Cancer Institute Research Articles

Survival of adult AML patients treated with chemotherapy in the U.S. population by age, race and ethnicity, sex, calendar-year period, and AML subgroup, 2001–2019

Population-based survival studies of adult acute myeloid leukemia (AML) have not simultaneously evaluated age at diagnosis, race and ethnicity, sex, calendar period or AML subtypes/subgroups among chemotherapy-treated patients. For 28,473 chemotherapy-treated AML patients diagnosed at ages ≥20 years in population-based cancer registry areas of the Surveillance, Epidemiology, and End Results Program (2001-2018, followed through 2019), we evaluated 1-month through 5-year relative survival (RS) and 95% confidence intervals (95% CI) using the actuarial method in the SEER∗Stat Survival Session and overall survival (OS) using multivariable Cox regression to estimate proportional hazard ratios (HR) and 95% CI. RS decreased with increasing age (20-39, 40-59, 60-74, 75-84, ≥85 years) at AML diagnosis. RS declined substantially within the first month and, except for acute promyelocytic leukemia, decreasing patterns continued thereafter for core binding factor AML, AML with antecedent condition/therapy, and all other AML. For all ages, acute promyelocytic leukemia RS stabilized after the first year. For total AML the hazard of death was significantly increased for non-Hispanic (NH)-Black (HR=1.18, 95% CI=1.12-1.24) and NH-Pacific Islander patients (HR=1.31, 95% CI=1.11-1.55) compared with NH-White patients. In contrast, NH-Asian and Hispanic patients had similar OS to NH-White patients across all ages and most AML subgroups. Males had significantly inferior survival to females with some exceptions. Compared to 2001-2006, in 2013-2018 OS improved for all age and AML subgroups. Chemotherapy-treated U.S. adults with AML have notable differences in survival by age, race and ethnicity, sex, calendar-year period, and AML subgroup. Despite survival gains over time, our findings highlight the need for improving early outcomes across all AML subgroups, older ages, and Black and Pacific Islander patients and long-term outcomes among most treated groups. Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology.

Thiazole Derivatives as RORγt Inhibitors: Synthesis, Biological Evaluation, and Docking Analysis

Background: Cancer is a serious concern in developing countries. Due to various worldwide impacts, it has surpassed coronary disorders becoming the leading cause of mortality. In cancer progression, the involvement of RORs (retinoic acid receptor-related orphan receptors) has gained attention in the search for versatile agents. Thiazole has the potential to be used as a scaffold in the development of anticancer drugs. Objective: This work’s major goal was to design and synthesize promising anticancer candidates. Methods: Docking investigations concerning the RORγt receptor were utilized in the design of the compounds. A series of novel thiazole derivatives was synthesized employing Hantsch synthesis. Melting points, TLC development, and spectral analyses were considered for the synthesized compounds' characterization. Corresponding spectra were analyzed and determined to be consistent with the assigned structure. On 60 human cancer cell lines, selected compounds were investigated in vitro by NCI (National Cancer Institute), USA, for anticancer action. Results: Varying ratios of anticancer potential were presented by the compounds in in vitro studies. Compound 3c was determined to be the most active compound in the series, with a -15.03 mean growth percent. In silico study revealed that the synthesized compounds could have anticancer possibilities. In the targeted pdb id (6q7a) binding site, compound 3c demonstrated excellent docking scores in molecular docking analyses, supporting its ability to be utilized as a lead compound in rational drug design. Conclusion: Compounds with satisfactory docking scores within the binding pocket of chosen pdb id (6q7a) validated their suitability for usage as lead compounds in rational drug design. Outcomes of in silico investigations were in agreement with the findings of the cytotoxicity experiments. Leukemia, renal, breast, and lung cancer cell lines were most sensitive to the substance-treated tumor cells. Electronwithdrawing groups were essential for antiproliferative action, according to the findings.

Comprehensive Assessment of the Intrinsic Pancreatic Microbiome.

We sought to comprehensively profile tissue and cyst fluid in patients with benign, precancerous, and cancerous conditions of the pancreas to characterize the intrinsic pancreatic microbiome. Small studies in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) have suggested that intra-pancreatic microbial dysbiosis may drive malignant transformation. Pancreatic samples were collected at the time of resection from 109 patients. Samples included tumor tissue (control, n=20; IPMN, n=20; PDAC, n=19) and pancreatic cyst fluid (IPMN, n=30; SCA, n=10; MCN, n=10). Assessment of bacterial DNA by quantitative PCR and 16S ribosomal RNA gene sequencing was performed. Downstream analyses determined the relative abundances of individual taxa between groups and compared intergroup diversity. Whole-genome sequencing data from 140 patients with PDAC in the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to validate findings. Sequencing of pancreatic tissue yielded few microbial reads regardless of diagnosis, and analysis of pancreatic tissue showed no difference in the abundance and composition of bacterial taxa between normal pancreas, IPMN, or PDAC groups. Low-grade dysplasia (LGD) and high-grade dysplasia (HGD) IPMN were characterized by low bacterial abundances with no difference in tissue composition and a slight increase in Pseudomonas and Sediminibacterium in HGD cyst fluid. Decontamination analysis using the CPTAC database confirmed a low-biomass, low-diversity intrinsic pancreatic microbiome that did not differ by pathology. Our analysis of the pancreatic microbiome demonstrated very low intrinsic biomass that is relatively conserved across diverse neoplastic conditions and thus unlikely to drive malignant transformation.

A population-based study of COVID-19 mortality risk in US cancer patients.

