Outcomes In Malignancies Research Articles

Abstract PO4-09-06: Area Deprivation Index (ADI) among Patients with Breast Cancer in Buffalo

Abstract Introduction: Socioeconomic and racial disparities can limit access to health care. Prior studies suggest that living in a disadvantaged neighborhood results in poorer outcomes in several malignancies. ADI is an index that categorizes areas based on socioeconomic variables. In this observational study, we aimed to investigate the ADI among patients (pts) with breast cancer (BC) seen at Roswell Park Comprehensive Cancer Center in Buffalo, New York, and study its association with clinical outcomes to identify the areas with the highest unmet need for possible intervention strategies. Methods: We reviewed data of 187 pts diagnosed with stages 1-3 and de-novo stage 4 BC between 2014 to 2018. We obtained information on ADI using pts’ home addresses via Neighborhood Atlas tool www.neighborhoodatlas.medicine.wisc.edu. ADI values were categorized into four quartiles Q1(80-100%), Q2(60-79%), Q3(40- 59%), and Q4(0-39%) from highest deprivation/poor social economic status areas to least disadvantaged areas, respectively. Demographic and clinicopathological characteristics including age, race, comorbidities, stage, type of insurance, duration on treatment were compared by ADI. Kruskal-Wallis and Chi-square was used for comparing continuous and categorical variables, respectively. Recurrence free survival (RFS), time to next treatment (TNT), and overall survival (OS) were estimated using Kaplan Meier method. Multivariate Cox regression model was used to analyze outcomes for pts with stage 4 in the most disadvantaged areas (ADI ≥60%) adjusting for relevant covariates. Analyses were performed using SAS v9.4 at a significance level of < 0.05. Results: 98% pts (183/187) were females, 85% (160/187) Whites, 9% (17/187) African Americans, and 3% (6/187) Asians. 62% (116/187) lived in the most disadvantaged areas: 37% (70/187) in Q1, and 24% (46/187) in Q2, while 27% (51/187) lived in Q3, and 11% (n=20/187) in Q4. 80% (150/187) pts were diagnosed with hormone receptor positive BC, 18% (34/187) HER2 positive, and 15% (28/187) triple negative BC. 45% of pts (83/187) had de novo stage 4, the rest were diagnosed with stages 1-3. There was no difference in the distribution of age, race, employment, insurance, comorbidities, substance use, smoking, access to contraception, screening mammogram, or adherence to anti-estrogen and radiation therapy by ADI. There was a significant difference in adherence to chemotherapy/anti HER2 therapy: 92% (36/39) in Q1,100% (24/24) in Q2 vs. 85% (24/28) in Q3 and 67% (6/9) in Q4, p=0.029. Among pts with stages 1-3, there was no difference in RFS (p= 0.700) or OS (p= 0.400) by ADI. Among stage 4 patients, there was an association between TNT and ADI, where patients living where there was a trend towards worse survival with increasingly disadvantaged neighborhoods, p=0.008 (Table 1). Moreover, there was a significant difference in OS by ADI, p=0.03 (Table 2). There was a significant association between ADI and both TNT and OS, even after adjusting to age, race, BC subtypes p= 0.004 and p= 0.034 respectively (Table 3). Conclusion: Our study in the Western New York region showed that BC pts living in disadvantaged areas had worse survival and shorter TNT despite being more adherent to chemotherapy/anti HER2 therapy. Our study validates prior studies showing that ADI is an important factor impacting BC outcomes. These data will help guide our future efforts to maximize resource allocation towards these disadvantaged areas to improve BC outcomes. Table 1 Table 2 Table 3 Citation Format: Malak Alharbi, Arya Mariam Roy, Archit Patel, Kayla Catalfamo, Kristopher Attwood, Angela Omilian, Elizabeth Bouchard, Ellis Levine, Tracey O'Connor, Amy Early, Shipra Gandhi. Area Deprivation Index (ADI) among Patients with Breast Cancer in Buffalo [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 PO4-09-06.

