American Association For Cancer Research Research Articles

Immune checkpoint inhibitor therapy as a neoadjuvant treatment for muscle-invasive bladder carcinoma

Abstract Background and objectives Immunotherapy has become a standard treatment for patients with advanced urothelial carcinoma, and neoadjuvant immunotherapy is being extensively explored. This review highlights the initial findings and key clinical therapeutic insights on immune checkpoint inhibitors in the early treatment of muscle-invasive bladder cancer across diverse patient populations. Materials and methods Relevant trials were retrieved from PubMed/MEDLINE and clinical trials databases. In addition, abstracts of major international oncology meetings (American Society of Clinical Oncology, American Association for Cancer Research, European Society of Medical Oncology, and European Council of Clinical Oncology) were reviewed until the European Society of Medical Oncology 2023 congress. The review also incorporated results from several exploratory investigations disclosed in recent years. Results This review focused on neoadjuvant immune checkpoint inhibitor monotherapy, combination therapy, and clinical biomarkers in relation to cisplatin-based chemotherapy tolerance. Most available literature consists of clinical investigations involving small sample, single-arm Phase II trials, with the primary endpoint being the pathologic complete response rate. The preliminary results from these studies are promising, demonstrating stage reduction rates comparable to or even exceeding those of standard chemotherapy, without compromising subsequent radical cystectomy. Conclusions Early results of immune checkpoint inhibitors in the neoadjuvant treatment of bladder cancer have demonstrated promising efficacy. However, these findings require confirmation in large Phase III clinical trials, with particular emphasis on long-term survival benefits and identifying patients who respond to treatment.

Amplification of MYC and Its Enhancer Correlates With Genetic Ancestry in Lung Squamous Cell Carcinoma.

In lung squamous cell carcinoma (LUSC), Black patients show significantly higher incidence and lower overall survival than White patients. Although socioeconomic factors likely contribute to this survival disparity, genomic factors have yet to be elucidated in LUSC. Using 416 LUSC tumor samples in the Cancer Genome Atlas (TCGA), we assessed genomic and transcriptomic profiles by ancestry. We replicated our analyses in pan-cancer data from TCGA, the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE), and Columbia University Medical Center. We found increased MYC amplification, LUSC-specific MYC enhancer amplification, and chromosome arm 8q (chr8q) gain to be significantly associated with genetic AFR (African) ancestry in LUSC in TCGA. Furthermore, expression of MYC target genes was significantly enriched in AFR samples. Local ancestry analysis identified correlation of chr8q gain with AFR ancestry at the MYC locus in TCGA. We also found a significant correlation between chr8q and AFR ancestry in multiple cancer types and pan-cancer in TCGA. Similarly, in a pan-cancer subset of AACR GENIE data, we found a significant correlation between chr8q gain and race. Together, our data suggest that ancestry may influence amplification of not only MYC but also its enhancer in LUSC. They also suggest a role for genetic ancestry in chr8q aneuploidy in cancer. These studies further define and expand patients who may benefit from future anti-MYC therapeutic approaches.

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.

Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.

Monitoring Overall Survival in Pivotal Trials in Indolent Cancers

Indolent cancers are characterized by lengthy overall survival (OS) times. Therefore, powering a clinical trial to provide definitive assessment of the effects of an experimental intervention on OS in a reasonable timeframe is generally infeasible. Instead, the primary outcome in many pivotal trials is an intermediate clinical response such as progression-free survival. In several recently reported pivotal trials of interventions for indolent cancers that yielded promising results on an intermediate outcome, however, more mature data or post-approval trials showed concerning OS trends. These problematic results have prompted a keen interest in quantitative approaches for monitoring OS that can support regulatory decision-making related to the risk of an unacceptably large detrimental effect on OS. The US Food and Drug Administration, the American Association for Cancer Research, and the American Statistical Association recently organized a one-day multi-stakeholder workshop entitled “Overall Survival in Oncology Clinical Trials.” In this article, we propose OS monitoring guidelines tailored for the setting of indolent cancers. Our pragmatic approach is modeled, in part, on the monitoring guidelines the FDA has used in cardiovascular safety trials conducted in Type 2 Diabetes Mellitus. We illustrate proposals through application to several examples informed by actual case studies.

