Predictor Of Poor Progression-free Survival Research Articles

Thoracic sarcopenia was a poor prognostic predictor in patients receiving immunotherapy retain-->for advanced non-small-cell retain-->lung cancer

Sarcopenia, as measured at the level of the third lumbar (L3) has been shown to predict the survival of cancer patients. However, many patients with advanced non-small cell lung cancer (NSCLC) do not undergo routine abdominal imaging. The objective of this study was to investigate the association of thoracic sarcopenia with survival outcomes among patients who underwent immunotherapy for NSCLC. In this retrospective study, patients who initiated immunotherapy for advanced NSCLC from 2019 to 2022 were enrolled. and detailed patient data were collected. Cross sectional skeletal muscle area was calculated at the fifth thoracic vertebra (T5) on pretreatment chest computed tomography (CT) scan. Gender-specific lowest quartile values was used to define sarcopenia. The risk factors were analyzed using Cox analyses. The log-rank test and the random survival forest (RSF) were used to compare progression free survival (PFS). The model's performance was assessed using calibration curve and the receiver operating characteristic curve (ROC). A total of 242 patients was included (discovery cohort n=194, validation cohort n=48). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p<0.001) than patients without sarcopenia. Univariate cox regression revealed that sarcopenia, lung cancer stage, body mass index, smoking status, and neutrophil-to-lymphocyte ratio were predictors of poor PFS. A RSF model was constructed based on the aforementioned parameters, to evaluate the model's efficacy, the ROC curve was utilized. with an area under the curve for predicting 6-month PFS of 0.68 and for 12-month PFS of 0.69. The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort. Sarcopenia at T5 is independent prognostic factors in patients who received immunotherapy for advanced NSCLC.

Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON–SEOM registry

BackgroundThe optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration.MethodsWe analyzed cases from the AGAMENON–SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors.ResultsAmong 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58–0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG–PS (Eastern Cooperative Oncology Group–Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand–foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%).ConclusionsFOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.

Spatial Proteome Analysis Identifies Lymphocyte CD44 as a Biomarker Associated with SBRT Resistance in Early-Stage Non-Small Cell Lung Cancer

To discover and validate spatially-resolved protein markers associated with resistance to SBRT in early-stage NSCLC patients. We initially evaluated a discovery cohort of 44 early-stage NSCLC patients treated with SBRT as first-line treatment at the Shandong cancer hospital. Using the GeoMx DSP system, 71 proteins were measured in five molecular compartments (tumor, leukocyte, lymphocyte, macrophage, and stroma) on pre-treatment samples. Candidate biomarkers were orthogonally validated with the Gem AQUA method of quantitative immunofluorescence (QIF). For internal independent cohort validation, we assessed pre-treatment samples derived from 150 NSCLC patients who receive radiotherapy. We further analyzed 100 radiotherapy untreated patients with operable NSCLC to address prognostic significance. Using continuous log-scaled data, we identified CD44 expression in the lymphocyte compartment (CD3+) as a novel predictor of poor progression-free survival (PFS) (multivariate HR = 7.323, p = 0.0079) and overall survival (OS) (multivariate HR = 8.65, p = 0.028) in the discovery set. High CD44 expression in the tumor compartment (pan-cytokeratin, CK+) predicted significantly shorter OS (multivariate HR = 2.208, p = 0.0212), with no significant difference in PFS. We validated by QIF that lymphocyte CD44 levels were associated with resistance to SBRT therapy and prognostic for poor outcomes. Using QIF in an independent radiotherapy treated cohort, we validated that CD44 levels in the lymphocyte compartment were associated with poor PFS and OS. High lymphocyte cell CD44 was not prognostic in non-radiotherapy-treated cohort. Using DSP data, intratumoral regions with elevated lymphocyte cell CD44 expression showed prominent upregulation of CD127, ARG1 and VISTA in the discovery Cohort. In conclusion, we identified and validated lymphocyte cell CD44 as a biomarker indicative of resistance to SBRT or radiotherapy in patients with NSCLC. Further evaluation is warranted to address the predictive value of lymphocyte cell CD44 in multi-institutional studies and clinical trials.

Surveillance of cfDNA Hot Spot Mutations in NSCLC Patients during Disease Progression.