In this study, we provide the largest analysis to date of a US-based cancer cohort to characterize death from COVID-19. A total of 4,020,669 patients across 15 subtypes living with cancer in 2020 and included in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database were abstracted. We investigated prognostic factors for death due to COVID-19 using a cox proportional hazards model and calculated hazard ratios (HRs). Standardized mortality ratios (SMRs) were calculated using observed mortality counts from SEER and expected mortality based on U.S. mortality rates. 291,323 patients died, with 14,821 (5.1%) deaths attributed to COVID-19 infection. The COVID-19 disease-specific mortality rate was 11.81/10,000-persons years, and SMR of COVID-19 was 2.30 (95% CI: 2.26-2.34, p < .0001). COVID-19 ranked as the second leading cause of death following ischemic heart disease (5.2%) among 26 non-cancer causes of death. Patients who are older (80+ vs < =49 years old: HR 21.47, 95% CI: 19.34-23.83), male (vs female: HR 1.46, 95% CI: 1.40-1.51), unmarried (vs married: HR 1.47, 95% CI: 1.42-1.53), and Hispanic or Non-Hispanic African American (vs Non-Hispanic White: HR 2.04, 95% CI: 1.94-2.14 and HR 2.03, 95% CI: 1.94-2.14, respectively) were at greatest risk of COVID-19 mortality. We observed that people living with cancer are at two times greater risk of dying from COVID-19 compared to the general US population. This work may be used by physicians and public health officials in the creation of survivorship programs that mitigate the risk of COVID-19 mortality.

Prevalence of micronutrient inadequacy differs by severity of food insecurity among adults living in Canada in 2015.

Household food insecurity is generally associated with poorer quality diets in Canada, but whether household food insecurity heightens the probability of inadequate micronutrient intakes is unknown. The objective of this research was to investigate how prevalence of micronutrient inadequacy differed by severity of household food insecurity among adults in Canada. Using the 2015 Canadian Community Health Survey Nutrition, this study included participants aged 19-64 years who completed up to two 24-hour dietary recalls and provided details about household food insecurity (n = 9486). Children and older adults were not included due to sample size limitations. Usual micronutrient intake distributions were estimated by a 4-level measure of food insecurity status using the National Cancer Institute method. Welch's t-tests assessed differences in prevalence of inadequacy for selected micronutrients. Prevalence differed for some micronutrients among those living in marginally and moderately food insecure compared to food secure households. The greatest differences in prevalence of inadequacy were observed between severely food insecure and food secure households: vitamin A (60.0%, SE=11.9 vs. 40.6%, SE=2.7, p<0.0001), vitamin B6 (42.7%, SE=9.1 vs. 12.8%, SE=2.5, p<0.0001), folate (39.4%, SE=10.0 vs. 15.9%, SE=2.2, p<0.0001), vitamin C (63.3%, SE=5.2 vs. 29.1%, SE=2.8, p<0.0001), calcium (78.6%, SE=6.4 vs. 58.7%, SE=1.3, p<0.0001), magnesium (75.6%, SE=9.5 vs. 48.7%, SE=1.2, p<0.0001), and zinc (34.9%, SE=10.0 vs. 23.2%, SE=2.4, p=0.0009). Apparent underreporting also differed by severity of food insecurity, with increased underreporting observed with worsening food insecurity. The probability of inadequate micronutrient intakes among adults rises sharply with more severe household food insecurity in Canada.

Accrual Quality Improvement Program for clinical trials.

The Early Phase Cancer Prevention Clinical Trials Program (Consortia), led by the Division of Cancer Prevention, National Cancer Institute, supports and conducts trials assessing safety, tolerability, and cancer preventive potential of a variety of interventions. Accrual to cancer prevention trials includes the recruitment of unaffected populations, posing unique challenges related to minimizing participant burden and risk, given the less evident or measurable benefits to individual participants. The Accrual Quality Improvement Program was developed to address these challenges and better understand the multiple determinants of accrual activity throughout the life of the trial. Through continuous monitoring of accrual data, Accrual Quality Improvement Program identifies positive and negative factors in real-time to optimize enrollment rates for ongoing and future trials. The Accrual Quality Improvement Program provides a web-based centralized infrastructure for collecting, analyzing, visualizing, and storing qualitative and quantitative participant-, site-, and study-level data. The Accrual Quality Improvement Program approaches cancer prevention clinical trial accrual as multi-factorial, recognizing protocol design, potential participants' characteristics, and individual site as well as study-wide implementation issues. The Accrual Quality Improvement Program was used across 39 Consortia trials from 2014 to 2022 to collect comprehensive trial information. The Accrual Quality Improvement Program captures data at the participant level, including number of charts reviewed, potential participants contacted and reasons why participants were not eligible for contact or did not consent to the trial or start intervention. The Accrual Quality Improvement Program also captures site-level (e.g. staffing issues) and study-level (e.g. when protocol amendments are made) data at each step of the recruitment/enrollment process, from potential participant identification to contact, consent, intervention, and study completion using a Recruitment Journal. Accrual Quality Improvement Program's functionality also includes tracking and visualization of a trial's cumulative accrual rate compared to the projected accrual rate, including a zone-based performance rating with corresponding quality improvement intervention recommendations. The challenges associated with recruitment and timely completion of early phase cancer prevention clinical trials necessitate a data collection program capable of continuous collection and quality improvement. The Accrual Quality Improvement Program collects cumulative data across National Cancer Institute, Division of Cancer Prevention early phase clinical trials, providing the opportunity for real-time review of participant-, site-, and study-level data and thereby enables responsive recruitment strategy and protocol modifications for improved recruitment rates to ongoing trials. Of note, Accrual Quality Improvement Program data collected from ongoing trials will inform future trials to optimize protocol design and maximize accrual efficiency.

Housing Assistance Among Patients with Cancer: SEER-Medicare U.S. Department of Housing and Urban Development Data Linkage.