Update on Genetic Counselor Practice and Recommendations for Pediatric Cancer Predisposition Evaluation and Surveillance.

In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop, at which international experts in pediatric cancer predisposition met to update the previously published 2017 consensus statements on pediatric cancer predisposition syndromes. Since 2017, advances in tumor and germline genetic testing and increased understanding of cancer predisposition in patients with pediatric cancer have led to significant changes in clinical care. Here, we provide an updated genetic counseling framework for pediatric oncology professionals. The framework includes referral indications and timing, somatic and germline genetic testing options, testing for adult-onset cancer predisposition syndromes in children with and without cancer, evolving genetic counseling models to meet the increased demand for genetic testing, barriers to cancer genetic testing and surveillance in children, and psychosocial and equity considerations regarding cancer genetic testing and surveillance in children. Adaptable genetic counseling services are needed to provide support to pediatric oncology provider teams and diverse patients with pediatric cancer, cancer predisposition, and their families.

24 Applying genomic analysis to refine unclassified renal cell carcinoma

Abstract Background Despite the improvements in genomic and pathological techniques to identify renal cell carcinoma (RCC), 2-6% of all patients with RCC cannot be classified into a particular subgroup, thus called “unclassified” RCC (uRCC). Ascertaining the genomic profile of those patients may help select proper treatment and find novel targets. Methods The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database v15.0 was used to select patients with RCC by using the OncoTree codes. All included patients were divided into four groups based on the most frequent subtypes of RCC: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and uRCC. The Cancer Genome Atlas (TCGA) was additionally used to assess corresponding oncogenic signaling pathways. We employed the chi-squared test to compare categorical variables and applied the Benjamini-Hochberg correction to calculate Q-values, thereby controlling the false discovery rate. Results Overall, 1,990 tumor samples from 1,888 patients were evaluated. uRCC was observed in 184 patients (9.7%), whereas most had ccRCC (n=1339, 70.9%), followed by pRCC (n=224, 11.9%) and chRCC (n=141, 7.5%). Age distribution at sample sequencing was comparable between uRCC and other RCC subtypes (P>0.05). The proportion of female patients with uRCC was higher at 38.4%, compared to 26.5% in ccRCC (Q=0.002) and 16.3% in pRCC (Q<0.001), yet was comparable to chRCC at 48.6% (Q=0.210). The prevalence of uRCC was also greater among black patients, accounting for 8.6% vs. 2.1% in ccRCC (Q=0.001). Among patients with uRCC (n=224), the most common genomic alterations (GAs) were detected in NF2 (15.8%), SETD2 (15.8%), TP53 (13.9%), TERT (13.4%), and VHL (11.8%). NF2 alterations were also more prevalent in patients with uRCC than in patients with ccRCC (1.8%, Q<0.001), chRCC (0.7%, Q<0.001), and pRCC (5.8%, Q=0.058). Notably, median overall survival (OS) was poorer in uRCC patients with altered NF2 (n=29) than in those with unaltered NF2 (n=155, 30.7 vs. 87.1 months, p=0.058). Of patients with uRCC, 135 (72.5%) samples were from primary tumors and 39 (20.9%) from metastatic sites, with no difference in GA frequencies between the two. CDKN2A and CDKN2B were the most frequent co-mutated genes in uRCC (Q<0.001), followed by VHL and BAP1 (Q<0.001), and SETD2 and PBRM1 (Q=0.023). GAs in uRCC were primarily observed in pathways related to TP53 (42.8%), cell cycle (33.3%), PI3K (23.5%), and HIPPO (7.7%). Conclusions uRCC exhibited a unique genomic profile distinct from other common RCC subtypes. Notably, NF2 alterations were frequent and correlated with a poorer prognosis.

