Differences In Tumor Biology Research Articles

Abstract P2-26-01: Prospective breast biopsy collection at an urban safety-net hospital serving a diverse patient population

Abstract Background: Despite advances in breast cancer imaging, research and treatment, higher mortality among racial/ethnic minority and low-income populations persists. Consent and enrollment of diverse and vulnerable patients into breast cancer research is critical. Given this urgent need for diversity in breast cancer research, successful collection and banking of fresh biospecimens from diverse patients is key to ameliorating some of the cancer disparities. Given our access to a unique and vulnerable patient population, we developed and implemented a clinical information and biospecimen repository for patients evaluated in the breast radiology and breast oncology outpatient clinics at Boston Medical Center (BMC). Our goal was to consent patients for donation of percutaneous breast biopsy samples, surgical tissue, and blood to develop a breast cancer biospecimen bank. Our long-term goal is to provide high-yield human samples for translational research studies in breast cancer from a diverse and vulnerable patient population. Methods: We designed a multi-disciplinary team of clinical providers and basic science researchers to envision a breast cancer biospecimen bank for research. Key stakeholders were identified, workflow was arranged, IRB obtained, and research staff trained. Patients presenting with suspicious mass on breast imaging (BI-RADS 4C and 5 categories) were eligible to enroll. Two percutaneous biopsy cores were obtained for research at the time of ultrasound guided biopsy. We leveraged the Hematology Oncology translational research program at Boston Medical Center and pilot finding to launch the project. Results: Since initiation in April 2021, we approached 68 patients and consented 44, for a successful consent rate of 64.7%. Of the 44 patients consented, 22 (50.0%) identified themselves as Black/African American, 11 (25.0%) as White/Caucasian, 10 (22.73%) as Hispanic and 1 (2.27%) as Asian. Of all patients enrolled, 41 (93.2%) had a breast malignancy, of which 27 (70.7%) were hormone-sensitive and 7 (17.1%) were TNBC. Additionally, of the 44 patients on study, only 9 (20.4%) had commercial insurance or managed care plan on the day of the consent. In total, 84 percutaneous biopsy cores were collected from 42 patients. Corresponding surgical tissue, plasma, serum and PBMCs were also obtained. Conclusion: Our program demonstrates that the enrollment of diverse and vulnerable breast cancer patients onto cancer research is achievable. We successfully created a breast biopsy program to provide access to diverse human samples for breast cancer translational research studies. Currently this repository serves to address many ongoing translational projects to understand: 1) the gap in knowledge of inherent differences in tumor biology and tumor environment, 2) metabolic regulation in the breast cancer microenvironment, and 3) heterogeneity of tumors and its effects on clinical outcomes and microenvironment interactions. Citation Format: Adrian Ilinski, Kiana Mahdaviani, Michael Fishman, Michael Cassidy, Naomi Ko. Prospective breast biopsy collection at an urban safety-net hospital serving a diverse patient population [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-01.

Abstract P2-13-04: Inclusion of Patients with Leptomeningeal Disease in Phase III Randomized Clinical Trials of Patients with Advanced Breast Cancer, Lung Cancer, and Melanoma: A Systematic Review

Abstract Introduction: Leptomeningeal disease (LMD) is a late complication of metastatic cancer that significantly limits patient survival. LMD is most prevalent in patients with melanoma, lung, and breast cancer, with incidence reaching 24.1% among those treated for brain metastases with both surgery and radiotherapy. As systemic treatment advances in oncology continue to improve patient survival, the incidence of LMD is expected to rise. This necessitates increased efforts to identify effective LMD therapies. Further, recent reporting of focal LMD in asymptomatic patients indicates that unique categories of LMD exist which may not necessarily portend a dismal prognosis. Unfortunately, exclusion of these patients from clinical trials has resulted in a paucity of high-quality evidence to guide management in this patient population. We therefore conducted a systematic review to determine the proportion and characteristics of phase III randomized clinical trials in breast cancer, lung cancer, and melanoma that included patients with LMD and/or included LMD-specific outcomes. Methods: The online ClinicalTrials.gov database was searched on December 22, 2020 for eligible phase III randomized control trials. No time limits were applied. The 1619 search results were screened by two independent reviewers for randomized, multi-arm therapeutic trials in advanced breast cancer, lung cancer, or melanoma. Results: 245 trials were included in this review, 75/245 (30.6%) of which included LMD-specific enrollment criteria. 67/245 (27.3%) trials explicitly excluded all patients with LMD, while 8 trials (3.3%) allowed conditional enrollment of patients with LMD; these stipulated that LMD must be asymptomatic/stable, and in some cases, treated. All 8 trials which conditionally allowed LMD patients to enroll were lung cancer trials. No temporal trend towards LMD inclusion was noted. CNS-specific outcomes, which did not include specific mention of LMD, were noted in 13/245 (5.4%) trials, 2 (15.4%) of which used standardized response criteria. No trials included LMD-specific outcomes. Conclusion: In this review, high rates of LMD exclusion and a complete lack of LMD-specific outcomes were noted in phase III trials for advanced breast cancer, lung cancer, and melanoma, despite these cancers carrying the highest risks of LMD. Lung cancer trials were most likely to include patients with LMD; this may be due to differences in tumor biology, drug penetration in the CNS and drug efficacy. Standardized and validated measures should be integrated into clinical trial design to facilitate inclusion of these patients when feasible and allow for meaningful assessment of LMD response to therapy. Table 1: Trial factors associated with exclusion of patients with leptomeningeal metastases a.based on study start date listed on clinicaltrials.gov, defined as “the actual date on which the first participant was enrolled in a clinical study.” b.based on studies with known location. Statistical test was between intercontinental versus single continent studies. Citation Format: Alisha Sharma, Kathryn Corbett, Maleeha Qazi, Hany Soliman, Arjun Sahgal, Sunit Das, Mary Jane Lim-Fat, Gregory R. Pond, Katarzyna Jerzak. Inclusion of Patients with Leptomeningeal Disease in Phase III Randomized Clinical Trials of Patients with Advanced Breast Cancer, Lung Cancer, and Melanoma: A Systematic Review [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-04.