Lack of stable and affordable housing is an important social determinant of health. Federal housing assistance may buffer against housing vulnerabilities among low-income households, but research examining the association of housing assistance and cancer care has been limited. We introduce a new linkage of SEER-Medicare and Housing and Urban Development (HUD) administrative data. Individuals enrolled in HUD public and assisted housing programs 2006-2021 were linked with cancer diagnoses 2006-2019 identified in the SEER-Medicare data from 16 states using Match*Pro probabilistic linkage software. HUD administrative data include timing and type of housing assistance and verified household income. Medicare administrative data are available through 2020. A total of 335,490 unique individuals who received housing assistance matched to SEER-Medicare data at any point in time, including 156,794 that recieved housing assistance around the time of their diagnosis (at least 6 months prior to diagnosis until 6 months after diagnosis or death). A total of 63,251 persons with housing assistance at the time of their diagnosis were aged 66 years and older and continuously enrolled in Medicare Parts A and B fee-for-service, 12,035 with lung, 8,866 with breast, 7,261 with colorectal, and 4,703 with prostate cancer. This novel data linkage will be available through the National Cancer Institute and can be used to explore the ways in which housing assistance is associated with cancer diagnosis, care, and outcomes, including the role of housing assistance status in potentially reducing or contributing to inequities across racialized and ethnic groups.

Adverse Event Reporting in Cancer Clinical Trials: Incorporating Patient-Reported Methods. A Systematic Scoping Review.

The history of clinical trials is fraught with unethical practices. Since 1945, robust frameworks have evolved to standardise the collection and reporting of safety data, most notably, the Common Terminology Criteria for Adverse Events (CTCAE) from the National Cancer Institute; used by investigators to report side effects experienced by participants. As medicine moves into the patient-centred model, interest has been growing to collect data on adverse events directly from participants (patient-reported adverse events). The aim of this systematic scoping review was to investigate the inclusion of patient-reported adverse event data within safety/tolerability analyses and explore the collection and reporting of patient-reported adverse event data. A database search was undertaken and the Covidence platform was used to manage the review; results were analysed descriptively. Sixty-eight studies were included in the analysis. An increase in the number of studies that incorporate patient-reported adverse event data was seen by year. Seventy instruments were used for the collection of patient-reported adverse event data with recall period, mode, frequency and site of administration varying across studies; the duration of data collection ranged from 28 days to 6 years. Frequently, information on these details was omitted from publications. The number of instruments used by studies to collect patient-reported adverse event data ranged from one to seven instruments. Despite growing calls for the inclusion of patient-reported adverse events, this has not yet translated into published reports. The collection and reporting of these data were variable and conducted using instruments that were not designed for purpose. To address these inconsistencies, standardisation of data collection and reporting using a purpose-built validated instrument is required.

[Pembrolizumab plus nab-paclitaxel and platinum as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma: a prospective phaseⅡstudy].

Objective: To evaluate the efficacy and safety of pembrolizumab plus nab-paclitaxel and platinum as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC). Methods: This was a prospective, single-arm, open label, phase 2 clinical study enrolling patients at the Cancer Hospital of the Chinese Academy of Medical Sciences with R/M HNSCC treated with pembrolizumab plus nab-paclitaxel and cisplatin or carboplatin. After six cycles of treatment, patients received pembrolizumab as maintenance therapy until disease progression or intolerable toxicity or completion of 35 cycles of treatment. The primary endpoint was objective response rate, and secondary endpoints included overall survival, progression-free survival, and safety profile. Efficacy was evaluated according to the response evaluation criteria in solid tumors 1.1, survival analysis was performed using the Kaplan-Meier method, and adverse events were assessed using the America National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Results: A total of 30 patients with R/M HNSCC were enrolled from 23 April 2021 to 22 March 2023, including 28 males and 2 females, with a median age of 67 years. The median follow-up time was 14.5 months, the objective response rate was 70.0%, the disease control rate was 96.7%, and the median progression-free survival and overall survival of all patients were 11.6 months and 18.8 months, respectively. Median duration of response was up to 17.3 months. Grade≥3 treatment-related adverse events were leukopenia (26.7%), neutropenia (26.7%), peripheral neurotoxicity (3.3%), rash (3.3%), hyperalgesia (3.3%), and immune-related pneumonitis (3.3%). The most common immune-related adverse event was hypothyroidism (40.0%). Conclusion: Pembrolizumab combined with nab-paclitaxel and platinum shows encouraging antitumor activity accompanied with a manageable safety profile in untreated R/M HNSCC patients in China.

Learning from conect4children: A Collaborative Approach towards Standardisation of Disease-Specific Paediatric Research Data

The conect4children (c4c) initiative was established to facilitate the development of new drugs and other therapies for paediatric patients. It is widely recognised that there are not enough medicines tested for all relevant ages of the paediatric population. To overcome this, it is imperative that clinical data from different sources are interoperable and can be pooled for larger post hoc studies. c4c has collaborated with the Clinical Data Interchange Standards Consortium (CDISC) to develop cross-cutting data resources that build on existing CDISC standards in an effort to standardise paediatric data. The natural next step was an extension to disease-specific data items. c4c brought together several existing initiatives and resources relevant to disease-specific data and analysed their use for standardising disease-specific data in clinical trials. Several case studies that combined disease-specific data from multiple trials have demonstrated the need for disease-specific data standardisation. We identified three relevant initiatives. These include European Reference Networks, European Joint Programme on Rare Diseases, and Pistoia Alliance. Other resources reviewed were National Cancer Institute Enterprise Vocabulary Services, CDISC standards, pharmaceutical company-specific data dictionaries, Human Phenotype Ontology, Phenopackets, Unified Registry for Inherited Metabolic Disorders, Orphacodes, Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP), and Observational Medical Outcomes Partnership. The collaborative partners associated with these resources were also reviewed briefly. A plan of action focussed on collaboration was generated for standardising disease-specific paediatric clinical trial data. A paediatric data standards multistakeholder and multi-project user group was established to guide the remaining actions—FAIRification of metadata, a Phenopackets pilot with RDCA-DAP, applying Orphacodes to case report forms of clinical trials, introducing CDISC standards into European Reference Networks, testing of the CDISC Pediatric User Guide using data from the mentioned resources and organisation of further workshops and educational materials.

