Late-stage Cancer Research Articles

Factors associated with surgical intervention in Native American patients with hepatocellular carcinoma.

e16279 Background: Hepatocellular carcinoma (HCC) is the prevailing type of primary liver cancer, exhibited at a higher frequency in individuals afflicted by chronic liver conditions. Past literature has demonstrated the impact certain socioeconomic factors have on the prognosis of HCC. Native American patients often face late-stage cancer diagnoses and have the lowest survival rates among racial and ethnic groups. While surgery offers potential for cure, factors related to surgical interventions in liver cancer for Native American patients remain largely unexplored. Through the NCDB, this study analyzed factors associated with surgical intervention and survival trends in Native American patients with HCC. Methods: The National Cancer Database (NCDB) was used to identify Native American patients diagnosed with Hepatocellular Carcinoma from 2004 to 2019 using the histology code 8170 and race code 03 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 27, and statistical significance was set at α = 0.05. Results: Of 1193 Native American patients included in this sample, 172 (14.4%) patients received surgical treatment for HCC, while 1021 (85.6%) patients did not receive surgical treatment for HCC. Native American patients who received surgery for HCC experienced a greater mean overall survival (90 months) when compared to the mean overall survival (24 months) in HCC Native American patients who did not receive surgical treatments (p < 0.001). When controlling for age, year of diagnosis, stage, grade, facility type and income status, receiving surgery showed an independent decrease in hazard (HR = 0.245; p < 0.05). HCC Native American patients who received surgery were more likely to be treated an at academic facility, have stage I disease, and have less aggressive tumors (grade) (p < 0.05). Native American patients who did not receive surgery were more likely to be older (62 vs 60 years old), have larger tumors, and have brain, bone, lung, and liver metastases (p < 0.05). No associations of surgical versus non-surgical treatment were seen in Charlson-Deyo score, urban or rural residence, and primary payor at diagnosis. Conclusions: Native American patients with HCC who received surgical intervention experienced improved overall survival compared to non-surgical treatment groups. Native American patients undergoing surgical intervention more often received care at academic or private institutions and had lower stages of HCC. These results follow previous trends, where cancer patients receiving adequate surgical intervention generally survive longer. Further research is needed to examine other treatment differences among Native American patients and how these findings compare across other disadvantaged groups.

Emulation and evaluation of tumor cell combined chemotherapy in isotropic/anisotropic collagen fiber microenvironments.

The rapid emergence of anisotropic collagen fibers in the tissue microenvironment is a critical transition point in late-stage breast cancer. Specifically, the fiber orientation facilitates the likelihood of high-speed tumor cell invasion and metastasis, which pose lethal threats to patients. Thus, based on this transition point, one key issue is how to determine and evaluate efficient combination chemotherapy treatments in late-stage cancer. In this study, we designed a collagen microarray chip containing 241 high-throughput microchambers with embedded metastatic breast cancer cell MDA-MB-231-RFP. By utilizing collagen's unique structure and hydromechanical properties, the chip constructed three-dimensional isotropic and anisotropic collagen fiber structures to emulate the tumor cell microenvironment at early and late stages. We injected different chemotherapeutic drugs into its four channels and obtained composite biochemical concentration profiles. Our results demonstrate that anisotropic collagen fibers promote cell proliferation and migration more than isotropic collagen fibers, suggesting that the geometric arrangement of fibers plays an important role in regulating cell behavior. Moreover, the presence of anisotropic collagen fibers may be a potential factor leading to the poor efficacy of combined chemotherapy in late-stage breast cancer. We investigated the efficacy of various chemotherapy drugs using cell proliferation inhibitors paclitaxel and gemcitabine and tumor cell migration inhibitors 7rh and PP2. To ensure the validity of our findings, we followed a systematic approach that involved testing the inhibitory effects of these drugs. According to our results, the drug combinations' effectiveness could be ordered as follows: paclitaxel + gemcitabine > gemcitabine + 7rh > PP2 + paclitaxel > 7rh + PP2. This study shows that the biomimetic chip system not only facilitates the creation of a realistic in vitro model for examining the cell migration mechanism in late-stage breast cancer but also has the potential to function as an effective tool for future chemotherapy assessment and personalized medicine.

Disparities in Palliative Care Use for Patients With Blood Cancer Who Died in the Hospital.

