CA-125 Changes Research Articles

Heart failure biomarkers and prediction of early left ventricle remodeling after acute coronary syndromes

IntroductionSeveral biomarkers are characteristically elevated in patients with acute heart failure (AHF). Our hypothesis was they could predict early changes in left ventricular (LV) characteristics in acute coronary syndrome (ACS) patients. The objective of this study was two-fold: a) compare circulating concentrations of NT-pro BNP, CA-125, ST2, galectin-3 and pro-adrenomedullin among 4 groups of individuals (healthy controls; patients with ACS without AHF; patients with ACS and AHF and patients admitted for AHF); and b) evaluate whether these biomarkers predict adverse LV remodeling and ejection fraction changes in ACS. Methods6 biomarkers (NT-pro BNP, CA-125, ST2, galectin-3, pro-adrenomedullin and C-reactive) were measured within the first 48 h of admission. Echocardiograms were performed during admission and at 3 months. Variables associated with LV end-diastolic volume (EDV) and ejection fraction (LVEF) change were assessed by multivariate linear regression. ResultsWe analyzed 51 patients with ACS, 16 with AHF and, 20 healthy controls. NT-pro BNP and ST2 concentrations were elevated at similar values in patients admitted for AHF and ACS complicated with HF but CA-125 concentrations were higher in AHF patients. NT-pro BNP concentrations were positively correlated with CA-125 (rho = 0.58; p < 0.001), ST2 (rho = 0.58; p < 0.001) and galectin-3 (rho = 0.37; p < 0.001)Median change (median days was 83 days after) in EDV and LVEF was 5 %. CA-125 concentrations were positively associated to LV EDV change (β-coefficient 1.56) and negatively with LVEF trend (β-coefficient = −0.86). No other biomarker predicted changes in EDV or LVEF. ConclusionsCA-125 correlates with early LV remodeling and LVEF deterioration in ACS patients.

Effects of nintedanib on circulating biomarkers of idiopathic pulmonary fibrosis

BackgroundBiomarkers that change in response to nintedanib in subjects with idiopathic pulmonary fibrosis (IPF) would be valuable. We investigated the effects of nintedanib on circulating biomarkers in subjects with IPF in the INMARK trial.MethodsSubjects with IPF were randomised 1:2 to receive nintedanib 150 mg bid or placebo for 12 weeks, after which all patients received open-label nintedanib for 40 weeks. Fold changes in adjusted mean levels of circulating biomarkers were analysed using a linear mixed model for repeated measures.Results346 subjects were treated (116 randomised to nintedanib, 230 to placebo). SP-D and CA-125, markers of epithelial injury, decreased in subjects treated with nintedanibversusplacebo. Fold changes from baseline in SP-D at week 12 corresponded to a 4% decrease and 3% increase in the nintedanib and placebo groups, respectively (ratio 0.94 [95% CI: 0.89, 0.99]; p=0.024). Fold changes in CA-125 at week 12 corresponded to a 22% decrease and 4% increase in the nintedanib and placebo groups, respectively (ratio 0.75 [95% CI: 0.71, 0.81]; p&lt;0.0001). A mediation analysis suggested that 42.1% of the effect of nintedanib on change in FVC over 12 weeks was attributable to the change in CA-125. A small increase in C3A and a small decrease in C3M, markers of extracellular matrix turnover, were observed in subjects treated with nintedanibversusplacebo.ConclusionsEffects of nintedanib on circulating markers of epithelial dysfunction and collagen degradation, most notably CA-125, were observed in patients with IPF.

Neoadjuvant chemotherapy for high-grade serous ovarian cancer: radiologic-pathologic correlation of response assessment and predictors of progression.

Neoadjuvant chemotherapy is often administered for high-grade serous ovarian carcinoma (HGSC) prior to cytoreductive surgery. We evaluated treatment response by CT (simplified peritoneal carcinomatosis index [S-PCI]), pathology (chemotherapy response score [CRS]), laboratory markers (serum CA-125), and surgical outcomes, to identify predictors of disease-free survival. For this retrospective, HIPAA-compliant, IRB-approved study, we identified 396 women with HGSC receiving neoadjuvant chemotherapy between 2010 and 2019. Two hundred and ninety-nine patients were excluded (surgery not performed; imaging/pathology unavailable). Pre- and post-treatment abdominopelvic CTs were assigned CT S-PCI scores 0-24 (higher score indicating more tumor). Specimens were assigned CRS of 1-3 (minimal to complete response). Clinical data were obtained via chart review. Univariate, multivariate, and survival analyses were performed. Ninety-seven women were studied, with mean age of 65years ± 10. Interreader agreement was good to excellent for CT S-PCI scores (ICC 0.64-0.77). Despite a significant decrease in CT S-PCI scores after treatment (p < 0.001), mean decrease in CT S-PCI did not differ significantly among CRS categories (p = 0.20) or between patients who were optimally versus suboptimally debulked (p = 0.29). In a survival analysis, lower CRS (more viable tumor) was associated with shorter time to progression (p < 0.001). A joint Cox proportional-hazard models showed that only residual pathologic disease (CRS 1/2) (HR 4.19; p < 0.001) and change in CA-125 (HR 1.79; p = 0.01) predicted progression. HGSC response to neoadjuvant therapy by CT S-PCI did not predict pathologic CRS score, optimal debulking, or progression, revealing discordance between imaging, pathologic, biochemical, and surgical assessments of tumor response.

