Predictors Of Early Recurrence Research Articles

Abstract 2400: Determinants of early recurrence in surgically-resected colon cancer: A multi-omics analysis

Abstract Introduction: Colon cancer is the third most common cancer worldwide. The mainstay treatment for localized disease is surgical resection, often followed by adjuvant chemotherapy in stage III patients, and stage II patients with high-risk features. Unfortunately, some patients experience early local and/or distant recurrence. Besides classic anatomical/pathological tumor features, insight into the genomic determinants of early recurrence in colon cancer is lacking. Herein, we utilize a multi-omics approach to identify early-recurrence-specific features that could aid in more accurate risk stratification. Methods: We utilized the Cancer Genomic Atlas Colon Adenocarcinoma (TCGA-COAD) Database. Clinical, histopathological and genomic data were retrieved through the cBioPortal database. Our analysis was limited to patients with stage 2 or 3 (n = 390) disease based on the American Joint Committee on Cancer Code. Early recurrence (ER) was defined as disease relapse/recurrence within 12 months of sample acquisition post-surgery. Accordingly, patients were categorized into the ER and non-early recurrence (NER) groups based on a cut-off point of 12 months of disease-free survival. Results: The colon cancer ER and NER group included 45 and 345 patients, respectively. Comparable age, sex and race percentages were found between both groups. The ER group had significantly worse overall, progression-free, and disease-specific survival (HR: 0.083 95% CI: 0.031-0.220, HR: 0.035 95% CI: 0.011-0.0109, HR: 0.021 95% CI: 0.006-0.076, respectively). ER patients had a significantly higher proportion of patients with T4 and N2 disease based on the TNM staging system. ER patients had significant (P< 0.05) expression of TRIM46, TRPC4, ELOVL7, CSMD1, BCLAF1, and CD70 mutations, while tumor mutational burden was comparable between both groups (median TMB in ER vs NER: 4.2 vs 3.62, p = 0.28). Differential gene expression analysis revealed 68 genes to be upregulated in the ER group which were found to be enriched in hypoxia and interleukin-11 pathway genes. Genes upregulated in the NER group (n = 49) were enriched in interferon-alpha response and glycolysis/gluconeogenesis pathway genes. Proteomics analysis revealed significantly higher levels of EIF4E, CCNE1, SRSF1, SCD, and PECAM1 proteins in NER patients .Conclusion: Our results highlight insights into molecular and genomic features unique to colon cancer patients with early recurrence. Understanding such predictors for early recurrence will aid in risk stratification and help in determining patients who would derive the most benefit from adjuvant treatment considerations. Citation Format: Salma Al-Aomar, Hassan Abushukair, Alaa Zaitoun, Sara Zytoon, Sara Illeyyan, Husam Almomani, Ghayda'a Al-Majali, Arafat Hammad, Khaled Obeidat, Fuad Turfah, Awni Shahait, Fadwa Ali. Determinants of early recurrence in surgically-resected colon cancer: A multi-omics 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 2400.

O138: Predictors of early recurrence of oesophagogastric adenocarcinoma after neoadjuvant FLOT

Abstract Background Although survival of patients with oesophagogastric adenocarcinomas has improved over the years, rates of cancer recurrence remain high. There is limited research on predictors for early recurrence (ER), especially in patients receiving FLOT chemotherapy. The aim of this study was to investigate ER and survival rates and identify risk factors of ER. Methods Patients receiving neoadjuvant chemotherapy with FLOT for oesophagogastric adenocarcinoma at single high-volume centre between August 2018 and October 2022 were evaluated for early recurrence defined as disease present within 1 year of surgery. Multivariable analysis was conducted to identify risk factors for ER. Patients who died in-hospital or within 90 days of surgery and those with positive longitudinal margin were excluded. Results 169 patients were included. 92.9% and 41.4% of patients completed all four neoadjuvant and adjuvant cycles of FLOT respectively. 51 patients (30.2%) developed recurrence in the follow up period with 24 patients (14.2%) having ER. Recurrence free survival and overall survival at one year were 84.1% and 91.7% respectively. The estimated median survival after recurrence was 4.8 months. Extracapsular spread was found to be independent risk factor for ER (OR 6.507, 95% CI 1.964-21.556, p=0.002) in multivariable analyses together with ypN3 stage (OR 7.204, 95% CI 1.118-46.403, p=0.038). Conclusions The variables identified in this study may be helpful in determining patients at a higher risk of ER following curative surgery. Understanding these predictors may help tailor the follow up care of these patients, such as regular surveillance imaging, treatment, and frequency of reviews.