Abstract PO3-15-01: Overexpression of N-glycosylation related gene OST4 promotes chemotherapy resistance in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with high malignancy and poor outcome. Resistance to chemotherapy leads to treatment failure. How to overcome drug resistance is the key point in TNBC treatment. Previously, we initiated a prospective multicenter single-arm NeoPath clinical study (ClinicalTrial.gov identifier: NCT03907800) to assess the efficacy and safety of nab-paclitaxel combined with carboplatin in the neoadjuvant therapy of triple negative and HER2-positive early breast cancer. A total of 99 TNBC patients were enrolled and the pCR rate in TNBC was 33.78%. Samples before and after treatment were collected. RNA-sequencing results showed that OST4 was of high-expression in drug-resistant TNBC tumor tissues compared with chemo-sensitive samples. To verify the clinical significance of OST4 expression levels in TNBC, we tested the expression of OST4 by immunohistochemical technique on a tissue microarray including 87 TNBC cases treated with chemotherapy. We found that high expression of OST4 was associated with poor tumor differentiation, and patients with high OST4 expression had more relapse after chemotherapy. Ex-vivo proliferation assay and foci formation assay further confirmed that over-expression of OST4 promoted chemo-resistance, whereas down-regulating OST4 could reverse resistance in TNBC cell lines. As an oligosaccharyltransferase, it is reported that OST4 played parts in N-glycosylation. So we try to elucidate the relationship between N-glycosylation and drug resistance. Glycoproteomics results verified the existence of differential N-glycosylation atlas in drug-resistant tumor tissues compared with drug sensitive samples. NGS1 was identified as a potential target of OST4 by co-immunoprecipitation and mass spectrometry. In conclusion, high expression of OST4 could promote chemotherapy resistance in TNBC trough N-glycosylation regulation. Targeting OST4 may help reverse drug-resistance and improve therapeutic effect in TNBC. Citation Format: Wei Wang, Deyue Liu, Shuning Ding, Yan Fang, Jiayi Wu, Li Zhu. Overexpression of N-glycosylation related gene OST4 promotes chemotherapy resistance in triple-negative 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 PO3-15-01.

Controlling the nutritional status score: a new tool for predicting postoperative mortality in patients with infrarenal abdominal aortic aneurysm treated with endovascular aneurysm repair.

AAA is a fatal condition that commonly occurs during vascular surgery. Nutritional status exerts a significant influence on the prognosis of various pathological conditions Scores from the CONUT screening tool have been shown to predict outcomes of certain malignancies and chronic diseases. However, the ramifications of nutritional status on AAA patients undergoing EVAR have not been elucidated in prior studies. In this study, we aimed to elucidate the correlation between CONUT scores and postoperative prognostic outcomes in patients with AAA undergoing EVAR. This was a retrospective review of 177 AAA patients treated with EVAR from June 2018 to November 2019 in a single center. Patient characteristics, CONUT scores, and postoperative status were collected. These patients were stratified into groups A and B according to CONUT scores. Subsequently, a comparative analysis of the baseline characteristics between the two cohorts was conducted. Cox proportional hazards and logistic regression analyses were employed to identify the autonomous predictors of mid-term mortality and complications, respectively. Compared with group A, patients in group B had higher midterm mortality (p < 0.001). Univariate analysis showed that CONUT scores; respiratory diseases; stent types; preoperative Hb, CRP, PT, and Fb levels were risk factors for death. Multivariate analysis confirmed that CONUT score [HR, 1.276; 95% CI, 1.029-1.584; p = 0.027] was an independent risk factor for mortality. Logistic regression analysis showed that prior arterial disease, smoking, and D-dimer levels were risk factors, although multivariate analysis showed smoking (OR, 3.492; 95% CI, 1.426-8.553; p = 0.006) was an independent risk factor. Kaplan-Meier curves showed that patients in group B had shorter mid-term survival than those in group A (log-rank p < 0.001). Malnutrition was strongly associated with mid-term mortality in patients with infrarenal AAA treated with EVAR.

Stealth transgenes enable CAR-T cells to evade host immune responses

BackgroundAdoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based...

"Myeloid" Mutations in ALL Are Not Uncommon: Implications for Etiology and Therapies.

In Blood Cancer Discovery, Saygin and colleagues report that somatic variants that are recurrent in myeloid malignancies can also occur with high frequency (16%) in adult acute lymphoblastic leukemia (ALL) where they correlate with older age, diagnosis following genotoxic therapy for a prior malignancy and worse outcome to chemotherapy. Mutations in these "myeloid" genes can precede ALL diagnosis and arise in hematopoietic stem or progenitor cells that clonally expand and differentiate into both lymphoblasts and nonmalignant myeloid cells, supporting a role for clonal hematopoiesis as premalignant state outside the context of myeloid malignancies and providing implications for both ALL etiology and therapeutic intervention. See related article by Saygin et al., p. 164 (4).