Background: Palliative care can enhance quality of life during a terminal hospitalization. Despite advances in diagnostic and treatment tools, blood cancers lag behind solid malignancies in palliative use. It is not clear what factors affect palliative care use in blood cancer. Methods: We used the 2016 to 2019 National Inpatient Sample to identify demographic and socioeconomic factors associated with receiving palliative care among patients over age 18 with any malignant hematological diagnosis during a terminal hospitalization lasting at least 3days, excluding those receiving a stem cell transplant. Results: Palliative care use was documented 54% of the time among 49,720 weighted cases (9944 distinct individual hospitalizations), approximately evenly distributed across the years 2016-2019. Palliative care use was lowest in 2016 (51%) and highest in 2018 (58%), and increased with age, reaching 58% for those 80years and older. Men and women were similarly likely to receive care. Patients of Hispanic ethnicity and African Americans received less palliative care (47% and 49%, respectively), as did those insured by Medicaid (48%), and those admitted to small or rural hospitals (52% and 47%, respectively). Charges for hospitalizations with palliative care were 19% lower than for those without it. Conclusions: This study highlights disparities in palliative care use among blood-cancer patients who died in the hospital. It seems likely that many of the 46% who did not receive palliative care could have benefitted from it. Interventions are likely needed to achieve equitable access to ideal levels of palliative care services in late-stage blood cancer.

Strong association between reduction of late-stage cancers and reduction of cancer-specific mortality in meta-regression of randomized screening trials across multiple cancer types.

Late-stage cancer incidence has been proposed as an early surrogate for mortality in randomized controlled trials (RCTs) of cancer screening; however, its validity has not been systematically evaluated across screening RCTs of different cancers. We conducted a meta-regression analysis of cancer screening RCTs that reported both late-stage cancer incidence and cancer mortality. Based on a systematic literature review, we included 33 RCTs of screening programs targeting seven cancer types, including lung (n = 12), colorectal (n = 8), breast (n = 5), and prostate (n = 4), among others. We regressed the relative reduction of cancer mortality on the relative reduction of late-stage cancer incidence, inversely weighted for each RCT by the variance of estimated mortality reduction. Across cancer types, the relative reduction of late-stage cancer incidence was linearly associated with the relative reduction of cancer mortality. Specifically, we observed this association for lung (R2 = 0.79 and 0.996 in three recent large trials), breast (R2 = 0.94), prostate (R2 = 0.98), and colorectal cancer (R2 = 0.75 for stage III/IV cancers and 0.93 for stage IV cancers). Trials with a 20% or greater reduction in late-stage cancers were more likely to achieve a significant reduction in cancer mortality. Our results also showed that no reduction of late-stage cancer incidence was associated with no or minimal reduction in cancer mortality. Meta-regression of historical screening RCTs showed a strong linear association between reductions in late-stage cancer incidence and cancer mortality.

Protein expression of the amino acid transporter SLC7A5 in tumor tissue is prognostic in early-stage colorectal cancer.

Proteins overexpressed in early-stage cancers may serve as early diagnosis and prognosis markers as well as targets for cancer therapies. In this study, we examined the expression of an essential amino acid carrier SLC7A5 (LAT1, CD98, or 4F2 light chain) in cancer tissue from two well-annotated cohorts of 575 cases of early-stage and 106 cases of late-stage colorectal cancer patients. Immunohistochemistry showed SLC7A5 overexpression in 72.0% of early-stage and 56.6% of late-stage cases. SLC7A5 expression was not influenced by patient gender, age, location, or mismatch repair status, although it appeared to be slightly less prevalent in tumors of mucinous differentiation or with lymphovascular invasion. Statistical analyses revealed a positive correlation between SLC7A5 overexpression and both overall survival and disease-free survival in early-stage but not late-stage cancers. Co-expression analyses of the TCGA and CPTAC colorectal cancer cohorts identified a network of gene transcripts positively related to SLC7A5, with its heterodimer partner SLC3A2 having the highest co-expression score. Network analysis uncovered the SLC7A network to be significantly associated with ncRNA such as tRNA processing and the mitotic cell cycle. Since SLC7A5 is also a marker of activated lymphocytes such as NK, T, and B lymphocytes, SLC7A5 overexpression in early colorectal cancers might trigger a strong anti-tumor immune response which could results in better clinical outcome. Overall, our study provides clear evidence of differential SLC7A5 expression and its prognostic value for early-stage colorectal cancer, although the understanding of its functions in colorectal tumorigenesis and cancer immunity is currently rather limited and awaits further characterization.

Efficacy of Recombinant Methioninase on Late-stage Patient Cancer in the Histoculture Drug Response Assay (HDRA) as a Potential Functional Biomarker of Sensitivity to Methionine-restriction Therapy in the Clinic.

The present study utilized the three-dimensional histoculture drug response assay (HDRA) to determine the efficacy of recombinant methioninase (rMETase) on tumor tissue resected from patients with late-stage cancer, as a functional biomarker of sensitivity to methionine restriction therapy. Resected peritoneal-metastatic cancer, including colorectal cancer, pancreatic cancer, ovarian cancer, and pseudomyxoma were placed on Gelform in RPMI 1640 medium for seven days and treated with rMETase from 2.5 U/ml to 20 U/ml. Cell viability was determined using the MTT assay. A total of 48 patients with late-stage cancer underwent testing for rMETase responsiveness using the HDRA. Colorectal cancer and pseudomyxoma had the highest sensitivity to rMETase. Pancreatic and ovarian cancer also responded to rMETase, but to a lesser degree. Patients with tumors with at least 40% sensitivity to rMETase in the HDRA are being considered as candidates for methionine restriction therapy, which includes the use of rMETase in combination with a low-methionine diet.