Risk factors for early recurrence after radical gastrectomy followed by adjuvant chemotherapy for stage II or III gastric cancer: a multicenter, retrospective study.

Radical gastrectomy followed by adjuvant chemotherapy is the standard treatment for stage II or III gastric cancer in Asian countries. Early recurrence during or after adjuvant chemotherapy is associated with poor prognosis; however, risk factors for early recurrence remain unclear. In this multicenter, retrospective cohort study including six institutions, we evaluated the clinicopathological factors of 553 patients with gastric cancer undergoing gastrectomy followed by adjuvant chemotherapy between 2012 and 2016. Patients were divided into the following groups: early recurrence (recurrence during adjuvant chemotherapy or within 6months after adjuvant chemotherapy completion) and non-early recurrence, which was further divided into late recurrence and no recurrence. Early-recurrence risk factors were investigated using multivariate Cox proportional hazard model. The chronological changes in the recurrence hazard were also examined for each factor. Early recurrence and late recurrence occurred in 83 (15.0%) and 73 (13.2%) patients, respectively. Based on the Cox proportional hazards model, a postoperative serum carcinoembryonic antigen level of ≥5ng/mL (hazard ratio: 2.220, 95% confidence interval: 1.089-4.526) and a neutrophil-to-lymphocyte ratio of >1.8 (hazard ratio: 2.408, 95% confidence interval: 1.479-3.92) were identified as independent risk factors of early recurrence, but not late recurrence. The recurrence hazard ratios for neutrophil-to-lymphocyte ratio significantly decreased over time (P<0.001) and carcinoembryonic antigen also had the same tendency (P=0.08). A carcinoembryonic antigen level of ≥5ng/mL and a neutrophil-to-lymphocyte ratio of >1.8 are predictors of early recurrence after radical gastrectomy and adjuvant chemotherapy for stage II or III gastric cancer.

Predictors for early recurrence beyond up-to-7 or distant metastasis after hepatocellular carcinoma resection: proposal for borderline resectable HCC.

The recurrence rate after curative resection for hepatocellular carcinoma (HCC) reaches over 70% after 5years and early recurrence (within 1year) is now recognized as having a poor prognosis and has limited treatment options. We retrospectively reviewed 184 consecutive patients who underwent curative hepatic resection for HCC. Severe early recurrence was defined as multiple (beyond up-to-7) liver recurrence or distant metastasis after hepatic resection within 1year. We divided the participants into two groups according to severe early recurrence and analyzed clinicopathological and long-term outcomes. Among the patients with multiple or distant metastasis (n = 59), 49 patients (83%) had recurrence within 1year. Overall survival (OS) and recurrence-free survival (RFS) were significantly worse in the severe early recurrence group than in the others group. Logistic regression analysis revealed that severe early recurrence was significantly associated with macroscopic vascular invasion (MVI), tumor burden score (TBS) > 4.70, and ALBI grade 2. In patients with scores of 2 and 3 (the sum of the three factors), OS and RFS rates were significantly poorer than those of patients with scores of 0 or 1. Positive predictive value and negative predictive value for severe early recurrence was 68.4% and 84.2%, respectively. Furthermore, a validation study demonstrated that cases with these factors were at high risk of severe early recurrence and had poor prognosis. In this retrospective analysis, MVI, TBS, and ALBI could predict severe early recurrence after hepatic resection for HCC, and patients with these risk factors had a poor prognosis.

Response to neoadjuvant therapy as a predictor of early recurrence in patients undergoing hepatectomy for colorectal liver metastasis: an analysis from the livermetsurvey international registry

Response to neoadjuvant therapy as a predictor of early recurrence in patients undergoing hepatectomy for colorectal liver metastasis: an analysis from the livermetsurvey international registry

The platelet-to-lymphocyte ratio is a complementary prognostic factor to tumor markers in predicting early recurrence of hepatocellular carcinoma after hepatectomy.