Abstract LB139: Disparities in oral precancerous lesion surveillance in the United States upper Midwest

Abstract Objective: To determine whether geographic representation and race of patients in a regional oral cancer surveillance program (University of Minnesota Cancer Active Surveillance Population (UMN CASP)) mirror characteristics in the corresponding National Cancer Institute (NCI) designated comprehensive cancer center catchment. Introduction: Oral cancer poses a significant public health concern that may be mitigated through lesion surveillance. Representation of patients for clinical trials throughout an NCI cancer center catchment area is a crucial goal to promote improved health outcomes. This study investigates the demographic landscape of patients with preneoplastic oral lesions seen at the CASP. Methods: Through the UMN Clinical and Translational Sciences Institute, we queried 30 International Classification of Disease (ICD) 9 and 10 codes corresponding to 120 unique mucosal oral precancerous lesion descriptors of CASP patients. Automated extraction of electronic medical record (EMR) data for 4,496 patients treated by the senior author between 2011 and 2023 identified 1,375 patients with preneoplastic lesions. The proportion of patients residing in three-digit zip code regions of Minnesota were compared to 2021 American Community Survey state population data. Additionally, race data were compared between CASP patients and the UMN Masonic Cancer Center (MCC) patient catchment data. Results: CASP patients were over-represented relative to state population distributions within the Minneapolis-St. Paul metropolitan area and surrounding suburbs (region 554 p&amp;lt;0.0001 and region 551 p&amp;lt;0.0001). Under-representation of CASP patients was observed in all western and southern border regions (regions 559 p&amp;lt;0.0001, 560 p&amp;lt;0.0001, 561 p&amp;lt;0.0001, 562 p=0.0037, 565 p&amp;lt;0.0001, and 567 p=0.0006) as well as portions of central (563 p&amp;lt;0.0001), northern (566 p=0.0015), and north-eastern (558 p&amp;lt;0.0001) Minnesota. Proportional representation was observed in several regions of central (553 and 564), eastern (550), and north-eastern (557 and 556) Minnesota. Comparisons of CASP race data revealed a higher proportion of black patients (CASP 8.59% [95% CI 7.17-10.27%] vs. MCC 7.16% [95% CI 7.14-7.17%]) and a lower proportion of Asian/Pacific Islander patients (CASP 3.74% [95% CI 2.82-4.94%] vs. MCC 5.32% [95% CI 5.30-5.34%]) relative to MCC catchment patients. White, American Indian/Alaskan Native, and mixed-race groups were proportionally represented in both data sets. Conclusions: These data show that system wide EMR searches can be implemented to identify patients in an NCI cancer center catchment area with precancerous or other at-risk conditions for cancer. Importantly, Native patients were proportionally represented in the screening program while several rural locations were under-represented. This information can instruct the expenditure of additional resources for under-represented groups and permit streamlined enrollment of patients for cancer prevention clinical trials. Citation Format: Alexander J. Dwyer, Lindsey Mortensen, Beverly R. Wuertz, Frank G. Ondrey. Disparities in oral precancerous lesion surveillance in the United States upper Midwest [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB139.

Abstract LB027: Identifying natural inhibitors of androgen receptor (AR) and its variants from NCI Natural Product Repository

Abstract Second-generation androgen ablation therapies (ADT), enzalutamide, and abiraterone are initially effective on metastatic castration-resistant prostate cancer (mCRPC). However, nearly 30-40% of patients eventually become resistant to these treatments due to the presence of androgen-receptor variants (AR-V), which lack a ligand-binding domain. The grim reality that metastatic CRPC is virtually incurable for most patients poses a significant challenge for clinicians striving to enhance these individuals' quality of life and lifespan. Considering drug discovery efforts, we partnered with the National Cancer Institute's (NCI) Natural Product Repository, which possesses a diverse collection of natural product extracts derived from plant, marine, and microbial organisms. We developed high-throughput phenotypic screening assays to screen the crude natural product extract libraries on AR and AR-variants CRPC cell lines (C4-2B and 22Rv1). Several extracts inhibited the growth of both CRPC cell lines and were further confirmed for dose-dependent cell viability inhibition assays. Once we determined the IC50 dose, we performed a Western blot analysis that confirmed the inhibition of AR and AR-V7 expression in CRPC cells.In subsequent studies, we narrowed down by fractionating the most potent extracts and confirmed their ability to inhibit AR expression and signaling on CRPC cell lines. Currently, we are characterizing the potent compounds and their inhibitory activity on AR and AR-variants, in vitro and in vivo CRPC models. Many nutraceuticals have been shown to target AR signaling, synthesis, or degradation which effectively inhibited the growth of CRPC. Our collaborative efforts with NCI will permit us find N-terminal AR degrading molecules (AF-1), which are essential for the AR transcriptional activities of CRPC. In sum, discovery of ovel small molecules from our drug development program have the potential to translate these effective natural products into drugs with clinical benefits to treat CRPC. Citation Format: Neha Tyagi, Sepideh Hosseiniporgham, Ashish Tyagi, Balaji Chandrasekaran, Katherine Bonilla, Inna Kriger, James Saccchettini, Chendil Damodaran. Identifying natural inhibitors of androgen receptor (AR) and its variants from NCI Natural Product Repository [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB027.