Detection of Oncogene Hotspot Mutations in Female NSCLC Tumor DNA and Cell-Free DNA.

Non-small-cell lung cancer (NSCLC) is the most prevalent type of lung cancer, with extensively characterized mutational spectra. Several biomarkers (such as EGFR, BRAF, KRAS gene mutations, etc.) have emerged as predictive and prognostic markers for NSCLC. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, prompting the search for alternatives. Cell-free DNA (cfDNA) found in plasma is emerging as a highly promising avenue or a supplementary method for assessing the efficacy of cancer treatments. This is especially valuable in instances where conventional biopsy specimens, like formalin-fixed, paraffin-embedded (FFPE), or freshly frozen tumor tissues prove inadequate for conducting molecular pathology analyses subsequent to the initial diagnostic procedures. By leveraging cfDNA from plasma, clinicians gain an additional tool to gauge the effectiveness of cancer therapies, thereby enhancing their ability to optimize tailored treatment strategies. In this study, 51 Lithuanian females with NSCLC were analyzed, with adenocarcinoma being the predominant pathology diagnosis in 40 cases (78%). Target mutations were identified in 38 out of 51 patients (74.5%) in tumor tissue samples, while in plasma samples, they were identified in only 10 patients' samples (19.6%). Even though we did not have enough voluminous plasma samples in our study, gene mutations were detected in plasma from ten women, three of whom were diagnosed with early stages of lung cancer (stages I and II). For these patients, the following mutations were detected: deletion in exon 19 of the EGFR gene and single nucleotide polymorphisms in the TP53 and MET genes. All other women were diagnosed with stages III or IV of lung cancer. This indicates that the later stages of cancer contribute more cfDNA in plasma, making extraction less complicated.

Abstract PO1-07-09: Benefit of Adherence to Annual Mammography Screening: Results from 8,305 Cancers in an Institutional Database

Abstract Purpose: There is much debate on the starting age and frequency for asymptomatic mammographic breast cancer screening. We analyzed data from our medical center to determine the effect of the frequency of screening on the likelihood of a woman being diagnosed with a late-stage cancer and on the all-cause mortality. Method: For this study, we used our institutional breast cancer care data mart, which contains data for all patients who had breast imaging or were treated for breast cancer at a University of Pittsburgh Medical Center (UPMC) facility between 2004 and 2019 inclusive. Including only women 40 years and older, 8,145 had at least one screening mammogram prior to their diagnosis of breast cancer. Screening exams less than 260 days apart were considered to be from the same screening episode. For the 8,145 women, we determined the interval between their two most recent screening mammograms and grouped them into: (i) Baseline (only 1 prior screening episode prior to diagnosis); (ii) Compliant (less than or equal to 15 months between the two most recent screening episodes); (iii) Delayed (more than 15 months but less than 27 months between the two most recent screening episodes); and (iv) Missed (more than 27 months between the two most recent screening episodes. Late-stage cancer was defined as TNM stage 2b or worst. In cancers arising in those with at least two prior screening examinations, we estimated and tested significance of effects of adherence category on risk of late-stage cancer using logistic regression. We estimated the corresponding effects on survival to death from any cause using proportional hazards model. The effect of compliance was evaluated univariately followed by the multivariable analysis accounting for demographic and clinical characteristics including age, race, and menopausal status. Analysis within practically relevant subgroups was performed for additional illustration. Results: For all-cause death 5-year mortality rate post-diagnosis was 4.2% for the Compliant group (n=3369, median follow-up 5.13 years), 5.9% for the Delayed group (n=1340, median follow-up 4.64 years), and 12.2% for the Missed group (n=1129, median follow-up 3.36 years). The overall 5-year mortality rate was 6.1% (n=8145, median follow 5.12 years). Both unadjusted and adjusted for age, menopausal status, and ethnicity, the poorer survival with lesser compliance was highly significant (with the adjusted hazard ratios relative to the baseline group of 0.5, 0.8, and 1.3 for the three compliance groups respectively, p< 0.001). In the population overall, there was a significant trend of increasing risk of stage 2B or worse with lesser adherence to annual screening, the proportions being 9%, 14%, and 19% for the compliant, delayed, and missed groups respectively (p< 0.001). This remained significant when adjusted for age, menopausal status, or ethnicity (p< 0.001). The trend was significant within major demographic subgroups, except for a relatively small subpopulation of women with unknown menopausal status. Conclusions: Annual mammographic screening resulted in lower all-cause mortality and lower risk of late-stage cancers, for both white and black women and pre- and post-menopausal women. Our study clearly shows a benefit to screening all women over the age of 40 annually over longer periods between screens. Table of Late-Stage Cancers by Screening Adherence and Demographic Factors Diagnosis of breast cancer at stage 2B or higher by screening adherence group and demographic factors Citation Format: Robert Nishikawa, Andriy Bandos, Stephen Duffy, Durwin Logue, Margarita Zuley. Benefit of Adherence to Annual Mammography Screening: Results from 8,305 Cancers in an Institutional Database [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-07-09.