The usefulness of inflammation-based prognostic scores for early recurrence (ER) after hepatectomy for hepatocellular carcinoma has rarely been reported. This study aimed to evaluate the potential of inflammation-based prognostic scores as predictors of ER and their relationship with tumor markers. We enrolled 338 patients who underwent hepatectomy for hepatocellular carcinoma between January 2007 and December 2021. Clinicopathological factors were compared between patients who developed ER (ER group) and those who did not develop ER (non-ER group). The association between inflammation-based prognostic scores and ER status was evaluated. These scores were compared with those of well-established tumor markers. The platelet-to-lymphocyte ratio (PLR) correlated with ER of hepatocellular carcinoma, with an area under the curve (AUC) value of 0.70, sensitivity of 68.1%, and specificity of 67.7%. In patients with low tumor marker levels, the PLR showed a strong correlation with ER of hepatocellular carcinoma, with an AUC value of 0.851, sensitivity of 100%, and specificity of 76.2%. Multivariate analysis revealed that the PLR was an independent prognostic factor for ER. The PLR is useful and complementary to tumor markers for predicting ER after hepatectomy for hepatocellular carcinoma.

O4-5 Circulating tumor DNA dynamics as an early predictor of recurrence in patients with radically resected colorectal cancer: GALAXY study in the CIRCULATE-Japan

O4-5 Circulating tumor DNA dynamics as an early predictor of recurrence in patients with radically resected colorectal cancer: GALAXY study in the CIRCULATE-Japan

Impact of Trinal Histological Glandular Differentiation Grade on the Prognosis of Patients with Intrahepatic Cholangiocarcinoma: a Multicenter Retrospective Study

IntroductionIt is unclear whether the histological glandular differentiation (HGD) score that evaluates the tumor grade of two dominant components is prognostic for survival in patients with intrahepatic cholangiocarcinoma (ICC). MethodWe retrospectively analyzed the clinical and histopathologic data of 235 consecutive patients with histologically confirmed ICC following hepatectomy at 5 university hospitals in the Kansai region of Japan. ResultsSurvival was statistically significantly stratified by trinal HGD grade (p < 0.05). Median disease-free survival (DFS) of patients with high HGD grade was significantly shorter compared with moderate HGD grade (13.0 vs 31.2 months, respectively; p = 0.004). By Cox proportional hazards regression analysis, HGD grade had the fifth-highest hazard ratio (HR = 1.77, p = 0.002) for DFS after vascular and/or biliary invasion, extrahepatic invasion, lymph node metastasis and multiple tumors. Multivariate logistic regression analysis revealed four predictors of early recurrence after hepatectomy (lymph node metastasis: odds ratio [OR] = 3.74, p = 0.001; tumor size > 50 mm: OR = 2.80, p = 0.002; HGD grade, high: OR = 2.11, p = 0.012; and vascular or biliary tract invasion: OR = 2.11, p = 0.048). ConclusionTrinal HGD grade had a significant prognostic impact on the survival of patients with ICC after radical hepatectomy.

Combination of carbohydrate antigen 19-9 level and tumor size after neoadjuvant chemoradiation therapy may predict early recurrence of resectable pancreatic ductal adenocarcinoma

BackgroundAlthough the overall survival rate of patients with resectable pancreatic cancer has gradually improved, some patients relapse early and have a poor prognosis. This study aimed to identify the preoperative risk factors for early recurrence after neoadjuvant chemoradiotherapy in patients with resectable pancreatic cancer. MethodsThis study analyzed patients who underwent pancreatectomy after receiving neoadjuvant chemoradiotherapy for resectable pancreatic cancer between January 2009 and June 2021 and excluded those with borderline resectable and unresectable pancreatic cancers. Early recurrence was defined as recurrence within 6 months after surgery. ResultsThis study included 203 patients, of whom 22 experienced early recurrence. The median survival time of patients with early recurrence was 18.3 months, which was significantly worse than that of patients with late recurrence (44.0 months, p < 0.001) or no recurrence (not reached, p < 0.001). Logistic regression analysis revealed that a carbohydrate antigen 19-9 level of >100 units/mL and a T status of ≥T2 after neoadjuvant chemoradiotherapy were independent predictive risk factors for early recurrence. The median recurrence-free survival time of patients with two risk factors was 9.7 months and significantly worse than that of those with either risk factors (20.5 months, p = 0.024) and those with no risk factor (26.2 months, p < 0.001). ConclusionsA combination of a high-level carbohydrate antigen 19–9 and a T status of ≥T2 after neoadjuvant chemoradiotherapy are predictors of early recurrence and may be helpful for selecting patients who require a stronger preoperative treatment.

Circulating tumor DNA dynamics as an early predictor of recurrence in patients with radically resected colorectal cancer: Updated results from GALAXY study in the CIRCULATE-Japan.