Prognostic value of dynamic changes of pre- and post-operative tumor markers in colorectal cancer.

Colorectal cancer (CRC) prognosis assessment is vital for personalized treatment plans. This study investigates the prognostic value of dynamic changes of tumor markers CEA, CA19-9, CA125, and AFP before and after surgery and constructs prediction models based on these indicators. A retrospective clinical study of 2599 CRC patients who underwent radical surgery was conducted. Patients were randomly divided into training (70%) and validation (30%) datasets. Univariate and multivariate Cox regression analyses identified independent prognostic factors, and nomograms were constructed. A total of 2599 CRC patients were included in the study. Patients were divided into training (70%, n = 1819) and validation (30%, n = 780) sets. Univariate and multivariate Cox regression analyses identified age, total number of resected lymph nodes, T stage, N stage, the preoperative and postoperative changes in the levels of CEA, CA19-9, and CA125 as independent prognostic factors. When their postoperative levels are normal, patients with elevated preoperative levels have significantly worse overall survival. However, when the postoperative levels of CEA/CA19-9/CA125 are elevated, whether their preoperative levels are elevated or not has no significance for prognosis. Two nomogram models were developed, and Model I, which included CEA, CA19-9, and CA125 groups, demonstrated the best performance in both training and validation sets. This study highlights the significant predictive value of dynamic changes in tumor markers CEA, CA19-9, and CA125 before and after CRC surgery. Incorporating these markers into a nomogram prediction model improves prognostic accuracy, enabling clinicians to better assess patients' conditions and develop personalized treatment plans.

BNT321, a novel monoclonal antibody targeting sialyl Lewis A: Phase 1 monotherapy and combination with mFOLFIRINOX in patients with advanced CA19-9 expressing cancers.

654 Background: BNT321 is a high affinity human monoclonal antibody targeting the sialyl Lewis A epitope of CA19-9. This Phase 1/1b dose escalation/expansion study investigated BNT321 as monotherapy and in combination with mFOLFIRINOX (mFFX) in patients (pts) with advanced CA19-9 expressing cancers. Methods: Eligible pts: progressive CA19-9 expressing solid tumors, liver transaminases ≤ 2 x ULN, bilirubin WNL, ECOG PS 0-1. BNT321 given on Qwk, Q2wk, and Q4wk schedules. Lead in dose (1 mg/kg given 1 wk prior to assigned dose) evaluated on Q2wk + Q4wk schedules. BNT321 + mFFX given Q2wk as 1L or 2L metastatic therapy (1L+2L met). Dexamethasone given as premedication. Endpoints: safety, MTD, RP2D, efficacy, PK, changes in serum CA19-9. Results: 82 pts received BNT321 monotherapy and 15 received BNT321 + mFFX. BNT321 monotherapy MTD was 2 mg/kg Q2wk and MTD with mFFX was 1 mg/kg. Schedule and lead in dose did not significantly alter MTD. Dose limiting toxicities (DLTs) for BNT321 monotherapy and with mFFX were elevations in hepatic AST and ALT with or without bilirubin elevations. These events generally occurred early (cycle 1), resolved with drug hold, and did not preclude subsequent reduced dose BNT321. Frequent related AEs (total %/ &gt; grade 3 %) for BNT321 include increased ALT (39%/19%), AST (35%/12%), T bilirubin (27%/9%), fatigue (21%/0%), infusion related reaction (IRR) (17%/1%) and for BNT321 + mFFX fatigue (67%/0%), increased AST (40%/27%), ALT (33%/20%), diarrhea (33%/0%), nausea (20%/0%). At combination MTD (n=7): fatigue (71%/0%), diarrhea (29%/0%), IRR (29%/0%), nausea (28%/0%), increased AST (14%/14%), ALT (14%/14%). BNT321 demonstrated a T1/2 of 11.75 days + dose proportional Cmax and AUC with intra-patient variability. Enhanced clearance observed among pts with higher baseline (BL) serum CA19-9. For BNT321 monotherapy stable disease (RECIST 1.1) was best response, with time on study &gt; 90 days and &gt; 180 days in &gt; 20% and 10% of pts, respectively. Correlation between time on study and post BL normalization of CA19-9 was observed. For BNT321 + mFFX (1L+2L met), PRs were observed in 3/11 (27%) response evaluable pts who had time on study 10.0-15.8 months. Conclusions: BNT321 and BNT321 + mFFX MTDs were 2 mg/kg and 1 kg/kg, respectively. DLTs were hepatic AST, ALT and T bilirubin elevations which were generally cycle 1 and did not preclude subsequent BNT321 at reduced dose. BNT321 monotherapy resulted in disease stabilization and prolonged time on study (&gt; 90 days for &gt; 20%) in pts with advanced line, metastatic PDAC and other CA19-9+ cancers. BNT321 significantly decreased CA19-9 in the majority of pts and PK was similar to other human monoclonal antibodies. BNT321 + mFFX (1L+2L met) demonstrated multicycle tolerability and a 27% PR rate with 10+ months duration on study. BNT321 + mFFX is being evaluated in resected PDAC in the adjuvant setting. Clinical trial information: NCT02672917 .