Non-small cell cancer (NSCLC) has been identified with a great variation of mutations that can be surveyed during disease progression. The aim of the study was to identify and monitor lung cancer-specific mutations incidence in cell-free DNA as well as overall plasma cell-free DNA load by means of targeted next-generation sequencing. Sequencing libraries were prepared from cell-free DNA (cfDNA) isolated from 72 plasma samples of 41 patients using the Oncomine Lung cfDNA panel covering hot spot regions of 11 genes. Sequencing was performed with the Ion Torrent™ Ion S5™ system. Four genes were detected with highest mutation incidence: KRAS (43.9% of all cases), followed by ALK (36.6%), TP53 (31.7%), and PIK3CA (29.3%). Seven patients had co-occurring KRAS + TP53 (6/41, 14.6%) or KRAS + PIK3CA (7/41, 17.1%) mutations. Moreover, the mutational status of TP53 as well an overall cell-free DNA load were confirmed to be predictors of poor progression-free survival (HR = 2.5 [0.8-7.7]; p = 0.029 and HR = 2.3 [0.9-5.5]; p = 0.029, respectively) in NSCLC patients. In addition, TP53 mutation status significantly predicts shorter overall survival (HR = 3.4 [1.2-9.7]; p < 0.001). We demonstrated that TP53 mutation incidence as well as a cell-free DNA load can be used as biomarkers for NSCLC monitoring and can help to detect the disease progression prior to radiological confirmation of the status.

Abstract 3249: Circulating cytokine associations with clinical outcomes in melanoma patients treated with checkpoint inhibitors

Abstract Background: aCTLA-4/aPD-1 combination therapy has significantly improved clinical outcomes in patients with metastatic melanoma, with 50%-60% of patients responding to treatment, but predictors of response are poorly characterized. In this study, we set out to evaluate the hypothesis that circulating cytokines and peripheral white blood cell composition may predict response to therapy. Methods: We quantified cytokines and complete blood counts from 89 patients with advanced melanoma treated with combination therapy from three points in time: pre-treatment, one month and approximately three months after starting therapy. We evaluated the association between peripheral blood circulating features, cytokines and clinical labs values, and clinical outcome using predictive modeling, and investigated the prognostic values of these features using survival analysis. Results: Pre-treatment, patients with durable clinical benefit (DCB) had higher IL23, lower CXCL6, and lower IL10 levels. The ratio of neutrophils to lymphocytes (NLR) pre-treatment was not associated with response, but higher NLR one month after starting therapy predicted poorer progression free survival (PFS) and overall survival (OS), primarily driven by an increase in absolute lymphocytes. A multivariate model demonstrated that baseline CXCL6, IL10, IL23 were independent predictors of therapy response, and the combined model has reached an area under the curve (AUC) of 0.8 in prediction of response to combination therapy. Low IL10 and CXCL6 identified an excellent prognosis group, while high CXCL6 and low IL23 characterized a very poor prognosis group of patients. Conclusions: Baseline measurement of cytokines IL23, CXCL6, and IL10 can predict metastatic melanoma patients’ response to ipi/nivo combination treatment. Higher neutrophils-to-lymphocytes ratio approximately one month after therapy started associates with worse survival outcome. Our study presented circulating features from a relatively accessible and less costly avenue, peripheral blood, to be predictive of response to combination immune checkpoint blockade. Citation Format: Jiajia Chen, Giuseppe Tarantino, Mariano Severgnini, Joanna Baginska, Anita Giobbie-Hurder, Michael Manos, Janice D. Russell, Jason L. Weirather, Kathleen Pfaff, Amy Y. Huang, Scott J. Rodig, Srinika Ranashinge, David Liu, F.Stephen Hodi. Circulating cytokine associations with clinical outcomes in melanoma patients treated with checkpoint inhibitors [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 3249.

A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors.

Background: The immunotherapy efficacy in gastric cancer (GC) is limited. Cancer-associated fibroblasts (CAFs) induce primary resistance to immunotherapy. However, CAF infiltration in tumors is difficult to evaluate due to the lack of validated and standardized quantified methods. This study aimed to investigate the impact of infiltrating CAFs alternatively using fibroblast-associated mutation scoring (FAMscore). Methods: In a GC cohort from Affiliated Hospital of Jiangsu University (AHJU), whole exon sequencing of genomic mutations, whole transcriptome sequencing of mRNA expression profiles, and immunofluorescence staining of tumor-infiltrating immune cells were performed. GC data from The Cancer Genome Atlas were used to identify genetic mutations which were associated with overall survival (OS) and impacted infiltrating CAF abundance determined by transcriptome-based estimation. FAMscore was then constructed through a least absolute shrinkage and selection operator Cox regression model and further validated in AHJU. The predictive role of FAMscore for immunotherapy outcomes was tested in 1 GC, one melanoma, and two non-small-cell lung cancer (NSCLC-1 and -2) cohorts wherein participants were treated by immune checkpoint inhibitors. Results: FAMscore was calculated based on a mutation signature consisting of 16 genes. In both TCGA and AHJU, a high FAMscore was an independent predictor for poor OS of GC patients. FAMscore was associated with immune-associated genome biomarkers, immune cell infiltration, and signaling pathways of abnormal immunity. Importantly, patients with high FAMscore presented inferiority in the objective response rate of immunotherapy compared to those with low FAMscore, with 14.6% vs. 66.7% (p<0.001) in GC, 19.6% vs. 68.2% (p<0.001) in NSCLC-1, 23.1% vs 75% (p = 0.007) in NSCLC-2, and 40.9% vs 75% (p = 0.037) in melanoma. For available survival data, a high FAMscore was also an independent predictor of poor progression-free survival in NSCLC-1 (HR = 2.55, 95% CI: 1.16–5.62, p = 0.02) and NSCLC-2 (HR = 5.0, 95% CI: 1.13–22.19, p = 0.034) and poor OS in melanoma (HR = 3.48, 95% CI: 1.27–9.55, p = 0.015). Conclusions: Alternative evaluation of CAF infiltration in GC by determining the FAMscore could independently predict prognosis and immunotherapy outcomes. The FAMscore may be used to optimize patient selection for immunotherapy.