3521 Background: Postoperative circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) is reported to be associated with a high risk of recurrence. Here, we present an updated analysis and the lead time interval (LTI) of ctDNA positivity to radiographic recurrence in patients (pts) with radically resected colorectal cancer (CRC), stage II-IV in the observational GALAXY study. Methods: Serial ctDNA was analyzed using personalized tumor-informed assay (Signatera bespoke multiplex-PCR NGS assay) at 1 (4-week MRD time point), 3, 6, 9, 12, 18, and 24 months after surgery until recurrence, and CT scans were conducted every 6 months. The primary endpoint was disease-free survival (DFS), defined as the time between the date of surgery and date of diagnosis with relapse or death due to any cause. The LTI was defined from the first ctDNA positive date at post-surgery to radiographic recurrence. Results: Among 3,615 CRC pts who were enrolled between May 2020 and April 2022 in GALAXY study, 2,083 pts that met the inclusion criteria were analyzed in this report. The median follow-up period was 16.3 months. Of 2,083 pts analyzed, 286 (14%) were ctDNA-positive at 4-weeks MRD time point and 1,797 (86%) were ctDNA-negative. Pts with ctDNA-positivity at 4-weeks MRD timepoint demonstrated an inferior DFS and were 12 times more likely to recur, compared to ctDNA-negative pts (HR:12, 95CI: 9.1-15%; p &lt; 0.0001). We further combined ctDNA status with BRAF V600E status at 4-week MRD time point and observed that pts with ctDNA-positivity and BRAF V600E mutation showed significantly shorter DFS compared to ctDNA-positive pts with BRAF wild-type (p &lt; 0.001). Whereas, in pts with ctDNA-negativity no significant difference in DFS was observed (p = 0.306). On performing ctDNA dynamics analysis between 4-weeks to 12 weeks, compared to pts who remained ctDNA-negative (N = 1529), a significantly shorter DFS was observed for pts who converted from ctDNA-negative to positive (N = 112, HR: 14.5, 95%CI: 8.8-23.8%, p &lt; 0.0001) or who remained positive (N = 124, HR: 25.4, 95%CI: 18.3-35.3; p &lt; 0.0001). Radiographic recurrence was observed in 186 pts (46%). Of these, 121 pts (65%) had CT imaging performed every 6 months, as per the protocol. The median LTI was 142 days (IQR, 43-189 days). Conclusions: Our study builds on the existing evidence from the recently published, prospective GALAXY study. ctDNA status at MRD time point post-surgery is prognostic of patient outcomes and is the most significant risk factor regardless of BRAF V600E status. ctDNA positivity predicted radiologic recurrence several months ahead of clinical recurrence. Pts with positive postoperative ctDNA should be examined carefully due to a high risk of recurrence. ctDNA-guided adjuvant strategy will further be established by ongoing randomized VEGA and ALTAIR studies in the CIRCULATE-Japan. Clinical trial information: UMIN000039205 .

Clinical Implications of FDG-PET in Pancreatic Ductal Adenocarcinoma Patients Treated with Neoadjuvant Therapy

PurposeTo evaluate the clinical significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy. MethodsAmong 285 consecutive patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma between 2015 and 2021, 86 who underwent preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography after completion of neoadjuvant treatment were reviewed. Among preoperative factors, including post-treatment maximum standardized uptake value, predictors of early recurrence and poor prognosis were identified using multivariate analysis for decision making in surgery. ResultsNineteen (22%) patients with pancreatic ductal adenocarcinoma demonstrated high maximum standardized uptake (≥ 4.5). High post-treatment maximum standardized uptake (≥ 4.5) predicted early recurrence within 6 months after surgery and correlated with shorter recurrence-free survival. Elevated post-treatment CA19-9 level (> 37 U/ml) and maximum standardized uptake ≥ 4.5 were independent prognostic factors. Post-treatment, a high maximum standardized uptake value indicated a poorer prognosis than a low maximum standardized uptake value in both patients with elevated CA19-9 and normal CA19-9 levels. The median overall survival in patients with elevated post-treatment CA19-9 and high maximum standardized uptake was only 17 months; 67% experienced early recurrence. Dynamic changes in maximum standardized uptake during neoadjuvant therapy were correlated with pathological response to neoadjuvant therapy, but not with radiological response or change in CA19-9 level. ConclusionsPost-treatment assessment using maximum standardized uptake value is useful for stratifying patients with pancreatic ductal adenocarcinoma who will benefit from surgery. Instead of subsequent curative resection, additional neoadjuvant therapy should be considered in patients with a persistently high maximum standardized uptake value.