Analysis of the treatment efficacy and prognostic factors of PD-1/PD-L1 inhibitors for advanced gastric or gastroesophageal junction cancer: a multicenter, retrospective clinical study.

Immune checkpoint inhibitors (ICIs) have transformed advanced gastric cancer treatment, yet patient responses vary, highlighting the need for effective biomarkers. Common markers, such as programmed cell death ligand-1 (PD-L1), microsatellite instability/mismatch repair (MSI/MMR), tumor mutational burden, tumor-infiltrating lymphocytes, and Epstein-Barr virus, face sampling challenges and high costs. This study seeks practical, minimally invasive biomarkers to enhance patient selection and improve outcomes. This multicenter retrospective study analyzed 617 patients with advanced gastric or gastroesophageal junction cancer treated with programmed cell death protein-1 (PD-1)/PD-L1 inhibitors from January 2019 to March 2023. Clinical data and peripheral blood marker data were collected before and after treatment. The primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoints included the objective response rate (ORR) and disease control rate (DCR). Least absolute shrinkage and selection operator (LASSO)-Cox and LASSO logistic regression analyses identified independent factors for OS, PFS, and ORR. Predictive nomograms were validated using receiver operating characteristic (ROC) curves, areas under the curve (AUCs), C-indices, and calibration curves, with clinical utility assessed via decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). OS-related factors included treatment line, T stage, ascites, pretreatment indirect bilirubin (pre-IBIL), posttreatment CA125, CA199, CA724, and the PLR. PFS-related factors included treatment lines, T stage, metastatic sites, pre-IBIL, posttreatment globulin (GLOB), CA125, and CA199 changes. ORR-related factors included treatment line, T stage, N stage, liver metastasis, pretreatment red cell distribution width-to-platelet ratio (RPR), CA125, and CA724 changes. The nomograms showed strong predictive performance and clinical utility. Early treatment, lower T stage, the absence of ascites, and lower pre-IBIL, post-CA125, CA199, CA724, and PLR correlate with better OS. Factors for improved PFS include early treatment, lower T stage, fewer metastatic sites, and lower pre-IBIL, post-GLOB, and post-CA125 levels. Nomogram models can help identify patients who may benefit from immunotherapy, providing valuable clinical guidance.

Executive Summary of the Ovarian Cancer Evidence Review Conference

ABSTRACT Ovarian cancer has the 17th highest incidence among all cancers in the United States; however, it is the deadliest gynecologic cancer and the fifth most common cause of cancer-related death in women in the United States. The Centers for Disease Control and Prevention funded the American College of Obstetricians and Gynecologists (ACOG) to create educational materials for clinicians on the early diagnosis and prevention of gynecologic cancers. This article is an evidence summary based on ACOG's extensive literature review on the early diagnosis and prevention of ovarian cancer. An expert panel was recruited from the Society for Academic Specialists in General Obstetrics and Gynecology and the Society of Gynecologic Oncology to review and summarize evidence from articles published between January 2000 and October 2021. Topics used to frame the literature review included the epidemiology of ovarian cancer, risk factors, prevention and risk reduction, screening strategies and early detection, health disparities, diagnosis and care coordination by primary care providers, and special considerations. The Ovarian Cancer Evidence Review Conference occurred in February 2022 where the expert panel and stakeholder professional and patient advocacy organizations discussed their findings and drafted summaries to develop educational materials. Review of the epidemiology revealed that in 2022 there were 19,880 new cases of ovarian cancer, 12,810 women died of ovarian cancer, 5-year survival is 49.7% and correlates strongly with stage at diagnosis, and fewer than 10% of women with stage 1 disease will have recurrence. Risk factors for ovarian cancer include older age, inactivity, nulliparity, early menarche, late menopause, postmenopausal hormone therapy, genetic mutations such as BRCA1 and BRCA2, and endometriosis. Risk-reducing bilateral salpingo-oophorectomy reduces incidence of ovarian cancer by 80% in BRCA1 and BRCA2 carriers (95% confidence interval, 0.12–0.39) and is recommended by ACOG for women at increased risk of ovarian cancer. Contraception, physical activity, and lactation may help reduce the risk of ovarian cancer. The most common methods studied for screening include transvaginal ultrasonography, bimanual palpation, and measuring tumor marker CA-125. The Risk of Ovarian Cancer Algorithm uses CA-125 and transvaginal ultrasound to estimate the risk of ovarian cancer based on age and change in CA-125; however, it is still being studied, and no established screening method exists for asymptomatic women. Several organizations including ACOG support identifying women at high risk and subsequent genetic counseling. Symptoms of ovarian cancer are nonspecific and include abdominal distention and pain, and while workup should include ultrasonography and CA-125 measurement, no high-quality studies have compared imaging, biomarkers, risk algorithms, or multimodal risk assessment tools for the primary evaluation of patients with high-risk symptoms. Regarding disparities, Black women consistently had worse outcomes compared with their White counterparts, and little evidence regarding other racial and ethnic groups or gender minorities was identified. Finally, care coordination is critical, and ACOG recommends a low bar for referral to a gynecologic oncologist for patients with suspicion of ovarian cancer, which has been shown to increase survival and offer other advantages. This evidence review identifies many research gaps and opportunities for ovarian cancer and provides a high-level educational summary of current best practices in the risk stratification, diagnosis, and prevention of ovarian cancer.