Naples prognostic score, a novel prognostic score for patients with high- and intermediate-risk gastrointestinal stromal tumours after surgical resection

BackgroundA novel multidimensional inflammatory and nutritional assessment system named the Naples prognostic score could serve as an independent prognostic indicator. However, its significance in patients with high- and intermediate-risk gastrointestinal stromal tumours remains unclear.MethodsWe performed this retrospective cohort study based on a prospectively collected database of gastrointestinal stromal tumours (GISTs) between March 2010 and December 2019. The Kaplan–Meier method and log-rank test were used for survival analyses. Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression analysis was used for univariate and multivariate analyses. Time-dependent receiver operating characteristic curves were generated to evaluate the discriminatory ability of the prognostic scoring systems. Differences in the areas under the curve were further compared.ResultsA total of 405 patients with regular follow-up were included and analysed in this study. Significant differences in progression-free survival and overall survival were observed between the groups (P < 0.001). Multivariate analysis demonstrated that the NPS was a significant predictor of poor progression-free survival (1 vs 0, HR = 4.622, P = 0.001; 2 vs 0, HR = 12.770, P < 0.001) and overall survival (2 vs 0, HR = 5.535, P = 0.002). Furthermore, time-dependent AUC analyses showed that the NPS was more accurate than other haematologic prognostic systems.ConclusionsThe present study demonstrates that the NPS could independently predict disease progression and survival among patients with high- and intermediate-risk GISTs. The NPS might be regarded and applied as one of the most convenient and effective preoperative risk stratification tools in the future, which should be validated by large-scale multicentre prospective cohort studies.

Abstract 388: Non-invasive biomarker potential of the fibroblast-derived collagen type III and collagen type XI for predicting outcome in metastatic melanoma patients treated with anti-PD-1 therapy

Abstract Background: Biomarkers for predicting immune checkpoint inhibitor (ICI) efficacy are essential for patient selection for current ICI regimens and new combination therapies. Patients with T-cell excluded tumors have poor effect on ICI therapy. T-cell exclusion is driven by upregulated TGF-β-signaling and activated fibroblasts, which produce increased levels of fibrillar collagens (desmoplasia). In this study, we investigated if non-invasive biomarkers reflecting deposition of the fibrillar collagen type III (PRO-C3) and collagen type XI (PRO-C11) associated with response and survival outcomes in patients treated with ICI therapy. Methods: N-terminal pro-peptides of collagen type III (PRO-C3) and collagen type XI collagen (PRO-C11) were measured with ELISAs in pre-treatment serum from metastatic melanoma patients treated with anti-PD-1 therapy (pembrolizumab) (n=35). The association between PRO-C3 and PRO-C11 levels and progression-free survival (PFS) and overall survival (OS) were assessed by Cox regression analyses, alone and after adjusting for tumor PDL1 expression and BRAF mutational status. Results: Univariate Cox regression identified high (&amp;lt;75th percentile) baseline PRO-C3 and PRO-C11 as predictors of poor PFS (PRO-C3: HR=2.77, 95%CI=1.01-7.55, p=0.047, and PRO-C11: HR=2.87, 95%CI=1.05-7.87, p=0.040) and OS (PRO-C3: HR=6.54, 95%CI=1.56-27.53, p=0.010, and PRO-C11: HR=4.58, 95%CI=1.13-18.65, p=0.034). Moreover, when PRO-C3 and PRO-C11 were adjusted for PDL1 expression (≥1%) and BRAF mutations, the biomarkers remained independently predictive of poor PFS (PRO-C3: HR=3.00, 95%CI=1.07-8.42, p=0.038, and PRO-C11: HR=3.66, 95%CI=1.22-10.98, p=0.021) and OS (PRO-C3: HR=6.20, 95%CI=1.47-26.12, p=0.013, and PRO-C11: HR=7.85, 95%CI=1.32-46.78, p=0.024). PRO-C3 was furthermore significantly elevated in patients with progressive disease compared to patients with complete response, partial response and stable disease (p=0.007). Conclusions: Non-invasive biomarkers of the fibroblast-derived collagen type III (PRO-C3) and collagen type XI (PRO-C11) reflecting fibroblast activity predict survival outcomes in metastatic melanoma patients treated with anti-PD-1 therapy independent of PD-L1 expression and BRAF mutational status. These findings support the link between desmoplasia (tumor fibrosis) and poor response to ICIs and indicate a promise of non-invasive collagen-based biomarkers for selecting metastatic melanoma patients for anti-PD-1 therapy at baseline and hereby improve the response rate. Citation Format: Christina Jensen, Anders Kverneland, Marco Donia, Neel I. Nissen, Morten A. Karsdal, Inge Marie Svane, Nicholas Willumsen. Non-invasive biomarker potential of the fibroblast-derived collagen type III and collagen type XI for predicting outcome in metastatic melanoma patients treated with anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 388.