The Impact of Surgery on Circulating Malignant Tumour Cells in Oral Squamous Cell Carcinoma.

The extent to which surgical management of oral squamous cell carcinoma (OSCC) disseminates cancer is currently unknown. To determine changes in numbers of malignant cells released into systemic circulation immediately following tumour removal and over the first seven post-operative days. An observational study from March 2019 to February 2021. This study was undertaken at Queen Mary University Hospital, Hong Kong. Patients with biopsy-proven oral SCC were considered for eligibility. Patients under 18 years of age, pregnant or lactating women and those unable to understand the study details or unable to sign the consent form were excluded. Twenty-two patients were enrolled (12 male and 10 female) with mean age of 65.5 years. Primary tumour management was performed in accord with multi-disciplinary team agreement. Anaesthesia and post-operative care were unaltered and provided in accord with accepted clinical practice. Three types of malignant cells detected in peripheral blood samples were enumerated and sub-typed based on the presence of chromosomal aneuploidy and immunohistochemical characteristics. To test the hypothesis that malignant cells are released by surgery, the numbers of single circulating tumour cells (CTCs), circulating tumour microemboli (CTM) and circulating endothelial cells (CTECs) were recorded pre-operatively, upon tumour removal and the second and seventh post-operative days. Of a potential 88 data collection points, specimens were not obtainable in 12 instances. Tumour removal resulted in a statistically significant increase in CTCs and a non-statistically significant rise in CTMs. CTCs, CTMs and CTECs were detected in the majority of patients up to the seventh post-operative day. Individual patients demonstrated striking increases in post-operative CTCs and CTECs numbers. Surgical management of OSCC has a significant impact on the systemic distribution of cancer cells. Malignant cells persisted post-operatively in a manner independent of recognised staging methods suggesting differences in tumour biology between individuals. Further investigation is warranted to determine whether circulating malignant cell enumeration can be used to refine risk stratification for patients with OSCC.

Molecular Imaging of Oxygenation Changes during Immunotherapy in Combination with Paclitaxel in Triple Negative Breast Cancer.

Hypoxia is a common feature of the tumor microenvironment, including that of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with a high five-year mortality rate. Using [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) imaging, we aimed to monitor changes in response to immunotherapy (IMT) with chemotherapy in TNBC. TNBC-tumor-bearing mice received paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 and anti-cytotoxic T-lymphocyte 4. FMISO-PET imaging was performed on treatment days 0, 6, and 12. Max and mean standard uptake values (SUVmax and SUVmean, respectively), histological analyses, and flow cytometry results were compared. FMISO-PET imaging revealed differences in tumor biology between treatment groups prior to tumor volume changes. 4T1 responders showed SUVmean 1.6-fold lower (p = 0.02) and 1.8-fold lower (p = 0.02) than non-responders on days 6 and 12, respectively. E0771 responders showed SUVmean 3.6-fold lower (p = 0.001) and 2.7-fold lower (p = 0.03) than non-responders on days 6 and 12, respectively. Immunohistochemical analyses revealed IMT plus PTX decreased hypoxia and proliferation and increased vascularity compared to control. Combination IMT/PTX recovered the loss of CD4+ T-cells observed with single-agent therapies. PET imaging can provide timely, longitudinal data on the TNBC tumor microenvironment, specifically intratumoral hypoxia, predicting therapeutic response to IMT plus chemotherapy.