Perioperative percent change in CA-125 in patients with high grade serous ovarian cancer undergoing primary cytoreductive surgery with complete gross resection (1205)

Perioperative percent change in CA-125 in patients with high grade serous ovarian cancer undergoing primary cytoreductive surgery with complete gross resection (1205)

Efficacy and safety analysis of chemotherapy combined with immunotherapy compared with standard chemotherapy for advanced biliary tract malignant tumors.

The treatment of biliary tract (BTC) cancer remains relatively limited, especially in the setting of advanced BTC. Immune checkpoint inhibitors (ICIs) have shown some effects in a variety of solid tumors, but their efficacy and safety in patients with advanced BTC are still elusive, which require in-depth analysis. The clinical information of 129 patients diagnosed with advanced BTC between 2018 and 2021 were retrospectively reviewed. All patients were treated with chemotherapy, while a portion of them (64 patients) were treated with ICIs, the other 64 patients were not. Therefore, we divided the patients into two groups, SC (standard chemotherapy) and CI (chemotherapy in combined with immunotherapy), then we analyzed the benefit of adding ICIs according to efficacy, adverse events, progression-free survival (PFS), progressive disease (PD), and the influence of various factors and effectiveness. The mean PFS was 9.67 months for CI group and 6.83 months for SC group. The PFS was prolonged by 2.84 months with ICI addition, and the difference was statistically significant (t = 3.114, 95% CI: 1.06-4.74, p < 0.001). The objective response rate (ORR) was 32.81% (21/64) for the CI group versus 10.77% (7/65) for the SC group, and the disease control rate (DCR) was 79.69% (51/64) versus 67.69% (44/65), respectively. Regression analysis showed that factors such as changes in CA19-9, the level of PD-L1 expression, tobacco and alcohol, and the neutrophil-lymphocyte (NLR) ratio all influenced PFS (p < 0.05 for all these factors). For the treatment-related adverse events (TRAEs), the highest grade 3-4 adverse effects were thrombocytopenia in 7.75% (10/129) and neutropenia in 3.1% (4/129), immune-related adverse events (irAEs) occurred in 32.8% (21/64), and all were grade 1-2. Our results showed that ICIs combined with chemotherapy exhibited good antitumor activity with acceptable safety and could be recommended as first-line treatment for patients with advanced BTC.

Transient Changes in Serum CEA, CA19-9, CRP, YKL-40, and IL-6 during Adjuvant Chemotherapy and Survival of Patients with Colorectal Cancer

Serum carcinoembryonic antigen (CEA) is frequently monitored to detect colorectal cancer (CRC) recurrence after surgery. The clinical significance of transiently increased CEA during adjuvant chemotherapy is poorly understood. Serum CEA, CA19-9, CRP, YKL-40, and IL-6 were measured before, during, and after adjuvant 5-fluorouracil-based chemotherapy in the randomised LIPSYT study population. The biomarker kinetic patterns were classified into three groups: no increase, a transient increase (≥10% increase followed by a decrease), and a persistent increase during the adjuvant treatment, and the associations of these patterns with disease free-survival (DFS) and overall survival (OS) were investigated by using Cox regression analyses. The findings were validated in two single-centre cohorts that received modern adjuvant chemotherapy. A transient increase in CEA occurred in about a half of the patients during chemotherapy, in all the cohorts. The patients with a transient increase had a roughly similar DFS and OS to the patients with no increase, and a more favourable survival compared to the patients with a persistent increase. In the LIPSYT cohort, the hazard ratio was 0.21 for DFS (CI95% 0.07-0.66) and 0.24 for OS (CI95% 0.08-0.76). Transient increases in CA19-9 and YKL-40 tended to be associated with a favourable survival. A transient increase in CEA during adjuvant chemotherapy is associated with a favourable survival when compared with a persistent increase.