Surgical Diagnosis and Treatment of Primary Retroperitoneal Liposarcoma.

Background: Primary retroperitoneal liposarcoma (PRPLS) is the most common soft tissue sarcoma of the retroperitoneum with high recurrence rate and short overall survival (OS).Methods: A retrospective review of 51 patients with PRPLS, treated between September 1, 2009 and November 30, 2020, was conducted to evaluate clinical outcomes of PRPLS resection. Patient demographics, histopathologic subtypes, overall survival (OS), progression-free survival (PFS), disease recurrence rate, and tumor stage were reviewed and analyzed. Univariate analysis was done to identify factors potentially affecting OS and PFS of PRPLS patients. Multivariate Cox proportional hazards analysis was used to evaluate the impact of various clinicopathological factors on OS and PFS of PRPLS patients.Results: Fifty-one PRPLS patients (28 Males, 23 Females; mean age 56.25 years) were evaluated. There was no significant effect of age, gender, contiguous organ resection, degree of differentiation and tumor size on the OS and PFS of the patients. Univariate analysis showed that negative surgical margin and early tumor stage significantly correlated with OS and PFS (all P < 0.001). Multivariate analysis showed that tumor stage [hazard ratio (HR) = 1.177, P = 0.001] was an independent predictors of poor progression-free survival, and surgical margins [HR = 4.0674 P = 0.038] and tumor stage [HR = 1.167 P = 0.001] were identified as independent predictors of poor overall survival.Conclusion: Negative surgical margin is a prognostic factor of OS, and can prolong the postoperative survival time of PRPLS patients. Tumor stage is a prognostic factor for OS and PFS, and can influence the survival of PRPLS patients. Earlier tumor stages of PRPLS are associated with significantly better outcomes.

Application value of plasma exosomal long RNA in SCLC diagnosis and prognosis.

8566 Background: Little research has focused on blood exosomal transcription profile in small cell lung cancer (SCLC). The aim of this study is to identify plasma exosomal specific transcriptional profile in SCLC and explore the application value of plasma exosomal long RNA (exLR) in SCLC diagnosis and prognosis. Methods: This study included 81 healthy people and 40 SCLC patients receiving standard first-line chemotherapy with etoposide and carboplatin/cisplatin. The efficacy was evaluated by progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). 19 Patients who achieved complete response (CR) or partial response (PR) as best response during the first-line therapy and had not progressed within the following 90 days after the end of first-line therapy were defined as chemosensitive. 21 Patients who achieved stable disease (SD) as best response or received progressive disease during the first-line therapy or within the following 90 days after the end of first-line therapy were defined as chemoresistant. Baseline plasma samples were collected from 40 SCLC patients (17 patients’ samples after 2 courses were collected) and 81 healthy people. Plasma exosomes were isolated and purified; exosomal RNA were extracted for high-throughout sequencing analysis. Results: We obtained plasma exLRs profiles from 81 healthy control samples and 57 SCLC samples (baseline samples from 40 patients plus samples collected by 17 patients after 2 courses). Bioinformatics analysis found that exLRs were significantly different between the SCLC and the healthy control group; between the chemosensitive and the chemoresistant group; between the baseline samples and the paired samples after 2 courses. For 40 SCLC patients receiving first-line chemotherapy, ORR was 65.0%, DCR was 90.0% and mPFS was 6.0 months (95% CI, 4.3-7.7 months). Multivariate analysis showed that baseline brain metastases and baseline bone metastases were independent predictors of poor PFS; and 223 genes were independent predictors of PFS. There were 10 genes (AC107954.1, H2AFZP2, CALB2, IFITM9P, GFPT2, PLA1A, CHST10, AC021231.2, SETP20, HILPDA) intersected in differentially expressed genes between the SCLC and the healthy control group, differentially expressed genes between the chemosensitive and the chemoresistant group and independent predictors of PFS. These 10 genes were highly expressed in both the SCLC group and the chemoresistant group, and their high expression was an independent risk factor for poor PFS. Conclusions: This study firstly identified the plasma exLRs profiles in SCLC patients, verified the feasibility and value of identifying biomarkers based on exLRs profiles in SCLC diagnosis and prognosis.