5 A Phase 1b, Open-Label, Safety, Tolerability, and Efficacy Study of HC-7366 in Combination with Belzutifan (WELIREGTM) in Patients with Advanced or Metastatic Renal Cell Carcinoma, NCT06234605

Abstract Background HC-7366 is a novel, orally administered, highly selective and potent activator of general control nonderepressible 2 (GCN2) kinase, a core regulator of metabolic stress through activation of the integrated stress response (ISR). Activation of GCN2 promotes cell survival, whereas prolonged activation induces apoptosis. GCN2 activation also suppresses general protein synthesis and induces cell cycle arrest, thereby preventing cell growth during nutrient scarcity. Additionally, HC-7366 decreases HIF expression and inhibits glycolysis, oxidative phosphorylation, and TCA cycle function. HC-7366 also inhibits HIF expression in immunosuppressive myeloid cells, including macrophages. These effects of HC-7366 on metabolism, HIF signaling, and immune suppression suggest therapeutic benefit in ccRCC with clear rationale for combinations with HIF2a antagonists and immune checkpoint inhibitors. HC-7366 (0.5-1 mg/kg), combined with belzutifan (1 mg/kg), exhibited combination benefit in HIF-2 dependent A-498 and 786-O RCC xenografts, yielding 90% tumor growth inhibition and a three-fold increase in complete responses, respectively. Additionally, HC-7366 drives significant monotherapy antitumor activity in PDX models that demonstrated belzutifan resistance. Mechanism of action studies have identified several pathway engagement and potential efficacy biomarkers (Stokes, et al., 2024). Trial design/schema This multicenter, open-label phase 1b study will identify the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd, in patients with advanced or metastatic RCC with renal cell histology irrespective of VHL gene mutation. Monotherapy HC-7366 will be evaluated in parallel. The monotherapy arm, HC-7366, 60 mg p.o. qd, includes patients who have relapsed after 1 to 4 prior lines of standard of care that may include belzutifan or another HIF-2α inhibitor. The combination arm includes patients who have received 1 to 3 prior lines of standard of care and are belzutifan or HIF-2α naïve. HC-7366 dose escalation arm evaluates combination fixed dose belzutifan, 120 mg po qd plus HC-7366 at 20, 40, or 60 mg po qd. Enrollment will start with the HC-7366 monotherapy arm. Subsequently, patients will begin to enroll in the combination therapy HC-7366 dose escalation arm, while the monotherapy arm will continue to enroll. Expansion will evaluate the combination of fixed dose belzutifan with two doses of HC-7366 selected from escalation. Assessments include safety, PK, and anti-tumor activity. The study will enroll up to 80 patients at US study sites. Significance and vision Combination HC-7366 plus belzutifan, supported by preclinical evidence, is being studied to assess antitumor activity in the RCC relapsed setting. Determining safety and evaluation of dose are foundational to this study. Reference Stokes M, Tameire F, Wojnarowicz P, et al. HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models. Meeting of the American Association for Cancer Research; 2024 Apr 5-10; San Diego (CA); AACR; 2024. Abstract 4615. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

The TRIPOD-LLM Statement: A Targeted Guideline For Reporting Large Language Models Use.

DSB: Editorial, unrelated to this work: Associate Editor of Radiation Oncology, HemOnc.org (no financial compensation); Research funding, unrelated to this work: American Association for Cancer Research; Advisory and consulting, unrelated to this work: MercurialAI. DDF: Editorial, unrelated to this work: Associate Editor of JAMIA, Editorial Board of Scientific Data, Nature; Funding, unrelated to this work: the intramural research program at the U.S. National Library of Medicine, National Institutes of Health. JWG: Editorial, unrelated to this work: Editorial Board of Radiology: Artificial Intelligence, British Journal of Radiology AI journal and NEJM AI. All other authors declare no conflicts of interest.

Is There a Mathematician on Board?