Abstract 5610: [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-inhibitor drug-target engagement as a biomarker of response in ovarian cancer

Abstract Purpose: Poly(ADP-ribose) polymerase enzyme inhibitors (PARPi) have become the standard-of-care treatment for homologous recombination deficient (HRD) high-grade serous ovarian cancer (HGSOC). However, not all HRD tumors respond to PARPi and biomarkers to predict response are needed. [18F]FluorThanatrace (FTT) is a PARPi-analog PET radiotracer that non-invasively measures PARP-1 expression. Herein, we evaluate the ability of FTT uptake to serve as a biomarker to predict response to PARPi in patient-derived xenograft (PDX) models and patients with HGSOC. Patients and Methods: In PDX models, FTT-PET was performed before and after PARPi (olaparib), ataxia-telangiectasia inhibitor (ATRi), or both. Changes in FTT were correlated with tumor size changes. Patients with HRD and HGSOC that were enrolled in CAPRI (PARPi+ATRi), LIGHT (PARPi only), or off-trial (PARPi only) were selected for this single-center, prospective, cohort, IRB-approved study. FTT-PET/CT imagining was obtained from the skull base to the proximal thighs on an Ingenuity TF scanner (Philips Healthcare) 60-90 minutes after intravenous infusion of 8-12 mCi FTT. Subjects were imaged with FTT-PET at baseline and after ~1 week of PARPi monotherapy treatment. Target lesions (primary tumor and/or metastases) were identified at the time of the baseline imaging on correlative anatomic imaging using RECIST 1.1 and maximum standardized uptake value (SUVmax) data, normalized by body weight, was collected. Changes in FTT-PET uptake were compared to changes in tumor size, CA-125, and progression free survival (PFS). Results: A decrease in FTT tumor uptake after 1 week of PARPi treatment correlated with response to PARPi+ATRi treatment in PARPi-resistant PDX models (r=0.81-0.83, P=0.1-0.22). In HGSOC patients (n=13), percent differences in FTT-PET after ~7 days of PARPi compared to baseline correlated with the first RECIST response (r=0.60, P=0.034), best RECIST response (r=0.75, P=0.01), best CA-125 response (r=0.73, P=0.033), and PFS (r=0.67, P=0.027). All patients with &amp;gt;50% reduction in FTT uptake had &amp;gt;6-month PFS and &amp;gt;50% reduction in CA-125 (P=0.004 and P=0.016, respectively). Utilizing only baseline FTT uptake correlated to best RECIST response (r=-0.65, P=0.035) but did not predict response when corelated with other measures. Importantly, a decrease in FTT uptake does not appear to be associated with a reduction in tumor burden or apoptosis in response to drug cytotoxic activity at this early timepoint, indicating specificity for drug-target engagement. Conclusions: The decline in FTT uptake shortly after PARPi initiation compared to baseline provides an in vivo measure of drug-target engagement and shows promise as an early biomarker to guide PARPi therapy. FTT-PET has both pre-clinical and clinical applications warranting further study, including guiding PARPi combination therapy. Citation Format: Sarah B. Gitto, Austin R. Pantel, Mehran Makvandi, Hyoung Kim, Sergey Medvedev, Joanna K. Weeks, Drew A. Torigian, Chia-Ju Hsieh, Benjamin Ferman, Nawar A. Latif, Janos L. Tanyi, Lainie P. Martin, Shannon M. Lanzo, Fang Liu, Quy Cao, Gordon B. Mills, Robert K. Doot, David A. Mankoff, Robert H. Mach, Lilie L. Lin, Fiona Simpkins. [18F]FluorThanatrace ([18F]FTT) PET Imaging of PARP-inhibitor drug-target engagement as a biomarker of response in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5610.

Association of CA19-9 and tumor size in treatment monitoring for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

693 Background: Although modern cancer treatment has significantly prolonged patient’s life, it comes with a high financial cost. Based on an NIH report on Financial Burden of Cancer Care, treating PDAC costs $108K, $18K, and $125K for initial treatment, during follow up, and in last year of life, respectively. Of these, CA19-9 and CT studies are obtained concurrently to evaluate tumor burden whose cost can be reduced by decreasing imaging frequency when CA19-9 remains stable. As a pilot study, we evaluated whether changes in CA19-9, an inexpensive laboratory study commonly used for monitoring treatment response, correlates with tumor size change on imaging studies. A positive correlation may lead us to design future studies to evaluate whether stable CA19-9 can serve as an indicator for stable disease on CT scan such that imaging frequency (and cost) may be reduced. Methods: We retrospectively identified PDAC patients from our tumor registry from 2016 to 2019. Subjects were included if they met the following criteria: 1) diagnosed with PDAC 2) had at least 2+ CA19-9 and CT/MR follow up assessments with the laboratory and imaging studies within one month of each other, and 3) had measurable lesions as defined by RECIST 1.1 criteria. Due to limited resources, we limited the maximum number of lesions to 4 instead of the usual 5 for RECIST 1.1. Two-dimensional orthogonal tumor sizes were measured on axial images with the largest cross-section. Changes in the values were obtained serially (from the immediately prior study). Nonparametric correlations (Spearman’s rho) were used to evaluate monotonicity. The significance level was set at p &lt; 0.05. Results: We screened 300 subjects from the tumor registry and identified 23 subjects suitable for our study. 13 subjects were female and 10 were male with ages ranging from 35 to 84. We identified 55 target lesions and 128 assessments (with both CA19-9 and imaging) from the 23 subjects. We analyzed the log absolute and log relative change in CA19-9 with change in tumor area. When absolute CA19-9 value, absolute change in CA19-9, and relative change in CA19-9 were tested against the absolute change in tumor size, the correlation was significant for the absolute value and absolute change of CA19-9 (p &lt; 0.01), but not for relative change of CA19-9 (p &lt; 0.11). When tested against relative change in tumor size, all three values were highly significant (p &lt; 0.001). Conclusions: Our finding of direct correlations between changes of CA19-9 and relative change of tumor size on imaging suggests that CA19-9 can serve as a surrogate measure of relative change of tumor burden for patients undergoing treatment. This provides motivation for future studies evaluating the possibility that stable CA19-9 can represent stable tumor burden such that expensive imaging studies may be obtained at longer time intervals to reduce financial cost to patients.