Pregnancy Does not Affect the Prognoses of Differentiated Thyroid Cancer Patients With Lung Metastases.

Pregnancy-related hormones may stimulate thyroid cancer growth, but whether pregnancy affects the prognoses of patients with lung metastases from differentiated thyroid cancer (DTC-LM) after surgery and radioiodine therapy is unclear. To assess the impact of pregnancy on DTC-LM through the comparison of prognoses between female patients with DTC-LM who did and did not become pregnant after surgery and radioiodine therapy. We retrospectively analyzed the records of 124 female patients aged 16 to 35 years who underwent surgery and radioiodine therapy for DTC-LM. These patients were divided into pregnancy group (n = 37) and nonpregnancy group (n = 87) according to whether they became pregnant after surgery and radioiodine therapy, regardless of whether they had a pregnant history before treatment. The 5- and 10-year progression-free survival rates were 94.52% and 63.22% in pregnancy group versus 89.82% and 58.13% in nonpregnancy group. The 5- and 10-year cumulative overall survival rates of pregnancy group were 97.30% and 85.77% versus 93.50% and 81.95% in nonpregnancy group (all P > 0.05). The median time of follow-up in the pregnancy and nonpregnancy groups was 82 months (25-136 months) and 68 months (13-133 months), respectively. Non-radioiodine-avid LM and primary tumors needing repeated resection were independent predictors of poor progression-free survival for patients in pregnancy group. Pregnancy does not affect the prognoses of patients with DTC-LM after surgery and radioiodine therapy. Non-radioiodine-avid LM and repeated primary tumor surgeries are independent risk factors for poor prognoses of pregnant patients.

Low Expression of Circular RNA hsa_circ_0078607 Predicts Poor Prognosis in High-Grade Serous Ovarian Cancer.

ObjectiveRecent studies have shown that circRNAs participate in ovarian cancer progression and act as potential biomarkers for ovarian cancer diagnosis and prognosis. In the present study, we aimed to investigate the expression pattern and prognostic significance of circ_0078607 in high-grade serous ovarian cancer (HGSOC).MethodsThe expression of circ_0078607 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in 49 cases of HGSOC. Clinical data of patients with HGSOC were retrospectively collected, and those patients were divided according to their expression of circ_0078607. Correlation between circ_0078607 and clinical features as well as the prognosis in patients with HGSOC was analyzed. t-test and chi-square test were used to compare continuous and categorical variables. The Cox hazard regression model was used to assess prognostic factors. Both progression-free survival (PFS) and overall survival (OS) curves were generated by Kaplan–Meier method.ResultsThe expression of circ_0078607 was significantly downregulated in ovarian cancer tissues compared with adjacent non-cancerous tissues. Besides, patients with low circ_0078607 expression exhibited parameters associated with poor prognosis, including advanced FIGO stage and higher serum CA125 level. Kaplan–Meier survival curve analysis showed that patients with low circ_0078607 expression had shorter PFS and OS. Cox regression analysis showed that low expression of circ_0078607 was a predictor for poor PFS and OS in HGSOC patients.ConclusionLow expression of circ_0078607 might be an adverse prognostic indicator for HGSOC.

Abstract 6478: Circulating stromal cells in resectable pancreatic cancer is associated with high pathological stage and poor clinical outcomes