Abstract IA038: Race and immune microenvironments in context of individual- and community-level covariates

Abstract Black women and women with African Ancestry have higher frequency of aggressive breast cancer subtypes, namely triple-negative breast cancer (TNBC) or Basal-like breast cancer, and often have tumors that show immunogenic features. Under a cells-to-society conceptual model of racialized breast cancer outcomes, differences in tumor biology and microenvironment interact with individual- and community-level variables so that differences in tumor biology reflect ancestry in combination with social determinants of health. Using data and biospecimens from the Carolina Breast Cancer Study, we evaluated immune expression by gene expression analysis and by immunofluorescence and other spatial techniques. Our results show that Black women more frequently have immunogenic tumors with a robust adaptive immune response, in accordance with higher frequency of Basal-like breast cancers. Adaptive immune response was also associated with specific breast cancer genetic features, such as p53 status, and was associated with differential recurrence outcomes. Immunogenic tumors of Basal-like subtype were also associated with individual-level socioeconomic factors (education, income, prediagnostic health care utilization) and community-level socioeconomic factors (census tract-level poverty and disadvantage). These data suggest that while some biologically-targeted therapies may help narrow disparities in breast cancer outcomes among those diagnosed with breast cancer, individual- and community-level variables are also important and may help to identify intervention strategies for prevention of aggressive subtypes. Citation Format: Melissa A. Troester. Race and immune microenvironments in context of individual- and community-level covariates [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA038.

Are Lymph Node Metastases Associated With Survival in Black Patients With Pancreatic Cancer?

IntroductionDespite aggressive surgical care and systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis. Recent studies show that racial disparities in outcome also exist. We sought to investigate the association lymph node (LN) metastases had with survival between Black and White patients with PDAC after resection. MethodsRetrospective analysis of 226 PDAC patients who underwent resection at a single institution from 2010 to 2018 was performed with attention to LN metastasis and patient race. The number of patients who received chemotherapy was also evaluated. ResultsOne Hundred Seventy Five (77.4%) PDAC patients were White and 51 (22.6%) were Black. 130 (59.3%) patients had LN metastasis (LN+). LN+ and LN- groups were similar in race (P = 0.93), sex (P = 0.10) and age at the time of diagnosis (P = 0.45). Patients with LN + disease were more likely to present with larger tumors (3.4 versus 2.8 cm, P = 0.02) and higher T status (P = 0.001). White and Black patients had similar rates of LN metastasis (59% versus 58.8%, P = 1.0). The median survival for LN- Black and White patients were similar (43.2 versus 30.2 mo, P = 0.82). LN + Black patients trended towards receiving more systemic therapy than White LN + patients (55% versus 42%, P = 0.10). The median survival for LN + Black patients was significantly less than LN + White patients (17.5 versus 24.6 mo, P = 0.04). ConclusionsBlack LN + PDAC patients have an inferior survival rate after resection when compared to their White counterparts. Our disparity in outcome cannot be solely explained by a difference in systemic treatment. Further investigation is warranted to determine racial differences in tumor biology or response to chemotherapy.

Human Immunodeficiency Virus Is Associated With Poor Overall Survival Among Patients With Head and Neck Cancer.

Head and neck squamous cell cancer (HNSCC) occurs at higher rates among persons with HIV (PWH). This study compares the impact of sociodemographic and clinicopathologic characteristics on outcomes among PWH-HNSCC compared with HNSCC patients without HIV. Patient data from HNSCC individuals were collected at a single academic hospital center between 2002 and 2018. Forty-eight patients with HIV (HIV-HNSCC) and 2894 HNSCC patients without HIV were included. Multivariate analysis determined predictors of survival using Cox proportional hazards regression model. HIV-positive and -negative tumors were analyzed by quantitative immunofluorescence for expression of CD4, CD8, CD20 and PD-L1. HIV-HNSCC patients had a lower median overall survival than HNSCC patients without HIV (34 [18-84] vs 94 [86-103] months; P < .001). In multivariate analysis that included age, sex, race/ethnicity, stage, site, tobacco use, time to treatment initiation, and insurance status, HIV was an independent predictor of poorer survival, with a hazard ratio of 1.98 (95% CI: 1.32-2.97; P < .001). PWH with human papillomavirus (HPV)-positive oropharyngeal tumors also had worse prognosis than HPV-positive oropharyngeal tumors in the population without HIV (P < .001). The tumor microenvironment among HIV-HNSCC patients revealed lower intratumoral CD8 infiltration among HIV+ HPV+ tumors compared with HIV- HPV+ tumors (P = .04). HIV-HNSCC patients had worse prognosis than the non-HIV population, with HIV being an independent predictor of poor clinical outcomes when accounting for important sociodemographic and clinicopathologic factors. Our findings highlight differences in tumor biology that require further detailed characterization in large cohorts and increased inclusion of PWH in immunotherapy trials.