As convergence science is emerging as a theme in cancer research, scientists from diverse backgrounds, including mathematics, are increasingly entering our research community. The captain of a Southwest Airlines flight recently paged in jest for a mathematician to help support fuel calculations that would enable a flight to arrive safely at the American Association for Cancer Research (AACR) Annual Meeting, epitomizing the need for well-trained mathematicians to address pressing problems. Here, we summarize the roles mathematicians can play in cancer research and the support needed to facilitate their entry into the cancer research field. The inclusion of scientific diversity across quantitative and engineering disciplines is critical for advancing the understanding and treatment of cancer.

Reflections and Roadmaps: Career Development beyond the FDA-AACR Oncology Educational Fellowship.

In 2020, the FDA's Oncology Center of Excellence, in collaboration with the American Association for Cancer Research, launched a novel educational partnership known as the FDA-AACR Oncology Educational Fellowship. This year-long program is aimed for hematology/oncology fellows, scientists, and early-career investigators, offering an in-depth exploration of the regulatory review process by blending didactic learning with practical cases discussing oncology drug approvals. The fellowship has been met with enthusiastic feedback, with participants lauding its role in demystifying the regulatory landscape and enhancing their professional careers. This article reflects on the experiences of four alumni, showcasing the program's transformative impact across diverse oncology career paths in government, academia, and industry.

Broadening Eligibility Criteria for Clinical Trials May Benefit Participating Patients

Results of a review published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR), seem to suggest that patients with treatment-refractory cancers who received eligibility and testing waivers to participate in a large basket/umbrella oncology trial, had similar rates of clinical benefit and adverse events as patients who participated in the trial without waivers.

Characterization of HER2 alterations in lung adenocarcinoma.

8534 Background: Mutations in the human epidermal growth factor receptor 2 (ERBB2; HER2) are oncogenic in lung adenocarcinoma (LUAD). An FDA-approved drug, trastuzumab deruxtecan, is now available as second line treatment (rx) of patients (pts) with HER2 mutated NSCLC. HER2 activation occurs via gene mutation (mt), gene amplification (amp), or protein overexpression. Further information is needed about HER2 alterations (alt) and the potential association with rx response. The purpose of this study is to describe the genomic landscape of a cohort of pts with HER2 alt LUAD in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). Methods: In a cohort of 16,241 NSCLC LUAD pts available in GENIE v.13.0, we analyzed the association of HER2 alt (mt/amp) with alt in other driver genes. Also, we assessed the relationship between HER2 alt and expression levels using TCGA and CPTAC cohorts (566 and 110 pts), and prognosis using GENIE NSCLC BPC cohort (1,846 pts). Results: LUAD pts were classified as having KRASmt (K; 6426 pts; 31.9%), EGFRmt (E; 5256 pts; 26%) or EML4-ALK fusion (A; 102 pts; 0.5%). The remainder were classified as “KRAS/EGFR/ALK other (KEAother).” HER2mt (6.06%) and amp (2.06%) were more frequent in the KEAother cohort(p<0.001). HER2 amp were also found more frequently in the E deletion(del) mt cohort (1.63%), compared to KA cohorts (p<0.001). Additionally, there was significant co-occurrence of HER2 mt and HER2 amp (OR 6.49; p<0.001) in the KEAother cohort. HER2mt/amp had significant odds of co-occurrence with TP53 alt (OR 1.43; p<0.001), CDKN2A del (OR 2.15; p<0.001), TERT amp (OR 2.37; p<0.001), RB1 alt (OR 1.6; p<0.001). Additionally, HER2 amp co-occurred with TP53 alt (OR 4.0; p<0.001), CDKN2A del (OR 3.44; p<0.001), while HER2 mt co-occurred with CDKN2A del (OR 2.03; p<0.001), TERT amp (OR 2.43; p<0.001). BRAF mts were mutually exclusive with HER2 mt/amp (OR 2.31; p<0.001) and HER2 mt (OR 1.93; p<0.001). In the E cohort, there was a significant rate of HER2 mt or amp co-occurring with RB1 alt (OR 2.95; p<0.001). Despite limited survival data in the GENIE database, HER2 mt and amp had a trend toward inferior mOS (HER2mt 29.4 months vs HER2amp 27.8 months vs HER2wt 51.0 months), but this difference was not statistically significant. High HER2 mRNA expression is associated with increased age, while low expression is associated with stage IV disease. Pts with high HER2 expression that never smoked, have a trend toward inferior mOS (p=0.19), but this is based on a limited number of pts (n=18). Conclusions: HER2 mts are found in 1-4% of pts with NSCLC but can be identified in up to 6% of KEAother NSCLC. In contrast to prior reports, there was a significant rate of co-occurring HER2 mt and HER2 amp. BRAF mts were mutually exclusive with both HER2 mt and amp. Further analysis using the Caris database is planned to evaluate clinical outcomes by HER2 alt, co-mts, and prior rx received.