Abstract Background: Pancreatic cancer (PC) is a difficult malignancy to diagnosis and properly stage, with extremely poor outcomes even for patients (pts) with resectable disease. Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common to the blood of cancer pts, whose presence and size (≥50µm) is a prognostic indicator of poor progression free survival (PFS) and overall survival (OS). However, the clinical value of CAMLs in PC has not been evaluated. We recruited treatment naïve PC pts referred for surgical resection before therapy induction to study CAML association to PFS/OS. We investigate whether a simple blood test can better identify pts with metastatic disease and act as a predictor for PFS and OS. Methods: 68 whole peripheral blood samples were drawn from untreated newly diagnosed PC pts referred for surgical resection prior to induction of therapy. Pts were recruited for a 2 year single blind prospective pilot study testing &amp;gt;5 CAMLs, CAML size (≥50µm), CA19-9, &amp; CEA to clinical stage (CS), pathological stage (PS), and resectability. Pts were referred based on CS with resectable (R) (n=23), borderline resectable (BR) (n=27), or locally advanced (LA)/metastatic (M) (n=16); Stage I (n=50), Stage II (n=12), Stage III (n=0), Stage IV (n=3), and unknown stage (n=2). Blood samples (7.5mL) were taken prior to any neoadjuvant therapy. Blood was filtered by CellSieveTM filtration and CAMLs quantified. Analysis of CAMLs, protein markers, and resectability were used to evaluate PFS and OS significance by log-rank testing. Results: CAMLs were found in 92% (n=61/66) of pt samples and averaged 7.5 CAMLs/7.5 mL blood. In pts that received surgery, 22 pts were upstaged with PS; stage I (n=20), Stage II (n=16), Stage III (n=5), Stage IV (n=18), &amp; 7 pts withdrawing prior to surgery. All early stage pts with ≥12 CAMLs (n=6) were upstaged to metastatic disease after surgical resection. CEA and CA19-9 serum were not significant for PFS (CEA HR 0.9, p=0.639 and CA19-9 HR 0.6, p=0.288). Further, R vs BR was not significant for PFS (HR 0.4 p=0.10) nor was BR vs LA (PFS HR=0.2 p=0.075), though in both comparisons resectability did trend non-significantly toward better PFS. &amp;gt;5 CAMLs was not a significant indicator of PFS or OS (PFS HR 0.6 p=0.175 and OS HR 1.0 p=0.902). However, ≥50µm CAMLs was a highly significant indicator of both PFS and OS (PFS HR 4.0 CI95% 2.0-7.8, p&amp;gt;0.001 and OS HR 2.3 CI95% 1.1-4.7, p=0.035). Conclusions: In PC, accurate staging/resectability is difficult, with 60% of pts being upstaged post-surgery and ~80% recurring in 2 years. There is a need for a better method to stratify surgical candidates that won't benefit from surgical resection. These data suggest that high CAML numbers at diagnosis identifies pts with metastatic disease which are less likely to benefit from surgical resection, and enlarged CAML size correlates to poorer PFS and OS. Citation Format: Kirby P. Gardner, Daniel L. Adams, Mohammed Aldakkak, Cha-Mei Tang, Susan Tsai. Circulating stromal cells in resectable pancreatic cancer is associated with high pathological stage and poor clinical outcomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6478.

The neutrophil-lymphocyte ratio has a role in predicting the effectiveness of nivolumab in Japanese patients with metastatic renal cell carcinoma: a multi-institutional retrospective study

BackgroundThe neutrophil-lymphocyte ratio (NLR) is a well-known prognostic marker in various cancers. However, its role as a predictive marker for the effectiveness of nivolumab in patients with metastatic RCC (mRCC) remains unclear. We evaluated the relationships between the NLR and progression-free survival (PFS) or overall survival (OS) in mRCC patients treated with nivolumab.MethodsThe data of 52 mRCC patients who received nivolumab therapy were collected from seven institutes and evaluated. The median follow-up period from treatment with nivolumab was 25.2 months (IQR 15.5–33.2).ResultsThe median duration of nivolumab therapy was 7.1 months (IQR 2.9–24.4). The objective response rate was 25% and the 1- and 2-year PFS rates were 46.2 and 25.2%, respectively. The median NLR values at baseline and 4 weeks were 3.7 (IQR 2.7–5.1) and 3.3 (IQR 2.4–5.7), respectively. In the multivariate analysis, an NLR of ≥3 at 4 weeks was an independent predictor of PFS (P = 0.013) and OS (P = 0.034). The 1-year PFS of patients with an NLR of < 3 at 4 weeks was better than that of those with an NLR of ≥3 (75% versus 29%, P = 0.011). The 1-year OS of patients with an NLR of < 3 at 4 weeks was also better than that of those with an NLR of ≥3 (95% versus 71%, P = 0.020).ConclusionsAlthough the baseline NLR was not associated with PFS or OS, an NLR of ≥3 at 4 weeks after the initiation of therapy might be a robust predictor of poor PFS and OS in mRCC patients undergoing sequential treatment with nivolumab.

The Agnostic Role of Site of Metastasis in Predicting Outcomes in Cancer Patients Treated with Immunotherapy.

Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients’ survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden (p = 0.0004), the presence of liver (p = 0.0009), bone (p = 0.0016), brain metastases (p < 0.0001), the other metastatic sites (p = 0.0375), the number of metastatic sites (p = 0.0039), the histology (p = 0.0034), the upfront use of immunotherapy (p = 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) ≥ 1 (p < 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver (p = 0.0105) and brain (p = 0.0026) metastases, the NSCLC diagnosis (p < 0.0001) and the ECOG PS (p < 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden (p = 0.0004), bone (p = 0.0098) and brain (p = 0.0038) metastases, the presence of other metastatic sites (p = 0.0063), the number of metastatic sites (p = 0.0007), the histology (p = 0.0007), the use of immunotherapy as first line (p = 0.0031), and the ECOG PS ≥ 1 (p ≤ 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain (p = 0.0088) and liver metastases (p = 0.024) and the ECOG PS (p < 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.