The role of ST3GAL4 in glioma malignancy, macrophage infiltration, and prognostic outcomes

BackgroundGlioma, a prevalent malignancy of the brain and spinal cord, poses a considerable threat to human health. The association between aberrant sialic acid modification and glioma progression has been suggested, but the precise mechanism is still elusive. ST3GAL4, a sialoglycosyltransferase, is implicated in increased metastatic potential and poor prognosis in various cancers; however, its specific role in glioma requires further elucidation. MethodsWe evaluated ST3GAL4 expression levels and their clinical relevance using the TCGA database, and we assessed immune infiltration via the Tumor Immune Evaluation Resource (TIMER) database. In vitro experiments were performed to determine the effects of ST3GAL4 knockdown on glioma cell malignancy, with additional co-culture assays to assess its impact on macrophage phenotype. ResultsST3GAL4 expression was markedly elevated in glioma tissues compared to normal brain tissues, with a strong correlation to glioma patient clinical characteristics. Survival analyses and receiver operating characteristic (ROC) curves suggested that ST3GAL4 is a feasible diagnostic and prognostic biomarker for glioma. Knockdown studies revealed that ST3GAL4 inhibition reduces glioma cell line proliferation, migration, and invasion, while causing G1 phase cell cycle arrest. ST3GAL4 appears to mediate glioma progression through extracellular matrix reorganization and EMT signaling pathway activation, further contributing to M2 macrophage polarization and infiltration within the tumor microenvironment. ConclusionOur research highlights the critical role of ST3GAL4 in glioma development, positioning it as a promising candidate for diagnostic and therapeutic interventions.

Impact of cachexia on disease recurrence and survival outcomes in endometrial cancer patients

ObjectiveCancer cachexia is progressive weight loss due to muscle/adipose tissue wasting and inadequate intake that occurs in response to malignancy. It is an independent predictor of disease recurrence and reduced survival in several cancers. However, cachexia’s relationship with gynecologic malignancy outcomes has only been examined in small studies with limited follow-up and inconsistent definitions of cachexia. This study investigated the impact of cachexia on disease recurrence and overall survival in high-risk endometrial carcinoma patients. MethodsThis retrospective cohort study examined data from patients with high-risk non-metastatic primary endometrial carcinoma treated at a single institution from 2015 to 2020. Treatment for all subjects included total hysterectomy, surgical staging, pelvic external beam radiotherapy with or without adjuvant chemotherapy. Radiation planning CT datasets were used to measure skeletal musculature at the L3 vertebral level. Skeletal muscle index (SMI) was defined as total L3 skeletal muscle cross sectional area (cm2)/height2 (m2), and cachexia was defined based on SMI. Results55 patients were eligible for analysis. Several SMI thresholds were used to define cachexia, and analysis was performed for each definition. Kaplan-Meier and Cox-proportional hazards regression analysis yielded no significant reduction in overall survival (OS) or progression-free survival (PFS) in patients with cachexia, regardless of threshold chosen. However, 4 of 13 definitions of cachexia showed significantly improved OS in patients without cachexia, relative to those with cachexia. There were no significant differences in disease recurrence. ConclusionsCachexia as defined in this study was not associated with poor outcomes in endometrial carcinoma patients based on OS, PFS, or disease recurrence.

Racial and ethnic disparities in Acute Myeloid Leukemia: 15-year experience at a safety net hospital system