High PD-L2 Predicts Early Recurrence of ER-Positive Breast Cancer.

T-cell-mediated cytotoxicity is suppressed when programmed cell death-1 (PD-1) is bound by PD-1 ligand-1 (PD-L1) or PD-L2. Although PD-1 inhibitors have been approved for triple-negative breast cancer, the lower response rates of 25%-30% in estrogen receptor-positive (ER+) breast cancer will require markers to identify likely responders. The focus of this study was to evaluate whether PD-L2, which has higher affinity than PD-L1 for PD-1, is a predictor of early recurrence in ER+ breast cancer. PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, localized or locoregional ER+ breast cancers were measured retrospectively by quantitative immunofluorescence histocytometry and correlated with progression-free survival (PFS) in the main study cohort (n = 684) and in an independent validation cohort (n = 273). All patients subsequently received standard-of-care adjuvant therapy without immune checkpoint inhibitors. Univariate analysis of the main cohort revealed that high PD-L2 expression in cancer cells was associated with shorter PFS (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.6; P = .001), which was validated in an independent cohort (HR, 2.3; 95% CI, 1.1 to 4.8; P = .026) and remained independently predictive after multivariable adjustment for common clinicopathological variables (HR, 2.0; 95% CI, 1.4 to 2.9; P < .001). Subanalysis of the ER+ breast cancer patients treated with adjuvant chemotherapy (n = 197) revealed that high PD-L2 levels in cancer cells associated with short PFS in univariate (HR, 2.5; 95% CI, 1.4 to 4.4; P = .003) and multivariable analyses (HR, 3.4; 95% CI, 1.9 to 6.2; P < .001). Up to one third of treatment-naive ER+ breast tumors expressed high PD-L2 levels, which independently predicted poor clinical outcome, with evidence of further elevated risk of progression in patients who received adjuvant chemotherapy. Collectively, these data warrant studies to gain a deeper understanding of PD-L2 in the progression of ER+ breast cancer and may provide rationale for immune checkpoint blockade for this patient group.

Early recurrence factors in patients with stage III non-small cell lung cancer treated with concurrent chemoradiotherapy.

The clinical characteristics and risk factors for cancer recurrence have not been well evaluated regarding early recurrence in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) who receive concurrent chemoradiotherapy (CRT). The aim of this study was to determine the clinical characteristics and risk factors of patients with stage III unresectable LA-NSCLC treated with CRT who developed early recurrence. We retrospectively reviewed the clinical records of 46 patients diagnosed with stage III unresectable LA-NSCLC treated with CRT at our center between July 2012 and July 2021. A tumor proportion score (TPS) < 50% was defined as "low expression" and a TPS > 50% was defined as "high expression." A total of 17 (37.0%) patients had a confirmed recurrence within 1year of treatment. More patients had a lower body mass index in the early recurrence group than in the later recurrence group (p= 0.038). A higher number of patients in the late recurrence group underwent surgery after CRT (p= 0.036). Patients with a higher TPS were more likely to experience late recurrence than early recurrence (p= 0.001), whereas more patients with stage N3 disease were in the early recurrence group (p= 0.011). Multivariate analysis identified lower TPS expression as an independent risk factor for early recurrence after CRT. Overall survival was prolonged in the late recurrence group (p < 0.001). A lower TPS may be a predictor of early recurrence after CRT in patients with LA-NSCLC. These patients should be closely monitored for post-treatment recurrence.

Long-term outcomes of staged liver resection for synchronous liver metastases from colorectal cancer and the clinical impact of early recurrence: A single-center retrospective cohort study.

This study was undertaken to evaluate the long-term outcomes of staged liver resection for synchronous liver metastases (SLM) from colorectal cancer (CRC), and to elucidate the prognostic impact and predictors of early recurrence (ER), which was defined as recurrence within 6 mo. Patients with SLM from CRC, except for initially unresectable SLM, from January 2013 to December 2020 were included. First, overall survival (OS) and relapse-free survival (RFS) after staged liver resection were evaluated. Second, eligible patients were classified as follows: patients who were unresectable after resection of CRC (UR), patients with ER, and patients without ER (non-ER), and their OS after resection of CRC were compared. In addition, risk factors for ER were identified. The 3-y OS and RFS rates after resection of SLM were 78.8% and 30.8%, respectively. Next, the eligible patients were classified as follows: ER (N=24), non-ER (N=56), and UR (N=24). The non-ER group had a significantly better OS than the ER (3-y OS: 89.7% vs 48.0%, P=.001) and UR (3-y OS: 89.7% vs 61.6%, P < .001) groups, while there was no significant difference between the ER and UR groups in OS (3-y OS: 48.0% vs 61.6%, P=.638). Increasing carcinoembryonic antigen (CEA) before and after resection of CRC was identified as an independent risk factor for ER. Staged liver resection for SLM from CRC was feasible and useful for oncological evaluation, as changes in CEA could predict ER, which was associated with a poor prognosis.