Representation of Hispanics with liver cancer in oncology genotype databases.

e13721 Background: Hispanic Individuals, constituting the second largest subpopulation in the United States after non-Hispanic Whites (NHW), experience significant ethnic disparities in the incidence and prevalence of liver cancer. Notably, Hispanics bear the highest burden, with 15.1% of liver cancer cases occurring in this group from 2015-2019, surpassing rates in Asian (12.5%), non-Hispanic Black (NHB, 11%), and non-Hispanic White (NHW, 7.5%) individuals. According to the SEER Database, in 2020, there were 15,878 Hispanics, 12,551 NHB and 57,483 NHW individuals living with liver cancer. Methods: We conducted a comprehensive analysis of larger oncology genotype databases encompassing all cancer types to assess the representation of Hispanic individuals with liver cancer. Five databases, including Cancer LivER, NCI GDC Data Portal, cBioPortal & American Association for Cancer Research (AACR) Project GENIE, The International Cancer Genome Consortium (ICGC) Data Portal, and HCCDB: Integrative Molecular Database of Hepatocellular Carcinoma, were analyzed. Ethnicity data and the number of Hispanic individuals with liver cancer were extracted from each. Results: The databases analyzed revealed significant underrepresentation of Hispanic individuals with liver cancer. NCI GDC Data Portal reported 834 cases, with only 2.5% identified as Hispanic. cBioPortal and AACR Project GENIE's TCGA-LIHC dataset included 377 cases, with 4.8% identified as Hispanic. The ICGC Data Portal encompassed 377 patients, but ethnicity is not available. HCCDB, consisting of 24 HCC datasets, did not include ethnicity information. Cancer LivER, with 115 dataset matrices also lacked ethnicity data. Conclusions: Hispanic Individuals exhibit the highest relative incidence rates of liver cancer among major racial or ethnic groups in the US, yet they are markedly underrepresented in oncology genotype databases, comprising less than 5% of liver cancer patients in those reporting ethnicity. This discrepancy poses a critical challenge to advancing the understanding of liver cancer in the Hispanic population. Addressing the lack of ethnic characteristics and increasing the number of Hispanic cases in these databases is essential for more comprehensive insights into liver cancer within this ethnic group.

First-in-human, phase 1/2 study of GSK4524101, an oral DNApolymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors.