Shedding a Light on the Challenges of Adolescents and Young Adults with Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a typical tumour of childhood but can occur at any age. Several studies have reported that adolescent and young adult (AYA) patients with RMS have poorer survival than do younger patients. This review discusses the specific challenges in AYA patients with pediatric-type RMS, exploring possible underlying factors which may influence different outcomes. Reasons for AYA survival gap are likely multifactorial, and might be related to differences in tumor biology and intrinsic aggressiveness, or differences in clinical management (that could include patient referral patterns, time to diagnosis, enrolment into clinical trials, the adequacy and intensity of treatment), as well as patient factors (including physiology and comorbidity that may influence treatment tolerability, drug pharmacokinetics and efficacy). However, improved survival has been reported in the most recent studies for AYA patients treated on pediatric RMS protocols. Different strategies may help to further improve outcome, such as supporting trans-age academic societies and national/international collaborations; developing specific clinical trials without upper age limit; defining integrated and comprehensive approach to AYA patients, including the genomic aspects; establishing multidisciplinary tumor boards with involvement of both pediatric and adult oncologists to discuss all pediatric-type RMS patients; developing dedicated projects with specific treatment recommendations and registry/database.

Resected Early-Onset Pancreatic Cancer: Practices and Outcomes in an International Dual-Center Study

BackgroundEarly-onset pancreatic cancer (EOPC), defined as age ≤ 45 years at diagnosis, accounts for 3% of all pancreatic cancer cases. Although differences in tumor biology have been suggested, available data are sparse and specific treatment recommendations are lacking. This study explores the clinicopathological features and oncologic outcomes of resected EOPC.Patients and MethodsPatients with EOPC undergoing resection between 2002 and 2018 were identified from the Heidelberg University Hospital and Johns Hopkins University registries. Median overall survival (OS) and recurrence-free survival (RFS) were analyzed, and prognostic factors were identified.ResultsThe final cohort included 164 patients, most of whom had pancreatic ductal adenocarcinoma (PDAC, n = 136; 82.9%) or IPMN-associated pancreatic cancer (n = 17; 10.4%). Twenty (12.1%) patients presented with stage 1 disease, 42 (25.6%) with stage 2, 75 (45.7%) with stage 3, and 22 (13.4%) with oligometastatic stage 4 disease. Most patients underwent upfront resection (n = 113, 68.9%), whereas 51 (31.1%) individuals received preoperative treatment. Median OS and RFS were 26.0 and 12.4 months, respectively. Stage-specific median survival was 70.6, 41.8, 23.8, and 16.9 months for stage 1, 2, 3, and 4 tumors, respectively. Factors independently associated with shorter OS and RFS were R1 resections and AJCC stages 3 and 4. Notably, AJCC 3-N2 and AJCC 3-T4 tumors had a median OS of 20 months versus 29.5 months, respectively.ConclusionDespite frequently presenting with advanced disease, oncologic outcomes in EOPC patients are satisfactory even in locally advanced cancers, justifying aggressive surgical approaches. Further research is needed to tailor current guidelines to this rare population.

Race and Ethnicity, Stage-Specific Mortality, and Cancer Treatment in Esophageal and Gastric Cancers: Surveillance, Epidemiology, and End Results (2000–2018)

Race and Ethnicity, Stage-Specific Mortality, and Cancer Treatment in Esophageal and Gastric Cancers: Surveillance, Epidemiology, and End Results (2000–2018)

Abstract PR002: Transcriptomic influences of racial disparities in Black patients with pancreatic neuroendocrine tumors