Abstract PO4-13-08: Mechanical conditioning (MeCo) score is higher in circulating tumor cells (CTCs) compared to primary tumors in early-stage breast cancer and even higher in metastases compared to CTCs in metastatic breast cancer

Abstract Background: The mechanical conditioning (MeCo) score is a gene expression signature that is acquired early by cancer cells in the primary breast tumor and is reflective of their responsiveness to matrix stiffness (fibrotic-like matrix rigidity). Further, chromatin remodeling in response to stiffness allows cancer cells to retain their aggressive features even in the absence of mechanical stimulation by the primary tumor microenvironment, for instance, during their dissemination through the circulation in metastasis. Importantly, patients who have high MeCo score tumors are at higher risk of developing metastatic breast cancer, compared to low MeCo scores (p< 0.0001; HR=2.2, 95%CI 1.7-2.7; Watson et al 2021, PMID: 34192535). Moreover, circulating tumor cells (CTCs) are associated with higher rate of metastatic dissemination, making CTC detection in the circulation of breast cancer patients a significant prognostic biomarker for breast cancer metastasis. Beyond their enumeration per blood volume units, specific prognostic features of CTCs are not fully explored. We sought to determine whether, compared to primary tumors, CTCs retain high MeCo scores and whether these scores are maintained during late-stage breast cancer in the metastatic sites. Methods: CTCs were isolated from peripheral blood of two patient cohorts: stage II-III breast cancer patients using immunomagnetic enrichment/FACS methodology (Lang et al 2018, PMID: 29868978) and of metastatic breast cancer patients using ANGLE Parsortix microfluidics system (Ring et al 2022, PMID: 35000083). Gene expression profiling using RNA-seq was performed in CTCs and in matching primary tumors (PT) and metastases (MET) for the early-stage and late-stage cohorts, respectively. A quantile normalization approach was used to allow comparison across cohorts. MeCo scores were computed for all samples as per Watson et al 2021. Wilcoxon matched-pairs signed rank test was performed for comparison of MeCo scores from matching samples within each cohort; Mann-Whitney unpaired test was used to compared MeCo scores of CTCs across cohorts. Results: In 12 pairs of early-stage breast cancer patient CTCs and PT, MeCo scores of CTCs were significantly higher than their matched PTs (p=0.026). Furthermore, in 26 pairs of metastatic patient’s CTCs and MET, MeCo scores of METs were significantly higher than matching CTCs (p=0.0004). MeCo scores of CTCs were similar between early- and late-stage breast cancer despite differing CTC isolation strategies (epitope-dependent and microfluidics size gradient). 98% of genes in the MeCo score were present in the evaluable CTC, MET and PT samples. Conclusions: Our results show that the MeCo score is higher in CTCs compared to PTs and in METs compared to CTCs in early- and late-stage breast cancer, respectively. Therefore, the MeCo score is progressively higher throughout the metastatic cascade in breast cancer. These findings demonstrate that mechanical conditioning is retained during metastatic progression, even as cancer cells transition through the circulation where the initial induction by matrix stiffness is lost. Further, these findings support that cancer cells with higher MeCo scores are more competent with–and potentially selected for by–metastatic progression. Importantly, these findings provide a novel feature of CTCs, mechanical conditioning (MeCo), which is associated with higher capacity for metastasis. Further, since the CTC MeCo score is elevated even in early-stage breast cancer, it could provide, in addition to CTC enumeration, a potential prognostic tool to predict metastatic risk in breast cancer patients. Citation Format: Gus Mouneimne, Adam Watson, Adam Grant, Daniel Campo, Alexander Ring, Pushpinder Bains, Julie Lang. Mechanical conditioning (MeCo) score is higher in circulating tumor cells (CTCs) compared to primary tumors in early-stage breast cancer and even higher in metastases compared to CTCs in metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-08.

Disparities in Cancer Stage Outcomes by Catchment Areas for a Comprehensive Cancer Center