Clinical significance of CA125 in unresectable pancreatic cancer treated with first-line chemotherapy.

745 Background: Serum CA125 is a potential biomarker for diagnosis of peritoneal metastasis in gastric cancer. However, its significance of pancreatic cancer (PC) has not been investigated. Therefore, we aimed to clarify association between serum CA125 and ascites burden, and its kinetics during first-line chemotherapy for PC. Methods: This multicenter retrospective study comprised PC patients who received FOLFIRINOX or gemcitabine plus nab-paclitaxel in first-line setting between Jan 2014 and Dec 2021. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before chemotherapy. The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and clinical response during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 109 patients from 3 hospitals were assessable. The overall survival (OS) was significantly shorter in elevated group than that in non-elevated group (median, 10.7 vs. 21.3 months, p = 0.0002). The median value of CA125 before chemotherapy was elevated according to ascites burden (Non, 36U/ml; mild, 173U/ml; moderate/severe, 575U/ml; p &lt; 0.0001). CA125 elevation, CA19-9 elevation, poor performance status and poor glasgow prognostic score were independent prognostic factors in multivariate analysis. After chemotherapy, the median first-time measure of CA125 was performed in day 41. Among patients with peritoneal dissemination, the median change of CA125 was correlated with clinical response (CR/PR, -0.55%/day; SD, -0.24%/day; PD, 3.35%/day, p = 0.004). After chemotherapy, first-time measure of CA125 was performed in a median of day 41. According to the ROC curve analysis, the optimal cut-off value of increase in CA125 for progressive disease was 1.56 %/day (specificity 94.1%, sensitivity 80%). The median PFS and OS were 1.4 and 6.6 months in increased group and 3.3 months and 14.0 months in non-increased group, respectively (p = 0.016 and p = 0.028). Conclusions: CA125 is considered a clinically useful marker in unresectable PC treated with first-line chemotherapy because CA125 above the ULN is a poor prognostic factor for OS and an increased CA125 can be an early predictor of progression in patients with peritoneal dissemination.

CA125 kinetics as a potential biomarker for ascites progression during taxane plus ramucirumab therapy in patients with advanced gastric cancer.

437 Background: Ascites and peritoneal metastases are major interruptive factors in sequential chemotherapy for advanced gastric cancer (AGC), although there are no established markers that predict ascites burden during treatment. Therefore, we aimed to clarify the association between serum CA125 and therapeutic efficacy for AGC treated with taxane plus ramucirumab (TAX/RAM). Methods: This multicenter retrospective study comprised AGC patients who received TAX/RAM in second or third line setting between Jun. 2015 to May 2019. Patient background and treatment outcome was assessed in CA125 elevated and non-elevated group before TAX/RAM (cut-off, 37 U/ml). The CA125 kinetics after chemotherapy was calculated based on baseline and first measure of CA125. Further, the association between early CA125 change and ascites burden during chemotherapy were evaluated based on optimal cut off value calculated receiver operating characteristic (ROC) curve analysis. Results: A total 73 patients from 5 hospitals were assessable. The proportion of poor PS, moderate/severe peritoneal effusion, low albumin was significantly larger in CA125 elevated group (n=31) than those in non-elevated group. The median value of CA125 before TAX/RAM was elevated according to ascites burden (none, 37.5 U/ml; mild, 57.9 U/ml; moderate/severe, 134.8 U/ml; p&lt;0.001). The overall survival was significantly shorter in elevated group than that in non-elevated group (median, 8.2 vs. 14.6 months, p=0.0004). Baseline CA125 elevation and peritoneal metastasis were independent prognostic factors in multivariate analysis. After TAX/RAM, first-time measure of CA125 was performed in a median of day 28. The median change of CA125 was correlated with ascites response (CR/PR, -1.86%/day; SD, 0.28%/day; PD, 2.33 %/day, p&lt;0.001). ROC curve analysis showed that the optimal cut-off value of CA125 kinetics for ascites progression was 0.0067%/day (specificity 74%, sensitivity 100%). The progression free survival in increased group was significantly shorter than that of non-increased group in patients with peritoneal dissemination (median, 2.5 vs 6.1 months, p=0.0008). Conclusions: The serum CA125 before TAX/RAM was associated with ascites burden. Further, early change of CA125 after TAX/RAM was associated with prognosis in AGC patients with peritoneal dissemination. CA125 monitoring may be biomarker in determining timing of treatment change.