Abstract Introduction: There are known disparities in outcomes between Black and White patients with pancreatic neuroendocrine tumors (pNETs). Recently, Black patients have been shown to have higher rates of lymph node metastasis in smaller tumors than White patients, indicating possible differences in tumor biology. Numerous prognostic gene expression differences between racial groups have been reported in other cancers, but no such analysis has been conducted in pNETs. This study aims to evaluate pNET transcriptomes for differential expression that may be influencing racially disparate outcomes. Methods: Quality control of archival resected pNETs and demarcation of cancer cells were performed by a board-certified pathologist. Cells were laser microdissected from formalin-fixed, paraffin-embedded specimens, and RNA isolated. Sequencing was performed on an Illumina NextSeq550 at 30 million reads/sample. Alignments to the GRCh38 transcriptome annotation were performed using Salmon and differentially expressed genes (DEG’s) determined using DESeq2. Significant DEGs were determined by FDR-adjusted p-value (q-value; qv) &amp;lt; 0.05 and log2 fold-change (log2FC) ≥ ±2. Gene set enrichment analysis was performed using clusterProfiler and the Gene Ontology (GO) consortium gene sets. Ingenuity Pathway Analysis (IPA) was then conducted to determine regulator effect networks. Results: RNA sequencing was conducted on 14 and 16 grade and sex-matched primary pNETs from self-identified Black and White patients, respectively. Mean age was 51 for Black and 56 for White patients. 11/16 (69%) of White and 9/14 (64%) of Black patients were female. 8 Black patients and 8 White patients had grade 1 tumors, while 6 Black patients and 8 White patients had Grade 2 tumors. Metastatic disease was present in 4 Black and 5 White patients. Overall, 372 genes were significantly differentially expressed and 179 GO gene sets were differentially enriched between groups. Notably, among the top 10 most significantly enriched biological processes were: angiogenesis/blood vessel and vasculature development (qv=1.34e-07, normalized enrichment score [NES]=1.89), positive regulation of cell migration and locomotion (qv=1.34e-07, NES=1.91), and humoral immune response (qv= 9.8e-07, NES=-2.06). Among the top 5 regulator effect networks identified by IPA were: angiogenesis of lesion/cell movement of monocytes (consistency score [CS]=19.3), activation of blood cells (CS=18.9), and activation of cells (17.9). Conclusion: Numerous gene sets and pathways related to blood vessel development and cellular migration, representing key elements in the development of metastatic disease, are significantly enriched in pNETs from Black patients. Additionally, gene sets and pathways related to the immune response are downregulated in Black patients. These data indicate differences in tumor biology that may influence disparate outcomes reported in Black patients with pNETS. Sequencing of additional samples and incorporation of genetic ancestry are necessary to validate these findings. Citation Format: Brendon Herring, Rachael Guenter, Deepti Dhall, Herbert Chen, Clayton Yates, John Bart Rose. Transcriptomic influences of racial disparities in Black patients with pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR002.

Proteomic Profiles of Cytokine Release Syndromes Following Lisocabtagene Maraleucel and Idecabtagene Vicleucel

Introduction: Adoptive cell therapy with chimeric antigen receptor (CAR) T-cells has improved responses in refractory diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Most CAR-T recipients experience cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) - similar yet clinically distinct inflammatory syndromes related to T-cell activation and expansion of multiple cytokines. Differences in tumor biology between MM and DLBCL and how they contribute to differences in cytokine expression is not well understood. Given different CAR T-cell constructs have varying levels of activation and toxicity, cytokine profiles between products and between different disease entities may inform management. In this study, we used multiplex proteomic profiling to evaluate differences in plasma cytokine signatures between two CAR T-cell products and diseases. Methods: Between September 2021 and March 2022, 20 patients received CAR T-cell therapy and consented to the Yale School of Medicine hematologic disease tissue bank (HIC#1401013259). Two longitudinal cohorts were prospectively enrolled: (1) patients who received lisocabtagene maraleucel (liso-cel) for DLBCL refractory after two lines of therapy, and (2) those who received idecabtagene vicleucel (ide-cel) for MM refractory after 4 lines of therapy. For each patient, the first sample was collected prior to lymphodepleting chemotherapy on day -5 with subsequent samples collected on days 0 (prior to CAR T-cell infusion) and 1, 2, 3, and 7 (after CAR T-cell infusion). Plasma samples were processed and frozen within 1 hour of collection. Proteomic profiling was performed at Eve Technologies (Calgary, Alberta, Canada). The Human 71-Plex Discovery Assay measuring 71 total cytokines and chemokines was used to interrogate each sample time point. Statistical analysis was performed in GraphPad Prism (GraphPad Software, San Diego, CA) and R (R Core Team). Levels of individual proteins were compared using Wilcoxon tests. P-values <0.05 were considered statistically significant. Results: Among 13 patients who received liso-cel for DLBCL (including 2 with transformed follicular lymphoma and 3 with double/triple hit pathology), the median age was 66 years (44-82), 7 (54%) were males, 8 (62%) had KPS ≥ 90, 8 (62%) had bulky disease, median lines of therapy were 4 (2-10), and 11 (85%) received systemic bridging therapy. Seven patients (54%) had any grade CRS, with one patient having grade 3 CRS; 2 (15%) had grade 1 and 2 ICANS. Four patients (31%) received an IL-6 inhibitor. At 3 months of follow-up, the objective response rate was 77% (10/13), of whom two patients had a complete response and 60% (6/10) had any grade CRS. Among 7 patients who received ide-cel for MM, with R-ISS score of 1, 2, and 3 in 4 (57%), 1 (14%), and 2 (29%) patients, respectively, the median age was 61 years (54-79), 5 (71%) were males, 4 (57%) had KPS ≥ 90, 3 (43%) had extramedullary disease, median lines of therapy were 7 (4-13), and 5 patients (71%) received systemic bridging therapy. Six patients (86%) had any grade CRS with no patients having grade ≥ 3 CRS; 3 (43%) had grade 1 ICANS. Four patients (57%) received an IL-6 inhibitor. Five patients (63%) received growth factor support on day 7. At 3 months of follow-up, the objective response rate was 86% (6/7) of whom two patients had a complete response and 83% (5/6) had any grade CRS. In a longitudinal analysis, significantly higher levels of IL-3, IL-5, IL-6, IL-10, IL-15, IL-309, and TNFα were noted during CRS (panel 1). In a comparison between CAR constructs, ide-cel was characterized by significantly higher levels of Eotaxin-2, FLT-3L, IL-5, IL-6, IL-15, I-309, MCP-1, and MCP-4 compared to liso-cel (panel 2). Many of these elevated cytokine proteins are implicated as chemoattractants for other leukocyte subtypes including but not limited to neutrophils, monocytes, eosinophils which may contribute to inflammation and may modulate response, toxicity, or relapse. Conclusions: Ide-cel is associated with a distinct cytokine and chemokine signature compared to liso-cel. This study provides pre-clinical evidence for the role of IL-5 inhibitors to treat or prevent CRS following MM-directed CAR T-cell therapy. Further studies with larger cohorts of patients are needed to validate these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