The National Cancer Institute comprehensive cancer centers (CCCs) lack spatial and temporal evaluation of their self-designated catchment areas. To identify disparities in cancer stage at diagnosis within and outside a CCC's catchment area across a 10-year period using spatial and statistical analyses. This cross-sectional, population-based study conducted between 2010 and 2019 utilized cancer registry data for the Johns Hopkins Sidney Kimmel CCC (SKCCC). Eligible participants included patients with cancer in the contiguous US who received treatment for cancer, a diagnosis of cancer, or both at SKCCC. Patients were geocoded to zip code tabulation areas (ZCTAs). Individual-level variables included sociodemographic characteristics, smoking and alcohol use, treatment type, cancer site, and insurance type. Data analysis was performed between March and July 2023. Distance between SKCCC and ZCTAs were computed to generate a catchment area of the closest 75% of patients and outer zones in 5% increments for comparison. The primary outcome was cancer stage at diagnosis, defined as early-stage, late-stage, or unknown stage. Multinomial logistic regression was used to determine associations of catchment area with stage at diagnosis. This study had a total of 94 007 participants (46 009 male [48.94%] and 47 998 female [51.06%]; 30 195 aged 22-45 years [32.12%]; 4209 Asian [4.48%]; 2408 Hispanic [2.56%]; 16 004 non-Hispanic Black [17.02%]; 69 052 non-Hispanic White [73.45%]; and 2334 with other or unknown race or ethnicity [2.48%]), including 47 245 patients (50.26%) who received a diagnosis of early-stage cancer, 19 491 (20.73%) who received a diagnosis of late-stage cancer , and 27 271 (29.01%) with unknown stage. Living outside the main catchment area was associated with higher odds of late-stage cancers for those who received only a diagnosis (odds ratio [OR], 1.50; 95% CI, 1.10-2.05) or only treatment (OR, 1.44; 95% CI, 1.28-1.61) at SKCCC. Non-Hispanic Black patients (OR, 1.16; 95% CI, 1.10-1.23) and those with Medicaid (OR, 1.65; 95% CI, 1.46-1.86) and no insurance at time of treatment (OR, 2.12; 95% CI, 1.79-2.51) also had higher odds of receiving a late-stage cancer diagnosis. In this cross-sectional study of CCC data from 2010 to 2019, patients residing outside the main catchment area, non-Hispanic Black patients, and patients with Medicaid or no insurance had higher odds of late-stage diagnoses. These findings suggest that disadvantaged populations and those living outside of the main catchment area of a CCC may face barriers to screening and treatment. Care-sharing agreements among CCCs could address these issues.

Abstract PO5-09-09: Incidence of Breast Cancer in Hispanic Women Across the US: A Focus on Texas

Abstract Introduction Breast cancer (BC) is one of the most common cancers affecting the female population in the United States, particularly among the Hispanic community. According to the CDC, the incidence rate of new breast cancer cases in Hispanic women is 95.6 per 100,000 annually, and the mortality rate is 13.7 per 100,000 women annually. Texas is home to one of the largest Hispanic communities in the US. By analyzing the prevalence, mortality, and access to healthcare services in Texas, we can shed light on the unique aspects of breast cancer within the Hispanic population. Overall, this study will provide valuable insights and identify potential avenues for reducing disparities and improving healthcare outcomes for Hispanic women affected by breast cancer. Materials and methods This study used comparative data from State Cancer Profiles on the CDC and NIH databases. The database was used to generate an overall comparison of breast cancer in Hispanic women across different US states. Comparison factors analyzed include incidence, mortality, insurance, and screening efforts. Significant differences were noted especially in Texas. Graphs and quantitative data for comparison factors were generated. This data is from 2015-2019 unless noted. Results The incidence of breast cancer in Hispanic women in Texas (TX) is 93.5 (Age-Adjusted Incidence Rate-cases per 100,000) with a CI of (92.2-94.8). The incidence of BC in Hispanic women in the US averages 99.0 with a CI of 98.7-99.9. From the incidence data, Hispanic women in Texas have a lower overall incidence of BC compared to the rest of the Hispanic females in the US. When analyzing the mortality rate, Hispanic women in TX have an Age-Adjusted Death Rate (deaths per 100,000) of 15.2 (CI of 14.7-15.8). In the US, Hispanic women have an Age-Adjusted Death Rate (deaths per 100,000) of 13.0 (CI of 13.4-13.9). To analyze preventative measures, a graph reporting mammogram use in 2020 by state was gathered. In TX 2020, the estimated age-adjusted prevalence of mammograms among Hispanic females from 50-74 years old was 75.0% (CI of 67.0%-81.7%). Nationally, the age-adjusted prevalence among Hispanic females 50-74 years who reported mammogram screening in 2 years was 79.7% (CI of 76.6 – 82.4). As for Texas insurance rates in 2020, Hispanic women under 65 years old, 27.4 % reported being uninsured. In comparison, other ethnicities such as African American (non-Hispanic) women, 16.5% reported to be uninsured, and white (non-Hispanic) women in Texas 11.8 % reported to be uninsured. Additionally, to further analyze if the lack of preventative measures was causing women to have a higher mortality rate, the instance of late-stage diagnosis of BC in Texan Hispanic women was analyzed. The age-adjusted incidence rate of late-stage breast cancer in Hispanic women was reported to be 33.4 (CI of 32.6-34.2) and the national incidence of late-stage BC in Hispanic women is 35.0 (CI of 35.1-35.8). Conclusion Even with Texas having one of the largest Hispanic communities, Hispanic women with breast cancer in Texas are faced with obstacles that lead to an increase in their mortality rate. As seen in the results, Hispanic women have less incidence of BC (including late stage) than their equivalent across the US but Hispanic women in TX have higher mortality rates in comparison. This is additionally accompanied by a decrease in insured women and a decrease in the utilization of cancer screenings. Lack of access to affordable healthcare and lack of regulatory cancer screenings cause Hispanic women to meet their premature death. Further analysis of the effects of affordable health care or further molecular investigation of this population is encouraged to research to fully conclude the reason behind this population's disparities. Citation Format: Catalina Esguerra, Kemely Santos Barbosa, Roy Khalife, Anthony Magliocco. Incidence of Breast Cancer in Hispanic Women Across the US: A Focus on Texas [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-09-09.