Changes in lung cancer-related serum tumor markers in patients with chronic kidney disease and determination of upper reference limit.

To investigate the changes in lung cancer-related serum tumor markers in patients with chronic kidney disease (CKD) and determine the upper reference limit for patients with different stages. Included inpatients diagnosed with CKD who did not receive dialysis temporarily in our hospital from March to September 2020. Changes in serum CA125, HE4, CYFRA21-1, SCCA, NSE and ProGRP in CKD patients were analyzed. The non-parametric method was used to estimate the upper reference limit of the above indicators in patients with CKD stages 2-5. The serum levels of HE4, CYFRA21-1, SCCA, and ProGRP in the CKD group were significantly higher than those in the healthy control group; CA125 and NSE levels were not statistically different. The false positives of SCC, CYFRA21-1, ProGRP, and HE4 increased significantly with the CKD stage. Still, NSE and CA125 did not show a significant increasing trend. Both HE4 and ProGRP have independent upper reference limits from CKD2 to CKD5 stage, namely 220.8 pmol/l and 101.4 pg/ml in the CKD2 stage, 496.7 pmol/l and 168.63 pg/ml in CKD3 stage, 4592.4 pmol/l and 272.8 pmol/l for CKD4 stage, CKD5 stage was 4778.2 pmol/l and 491.6 pmol/l. This study preliminarily determined the upper reference limits of Lung cancer-related tumor markers in patients with different CKD stages and provided laboratory support for the rational use and interpretation of Lung cancer-related tumor markers in special populations.

Abstract A041: Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for monitoring disease burden in patients with pancreatic cancer

Abstract Pancreatic cancer is a highly lethal disease that is often diagnosed at a late stage, when it has metastasized to other organs. Several therapeutic options have been shown to be effective at significantly shrinking the tumor and improving survival. Unfortunately, very few of these treatments lead to the total disappearance of tumor and therefore require changes to the treatment strategy. One of the challenges is rapidly identifying if a treatment works or when it stops working so patients can be switched to another regimen. Currently, the best blood-based marker for tracking disease burden in patients with pancreatic cancer is CA19-9. Unfortunately, 15-20% of pancreatic cancer patients do not have elevated levels of this marker with a disproportionate number of non-CA19-9 elevated cases being African American and Hispanic patients. In addition, changes in this marker do not always correlate with disease burden since there are other factors that can change CA19-9 levels. In this study, we have identified two blood extracellular vesicle (EV) based protein markers THBS2 (Thrombospondin 2) and ALPPL2 (Alkaline phosphatase, placental-like 2) that aid in monitoring pancreatic cancer disease burden in both CA19-9 secretors and non-secretors. We found that the number of THBS2+ or ALPPL2+ EVs was significantly higher in serum samples from patients with pancreatic cancer than those from healthy controls. The level of THBS2+ or ALPPL2+ EVs in patients with pancreatic cancer correlated with a patient's response to treatment. In patients who have elevated CA19-9, the level of THBS2+ or ALPPL2+ EVs correlates with the changes in CA19-9 upon treatment. In CA19-9 negative patients, the level of THBS2+ EVs or ALPPL2+ EVs correlates with the tumor size changes (RECIST response) upon treatment. Hence, EVs containing THBS2 or ALPPL2 can potentially serve as additional and more informative biomarkers for monitoring disease burden in patients with pancreatic cancer regardless of their CA19-9 status. This work was supported by the Flinn Foundation and the HonorHealth Research Institute). Citation Format: Kuntal Halder, Gayle Jameson, Erkut Borazanci, Amber Vrana, Derek Cridebring, Daniel Von Hoff, Haiyong Han. Extracellular vesicle based ALPPL2 and THBS2 as biomarkers for monitoring disease burden in patients with pancreatic cancer [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 A041.

Tailoring Adjuvant Chemotherapy to Biologic Response Following Neoadjuvant Chemotherapy Impacts Overall Survival in Pancreatic Cancer

BackgroundThe role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment. MethodsPatients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response. ResultsWe identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014). ConclusionCA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.

The clinical and prognostic significance of pre-chemotherapy serum CA-125 in high-risk early stage ovarian cancer: An NRG/GOG ancillary study

ObjectivesTo determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients. MethodsAll patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). ResultsOf 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31–129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0–10 vs. 11–35 U/mL) were not predictive of outcome (p = 0.4). ConclusionsNormal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients.