TPS3174 Background: Double-stranded DNA breaks (DSBs) in human cells are typically repaired via nonhomologous end joining (NHEJ) or homologous recombination (HR). Deficiency of HR-mediated DNA repair plays a role in the initiation and progression of many tumor types. In tumors with HR deficiency, PARP inhibition leads to generation of DSBs that cannot be effectively repaired because of the HR defect, resulting in synthetic lethality. This finding has led to the clinical development and approval of several PARPi for the treatment of various tumors including certain ovarian, breast, prostate, and pancreatic cancers that are prone to display HR deficiency (HRd). DNA polymerase theta (encoded by POLQ) mediates an alternative DNA repair mechanism, microhomology-mediated end joining (MMEJ). DNA polymerase theta is generally not detectable in normal tissues but is upregulated in many tumor types. In preclinical studies, POLQi plus PARPi treatment demonstrated superior efficacy to PARPi alone in preventing the growth of HRd tumors. To evaluate the clinical potential of combining POLQi and PARPi, this first-in-human study investigates treatment with GSK4524101, an investigational POLQi, with or without the PARPi niraparib, in patients with solid tumors. Methods: This open-label, multicenter, phase 1/2 study (NCT06077877) opened in October 2023 and comprises dose-finding (part 1, including a food-effect cohort) and dose-expansion (part 2) parts. This trial aims to assess the maximum-tolerated dose, pharmacokinetics, safety, and preliminary antitumor activity of oral GSK4524101 with or without niraparib. The primary endpoints are safety (part 1) and confirmed objective response rate (part 2). Secondary endpoints include pharmacokinetics, safety, progression-free survival (part 2), and response duration (part 2). Up to 135 patients may be enrolled. To be eligible, patients must be aged ≥18 years; have an advanced or metastatic solid tumor, an Eastern Cooperative Oncology Group performance status score of 0–2, and a life expectancy of ≥3 months; and have exhausted all standard treatment options. Individuals are ineligible if they have not recovered from chemotherapy-associated adverse events or have symptomatic uncontrolled brain or leptomeningeal metastases, a history of myelodysplastic syndrome or acute myeloid leukemia, uncontrolled hypertension, or a second malignancy that has progressed or required active treatment in the previous 2 years. The study is actively recruiting in the US and Canada; as of January 1, 2024, 1 patient has been dosed. Patients enrolled in part 1 will receive GSK4524101 alone or GSK4524101 plus niraparib; patients enrolled in part 2 will be randomized to either GSK4524101 plus niraparib or niraparib alone. Part 1 of this study is expected to complete in 2025. Data presented on behalf of the original authors with their permission. Presented at the American Association for Cancer Research (AACR) Annual Meeting 2024; April 5-10, 2024; San Diego, CA. Final publication number: 9686. Reused with permission. Clinical trial information: NCT06077877 .

AACR Cancer Disparities Progress Report 2024: Achieving the Bold Vision of Health Equity.

Advances in cancer prevention, early detection and treatments have led to unprecedented progress against cancer. However, these advances have not benefited everyone equally. Because of a long history of structural inequities and systemic injustices in the United States, many segments of the US population continue to shoulder a disproportionate burden of cancer. The American Association for Cancer Research (AACR) Cancer Disparities Progress Report 2024 (CancerDisparitiesProgressReport.org) outlines the recent progress against cancer disparities, the ongoing challenges faced by medically underserved populations, and emphasizes the vital need for further advances in cancer research and patient care to benefit all populations.

Abstract 4977: The prevalence of key oncogenic driver mutations in stage I-III non-small cell lung cancer: Results from the AACR GENIE BPC dataset

Abstract Background: While there is growing interest in targeted therapy for non-small cell lung cancer (NSCLC) in perioperative settings, data on key oncogenic driver mutations is limited in early-stage NSCLC. This real-world database study aims to evaluate the prevalence of select genomic alterations in stage I-III NSCLC. Methods: From the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) V2.1-consortium dataset, we included adult patients with a confirmed diagnosis of NSCLC who had genomic testing using stage I-III NSCLC tissue samples. Descriptive statistics were used to summarize baseline characteristics and the prevalence of select genomic alterations. Results: A total of 465 patients were included in this study, of whom 61% were female, 85% were white, 19% were never smokers, and 77% had adenocarcinoma. Less than 2% of the study population had BRAF V600E, HER2 activating mutations, HER2 amplification, MET amplification, HER3 amplification, RET fusion, ALK fusion, or ROS1 fusion. Among genomic alterations with a prevalence of 2% or higher, such as EGFR sensitizing mutations, KRAS G12C, MET exon 14 skipping, STK11, KEAP1, and TP53, some variations in prevalence were observed across baseline patient and disease characteristics such as race, smoking status, and histology (Table 1). Conclusion: The prevalence of key oncogenic drivers and its relationship to select baseline disease characteristics among patients with early-stage NSCLC are similar to those of advanced NSCLC observed in other real-world clinico-genomic databases. Table 1. Prevalence of Select Genomic Alterations in Stage I-III NSCLC (N=465) Prevalence of Positive Biomarker Status (%) EGFR KRAS G12C MET Exon 14 Skipping STK11* KEAP1* TP53 Overall 17.6 12.7 4.5 16.0 11.0 52.7 Gender Male 7.1 9.3 5.5 18.5 18.5 59.6 Female 24.5 15.9 3.9 14.3 6.3 48.2 Race White 15.6 14.1 4.5 16.5 12.0 53.7 Black 15.0 5.0 5.0 22.2 11.1 60.0 Asian 44.0 4.0 8.0 8.3 4.2 44.0 Smoking Status Never smoker 41.4 1.2 6.9 4.7 1.2 36.8 Former smoker 13.7 16.0 4.6 17.4 12.9 52.4 Current smoker 5.7 12.9 1.4 23.9 15.4 72.9 Histology Adenocarcinoma 20.1 14.3 4.6 18.1 10.4 46.0 Squamous cell carcinoma 0 2.9 4.4 4.6 14.1 86.8 *The numbers of patients tested for STK11 and KEAP1 were 457 and 445, respectively. Citation Format: Ke Zu, Jiemin Ma, Cai Chen, Christine Pierce. The prevalence of key oncogenic driver mutations in stage I-III non-small cell lung cancer: Results from the AACR GENIE BPC dataset [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4977.