NIMG-101. COMPARISON OF PRE-SURGICAL MRI FINDINGS FROM LONG-TERM (≥ 3 YRS) VERSUS SHORT-TERM (&amp;lt; 3 YRS) GLIOBLASTOMA SURVIVORS: A BLINDED, CASE-CONTROL REVIEW

Abstract BACKGROUND The median overall survival of patients with glioblastoma (GBM) is 10-12 months and the five-year survival ranges from 5-10%. Favorable clinical and molecular prognostic markers have been described in the literature, although an individual patient’s prognosis cannot easily be predetermined on these features as shown in the NOB-LTS project by Briceno et al. (SNO 2021). Until now, no radiologic characteristics have been correlated with better patient outcomes. We reviewed eighteen MRI features to determine if these could aid the identification of long-term survivors (LTS). METHODS From the NOB-LTS cohort of our Natural History Study, 16 long-term survivals (LTS; ≥ 3 years survival post-diagnosis) were matched based on sex, age, and extent of resection to 32 control (STS, &amp;lt; 3 years survival post-diagnosis) patients with NGS-confirmed IDH-wt glioblastoma. Pre-surgical MRIs (T1, T1 post-contrast, T2, T2/FLAIR, DWI, ADC) were reviewed by three blinded reviewers and analyzed based on pre-set criteria. RESULTS T1 hypointensity occurred commonly in the LTS (71%) vs STS (29%) while central heterogeneous signal occurred commonly in the STS (73%) vs LTS (50%) patients. Restricted diffusion was seen in 82% of STS and 70% of LTS cases. No difference was seen in irregular enhancement, peripheral and grey matter enhancement on T1 post-contrast images. Evaluation of T2/FLAIR images showed no difference in the number of lobes involved, presence of mass effect, heterogeneity of the signal or the perilesional signal abnormality or involvement of grey matter. CONCLUSION Our results suggest that pre-surgical MRI might be a useful prognostic tool as T1 hypointensity more frequently, and T1 central heterogeneity less commonly seen in the LTS group. These imaging findings may provide additional insights regarding the differences in tumor biology between LTS and STS. Further validation and correlation with histological/molecular characteristics are planned to better predict patient outcomes with newly diagnosed glioblastoma.

Mechanism of Sex Differences in Bladder Cancer: Evident and Elusive Sex-biasing Factors.

Bladder cancer incidence is drastically higher in males than females across geographical, racial, and socioeconomic strata. Despite potential differences in tumor biology, however, male and female bladder cancer patients are still clinically managed in highly similar ways. While sex hormones and sex chromosomes have been shown to promote observed sex differences, a more complex story lies beneath these evident sex-biasing factors than previously appreciated. Advances in genomic technology have spurred numerous preclinical studies characterizing elusive sex-biasing factors such as epigenetics, X chromosome inactivation escape genes, single nucleotide polymorphism, transcription regulation, metabolism, immunity, and many more. Sex-biasing effects, if properly understood, can be leveraged by future efforts in precision medicine based on a patient’s biological sex. In this review, we will highlight key findings from the last half century that demystify the intricate ways in which sex-specific biology contribute to differences in pathogenesis as well as discuss future research directions.