Cell Membrane-Camouflaged Chitosan-Polypyrrole Nanogels Co-Deliver Drug and Gene for Targeted Chemotherapy and Bone Metastasis Inhibition of Prostate Cancer.

The development of functional nanoplatforms to improve the chemotherapy outcome and inhibit distal cancer cell metastasis remains an extreme challenge in cancer management. In this work, a human-derived PC-3 cancer cell membrane-camouflaged chitosan-polypyrrole nanogel (CH-PPy NG) platform, which can be loaded with chemotherapeutic drug docetaxel (DTX) and RANK siRNA for targeted chemotherapy and gene silencing-mediated metastasis inhibition of late-stage prostate cancer in a mouse model, is reported. The prepared NGs with a size of 155.8nm show good biocompatibility, pH-responsive drug release profile, and homologous targeting specificity to cancer cells, allowing for efficient and precise drug/gene co-delivery. Through in-vivo antitumor treatment in a xenografted PC-3 mouse tumor model, it is shown that such a CH-PPy NG-facilitated co-delivery system allows for effective chemotherapy to slow down the tumor growth rate, and effectively inhibits the metastasis of prostate cancer to the bone via downregulation of the RANK/RANKL signaling pathway. The created CH-Ppy NGs may be utilized as a promising platform for enhanced chemotherapy and anti-metastasis treatment of prostate cancer.

Abstract PO1-07-10: Blood Based Early Cancer Detection Assay

Abstract Background: Breast cancer screening programs utilizing mammography have been shown to be highly effective in identifying breast cancer in women over the age of 40. High breast density is an independent risk factor for breast cancer and makes mammograms more difficult to interpret, decreasing their sensitivity. In the spring of 2023, the FDA, who certifies all mammography facilities under the Mammography Quality Standards Act, updated its regulations to require that breast density status be reported to all individuals receiving a mammogram. The new guidelines now require individuals with dense breast tissue be notified of this status. The guidelines also recommend these women discuss additional screening options with their healthcare providers1. These additional screening options may include breast tomosynthesis, breast MRI, breast ultrasound, and/or molecular breast imaging. Many of these options require additional exposure to radiation, are expensive, and are not equitably available across the country. In addition, they all require a follow-up appointment. Compliance can be challenging given the top barriers to mammography cited include the need for transportation, child-care, and the ability to take time off from work2. Genece Health is developing a simpler and less expensive screening solution that identifies the presence of early to late-stage breast cancer using cfDNA from a single blood draw. The Genece Health assay utilizes an algorithm that leverages Artificial Intelligence and Machine Learning to analyze fragment size and end motif patterns in cfDNA as well as regional mutational density to detect presence of ctDNA originating from breast cancer. This algorithm provides highly sensitive and specific results in a preliminary data set. Methods: The preliminary data set, presented herein, is a cohort of over 50 retrospective breast cancer plasma samples and over 100 presumed normal samples. The breast cancer samples were collected at all stages of progression, from stage 0, or ductal carcinoma in situ (DCIS), through stage IV. The majority ( >50%) were from stage I breast cancer. 400 µL of double spun plasma, collected in Streck BCT devices, was processed to purify and isolate cfDNA. cfDNA was used to create WGS libraries that were sequenced on a NovaSeq 6000. Sequence data were analyzed using a bioinformatics pipeline that yields an ensemble probability that correlates to the presence or absence of ctDNA from breast cancer. Results: The Genece Health assay and algorithm performed with a specificity greater than 85%. With this specificity, the assay had a sensitivity greater than 85% in samples from stages II to IV and a slightly lower sensitivity in stage 0 and I samples. Follow-up analyses were conducted to stratify performance based on breast cancer type (e.g. invasive ductal carcinoma vs invasive lobular carcinoma) and HR, PR, and HER2 status (e.g. HER2-negatives vs HER2-positives). Conclusions: The presented preliminary data indicate that the Genece Health technology can be leveraged as a complement to mammography in indications, such as dense breast tissue, where there is an unmet need for an easy and cost-effective way to monitor for breast cancer. The ability to have a blood-based test to complement mammography could reduce the access barriers most cited by females in the United States. Follow-up studies with greater numbers of samples and additional training and optimizations of the algorithm will yield performance improvements that allow the assay to detect all types and stages of breast cancer.