Abstract CT176: A phase 1 open label, first in human trial to study safety and tolerability of NK-T cells combined with vvDD: An accelerated dose escalation in multiple tumor types

Abstract Introduction: BioEclipse Therapeutics has developed CRX100 an adoptive NK-T Cells therapy combined with vaccinia vvDD, an oncolytic virus. vvDD is a Western Reserve (WR) strain vaccinia virus (VACV) that has been further attenuated by the removal of the viral thymidine kinase and growth factor genes, and hence its replication and lytic activity is confined to tumor cells. In preclinical studies in immunocompetent mice the combined therapy eradicated tumor cells and initiated an adaptive immune response. Trial Design: Our ongoing phase 1 safety clinical trial (IND 19222 at Clinicaltrials.gov) began in January 2021 and includes planned treatment of approximately 24 patients with the potential for 2 doses each. With the dose of ex vivo activated autologous NK-T cells held constant (2-5 X 109), the dose of vvD is increased at 5 dose levels, 3X107, 1x108, 3x108, 1x109 and 3x109 pfu/dose. The first five doses are accelerated in cohorts of one patient and followed by a non-accelerated phase with a cohort of two patients and then 3 cohorts of three patients to determine the MTD, with an additional 8 patients then treated at the MTD. Dose limiting toxicities evaluated by a BOIN design will assist in the dose decision for phase 2. Inclusion and exclusion criteria: Patients will have tumor progression and have failed standard of care in the indications, triple negative breast cancer, gastric cancer, colorectal carcinoma, hepatocellular carcinoma, ovarian cancer or osteosarcoma. Results: To date, 4 patients have been treated, including 2 patients with ovarian cancer and 2 with CRC at 4 dose levels. No dose limiting toxicities have been observed. The most common AE is mild fever at 6-12 hours after infusion. Two CRC patients treated at a vvDD dose of 3x107 and 1x109 experienced disease progression. Patient 101-005 with ovarian cancer received two separate infusions 3 months apart each at a dose of 1x108 PFU vvDD combined with 2-5 X 109 ex-vivo activated autologous NKT. Tumor assessment after the first dose showed stable disease (+17.2%) by iRECIST. The CA125 serum biomarker increased temporarily about 3 weeks after infusion. The second ovarian patient (101-007) treated with 3x108 vvDD combined with 2-5 X 109 ex-vivo activated autologous NKT had unconfirmed progression (+21%). There was a slight increase and then a decrease of the CA-125 from 303 to 268. The patient developed new ascites 4 weeks after infusion and required a paracentesis. The ascites did not recur after the paracentesis. Conclusion: Thus far in escalation, all doses of the therapy have been safe and well-tolerated. Two patients with ovarian cancer treated with the adoptive NKT cell therapy combined with an oncolytic virus demonstrated changes in CA-125 potentially consistent with immune inflammation. Peripheral blood obtained at 3 and 6 month will be analyzed to assess specific immune responses. Dose escalation and enrollment continue for this study. Citation Format: Oliver Dorigo, Pamela Reilly Contag, Justin Moser, Sandip Pravin Patel, Mark W. Frohlich. A phase 1 open label, first in human trial to study safety and tolerability of NK-T cells combined with vvDD: An accelerated dose escalation in multiple tumor types [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 CT176.

Standard Versus Extended Neoadjuvant Chemotherapy: A Canadian Tertiary Centre Cohort Study of Ovarian Cancer Care Amidst the COVID-19 Pandemic

To compare treatment response in patients with ovarian cancers treated with extended neoadjuvant chemotherapy compared to standard chemotherapy, a strategy adopted during the COVID-19 operating room closures. This retrospective cohort study included patients with ovarian cancers treated with neoadjuvant chemotherapy before interval debulking surgery at a Canadian tertiary care centre during the COVID-19 pandemic. Patients with extended neoadjuvant chemotherapy consisting of 6 cycles of chemotherapy prior to surgery were compared to patients receiving the standard 3 cycles of neoadjuvant chemotherapy followed by 3 cycles after surgery. The primary outcome was disease response to treatment measured by percent change in the biomarker CA-125. Secondary outcomes were disease extent at time of surgery, chemotherapy response scores, perioperative morbidity, and chemotherapy adverse events. Binary outcomes were ascertained by chi-square or Fischer exact tests and continuous outcomes were obtained by the Wilcoxon-rank sum test. A total of 9 patients received extended neoadjuvant chemotherapy and 18 patients received standard chemotherapy. Percent change in CA-125 levels between cycles 0–3 were similar between the extended neoadjuvant cohort (median 88.0%, IQR 52.4, 92.1) and the standard chemotherapy cohort (median 91.7%, IQR 79.8, 96.2), P = 0.38. The 6-cycle group had statistically significant less change in CA-125 between cycles 3–6 (median 31.9%, IQR 25.0, 46.7) compared to the standard group (median 90.7, IQR 76.9, 95.3), P = 0.001. The extent of disease at the time of surgery, chemotherapy response scores, perioperative outcomes and chemotherapy adverse events were similar between groups. Biochemical disease response to neoadjuvant chemotherapy slows after 3 cycles of chemotherapy.