Despite recent therapeutic advances, ethnic minorities in the U.S. continue to have disproportionately poor outcomes in many hematologic malignancies including AML. We identified 162 adult AML patients treated at a non-transplant safety net hospital from 2007 to 2022 and evaluated differences in disease characteristics, treatment and clinical outcomes based on race and ethnicity. Our cohort consisted of 82 (50.6%) Hispanic, 36 (22.2%) non-Hispanic black and 44 (27.2%) non-Hispanic white and Asian patients. Median age at diagnosis was 42.5, 49.0 and 52.5 years respectively (p=0.025). Hispanics had higher rates of intermediate and high-risk disease (p=0.699) and received high intensity induction and consolidation chemotherapy at lower rates (p=0.962), although differences did not reach statistical significance. Despite this, similar remission rates were achieved. Hispanics with high-risk disease had longer overall survival (OS) than the combined non-Hispanic cohort (mOS 14 m vs 7 m, p=0.030). Multivariate regression analysis showed that OS was negatively associated with age (HR 1.023, p=0.006), intermediate (HR 3.431, p=0.0003) and high-risk disease (HR 4.689, p<0.0001) and positively associated with Hispanic ethnicity (HR 0.614, p=0.026). This report suggests that contrary to other studies, Hispanics, particularly those with high-risk AML, may have improved OS compared to other ethnic groups. These results are unique to our safety net hospital setting where common barriers to medical care and healthcare disparities are largely mitigated.

Association between lactate dehydrogenase to albumin ratio and acute kidney injury in patients with sepsis: a retrospective cohort study.

Serum lactate dehydrogenase to albumin ratio (LAR) is associated with poor outcomes in malignancy and pneumonia. However, there are few studies suggesting that LAR is associated with the occurrence of acute kidney injury (AKI) in patients with sepsis, which was investigated in this study. We conducted a retrospective cohort study based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary outcome was the occurrence of AKI within 2days and 7days. Multivariable logistic regression models were used to calculate odds ratios to validate the association between LAR and AKI, in-hospital mortality, RRT use, and recovery of renal function, respectively. A total of 4010 participants were included in this study. The median age of the participants was 63.5years and the median LAR was 10.5. After adjusting for confounding variables, patients in the highest LAR quartile had a higher risk of AKI than those in the lowest LAR quartile within 2days and 7days, with odds ratios of 1.37 (95% confidence interval [CI]: 1.23-1.52) and 1.95 (95% CI: 1.72-2.22), respectively. The adjusted odds of AKI within 2 and 7days were 1.16 (95% CI: 1.12-1.20) and 1.29 (95% CI: 1.24-1.35) for each 1unit increase in LAR(log2), respectively. This study demonstrated that elevated LAR was associated with poor prognosis in patients with sepsis. The risk of AKI and in-hospital mortality increased, the need for RRT increased, and the chance of recovery of renal function decreased with the increase of LAR.

Lidocaine attenuates TMZ resistance and inhibits cell migration by modulating the MET pathway in glioblastoma cells.

Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Currently, the predominant clinical treatment is the combination of surgical resection with concurrent radiotherapy and chemotherapy, using temozolomide (TMZ) as the primary chemotherapy drug. Lidocaine, a widely used amide‑based local anesthetic, has been found to have a significant anticancer effect. It has been reported that aberrant hepatocyte growth factor (HGF)/mesenchymal‑epithelial transition factor (MET) signaling plays a role in the progression of brain tumors. However, it remains unclear whether lidocaine can regulate the MET pathway in GBM. In the present study, the clinical importance of the HGF/MET pathway was analyzed using bioinformatics. By establishing TMZ‑resistant cell lines, the impact of combined treatment with lidocaine and TMZ was investigated. Additionally, the effects of lidocaine on cellular function were also examined and confirmed using knockdown techniques. The current findings revealed that the HGF/MET pathway played a key role in brain cancer, and its activation in GBM was associated with increased malignancy and poorer patient outcomes. Elevated HGF levels and activation of its receptor were found to be associated with TMZ resistance in GBM cells. Lidocaine effectively suppressed the HGF/MET pathway, thereby restoring TMZ sensitivity in TMZ‑resistant cells. Furthermore, lidocaine also inhibited cell migration. Overall, these results indicated that inhibiting the HGF/MET pathway using lidocaine can enhance the sensitivity of GBM cells to TMZ and reduce cell migration, providing a potential basis for developing novel therapeutic strategies for GBM.