Single-cell analyzing of tumor microenvironment and cell adhesion between early and late-stage lung cancer

Lung adenocarcinoma (LUAD) is a highly heterogeneous disease that threaten human life with serious incidence and high mortality. High heterogeneity of tumor microenvironment (TME) was reported in multiple studies. However, the factor of controlling the tumor migration progression between eary and late-stage LUAD is still not fully understood. In this study, we conducted a comprehensive analysis of single-cell RNA sequencing (scRNA-seq) data of LUAD obtained from the GEO database. The identification of cell clusters revealed significant expansion of epithelial cells in late-stage patients. Interpretation of the cell-cell communication results between early-stage and late-stage patient samples indicated that early tumor cells may interact with epithelial cells through the TGF-β pathway to promote tumor progression. The cell cycle analysis demonstrated a significant increase in the number of cells in the G2 and M phases in late-stage lung cancer. Further analysis using Non-negative Matrix Factorization (NMF) revealed early-stage cell-specific gene features involved in cell adhesion-related biological processes. Among these, the Tensin (TNS) gene family, particularly TNS1, showed high expression in epithelial cells and fibroblasts of early-stage samples, specifically associated with cell adhesion. Survival analysis using TCGA database for LUAD demonstrated that patients with high expression of TNS1 exhibited significantly higher overall survival rates compared to those with low expression. Immunofluorescence experiments have demonstrated co-expression of TNS1 with fibroblast and tumor cell markers (α-SMA and EPCAM). Immunohistochemistry experiments further validated the significantly higher expression levels of TNS1 in early-stage LUAD tissues compared to late-stage lung cancer tissues (P<0.05). Pathway experiments have shown that early-stage tumor patients with high expression of TNS1 exhibit stronger phosphorylation levels of Akt and mTOR, indicating a more potent activation of the Akt/mTOR signaling pathway. In conclusion, the results of this study demonstrate that TNS1 is an adhesive molecule in the immune microenvironment of early-stage tumor cells, and it may serve as a novel prognostic marker for lug cancer.

Development and therapeutic evaluation of 5D3(CC-MLN8237)3.2 antibody-theranostic conjugates for PSMA-positive prostate cancer therapy.

Prostate cancer (PC) is an aggressive cancer that can progress rapidly and eventually become castrate-resistant prostate cancer (CRPC). Stage IV metastatic castrate-resistant prostate cancer (mCRPC) is an incurable late-stage cancer type with a low 5-year overall survival rate. Targeted therapeutics such as antibody-drug conjugates (ADCs) based on high-affinity monoclonal antibodies and potent drugs conjugated via smart linkers are being developed for PC management. Conjugating further with in vitro or in vivo imaging agents, ADCs can be used as antibody-theranostic conjugates (ATCs) for diagnostic and image-guided drug delivery. In this study, we have developed a novel ATC for PSMA (+) PC therapy utilizing (a) anti-PSMA 5D3 mAb, (b) Aurora A kinase inhibitor, MLN8237, and (c) for the first time using tetrazine (Tz) and trans-cyclooctene (TCO) click chemistry-based conjugation linker (CC linker) in ADC development. The resulting 5D3(CC-MLN8237)3.2 was labeled with suitable fluorophores for in vitro and in vivo imaging. The products were characterized by SDS-PAGE, MALDI-TOF, and DLS and evaluated in vitro by optical imaging, flow cytometry, and WST-8 assay for cytotoxicity in PSMA (+/-) cells. Therapeutic efficacy was determined in human PC xenograft mouse models following a designed treatment schedule. After the treatment study animals were euthanized, and toxicological studies, complete blood count (CBC), blood clinical chemistry analysis, and H&E staining of vital organs were conducted to determine side effects and systemic toxicities. The IC50 values of 5D3(CC-MLN8237)3.2-AF488 in PSMA (+) PC3-PIP and PMSA (-) PC3-Flu cells are 8.17nM and 161.9nM, respectively. Pure MLN8237 shows 736.9nM and 873.4nM IC50 values for PC3-PIP and PC3-Flu cells, respectively. In vivo study in human xenograft mouse models confirmed high therapeutic efficacy of 5D3(CC-MLN8237)3.2-CF750 with significant control of PSMA (+) tumor growth with minimal systemic toxicity in the treated group compared to PSMA (-) treated and untreated groups. Approximately 70% of PSMA (+) PC3-PIP tumors did not exceed the threshold of the tumor size in the surrogate Kaplan-Meyer analysis. The novel ATC successfully controlled the growth of PSMA (+) tumors in preclinical settings with minimal systemic toxicities. The therapeutic efficacy and favorable safety profile of novel 5D3(CC-MLN8237)3.2 ATC demonstrates their potential use as a theranostic against aggressive PC.

