had significantly less CD8+ and greater CD4+ T cell fractions compared to WT. Neutrophil and M2 macrophage cell fractions were significantly higher in exon 19 deletion, L858R, and exon 20 insertion tumors compared to WT. Conclusions: Most subtypes of EGFR have profiles consistent with decreased immunogenicity; however L861Q and C719X tumors have a greater percentage with high TMB or TP53 co-mutations. Such features in uncommon EGFR subtypes may correlate with responsiveness to immune-based therapies and warrant further study. Tumor Characteristic EGFR WT(n=4719) Exon 19 del(n=393) L858R(n=260) Exon 20 ins(n=103) L861Q(n=23) G719X(n=12) PD-L1 positive (≥1%) 57.7% 51.0% 49.0% a 49.5% 47.8% 50.0% PD-L1 high (≥50%) 30.6% 19.7% a 18.8% a 14.4% a 21.7% 16.7% TMB high (≥10 mut/Mb) 35.3% 1.0% a 3.7% a 1.0% a 9.5% 18.2% TP53 co-mutation 53.9% 61.7% 63.6% a 59.2% a 69.6% a 83.3% a Median % cell fraction CD8+ 0.7 0.3 a 0.4 a 0.3 0.6 0.2 CD4+ 0.0 0.6 a 0.8 a 1.3 a 1.7 1.1 Neutrophils 5.5 8.0 a 7.3 a 7.8 a 7.4 6.4 M2 macrophages 5.5 6.4a 6.9a 6.7a 5.8 4.3 aq-value &lt; 0.05 when compared to EGFR WT (corrected for multiple comparisons) Citation Format: J. Nicholas Bodor, Joanne Xiu, Vinicius Ernani, Supreet Kaur, Hirva Mamdani, Pavel Brodskiy, Sai-Hong I. Ou, Patrick C. Ma, Margie L. Clapper, W. Michael Korn, Joseph Treat. Genomic and immune characteristics of EGFR subtypes in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4119.

Abstract Lung cancer (LC) is the most common cause of cancer mortality and the third most common cancer by incidence in the United States. While environmental factors play an important role in its development, LC risk also exhibits a high degree of heritability. Linkage analyses and genome-wide association studies have identified multiple loci associated with increased LC risk; however, much of the heritability has yet to be explained by these loci. Structural mutations, including copy number variations (CNVs), contribute to phenotypic diversity through dosage and/or cis-regulatory effects. Unbiased CNV mapping is only possible with the use of high-depth, short-read sequencing and remains much more complicated and prone to false positives than SNP detection. As the tools necessary for CNV detection have improved, both somatic and germline CNVs have been shown to play an important role in disease, especially cancer, and often they account for a significant proportion of pathogenic variants. Little has been done to understand the role of germline CNVs in the biological pathways of hereditary lung cancer (HLC). The goal of the current project is to utilize the whole exome sequencing (WES) data in identifying the CNVs in the HLC families (≥3 LC/family) recruited by the Genetic Epidemiology of Lung Cancer Consortium (GELCC). This work uses germline WES data from 203 individuals (60 with a LC diagnosis) from 25 HLC families (≥3 LC affected/family). We limited our investigation to CNVs called by two independent tools using read depth to infer copy number changes and genomic breakpoints: GATK 4 (https://gatk.broadinstitute.org) and XHMM (https://atgu.mgh.harvard.edu/xhmm/). We have identified CNVs (deletions) in the following protein coding genes: KIR2DL1 (19q13.42; OR=1.77), DMBT1 (10q26.13; OR=1.56), SIBPB1 (20p13; OR=1.53), LILRA6 (20p13; OR=1.53), and HLA-DRB5 (6p21.32; OR=1.64) in ≥3 families in at least two individuals/family. All of these genes with the exception of HLA-DRB5 were previously reported in LC studies; HLA-DRB5 was reported in other cancer studies. DMBT1 was reported to be a candidate tumor suppressor gene and frequent loss of heterozygosity (LOH) was observed in several human tumors. It is highly expressed in lung and loss of expression was reported in LC cell lines. All CNVs identified in our study are consistent with Mendelian expectations and appear to be uncommon in the general population. CNVs in these genes may contribute to the lung cancer risk in the HLC families. Further validation of the identified variants is ongoing. We will consider overall CNV burden and disease association with identified deletions and duplications. The enrichment of rare variants in oncogenically associated genes that co-segregate with LC provides specific mutations for future work and improves our understanding of the inheritance and pathogenesis of LC. Citation Format: John Waldron, Kirsten W. Termine, Anthony M. Musolf, Mariza de Andrade, Colette Gaba, Ramaswamy Govindan, Ping Yang, Ming You, Ellen Jaeger, Angelle F. Bencaz, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson, Diptasri M. Mandal. Analyses of whole exome sequencing (WES) data of hereditary lung cancer families identify germline copy number variations (CNVs) in multiple genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1452.