Incidence &amp; Feto - Maternal Outcome of Malignancies Complicating Pregnancy in a Tertiary Care Center

Incidence &amp; Feto - Maternal Outcome of Malignancies Complicating Pregnancy in a Tertiary Care Center

A meta-analysis to assess the risk of bleeding and thrombosis following chimeric antigen receptor T-cell therapy: Communication from the ISTH SSC Subcommittee on Hemostasis and Malignancy

BackgroundChimeric antigen receptor T-cell (CAR T-cell) therapy is increasingly utilized for treatment of hematologic malignancies. Hematologic toxicities including thrombosis and bleeding complications have been reported. Accurate estimates for thrombotic and bleeding outcomes are lacking. ObjectivesWe performed a systematic review and meta-analysis in patients who received CAR T-cell therapy for an underlying hematologic malignancy with the objective to: a) assess the thrombosis and bleeding risk associated with CAR T-cell therapy, b) assess the impact of CRS and ICANS on the risks of thrombosis and bleeding, and c) assess the safety of anticoagulant or antiplatelet use in the period following treatment with CAR T-cell therapy. MethodsWe searched MEDLINE, EMBASE, and Cochrane CENTRAL up to February 2022 for studies reporting thrombotic or bleeding outcomes in patients receiving CAR T-cell therapy. Pooled event rates were calculated using a random-effects model. We performed subgroup analyses stratified by follow-up duration, CAR T-cell target antigen, and underlying hematologic malignancy. ResultsWe included 47 studies with a total of 7040 patients. High heterogeneity between studies precluded reporting of overall pooled rates of thrombotic and bleeding events. In studies with follow-up duration of ≤6 months, the pooled incidence of venous thrombotic events was 2.4% (95% CI, 1.4%-3.4%; I2 = 0%) per patient-month, whereas the rate was 0.1% (95% CI, 0%-0.1%; I2 = 0%) per patient-month for studies with longer follow-up periods (>6 months). The pooled incidences of any bleeding events per patient-month in studies with follow-up duration of ≤6 months and >6 months were 1.9% (95% CI, 0.6%-3.1%; I2 = 78%) and 0.3% (95% CI: 0%-0.8%, I2 = 40%), respectively. Secondary analyses by CAR T-cell target antigen, underlying malignancy, and primary outcome of the studies did not reveal significant differences in the rates of thromboembolism, any bleeding events, or major bleeding events. ConclusionThe risk of both thrombosis and bleeding following CAR T-cell therapy appears to be highest in the initial months following infusion.

Cytologic Parameters in Predicting the Outcome of Atypical Glandular Cells on Papanicolaou Smears: A Single-Institutional Experience.

Atypical glandular cells (AGCs) diagnosis on Pap (Papanicolaou) smears are uncommon and may represent various benign and malignant lesions. This study aims to report the incidence of AGC on Pap smear, to study the relationship of AGC with malignancy, and to determine cytomorphological features that help in predicting malignancy. Retrospective analytical study conducted in the Department of Oncopathology at Tertiary Cancer and Research Institute. In this retrospective study, we included cases diagnosed with AGC between July 2017 to July 2022. All slides were reviewed and subclassified according to the Bethesda 2014 classification system (TBS). The predetermined cytomorphological features observed in the smears were recorded. The follow-up histopathological diagnoses of the cases were retrieved. The significant cytomorphological and clinicopathological findings for malignancy were determined. Pearson χ2 test with SPSS software version 22 to compare cytologic features of cases with benign and malignant follow-up. The significant cytomorphological features observed in neoplastic cases were cells in 3-dimensional clusters, nuclear overlapping, reniform nucleus, irregular nuclear membrane, increased nuclear size, single macronucleoli, engulfed neutrophils, and prominently vacuolated cytoplasm. The diagnosis of AGC on cytology is associated with clinically significant lesions, and cytomorphologic parameters can be used to predict the benign and malignant outcome.

(458) - History of Malignancy and Rejection Outcomes Assessed by Molecular Microscope (MMDx)

(458) - History of Malignancy and Rejection Outcomes Assessed by Molecular Microscope (MMDx)

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

Feasibility and safety of minimally invasive multivisceral resection for T4b rectal cancer: A 9-year review.