Computed Tomography–Determined Sarcopenia Is a Useful Imaging Biomarker for Predicting Postoperative Outcomes in Elderly Colorectal Cancer Patients

PurposeThis study aimed to establish whether computed tomography (CT)–determined sarcopenia is a useful imaging biomarker for postoperative outcome in elderly colorectal cancer (CRC) patients, and construct sarcopenia-based nomograms to predict individual outcomes after surgery.Materials and MethodsCT imaging data of 298 elderly CRC patients who underwent surgery in 2012-2014 were retrospectively analyzed. Skeletal muscle mass was determined by CT, and sarcopenia was diagnosed based on the optimal cutoff value determined by X-tile program. The correlation between sarcopenia and risk of preoperative nutrition and postoperative complications was evaluated. A Cox proportional hazards model was used to determine survival predictors. Sarcopenia-based nomograms were developed based on multivariate analysis, and calibrated using concordance index and calibration curves.ResultsA total 132 patients (44.3%) had sarcopenia based on the optimum cutoff values (29.9 cm2/m2 for women and 49.5 cm2/m2 for men). Sarcopenia was an independent risk factor for preoperative nutrition (p < 0.001; odds ratio [OR], 3.405; 95% confidence interval [CI], 1.948 to 5.954) and postoperative complications (p=0.008; OR, 2.192; 95% CI, 1.231 to 3.903). Sarcopenia was an independent predictor for poor progression-free survival (p < 0.001; hazard ratio [HR], 2.175; 95% CI, 1.489 to 3.179) and overall survival (p < 0.001; HR, 2.524; 95% CI, 1.721 to 3.703). Based on multivariate analysis, we produced four nomograms that had better predictive performance.ConclusionCT-determined sarcopenia is a useful imaging biomarker for predicting preoperative nutritional risk, postoperative complications, and long-term outcomes in elderly CRC patients. The sarcopenia-based nomograms can provide a scientific basis for guiding therapeutic schedule and follow-up strategies.

Systemic inflammatory response predicts poor prognoses in Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma with transarterial chemoembolization: a prospective study

Background: Chronic inflammation has been demonstrated to be an important factor in the initiation, promotion, and progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic values of systemic inflammation markers in Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Methods: A prospective non-randomized study was performed from June 2016 to May 2017; 51 of 123 BCLC stage B/C HCC patients were enrolled and received transarterial chemoembolization (TACE). Clinical and laboratory data were recorded. Serum IL-6, IL-10, C-reactive protein (CRP), and blood-neutrophil-to-lymphocyte ratio (NLR) levels were analyzed during the perioperative period. Patient prognosis was investigated. Twenty-eight stage A cases and 10 stage B/C patients who received resection were also collected as controls. Results: Compared to the stage A group, the BCLC stage B/C HCC patients had significantly higher serum IL-6, CRP, and blood NLR levels. Serum IL-6, IL-10, CRP, and blood NLR levels increased significantly 3 days after treatment (TACE/resection) and returned to baseline levels after 30 days. By univariate analyses, tumor size, high pretreatment serum IL-6, CRP, and blood NLR levels predicted worse progression-free survival (PFS) after TACE (log-rank test P Conclusions: Serum IL-6, CRP, and blood NLR levels were significantly elevated in stage B/CHCC. Serum IL-6 and CRP were independent predictors of poor PFS while NLR independently predicted worse OS in BCLC stage B/C HCC.

Metabolic tumor volume predicts overall survival in patients with primary pulmonary lymphoepithelioma-like carcinoma.

Pretreatment tumor metabolic burden, measured using fluorine-18 fluorodeoxyglucose positron emission tomography/computerized tomography (18F-FDG PET/CT), has been demonstrated to predict outcomes in various types of malignancies. Additionally, Epstein-Barr virus (EBV) serum titer is associated with stages of pulmonary lymphoepithelioma-like carcinoma (LELC). The present study aimed to investigate the prognostic value of the functional parameters of 18F-FDG PET/CT in pulmonary LELC and their association with serum EBV DNA. The present retrospective study analyzed data from 71 patients with pulmonary LELC; among these, 32 patients with pulmonary LELC underwent pretreatment 18F-FDG PET/CT staging between January 2008 and December 2016. EBV viral load and functional parameters of 18F-FDG PET/CT were used for survival analysis. Multivariate analysis identified tumor stage IV as a significant predictor of poor progression-free survival [hazard ratio (HR), 4.85; P=0.049], whereas elevated total metabolic tumor volume (MTV ≥72.6 ml) independently predicted worse overall survival (OS; HR, 12.59; P=0.024). Pretreatment serum EBV DNA titer was significantly positively associated with total MTV (P=0.0337) and total lesion glycolysis (TLG; P=0.0093), but could not predict outcomes. Total MTV was an independent predictor of OS, and may guide clinical management for pulmonary LELC.