34151 Association of type II diabetes mellitus with characteristics and outcomes for patients undergoing sentinel lymph node biopsy for cutaneous melanoma

Background: Limited data exist describing patients with type II diabetes mellitus (T2DM) who are diagnosed with clinically localized primary cutaneous melanoma and require sentinel lymph node (SLN) biopsy. Methods: Consecutive patients diagnosed with AJCC clinical Stage I-II melanoma who underwent wide excision and SLN biopsy at a single institution (2007-2016) were identified, and patients with and without T2DM at the time of melanoma diagnosis were compared using logistic regression analysis. Patients were further stratified by whether their T2DM was non-insulin dependent (NID-T2DM) or insulin dependent (ID-T2DM). Associations between factors and outcomes were analyzed using Cox proportional hazards regression analysis. Results: Of the 1128 patients evaluated, 111 (9.8%) had T2DM (n = 94 [84.7%] NID-T2DM; n = 17 [15.3%] ID-T2DM). On multivariable analysis controlling for patient and tumor factors, T2DM patients were more likely to be older (odds ratio [OR] 1.04, p 1.0 mm thick (OR 1.91, P = .019), and have microsatellitosis (OR 2.27, P = .029). Ten-year cumulative incidence of melanoma recurrence was significantly greater for those with ID-T2DM (64.4% ID-T2DM vs. 34.4% NID-T2DM vs. 21.8% no T2DM, P < .001). On multivariable analysis, ID-T2DM was independently associated with melanoma recurrence (hazard ratio [HR] 2.58, P = .015); this association was not seen with NID-T2DM (HR 0.82, P = .421). Conclusion: Patients with insulin-dependent type II diabetes mellitus appear to present with more advanced melanoma and are at increased risk for melanoma recurrence. Further study as to whether this reflects differences in tumor biology or host differences in immune response is warranted.

Immune Gene Signature Expression Differs between African American and Caucasian Patients with Renal Cell Carcinoma

BACKGROUND: Predictive immune signatures such as the T-effector, the 26-gene “Renal 101 Immuno signature” and the 18-gene T-cell inflamed gene expression profile were developed in clinical trials enrolling predominantly Caucasians and there is a dearth of literature comparing tumor biology between African American (AA) and Caucasian patients. OBJECTIVE: To compare the immune gene signature expression in AA (n = 55) and Caucasian (n = 457) patients. METHODS: Raw gene expression count data were downloaded from the TCGA KIRC dataset and tumor samples from “white” and “black or AA” patients were selected. The gene expression values of the immune signatures were VST-transformed normalized counts and compared between the groups. RESULTS: There were 457 Caucasian and 55 AA patients in the TCGA. The immune gene expression in all three signatures was significantly lower in AA patients compared to Caucasians (p &lt; 0.05). We validated our findings in an independent dataset using Nanostring Immune Profile Panel. Since the majority of AA tumors in TCGA were stage I (71%), we compared gene expression between stage I AA tumors (n = 39) with stage I Caucasian tumors (n = 220). Once again, the immune gene expression was significantly lower in AA patients compared to Caucasians (p &lt; 0.05), indicating differences in tumor biology between the races. CONCLUSIONS: Low expression of predictive immune gene signatures in AA compared to Caucasian patients indicates a possible difference in the biology of their tumors. Future studies are needed to validate our findings in other datasets and to study the predictive role of these signatures in AA patients.

Association of type II diabetes mellitus with characteristics and outcomes for patients undergoing sentinel lymph node biopsy for cutaneous melanoma.

Type II diabetes mellitus (T2DM) can lead to an immunosuppressed state, but whether T2DM is associated with worse outcomes for patients with melanoma has not been well studied. Consecutive patients diagnosed with clinical stage I-II cutaneous melanoma who underwent sentinel lymph node biopsy at a single institution (2007-2016) were identified. Melanoma characteristics and recurrence/survival outcomes were compared between patients with and without T2DM at the time of melanoma diagnosis. Of 1128 patients evaluated, 111 (9.8%) had T2DM (n = 94 [84.7%] non-insulin dependent [NID-T2DM]; n = 17 [15.3%] insulin dependent [ID-T2DM]). T2DM patients were more likely to be older (odds ratio [OR] 1.04, p < 0.001), male (OR 2.15, p = 0.003), have tumors >1.0 mm (OR 1.88, p = 0.023), and have microsatellitosis (OR 2.29, p = 0.030). Five-year cumulative incidence of melanoma recurrence was significantly higher for patients with ID-T2DM (46.7% ID-T2DM vs. 25.7% NID-T2DM vs. 17.1% no T2DM, p < 0.001), and on multivariable analysis, ID-T2DM was independently associated with melanoma recurrence (hazard ratio 2.57, p = 0.015). No difference in 5-year disease-specific survival was observed between groups. ID-T2DM appears to be associated with more advanced melanoma and increased risk for melanoma recurrence. Further study as to whether this reflects differences in tumor biology or host factors is warranted.

CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women.