Patterns of Smoking Cessation Strategies and Perception of E-cigarette Harm Among Bladder Cancer Survivors.

Cigarette smoking is the leading preventable cause of bladder cancer (BC). Some proponents of e-cigarettes describe their use as a risk mitigation strategy despite potential carcinogen exposure and uncertain long-term risks. We assessed smoking cessation strategies, including e-cigarette use, and harm perception among patients with BC. We performed a cross-sectional study on a convenience sample of patients with BC at a single institution from August 2021 - October 2022. The survey instrument was sourced from the Cancer Patient Tobacco Use Questionnaire (C-TUQ) from the American Association for Cancer Research with standardized questions on tobacco use, cessation questions, and e-cigarette harm perceptions. Of the 104 surveyed BC patients (mean age: 72 years; 27% female; 55% with muscle-invasive disease), 20% were current smokers (median pack years: 40) and 51% were former smokers (median pack years: 20). A minority (9%) had quit smoking at the time of diagnosis. Pharmacotherapy for smoking cessation included nicotine patches (25%), gum (21%), lozenges (8%), e-cigarettes (8%), and Varenicline/Bupropion (4%). Notably, 43% of patients who continued to smoke expressed willingness to switch to e-cigarettes as a cessation aid. E-cigarette users (11%) more commonly perceived e-cigarettes as non-harmful compared to former (4%) and non-smokers (4%) (P = .048), though all groups regarded e-cigarettes as equally addictive as traditional cigarettes. Despite the prevalence of BC survivors who continue to smoke, a significant proportion perceive e-cigarettes as a viable and less harmful cessation aid. The infrequent use of FDA-approved pharmacotherapies underscores potential implementation gaps. These findings highlight the need for further research and targeted interventions in addressing smoking cessation among BC survivors.

Abstract A002: Collaboration between the physician/researcher and patient/survivor is key