Inhibition of δ-catenin palmitoylation slows the progression of prostate cancer

Prostate cancer (PCa) is the second leading cause of death in males. It has been reported that δ-catenin expression is upregulated during the late stage of prostate cancer. Palmitoylation promotes protein transport to the cytomembrane and regulates protein localization and function. However, the effect of δ-catenin palmitoylation on the regulation of cancer remains unknown. In this study, we utilized prostate cancer cells overexpressing mutant δ-catenin (J6A cells) to induce a depalmitoylation phenotype and investigate its effect on prostate cancer. Our results indicated that depalmitoylation of δ-catenin not only reduced its membrane expression but also promoted its degradation in the cytoplasm, resulting in a decrease in the effect of EGFR and E-cadherin signaling. Consequently, depalmitoylation of δ-catenin reduced the proliferation and metastasis of prostate cancer cells. Our findings provide novel insights into potential therapeutic strategies for controlling the progression of prostate cancer through palmitoylation-based targeting of δ-catenin.

Advancing Evidence Generation for Circulating Tumor DNA: Lessons Learned from A Multi-Assay Study of Baseline Circulating Tumor DNA Levels across Cancer Types and Stages.

Circulating tumor DNA (ctDNA) holds promise as a biomarker for predicting clinical responses to therapy in solid tumors, and multiple ctDNA assays are in development. However, the heterogeneity in ctDNA levels prior to treatment (baseline) across different cancer types and stages and across ctDNA assays has not been widely studied. Friends of Cancer Research formed a collaboration across multiple commercial ctDNA assay developers to assess baseline ctDNA levels across five cancer types in early- and late-stage disease. This retrospective study included eight commercial ctDNA assay developers providing summary-level de-identified data for patients with non-small cell lung cancer (NSCLC), bladder, breast, prostate, and head and neck squamous cell carcinoma following a common analysis protocol. Baseline ctDNA levels across late-stage cancer types were similarly detected, highlighting the potential use of ctDNA as a biomarker in these cancer types. Variability was observed in ctDNA levels across assays in early-stage NSCLC, indicative of the contribution of assay analytical performance and methodology on variability. We identified key data elements, including assay characteristics and clinicopathological metadata, that need to be standardized for future meta-analyses across multiple assays. This work facilitates evidence generation opportunities to support the use of ctDNA as a biomarker for clinical response.

Demographic and clinical characteristics associated with advanced stage colorectal cancer: a registry-based cohort study in Saudi Arabia

BackgroundIn Saudi Arabia, approximately one-third of colorectal cancer (CRC) patients are diagnosed at an advanced stage. Late diagnosis is often associated with a worse prognosis. Understanding the risk factors for late-stage presentation of CRC is crucial for developing targeted interventions enabling earlier detection and improved patient outcomes.MethodsWe conducted a retrospective cohort study on 17,541 CRC patients from the Saudi Cancer Registry (1997–2017). We defined distant CRCs as late-stage and localized and regional CRCs as early-stage. To assess risk factors for late-stage CRC, we first used multivariable logistic regression, then developed a decision tree to segment regions by late-stage CRC risk, and finally used stratified logistic regression models to examine geographical and sex variations in risk factors.ResultsOf all cases, 29% had a late-stage diagnosis, and 71% had early-stage CRC. Young (< 50 years) and unmarried women had an increased risk of late-stage CRC, overall and in some regions. Regional risk variations by sex were observed. Sex-related differences in late-stage rectosigmoid cancer risk were observed in specific regions but not in the overall population. Patients diagnosed after 2001 had increased risks of late-stage presentation.ConclusionOur study identified risk factors for late-stage CRC that can guide targeted early detection efforts. Further research is warranted to fully understand these relationships and develop and evaluate effective prevention strategies.

Intracellular delivery of oncolytic viruses with engineered Salmonella causes viral replication and cell death

Intracellular delivery of oncolytic viruses with engineered Salmonella causes viral replication and cell death

CDK9 inhibition activates innate immune response through viral mimicry.

Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity to compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details of CDK9 inhibition-induced cancer cell-selective anti-proliferative effects remain largely unknown. Here, we discover that CDK9 inhibition activates the innate immune response through viral mimicry in cancer cells. In MYC over-expressing prostate cancer cells, CDK9 inhibition leads to the gross accumulation of mis-spliced RNA. Double-stranded RNA (dsRNA)-activated kinase can recognize these mis-spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Using time-resolved transcriptional profiling (SLAM-seq), targeted proteomics, and ChIP-seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows selective transcription and translation of cytokines related to the innate immune response. In particular, CDK9 inhibition activates NFκB-driven cytokine signaling at the transcriptional and secretome levels. The transcriptional signature induced by CDK9 inhibition identifies prostate cancers with a high level of genome instability. We propose that it is possible to induce similar effects in patients using CDK9 inhibition, which, we show, causes DNA damage invitro. In the future, it is important to establish whether CDK9 inhibitors can potentiate the effects of immunotherapy against late-stage prostate cancer, a currently lethal disease.