Breast cancer is the most diagnosed cancer worldwide and remains the second leading cause of cancer death. While breast cancer mortality has steadily declined over the past decades through medical advances, an alarming disparity in breast cancer mortality has emerged between African American women (AAW) and Caucasian American women (CAW). New evidence suggests more aggressive behavior of triple-negative breast cancer (TNBC) in AAW may contribute to racial differences in tumor biology and mortality. Progesterone (PRG) can exert its cellular effects through either its classic, non-classic, or combined responses through binding to either classic nuclear PRG receptors (nPRs) or non-classic membrane PRG receptors (mPRs), warranting both pathways equally important in PRG-mediated signaling. In our previous report, we demonstrated that the CCM signaling complex (CSC) consisting of CCM1, CCM2, and CCM3 can couple both nPRs and mPRs signaling cascades to form a CSC-mPRs-PRG-nPRs (CmPn) signaling network in nPR positive(+) breast cancer cells. In this report, we furthered our research by establishing the CSC-mPRs-PRG (CmP) signaling network in nPR(-) breast cancer cells, demonstrating that a common core mechanism exists, regardless of nPR(+⁣/⁣-) status. This is the first report stating that inducible expression patterns exist between CCMs and major mPRs in TNBC cells. Furthermore, we firstly show mPRs in TNBC cells are localized in the nucleus and participate in nucleocytoplasmic shuttling in a coordinately synchronized fashion with CCMs under steroid actions, following the same cellular distribution as other well-defined steroid hormone receptors. Finally, for the first time, we deconvoluted the CmP signalosome by using systems biology and TNBC clinical data, which helped us understand key factors within the CmP network and identify 6 specific biomarkers with potential clinical applications associated with AAW-TNBC tumorigenesis. These novel biomarkers could have immediate clinical implications to dramatically improve health disparities among AAW-TNBCs.

Protein expression of the gp78 E3 ligase predicts poor breast cancer outcome based on race.

Women of African ancestry suffer higher rates of breast cancer mortality compared with all other groups in the United States. Though the precise reasons for these disparities remain unclear, many recent studies have implicated a role for differences in tumor biology. Using an epitope-validated antibody against the endoplasmic reticulum–associated E3 ligase, gp78, we show that elevated levels of gp78 in patient breast cancer cells predict poor survival. Moreover, high levels of gp78 are associated with poor outcomes in both ER+ and ER– tumors, and breast cancers expressing elevated amounts of gp78 protein are enriched in gene expression pathways that influence cell cycle, metabolism, receptor-mediated signaling, and cell stress response pathways. In multivariate analysis adjusted for subtype and grade, gp78 protein is an independent predictor of poor outcomes in women of African ancestry. Furthermore, gene expression signatures, derived from patients stratified by gp78 protein expression, are strong predictors of recurrence and pathological complete response in retrospective clinical trial data and share many common features with gene sets previously identified to be overrepresented in breast cancers based on race. These findings implicate a prominent role for gp78 in tumor progression and offer insights into our understanding of racial differences in breast cancer outcomes.

Abstract 474: Integrating imaging and multi-omics data to elucidate racial differences in breast tumor biology to optimize precision oncology approaches and patient outcome

Abstract Background: Racial disparities in breast cancer incidence and clinical outcome have been well characterized. In particular, African American (AA) patients have higher mortality rates than other racial groups. Research into these racial disparities has primarily focused on socioeconomic determinants, with some studies exploring potential molecular determinants and limited biological differences found between AA and Caucasian patient tumors. Tumor intrinsic and extrinsic factors that promote racial differences in breast cancer development and patient outcome are not fully understood and strategies to address this are scarce. As a result, we have developed a platform that combines patient-specific imaging and multi-omics data to elucidate how biological differences integrate to promote racial disparities in tumor behavior and patient outcome. Methods: Imaging and transcriptomic data from over 500 patients were integrated within the SimBioSys TumoScope biophysical modeling software to understand racial differences in tumor biology and coordinated tumor behavior. Results: AA patients have tumors that display higher growth rates, characteristically have higher adipose tissue around the tumor, higher spatial variation in drug secretion, lower spatial variation in blood flow/and increased tumor stiffness. Conclusion: Using a transdisciplinary approach, our results show that metabolic and structural tumor features are associated with the disproportionately poor survival rates observed in AA breast cancer patients. By characterizing racial-specific tumor intrinsic and extrinsic biological factors and their potential interactions, strategies may emerge to personalize clinical management based on racial differences. In this way, precision oncology approaches can be applied to increase life-expectancy for racial minorities with breast cancer. Citation Format: Nicole Liadis, Tyler Earnest, Eduardo Braun, Anu Antony, Lance Munn, Michael Hallock, Daniel Cook, The SimBioSys Team. Integrating imaging and multi-omics data to elucidate racial differences in breast tumor biology to optimize precision oncology approaches and patient outcome [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 474.