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Abstract Background: Acquired, somatic TP53 mutations leading to loss of p53 tumor suppressive functions are the most common genomic alteration across many cancer types. Breast cancer (BC) is the most common malignancy in females, and 50-75% of estrogen receptor (ER)-negative BC (with or without HER2 amplification) and 10-15% of ER+ BC acquire TP53 alterations. Pathogenic germline variants (PGVs) in TP53 occur in approximately 1:5000 people and lead to the Li Fraumeni Syndrome (LFS) in which individuals have an up to 90% risk of developing cancer over their lifetimes. The most common cancer in females with LFS is BC which occurs at a median age of onset of 30-35, nearly 30 years younger than sporadic BC. The distribution of BC subtypes is significantly different in LFS-BC patients compared to sporadic BC, with over half of LFS-BC being HER2+ BC and over 90% being ER+. The characteristics of LFS-BC, namely early onset and predominance of HER2+ disease, suggest different tumorigenesis mechanisms compared to sporadic breast cancer that may have implications for early detection, interception and treatment. Patients and Methods: We performed deep phenotyping on 93 LFS patients with 130 LFS-BC compared to 198 control patients with 209 nonLFS-BC. Controls were defined as having BC diagnosed age&amp;lt;50 and negative germline cancer susceptibility gene testing. We obtained clinical cases and/or blocks for histopathological analysis. DNA and RNA was extracted from available FFPE tumor blocks and analyzed using a targeted capture panel with copy number backbone-based DNA sequencing and RNAseq of ribosomal RNA depleted total RNA. A subset of LFS-BC underwent whole genome sequencing. Finally, slides underwent both single and multiplex immunohistochemistry (IHC) of immune markers. This series includes results of 22 LFS-BC, including seven cases of LFS ductal carcinoma in situ (LFS-DCIS) and 15 invasive ductal carcinomas (LFS-IDC). In addition, matched germline blood for all cases and surrounding (n=15) and/or contralateral (n=11) normal was analyzed. Finally, 27 non-LFS early onset breast cancer controls with matched blood normal were analyzed by the same pipeline. Results were also compared to sporadic BC from The Cancer Genome Atlas (TCGA). Results: Of the 137 adult women in our LFS cohort, 93 (68%) had developed at least one BC, with a total of 110 LFS-BC. The prevalence of BC in our cohort was nearly identical to the prevalence in the National Cancer Institute (NCI) public LFS database (69% of 698 females, p=0.82). The median (IQR) age of first BC diagnosis in our cohort was 36 (29,45) years, similar to the public cohort with a median (IQR) of 31 (27,38) years at first BC diagnosis. Of the 93 adult BC patients in our LFS cohort, 60 (64%) had developed synchronous or metachronous bilateral BC. In contrast, only 36 (18%) of the early-onset nonLFS-BC control cohort developed more than one BC (p&amp;lt;0.0001). LFS-BC was more commonly HER2+ compared nonLFS-BC (51% vs 20%, p&amp;lt;0.0001) Sixty pathological cases from LFS-BC were obtained including 40 (66%) invasive carcinomas, 19 (31%) pure DCIS, one malignant phyllodes. The majority of the invasive carcinomas were ductal (35, 88%) the other five were lobular, mixed ductal and lobular, and micropapillary types. All 40 invasive carcinomas were high grade, with associated DCIS in 27 (68%), lymphovascular invasion in 16 (40%), and sclerotic stroma in eight (20%). The majority of DCIS (either pure or with invasive carcinoma) was high grade (29, 63%) with comedonecrosis (19, 41%), and with associated calcifications (16). High-risk lesions such as radial scar, papilloma, atypical ductal hyperplasia, and lobular neoplasia were present in seven tumors. High p53 IHC nuclear expression (&amp;gt;50%) was seen in the majority of tumors from patients with missense mutations; whereas no protein expression (&amp;lt;1%, null pattern) was seen in majority of tumors from carriers of large exonic deletion, truncating, and splicing mutations in TP53. Using p53 IHC and sequencing results, we found evidence of biallelic loss of TP53 (fully mutant p53) in 21 of 22 (95%) LFS-BC, two of 15 surrounding normal (13%) and no contralateral normal breast tissue. Nearly all LFS-BC underwent biallelic loss of TP53 via focal copy neutral or deletion loss of heterozygosity (89%) or a somatically acquired TP53 mutation (9%). No recurrent oncogenic variants were identified except ERBB2 (HER2) copy number amplification. In contrast, recurrent oncogenic alterations in PIK3CA, GATA3 and MAP3K1 were seen in early onset nonLFS-BC, similar to sporadic BC in TCGA. Compared to nonLFS-BC, LFS-BC had lower or similar tumor mutational burden, copy number burden and aneuploid chromosome arm number. LFS-BC were instead marked by elevated focal segments of loss of heterozygosity (LOH) and allelic imbalance. Accordingly, copy number signature analysis from whole genome sequencing showed nearly all LFS-BC had undergone chromothripsis (CN5) with focal LOH on a diploid background (CN9). We identified 5115 significantly differentially expressed genes comparing LFS-BC to normal breast tissue from LFS patients. Using Gene Set Enrichment Analysis (GSEA), we found most significantly up and down regulated pathways in LFS-BC were similarly regulated in non-LFSBC compared to normal breast tissue. Notably, the apoptosis pathway was significantly down-regulated in LFS-BC but up-regulated in HER2+ early onset nonLFS-BC, likely reflecting a loss of p53 regulation of genes such as BAX and TP53I3. In addition, cholesterol homeostasis and androgen response pathways were significantly up-regulated in LFS-BC; whereas they were significantly down-regulated in both ER+Her2- and HER2+ non-LFSBC. We then performed multiplex IHC on ER+ TP53WT nonLFS-BC (n=7), nonLFS-TNBC (n=16), and LFS-BC (n=33). We found that CD8+ T cell infiltration in LFS-BC was comparable to non-LFS triple-negative BC (TNBC), a tumor type which responds well to immune checkpoint blockade therapy, and higher than in ER+ nonLFS-BC. CD20+ infiltration in LFS-BC was lower than both TNBC and ER+ nonLFS-BC. Using single stain IHC and comparing an LFS breast tumor to its surrounding normal, we found that FoxP3+ Tregs, CD68+ and CD20+ cells were enriched in the tumors compared to surrounding normal breast tissue. Finally, we compared genomic, transcriptomic and immune cell differences between DCIS and IDC in LFS. Interestingly, all genomic instability measures and gene expression profiles were similar, including focal LOH and allelic imbalances. However, CD4+ and CD8+ T-cells and CD20+ B-cells became more excluded from the tumor tissue with increasing stage of tumor. Using the ACT activity assay, we found that there was significantly higher Ki67+ and Granzyme B in LFS-DCIS as compared to LFS-IDC indicating active T-cell killing. Finally, FoxP3+ T-regulatory cell and CD68+ macrophages were lower in LFS-IDC compared to LFS-DCIS. Conclusions: Overall, our data suggest that TP53 related breast tumor formation, at least in the germline state, requires biallelic loss of TP53 as a first step. Loss of p53 tumor suppressive function in the female breast leads to focal genomic instability events, possibly with selection for ERBB2 amplification. p53 deficiency in LFS-BC leads to failure to induce apoptosis but maintained cell cycle arrest. LFS-BC resemble sporadic TNBC with high CD8+ T-cells but low CD20+ B-cells. Genomic instability and p53 transcriptional dysfunction occur very early in tumor formation; whereas the immune microenvironment evolves to be more tumor supportive during the progression from DCIS to IDC in LFS-BC. This work provides the first insights into the mechanism of germline TP53 mutation driven breast tumor formation in humans. Citation Format: Kara N. Maxwell. Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr NG02.