Colorectal cancer is the third most common cancer and the second highest cause of cancer-related mortality worldwide. About 5%-10% of patients are diagnosed with locally advanced rectal cancer (LARC) on presentation. For LARC invading into other structures (i.e. T4b), multivisceral resection (MVR) and/or pelvic exenteration (PE) remains the only potential curative surgical treatment. MVR and/or PE is a major and complex surgery with high post-operative morbidity. Minimally invasive surgery (MIS) has been shown to improve short-term post-operative outcomes in other gastrointestinal malignancies, but there is little evidence on its use in MVR, especially so for robotic MVR. To assess the feasibility and safety of minimally invasive MVR (miMVR), and compare post-operative outcomes between robotic and laparoscopic MVR. This is a single-center retrospective cohort study from 1st January 2015 to 31st March 2023. Inclusion criteria were patients diagnosed with cT4b rectal cancer and underwent MVR, or stage 4 disease with resectable systemic metastases. Patients who underwent curative MVR for locally recurrent rectal cancer, or metachronous rectal cancer were also included. Exclusion criteria were patients with systemic metastases with non-resectable disease. All patients planned for elective surgery were enrolled into the standard enhanced recovery after surgery pathway with standard peri-operative management for colorectal surgery. Complex surgery was defined based on technical difficulty of surgery (i.e. total PE, bladder-sparing prostatectomy, pelvic lymph node dissection or need for flap creation). Our primary outcomes were the margin status, and complication rates. Categorical values were described as percentages and analysed by the chi-square test. Continuous variables were expressed as median (range) and analysed by Mann-Whitney U test. Cumulative overall survival (OS) and recurrence-free survival (RFS) were analysed using Kaplan-Meier estimates with life table analysis. Log-rank test was performed to determine statistical significance between cumulative estimates. Statistical significance was defined as P < 0.05. A total of 46 patients were included in this study [open MVR (oMVR): 12 (26.1%), miMVR: 36 (73.9%)]. Patients' American Society of Anesthesiologists score, body mass index and co-morbidities were comparable between oMVR and miMVR. There is an increasing trend towards robotic MVR from 2015 to 2023. MiMVR was associated with lower estimated blood loss (EBL) (median 450 vs 1200 mL, P = 0.008), major morbidity (14.7% vs 50.0%, P = 0.014), post-operative intra-abdominal collections (11.8% vs 50.0%, P = 0.006), post-operative ileus (32.4% vs 66.7%, P = 0.04) and surgical site infection (11.8% vs 50.0%, P = 0.006) compared with oMVR. Length of stay was also shorter for miMVR compared with oMVR (median 10 vs 30 d, P = 0.001). Oncological outcomes-R0 resection, recurrence, OS and RFS were comparable between miMVR and oMVR. There was no 30-d mortality. More patients underwent robotic compared with laparoscopic MVR for complex cases (robotic 57.1% vs laparoscopic 7.7%, P = 0.004). The operating time was longer for robotic compared with laparoscopic MVR [robotic: 602 (400-900) min, laparoscopic: Median 455 (275-675) min, P < 0.001]. Incidence of R0 resection was similar (laparoscopic: 84.6% vs robotic: 76.2%, P = 0.555). Overall complication rates, major morbidity rates and 30-d readmission rates were similar between laparoscopic and robotic MVR. Interestingly, 3-year OS (robotic 83.1% vs 58.6%, P = 0.008) and RFS (robotic 72.9% vs 34.3%, P = 0.002) was superior for robotic compared with laparoscopic MVR. MiMVR had lower post-operative complications compared to oMVR. Robotic MVR was also safe, with acceptable post-operative complication rates. Prospective studies should be conducted to compare short-term and long-term outcomes between robotic vs laparoscopic MVR.

Abstract 206: Intratumoral accumulation of CD38 enhances immune evasion and metastasis in models of breast cancer with EMT plasticity