Abstract 3141: The relationship between BRAF/NRAS/KIT genomic driver mutations and anti-PD1 immunotherapy responses in patients with advanced melanoma

Abstract Background: Anti-PD1 immunotherapy, when used alone or in combination (combo) with anti-CTLA4, prolongs overall (OS) and progression-free survival (PFS) of patients (pts) with advanced melanoma, compared to single-agent (SA) anti-CTLA4. Combo immunotherapy is more toxic than SA anti-PD1, therefore it is of interest to identify patients most likely benefit from SA anti-PD1 to spare these pts the toxicity of combo immunotherapy. We asked whether genomic driver mutations (mts) in BRAF, NRAS or KIT could predict anti-PD1 responses in melanoma pts. Methods: We preformed a single-center retrospective analysis of 292 melanoma pts who received SA or combo anti-PD1 immunotherapy at Princess Margaret Hospital between 2012-17. BRAF/NRAS/KIT mts and other covariates were abstracted from chart review. Multivariable Cox models were used to assess differences in OS/PFS. Results: We identified 209 and 83 melanoma patients who received SA-anti-PD1 or combo immunotherapy, respectively. Pt characteristics were: mean age 59 yrs; 56% male; 77% cutaneous/unknown primary 23% uveal or mucosal; 17% brain metastases; 34% stage M0/M1a/M1b, 66% stage M1c/M1d, 51% BRAF/NRAS/KIT mt. Among pts receiving SA anti-PD1, presence of a BRAF, NRAS, or KIT mt was an independent predictor of poor PFS (HR 1.84; 95% CI 1.21-2.81) and OS (HR 1.93; 95% CI 1.17-3.22) in multivariate models. Other negative predictors of poor survival were: elevated LDH, multiple previous lines of therapy, 3 or more sites of metastasis, and uveal or mucosal histology. Combo immunotherapy was independently associated with longer OS compared to SA anti-PD1 in BRAF/NRAS/KIT mt pts (HR 0.43; 95% CI 0.20-0.90), but not in BRAF/NRAS/KIT wild-type pts (HR 1.34; 95% CI 0.46-3.90). Conclusions: In this retrospective study, the presence of a BRAF NRAS or KIT mt was an independent predictor of poor PFS/OS in melanoma pts treated with SA anti-PD1. Combo immunotherapy prolonged survival vs SA anti-PD1 in BRAF/NRAS/KIT mt melanoma, but not in BRAF/NRAS/KIT wild-type melanoma. These data suggest that BRAF/NRAS/KIT wild-type melanoma pts may derive less added benefit from combo immunotherapy (vs single agent anti-PD1) compared to pts with BRAF/NRAS/KIT mutations. Validation analyses are on-going. Citation Format: April A.N. Rose, Susan M. Armstrong, David Hogg, Marcus Butler, Anthony M. Joshua, Danny Ghazarian, Suzanne Kamel-Reid, Ayman Al Habeeb, Mary Anne Chappell, Kendra Ross, Eitan Amir, Phillippe L. Bedard, Lillian Siu, Anna Spreafico. The relationship between BRAF/NRAS/KIT genomic driver mutations and anti-PD1 immunotherapy responses in patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3141.

Cytoplasmic Keap1 Expression Is Associated With Poor Prognosis in Endometrial Cancer.

Oxidative stress is involved in several carcinogenic pathways. Nuclear factor erythroid 2-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1) and Park7 (DJ-1) are the main regulators of antioxidant enzymes eliminating reactive oxidative species (ROS). The roles of these proteins were studied as potential prognostic factors in endometrial cancer. Nrf2, Keap1 and DJ-1 expression in endometrial carcinomas was analyzed immunohistochemically. Correlations between staining patterns and clinical prognostic variables were evaluated. Extensive cytoplasmic Keap1 staining correlated to several factors associated with poor prognosis of endometrial cancer including advanced stage, poor histological differentiation, lymphovascular invasion, pelvic lymph node metastasis and deep myometrial invasion. In multivariate analysis, cytoplasmic Keap1 was a stronger predictor of poor progression-free survival than grade. Nuclear Nrf2 staining was seen in all patients with lymph node metastasis while DJ-1 staining was associated with clinically favourable disease types. Cytoplasmic Keap1 expression indicates poor prognosis in endometrial cancer.