Abstract LB012: Evaluating computational approaches for CPTAC pan-cancer cross-cohort protein expression comparison

Abstract Recently, the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) has generated harmonized genomic, transcriptomic, proteomic, and clinical data for &amp;gt;1000 tumors in 10 cohorts to facilitate pan-cancer discovery research. However, protein expression comparison across CPTAC cohorts remains challenging due to non-uniform missing data and protein expression distribution patterns across tumor types. Here we present our efforts to evaluate various missing data handling and normalization strategies to generate a normalized pan-cancer protein expression dataset. First, we developed a novel algorithm to select robustly expressed proteins in tumors in any of the CPTAC cohorts, Second, we applied a cohort hybrid imputation approach to protein abundance values from FragPipe within each cohort based on protein expression distribution patterns. Third, we calculated iBAQ using protein abundance value and applied global quantile normalization or smooth quantile normalization methods. To assess if our missing data imputation and normalization strategy affected downstream analyses, we compared the fold change in differential protein expression between tumor and matched normal for each cohort using non-normalized, global quantile normalized and smooth quantile normalized protein iBAQ values. Our results demonstrate a strong correlation in fold change between global quantile normalized data and non-normalized data (Pearson r = 0.97 (ccRCC), r = 0.96 (COAD), r = 0.99 (LUAD) and r = 0.99 (LSCC)). Similar results were observed comparing smooth quantile normalized data to non-normalized data (Pearson r = 1.00 for ccRCC, COAD, LUAD, and LSCC), indicating both normalization methods retained biological differences between tumor and matched normal tissues within cohorts. Lastly, we identified several proteins (ERAP2, CA9, GSTM3, MX1, STAT1) whose protein and RNA expression were highly correlated across eight CPTAC cohorts (r &amp;gt; 0.7 for COAD, BRCA, LUAD, ccRCC, PDAC, UCEC, HNSCC, and LSCC). We then compared their protein expression rank across CPTAC cohorts with their RNA expression rank across corresponding TCGA cohorts. Specifically, median log2(iBAQ) of CPTAC and median log2(TPM) of TCGA are calculated for those proteins within indications, then indications are ranked by median log2(iBAQ) and median log2(TPM) in CPTAC and TCGA, respectively. Weighted rank correlation was used to measure rank agreement. Global quantile normalization has the highest rank correlation (weighted rank correlation between 0.597 to 0.931) compared to smooth quantile normalization or without normalization. These results suggest that combination of cohort hybrid imputation and global quantile normalization is a reasonable approach to generate a normalized CPTAC pan-cancer protein dataset that could be leveraged to interrogate protein expression across different cancer types. Citation Format: Jixin Wang, Xiaowen Tian, Wen Yu, John Bullen, Elaine Hurt, Wenyan Zhong. Evaluating computational approaches for CPTAC pan-cancer cross-cohort protein expression comparison [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB012.

Abstract CT283: Phase 3 MK-2870-007 study: MK-2870 (SKB264) plus pembrolizumab vs pembrolizumab alone as first-line treatment for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50%