Abstract Background- Triple-negative breast cancer (TNBC) is challenging to treat due to fewer clinically detectable targets and its propensity to metastasize. Epithelial to mesenchymal transition (EMT) is a key feature of the metastatic cascade. Recent data highlights the enhanced metastatic potential of hybrid epithelial-mesenchymal (EM) phenotypes from partial activation of EMT. However, mechanistic insights and targetable vulnerabilities within hybrid EM remain elusive. We identified that hybrid EM tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies. Hence, we sought to investigate role of CD38 in hybrid EM-driven metastasis. We hypothesize that hybrid EM tumors drive metastasis via intratumoral accumulation of CD38, promoting an immunosuppressive tumor microenvironment (TME). Methods- Reverse Phase Protein Array, cell migration/invasion assays, flowcytometry and immunohistochemistry were used to evaluate phenotype, immune cell populations and molecular mechanisms upon CD38 knockdown (KD) and overexpression (OE) in vivo. Results- CD38 KD weakened the process of EMT and reduced cell migration and invasion. Tumors lacking CD38 showed increased infiltration of CD8 T cells and M1-like (anti-tumor) macrophages coupled with a decrease in immunosuppressive regulatory T cells (Tregs) and M2-like (pro-tumor) macrophages. In contrast, cancer cells with CD38 OE maintained a hybrid phenotype through co-expression of epithelial and mesenchymal markers and also showed significant increase in cell migration and invasion. Tumors arising from CD38 OE cells displayed a significant increase in Tregs. Most strikingly, hybrid EM tumors that no longer express CD38 show reduction in lung metastases and circulating tumor cell colonies. Taken together, these findings suggest that CD38 is important for the metastatic and immune evasive potential of hybrid EM breast cancers. Conclusion- Our data exposes CD38 as a survival strategy in hybrid EM tumors to suppress immune cells and sustain metastasis with strong implications in other carcinomas which have hybrid EM properties. Citation Format: Tanvi Visal. Intratumoral accumulation of CD38 enhances immune evasion and metastasis in models of breast cancer with EMT plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 206.

Abstract 7449: Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients

Abstract Introduction: The incidence of colorectal cancer in the younger population (20-49) continues to rise at a rapid pace. EOCRC patients are potentially at risk for developing additional secondary malignancies. There is a lack of reported data in the EOCRC space. In this analysis, we seek to examine the incidence, trends, and outcomes of secondary malignancies in EOCRC patients. Methods: The surveillance, epidemiology, and end-result (SEER) database was utilized to assess and compare the incidence and factors associated with development of secondary malignancies among EOCRC patients. Patient characteristics were summarized by secondary cancer status and compared using the Pearson chi-square test. Further OS was assessed using Kaplan- -Meier methods and compared across groups using the log-rank test. Multivariable Logistic regression models using backward selection approach were used to evaluate the association between patient characteristics and risk of secondary cancers. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: Of the 53,891 patients analyzed, 2578 (4.8%) patients with EOCRC developed a secondary malignancy in the SEER database from 2000-2019. The mean age for developing a secondary malignancy was 47.6 yo (median 48 yo; range 20-69). There was a higher likelihood of second cancers among men(56%), white patients (61.4%), those with stage II (25.5%). and III (32.8%) CRC. The patients who most commonly developed a secondary malignancy were in the age group 40-49(p &amp;lt;.001). Of the patients who developed a secondary malignancy, 1843 (71.5%) initially had a primary colon cancer compared to 920 (22.6%) having rectal cancer, with the remainder having a rectosigmoid cancer. Of the patients who developed secondary malignancies, a majority had received prior chemotherapy (58.5%), and a minority of patients received radiation therapy (20.6%) Patients who had a partner had a higher incidence of secondary malignancy (59.5%) and they were more likely to have resided in a metropolitan area compared to a nonmetropolitan area (86.6 versus 13.2% respectively). The most common sites of secondary malignancy were: an additional colorectal cancer (47.7%), followed by breast cancer (8.2%) urinary tract cancer (7.1%), thyroid cancer (7%) and prostate cancer (5%). Patients who developed a secondary cancer were found to have an improved disease specific survival (DSS) compared to those who did not develop a secondary malignancy (3 year mDSS 89% vs 74%; p &amp;lt;.001)The overall survival of patients who developed a secondary malignancy was worse than those who did not develop one (mOS 208 months vs 229 mos respectively). Conclusion: EOCRC patients are likely to develop secondary malignancies. Long-term screening should be recommended for these patients and integrated into their survivorship plans. Citation Format: Deepak Vadehra, Kristopher Attwood, Anthony George, Shailesh Advani, Sahithi Sonti, Sarbajit Mukherjee. Incidence of secondary malignancies in early onset colorectal cancer (EOCRC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7449.