Abstract In May 2009, I went to see my primary care physician for a routine annual physical exam. I told her that I thought I was starting menopause. She did a typical physical including a pelvic exam and did not notice anything abnormal; but she decided to send me for a vaginal ultrasound. The ultrasound revealed that both my ovaries were massive. My physician sent me to my gynecologist for further follow up. My gynecologist advised me to have a complete hysterectomy and she had a CA-125 blood test done. It came back elevated. She told me I had ovarian cysts. A family friend, an OB-GYN, reviewed my test results and urged me to get a second opinion with a gynecological oncologist. Fortunately, I was able to see a Gyn-Onc who scheduled surgery. This doctor confirmed that I had complex ovarian cysts but could not determine if there was any malignancy until my surgery. Urging patients to see gynecological oncologists is one of the most important things that can be done to save women’s lives. During my debulking surgery it was discovered that I had High Grade Epithelial Ovarian Cancer. I started a six-month chemotherapy regime of Taxol and Carboplatin. It was hard on my body—I became anemic, required blood transfusions, had digestive problems, and experienced a level of fatigue that I never knew existed. Halfway through chemo I had genetic counseling and decided to take the BRCA1 gene mutation test. I tested positive—most likely because of my Eastern European Ashkenazi Jewish heritage. There is a history of breast cancer, pancreatic cancer, colon cancer and brain cancer in my family. Due to my BRCA1+ status I had a prophylactic mastectomy and breast reconstruction which took place in December 2010. Here is a video that I created to help bring awareness to the importance of genetic testing: https://youtu.be/Fm72svK2zKw I am a Research Advocate for OVCA patients and survivors. I participate in clinical trials. I teach yoga and mindfulness practices at retreats for cancer survivors. I participate in OCRA’s Survivors Teaching Students program at the University of Washington Medical School. I am a peer mentor for Imerman’s Angels, OCRA and Sharsheret. I serve as a Survivor Ambassador for: Clearity Foundation, Amy K. Rosenthal Foundation, Rivkin Foundation and Powell Drescher OVCA Research Foundation. I am a peer reviewer for the DOD’s Ovarian OCRP. In April 2023 I attended the Annual Meeting of American Association for Cancer Research as part of the AACR Scientist↔Survivor Program. During the poster sessions I met almost 100 researchers whose focus is Ovarian Cancer and only six of them had ever met an actual Ovarian Cancer patient/survivor. I want my survivorship to impact the discovery of effective tests for early diagnosis and treatment of OVCA. I believe that the collaboration between the physician/researcher and the patient/survivor will bring new solutions to dealing with an OVCA diagnosis and treatments. Citation Format: Deborah J. Binder. Collaboration between the physician/researcher and patient/survivor is key [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A002.

Genomic drivers in craniopharyngiomas: Analysis of the AACR project GENIE database.

Craniopharyngiomas are rare tumors originating in the sellar region, with limited information on their somatic mutational landscape. In this study, we utilized a publicly available genomic database to profile the somatic mutational landscape of craniopharyngioma patients and interrogate differences based on histologic subtype. We utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE)® database accessed from cBioPortal (v13.1-public) to query all patients with craniopharyngiomas. Of the 336 patients with sellar tumors, 51 (15.2%) had craniopharyngiomas. Of these 51 patients, 42 (82.4%) were adamantinomatous subtype and 9 (17.6%) were papillary subtype. In this cohort, 32 (62.7%) patients were pediatric, while 19 (37.3%) were adult. The top mutations in the cohort were: CTNNB1 (n = 37; 73%), BRAF (n = 7; 14%), ARID1B (n = 5; 10%), KMT2D (n = 4; 8%), FANCA (n = 4; 8%), ATM (n = 4; 8%), and TERT (n = 3; 8%). Of the 37 patients with CTNNB1 mutations, 8 (21.6%) had S33X, 9 (24.3%) had S37X, 7 (18.9%) had T41X, and 5 (13.5%) had D32X. In this cohort, CTNNB1 mutations tended to co-occur with ATM (n = 4; 10.8%), KMT2C (n = 4; 10.8%), TERT (n = 3; 8.1%), BLM (n = 3; 8.1%), and ERBB2/3 (n = 3; 8.1%), suggesting CTNNB1 mutations tended to co-occur with mutations in genes important in cell growth and survival, chromatin accessibility, and DNA damage response pathways. CTNNB1 mutations account for a large proportion of somatic mutations in craniopharyngiomas. Identification of specific point mutations and secondary drivers may advance development of novel craniopharyngioma preclinical models for targeted therapy testing.

Translating Science into Survival: Report on the Seventh International Cancer Immunotherapy Conference.

From September 20 to 23, 2023, the Seventh International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the European Network for Cancer Immunotherapy (ENCI), and the American Association for Cancer Research (AACR) in Milan, Italy. The four-day event covered the latest advances in cancer immunology and immunotherapy.