Abstract Background: An elevated risk of developing non-Hodgkin's lymphoma (NHL) has been associated with a family history of NHL and several other malignancies, but the magnitude of risks and mechanisms are uncertain. Methods: We used self-reported family history data from a recent multicenter U.S.-based case-control studies of NHL to evaluate familial aggregation of NHL with various hematolymphoproliferative and other cancers. Estimates of familial aggregation were obtained as hazard ratios (HR) that compare incidence of different cancers in first-degree relatives of NHL cases with that in the first-degree relatives of NHL controls. Limitations of the study included low participation rates (76% for cases and 52% for controls) and potential differential accuracy of recall. Results: Risk of NHL was elevated in relatives of NHL cases [HR, 2.9; 95% confidence interval (95% CI), 0.95–8.53]; the aggregation seems to be stronger for siblings (HR, 7.6; 95% CI, 0.98–58.8) and for male relatives (HR, 6.2; 95% CI, 0.77–50.0). Risk of Hodgkin's lymphoma seems to be also elevated among relatives of early-onset (&lt;50 years) NHL cases (HR, 3.2; 95% CI, 0.88–11.6). Evaluation of family history of other cancers provided modest evidence for an increased risk of melanoma of the skin (HR, 2.9; 95% CI, 1.08–7.75), pancreatic cancer (HR, 2.1; 95% CI, 0.96–4.43), stomach cancer (HR, 1.8; 95% CI, 0.91–3.63), and prostate cancer (HR, 1.3; 95% CI, 0.87–1.99). Conclusions: These results are consistent with previous findings of familial aggregation of NHL, Hodgkin's lymphoma, and a few other cancers. The pattern of male-specific and sibling-specific familial aggregation of NHL we observed, if confirmed, may shed new light on the possible mechanisms that underlie familial aggregation of the disease.

12107 Background: Chemotherapy-induced nausea and vomiting (CINV), a major adverse effect of cancer treatment, can attenuate life quality. Multiple international antiemetic guidelines have recommended a 4-drug regimen (corticosteroid, 5-HT3 receptor antagonist, NK-1 receptor antagonist, and the antipsychotic medication olanzapine) for decreasing highly emetogenic CINV. This raised a question regarding whether antiemetic therapy regimens for highly emetogenic chemotherapy could be de-intensified, decreasing cost and side effects from anti-emetogenic agents. Methods: Study A221602 was developed to compare two olanzapine-containing antiemetic regimens, one with the use of an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Patients (pts) received intravenous highly emetogenic chemotherapy as either 1) cisplatin, given on one day, at a dose of ≥ 70 mg/m2, with or without other chemotherapy agent(s) or 2) doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) on one day. Pts in both arms received 1) a 5-HT3 receptor antagonist (palonosetron 0.25 mg IV or ondansetron 8-16 mg IV or 16-24 mg PO,) on day one, 2) dexamethasone (12 mg PO, day one followed by 8 mg PO, days 2-4), and 3) olanzapine (10 mg/day PO, days 1 to 4). On Day 1, all agents were given prior to chemotherapy, with the exception that olanzapine could be taken prior to chemotherapy or at bedtime. Additionally, pts were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV; 346 pts) or a matching placebo (344 pts). The primary objective was to compare the proportion of patients with no nausea for 5 days following receipt of their chemotherapy between the two study arms. Results: While there was no suggestion of outcome differences on day 1 between the two study arms, fewer pts (7.4%; upper limit of the 95% confidence interval was 13.5%) without NK-1 receptor antagonists were without nausea for the complete 5-day study period. Conclusions: Per the study design, created to exclude a 10% benefit for NK-1 receptor antagonists, the results did not provide sufficient evidence to reject the hypothesis that the 4-drug regimen was superior to the protocol 3-drug regimen (p=0.24). Support: UG1CA189823; Clinical trial information: NCT03578081.

8055 Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The most commonly mutated genes are N- and K-Ras, which increase in prevalence as the disease progresses. Case reports and retrospective data suggest efficacy of targeting the MAPK pathway in N/K-Ras mutated MM. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with standard therapies in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Subjects undergo molecular profiling of their MM cells and are assigned to a targeted arm if a variant allele frequency (VAF) over 25% is identified. The targeted mutated genes and respective agents (approved for non-MM indications and with a known phase 2 dose) are: KRAS/NRAS/BRAF (cobimetinib), FGFR3 (enasidenib), IDH (erdafitinib), CDKN2C (abemaciclib), t(11;14) (venetoclax). Patients receive the investigational drug for 2 cycles as a single agent followed by addition of an active MM combination (ixazomib, pomalidomide and dexamethasone, IPd). Limited dose escalation was performed with the single agent followed by dose assessment in combination with IPd. Here we present the results of the dose escalation portion of C1 arm exploring cobimetinib in patients with N/K-RAS or BRAF mutations. Cobimetinib was administered at 40 mg daily in combination with standard doses of IPd. Results: Eleven subjects with BRAF/RAS mutations were screened between August 2019 and October 2020, with 4 screen failures. Seven were enrolled, 5 males, median age 65 years, and median time from diagnosis of 30 months. N-RAS, K-RAS or BRAF mutations were seen in 4, 2, and 1 subject(s), respectively, with VAF ranging from 33-93%. Median number of prior lines of therapy was 1 (1-3), 3 patients had extramedullary disease, and 1 patient had high risk cytogenetics. Median duration of therapy was 12 months. One patient was not evaluable for dose limiting toxicity. All but 1 patient had at least one cycle delayed due to adverse events (AEs), but no dose reductions were required. No dose limiting toxicities were observed across the cycles, either during single agent therapy (Cycles 1-2) or in combination with IPd (Cycles 3 and 4). Six patients responded to therapy (4 PR, 2 VGPR). One patient was not response evaluable. Fatigue was the most common non-hematological AE followed by diarrhea. Conclusions: Here we report on the feasibility of genomically-guided, precision medicine therapy in K/N-RAS/BRAF-mutated MM. The MEK inhibitor cobimetinib in combination with IPd appears safe in functionally high-risk patients. Ongoing study will provide more information regarding the efficacy of this approach. Clinical trial information: NCT03732703.