Abstract Background: Pembrolizumab (anti-PD-1) monotherapy is a standard of care first-line treatment for advanced or metastatic non-small-cell lung cancer (NSCLC) with PD-L1 TPS ≥50% without actionable genetic alterations; however, some patients do not respond to therapy or experience disease progression. Trophoblast cell-surface antigen 2 (TROP2) is another candidate for anticancer treatment and overexpression of TROP2 is associated with poor prognosis in patients with NSCLC. MK-2870 (SKB264) is an antibody-drug conjugate (ADC) composed of the humanized TROP2 monoclonal antibody, a hydrolytically cleavable linker, and the cytotoxic drug KL610023. In patients with relapsed or refractory locally advanced or metastatic NSCLC, MK-2870 monotherapy showed encouraging antitumor activity with a manageable safety profile. The complementary mechanisms of action of MK-2870 and pembrolizumab may provide more potent antitumor activity when given in combination compared with each therapy alone. To investigate this further, the MK-2870-007 study will evaluate the efficacy and safety of the addition of MK-2870 to pembrolizumab vs pembrolizumab alone in patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥50%. Trial Design: Approximately 614 eligible patients aged ≥18 y with previously untreated histologically or cytologically confirmed stage IV (per American Joint Committee on Cancer v8.0) NSCLC, PD-L1 TPS ≥50% and no EGFR, ALK, or ROS1 alterations (nonsquamous only); ECOG PS 0 or 1; and measurable disease per RECIST v1.1 will be enrolled. Patients with well-controlled HIV are permitted. Patients will be randomized 1:1 to receive either pembrolizumab 400 mg Q6W for up to 18 cycles plus MK-2870 4 mg/kg Q2W or pembrolizumab 400 mg IV Q6W alone until progressive disease, intercurrent illness, patient withdrawal, unacceptable toxicity, prolonged interruption of study drug, or until maximum number of cycles (18 cycles for pembrolizumab). Randomization stratification factors include ECOG PS (0 vs 1), histology (squamous vs nonsquamous), TROP2 expression (low vs medium vs high), and geographic region (East Asia vs North America/Western Europe/Australia vs Rest of World). The primary endpoint is OS. Secondary endpoints include PFS, ORR, and duration of response per RECIST v1.1 by blinded independent central review, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, Q6W until wk 48, and Q12W thereafter until PD, start of new anticancer treatment, or withdrawal of consent. PD-L1 TPS will be assessed centrally using PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA). AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Enrollment began in December 2023 and is currently ongoing. Citation Format: Nikolaj Frost, Razi Ghori, Ananya Roy, Ana Tablante Nunes, James Chih-Hsin Yang. Phase 3 MK-2870-007 study: MK-2870 (SKB264) plus pembrolizumab vs pembrolizumab alone as first-line treatment for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50% [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT283.

Abstract CT158: A dose escalation and cohort expansion study of the CDK9 inhibitor KB-0742 in relapsed, refractory and transcriptionally addicted solid tumors

Abstract Background MYC transcriptional deregulation is a hallmark of cancer and is associated with poor clinical outcomes. MYC deregulated solid tumors including non-small cell (NSCLC), small cell lung cancer (SCLC), triple negative breast cancer (TNBC), and ovarian cancer are known for their aggressiveness and frequent relapse. Analysis of a real-world solid tumor cohort including NSCLC (n= 20,470), SCLC (n=1,517), TNBC (n=2,576) and ovarian cancer (n=1,667) demonstrated MYC family overexpression and/or genomic amplification in 47% to 87% of patients. Although MYC remains difficult to drug, targeting of its cofactors has emerged as an attractive strategy to inhibit MYC oncogenic activity. Cyclin-dependent kinase 9 (CDK9), a MYC cofactor, is a critical regulator of oncogenic MYC expression and activity. KB-0742 is a potent, selective, and orally bioavailable inhibitor of CDK9 with a long plasma half-life. KB-0742 is being evaluated in an ongoing Phase 1/2 study in advanced solid tumors (NCT04718675). Methods The Phase 1/2 study is being conducted in two parts: dose escalation and dose expansion. Part 1 dose escalation comprises patients with relapsed or refractory solid tumors. Part 2 dose expansion comprises patients with solid tumors that have a high prevalence of MYC overexpression including ovarian cancer, NSCLC, TNBC and SCLC. KB-0742 is dosed orally once daily for 3 consecutive days followed by 4 days off on a weekly basis in 28-day cycles until unacceptable toxicity or disease progression. Eligibility criteria include age &amp;gt; 18 years acceptable organ function and ECOG PS &amp;lt; 2. Up to 170 patients are planned to be enrolled in the study. Primary objectives include evaluation of pharmacokinetics (PK), pharmacodynamics (PD), safety, tolerability, and preliminary anti-tumor activity with the goal of identifying a maximum tolerated dose (MTD). Plasma PK measurements include Cmax, tmax, AUC0-last, accumulation ratio (Racc) and t1/2. Safety data will be evaluated per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. RP2D is informed by PD in peripheral blood mononuclear cells using assays to evaluate phosphorylation of the CDK9 substrate serine 2 on the RNA Polymerase II C-terminal domain (pSER2) and CDK9-responsive gene expression. Radiographic tumor response is assessed using RECIST 1.1 criteria. Exploratory objectives include assessment of KB-0742 PD in tumor tissue and profiling of treatment-related genomic, transcriptomic, and proteomic changes. The study is continuing as planned; the next data analysis will occur in 2024. Citation Format: Miguel Villalona Calero, Mark Agulnik, Monica Mita, Alain Mita, Noah Federman, Drew Rasco, David Spigel, Jia Luo, Glenn Hanna, Gregory Cote, Mohamad A. Salkeni, Rashmi Chugh, Natraj R. Ammakkanavar, Satish A. Shah, Amol Rao, Kamalesh Kumar Sankhala, Richard E. Cutler, Tressa Hood, Luis Carvajal, Crystal MacKenzie, Charles Lin, Jorge DiMartino, Elizabeth A. Olek, Brian Van Tine. A dose escalation and cohort expansion study of the CDK9 inhibitor KB-0742 in relapsed, refractory and transcriptionally addicted solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT158.