Abstract 4744: Overcoming MK1775 resistance in upper gastrointestinal cancers with combined WEE1 and CHK1 inhibition

Abstract Background: Upper gastrointestinal cancers (UGC), encompassing esophageal and gastric cancers, rank among the top causes of cancer-related deaths globally, with esophageal cancer being the sixth and gastric cancer the fourth leading cause. Esophageal adenocarcinoma (EAC), predominant in the western world, shares histopathological and molecular characteristics with gastric cancer (GC). Despite these similarities, treatment challenges persist, exemplified by the limited efficacy of the WEE1 inhibitor MK1775 in clinical trials due to drug resistance. Our study investigates novel mechanisms underlying this resistance in UGC. Methods and results: RNA sequencing and immunohistochemistry staining demonstrated notable overexpression of WEE1 in over two hundred human EAC and GC samples compared to normal tissues. Concurrently, Western blot analysis revealed a positive correlation between WEE1 and CHK1 overexpression across 16 UGC cell lines. To categorize UGC cells based on their sensitivity to MK1775, we conducted ATP-glo cell viability assays, determining their half-maximal inhibitory concentration (IC50) values. Utilizing nuclear-cytosol separation, our data intriguingly uncovered, for the first time, that in MK1775-resistant cells, MK1775 treatment induces the abnormal translocation of phosphorylated CHK1 (p-CHK1) from the nucleus to the cytoplasm, a shift not observed in MK1775-sensitive cells. Further analysis through Western blot suggested that the cytoplasmic presence of p-CHK1 might trigger the activation of oncogenic STAT3 following MK1775 treatment. This activation appears to stimulate the expression of genes that promote cancer cell survival and drug resistance by enhancing cell survival and inhibiting apoptosis. Notably, combining the WEE1 inhibitor with the CHK1 inhibitor CHIR124 effectively inhibited CHK1 kinase activity and abrogated STAT3 phosphorylation, DNA binding, and transcriptional activity in UGC cells. Our findings strongly indicate that a combined therapy of WEE1 and CHK1 inhibitors could be a promising strategy to overcome MK1775 resistance in UGC cells. Our ongoing research will employ human-derived UGC organoids, patient-derived xenografts (PDXs), and human tissue samples to further validate these findings. Conclusions: Our study underscores the potential of combining WEE1 and CHK1 inhibitors to effectively combat MK1775 resistance in UGC, offering a promising direction for improved treatment strategies and patient outcomes in these challenging malignancies. Citation Format: Krishnapriya Thangaretnam, MD Obaidul Islam, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, EL-Rifai Wael, Zheng Chen. Overcoming MK1775 resistance in upper gastrointestinal cancers with combined WEE1 and CHK1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4744.

Abstract 6445: Exploring the relationship between PSCA and PD-L1 by a comprehensive tumor immunohistochemical analysis

Abstract Prostate Stem Cell Antigen (PSCA) is a well-established diagnostic marker in various cancers and a promising target for immunotherapy. Programmed Death-Ligand 1 (PD-L1) plays a crucial role in cancer immune regulation and is known to influence patient response to checkpoint inhibitors. The objective of this study is to elucidate the relationship between PSCA and PD-L1 in diverse cancer types and to provide valuable insights for the development of an effective immunotherapy strategy. To accomplish this, immunohistochemical (IHC) analysis was conducted on paraffin-embedded Cytosections obtained from 20 lung cancers, 20 prostate cancers, 32 bladder cancers, and 20 normal tissues for each respective cancer type. Antibodies generated by Origene were utilized to detect the expression of PSCA and PD-L1 on the cell surface. The IHC results of tumor tissue were standardized against corresponding normal samples, and the correlation between these two genes was statistically analyzed using analysis of variance (ANOVA). The findings reveal a significant positive correlation between the expression of PSCA and PD-L1 (r=+0.78, P=0.016), suggesting an underlying mechanism driving their co-expression in the studied cancers. Understanding PSCA and PD-L1 coexpression in bladder, lung, and prostate cancers has great potential for informing tailored immunotherapies. Future research should explore functional consequences within the tumor microenvironment, advancing precision immunotherapy for improved outcomes in these challenging malignancies. Citation Format: Yichen Guo, Rachel Gonzalez, Jina Yom, Bailey Gilmore, Tianli Qu, Xiaomin Hu, Andy (Xi) Han, Zhaoying Guo, Eden Zewdu, Xuan Liu, Wei Fu. Exploring the relationship between PSCA and PD-L1 by a comprehensive tumor immunohistochemical analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6445.