Abstract CT159: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495)

Abstract Background: Human epidermal growth factor receptor 2 (HER2) overexpression, amplification, or mutation occurs across a variety of solid tumors. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has been approved by the FDA for HER2-overexpressed advanced breast, gastroesophageal cancers, HER2-low breast cancer, and HER2-mutated non-small cell lung cancer. However, some patients do not derive clinical benefit from T-DXd, and drug resistance is inevitable. Preclinical studies demonstrated that neratinib, an oral irreversible pan-HER tyrosine kinase inhibitor, can increase uptake of HER2-targeting ADCs, including ado-trastuzumab emtansine and T-DXd, in vivo. Enhanced uptake of ADC is postulated to be secondary to hindering HSP90 binding to the HER2 receptor, thereby inducing receptor ubiquitination and internalization. This finding was further confirmed in patient-derived xenograft models from two patients with HER2-mutated, but non-amplified, low-expressing advanced breast cancer. Therefore, we hypothesized that the combination of T-DXd and neratinib in patients with advanced solid tumors with a HER2 alteration will enhance the efficacy of T-DXd. As T-DXd and neratinib may have overlapping toxicities in patients, a phase I study to establish the safety of the combination is warranted. Methods: This is a multi-center, phase I clinical trial (NCT05372614, NCI 10495) with a 3+3 design to study the safety and tolerability of T-DXd and neratinib. The trial is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network. Eligible patients have advanced solid tumors with HER2 overexpression, amplification by ISH/NGS, or an activating HER2 mutation. Up to 18 evaluable patients will be enrolled in the dose escalation portion (Part 1), and 12 patients will be enrolled in the pharmacodynamic cohort (Part 2). During Part 1, the maximum tolerated dose and recommended phase 2 dose will be determined for neratinib. The dose of T-DXd is fixed at 5.4 mg/kg. We are actively enrolling patients in Part 1. The primary endpoint is dose-limiting toxicities of the combination during the first 2 cycles of treatment (42 days). Key secondary objectives of the study include T-DXd payload (DXd/MAAA-1181a) in tumor tissue obtained before and after co-treatment with neratinib to assess the potential enhanced payload concentration with the combination and quantitative HER2 assessed by mass spectrometry using multiplex reaction monitoring. Citation Format: Andrew A. Davis, Ecaterina E. Dumbrava, Aparna Kalyan, Nataliya V. Uboha, Haider S. Mahdi, Reema A. Patel, Farshid Dayyani, Jessica Porzel, Whitney L. Hensing, Cynthia X. Ma, Ron Bose, Haeseong Park. Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT159.

Targeting fusion oncoproteins in childhood cancers: Challenges and future opportunities for developing therapeutics.

Fusion oncoproteins are associated with childhood cancers and have proven challenging to target, aside from those that include kinases. As part of its efforts for targeting childhood cancers, the National Cancer Institute recently conducted a series on 'Novel Chemical Approaches for Targeting Fusion Oncoproteins'. Key learnings on leading platforms and technologies which can be utilized to advance the development of molecular therapeutics that target fusion oncoproteins in childhood cancers are described. Recent breakthroughs in medicinal chemistry and chemical biology provide new ground and creative strategies to exploit for the development of targeted agents for improving outcomes against these recalcitrant cancers.

Superior mesenteric artery syndrome in oncology: Report of two cases and review of the literature

A rare cause of abdominal pain is the superior mesenteric artery syndrome (SMAS), characterized by an extrinsic compression of the third portion of the duodenum by the superior mesenteric artery. It occurs in the context of rapid weight loss, because of the decrease of intra-abdominal fat causing a reduction in the exit angle of this important vascular structure. Cancer patients frequently present with weight loss, often severe, making them a population at risk of presenting this syndrome. Because symptoms are vague and could be secondary to oncologic treatments, the diagnosis of SMAS is often overlooked. We present two cases of oncology patients evaluated in the National Cancer Institute in Chile who presented with symptoms suggestive of SMAS, weight loss greater than 5 kg in a short period of time associated with abdominal pain and vomiting. Both cases were confirmed by images [computed tomography (CT) scan] and treated with nutritional support only. We present both cases along with a brief review of the literature on this rare syndrome, which is usually a diagnostic challenge.

National Estimates of the Participation of Patients With Cancer in Clinical Research Studies Based on Commission on Cancer Accreditation Data.

National estimates of cancer clinical trial participation are nearly two decades old and have focused solely on enrollment to treatment trials, which does not reflect the willingness of patients to contribute to other elements of clinical research. We determined inclusive, contemporary estimates of clinical trial participation for adults with cancer using a national sample of data from the Commission on Cancer (CoC). The data were obtained from accreditation information submitted by the 1,200 CoC programs, which represent more than 70% of all cancer cases diagnosed in the United States each year. Deidentified, institution-level aggregate counts of annual enrollment to treatment, biorepository, diagnostic, economic, genetic, prevention, quality-of-life (QOL), and registry studies were examined. Overall, study-type estimates for the period 2013-2017 were estimated. Multiple imputation by chained equations was used to account for missing data, with summary estimates calculated separately by type of program (eg, National Cancer Institute [NCI]-designated cancer centers) and pooled. The overall estimated patient participation rate to cancer treatment trials was 7.1%. Patients with cancer participated in a wide variety of other studies, including biorepository (12.9%), registry (7.3%), genetic (3.6%), QOL (2.8%), diagnostic (2.5%), and economic (2.4%) studies. Treatment trial enrollment was 21.6% at NCI-designated comprehensive cancer centers, 5.4% at academic (non-NCI-designated) comprehensive cancer programs, 5.7% at integrated network cancer programs, and 4.1% at community programs. One in five patients (21.9%) participated in one or more cancer clinical research studies. In a first-time use of national accreditation information from the CoC, enrollment to cancer treatment trials was 7.1%, higher than historical estimates of <5%. Patients participated in a diverse set of other study types. Contributions of adult patients with cancer to clinical research is more common than previously understood.