Predictive factors for early recurrence after pancreaticoduodenectomy in patients with resectable pancreatic head cancer: A multicenter retrospective study

BackgroundPatients diagnosed with resectable pancreatic ductal adenocarcinoma often experience early recurrence even after upfront R0 resection. This study aimed to define early recurrence and identify preoperative risk factors for early recurrence after upfront pancreaticoduodenectomy in patients with resectable pancreatic ductal adenocarcinoma of the pancreatic head. MethodsThis multicenter, retrospective study involved 500 patients who underwent pancreaticoduodenectomy resectable pancreatic ductal adenocarcinoma of the pancreatic head at 10 institutions between 2007 and 2016. Preoperative, intraoperative, and postoperative clinicopathological results were compared between early and non-early recurrence groups. Predictors of early recurrence were determined using statistical analyses. ResultsLog-rank tests revealed a significant difference (P < .001) between recurrence within 3 to 6 months and 6 to 9 months. Early recurrence was subsequently defined as recurrence within 6 months. Patients were categorized into early recurrence (n = 104) and non-early recurrence groups (n = 389). The median overall survival of the early and non-early recurrence groups was 8.6 months and 42.6 months (P < .001), respectively. Preoperatively, high carbohydrate antigen 19-9 levels ≥120 U/mL, retroperitoneal invasion, and diabetes mellitus were identified as independent predictive risk factors for early recurrence according to multivariate analysis. Comparing survival rates among patients with 3, 2, 1, or none of these factors, the median overall survival was 17.6 (n = 90), 21.2 (n = 184), 47 (n = 141), and 61.5 (n = 73) months, respectively. ConclusionThe optimal period that defines the early recurrence for resectable pancreatic ductal adenocarcinoma of the pancreatic head is 6 months. Tumor size ≥20 mm, preoperative carbohydrate antigen 19-9 levels ≥120 U/mL, retroperitoneal invasion of the tumor, and the presence of diabetes mellitus are independently associated with early recurrence.

Uncovering the Heterogeneity and Clinical Relevance of Circulating Tumor-Initiating Cells in Hepatocellular Carcinoma Using an Integrated Immunomagnetic-Microfluidic Platform.

Circulating tumor-initiating cells (CTICs) with stem cell-like properties play pivotal roles in tumor metastasis and recurrence. However, little is known about the biology and clinical relevance of CTICs in hepatocellular carcinoma (HCC). Here, we investigated the molecular heterogeneity and clinical relevance of CTICs in HCC using a novel integrated immunomagnetic-microfluidic platform (iMAC). We constructed the iMAC and evaluated its ability to detect CTICs using a series of spiked cell experiments. A four-channel microfluidic chip was applied to investigate the composition of CTICs in patients with primary and recurrent HCC utilizing microbeads labeled with one of four stem-related markers: epithelial cell adhesion molecule (EpCAM), CD133, CD90, and CD24. The dynamic changes of these four CTIC subsets were serially monitored during treatment courses. Finally, single-cell RNA profiling was used to reveal the molecular characteristics of the four CTIC subsets. The iMAC platform detected significantly more EpCAM+ CTICs in the blood samples from 33 HCC patients than the FDA-approved CellSearch system (0.92 ± 0.94 vs 0.23 ± 0.36, P < 0.001). The number of EpCAM+ CTICs (≥0.75/mL) detected by iMAC was a predictor of early recurrence (P = 0.007). The distinct stem-related markers' expression of CTICs could distinguish primary HCC, recurrent HCC, and TACE-resistant HCC. Single-cell transcriptional profiling proved the heterogeneity among individual CTICs and separated the four CTIC subsets into distinct phenotypes. Dissecting the heterogeneity of CTICs using the iMAC represents a novel and informative method for accurate CTIC detection and characterization. This innovative technology will enable more indepth cancer biology research and clinical cancer management than is currently available.

Clinical Impact of Dual Time Point 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Fusion Imaging in Pancreatic Cancer.

Simple SummaryIn pancreatic cancer, recurrence rates after surgery remain high. The ability to identify patients at risk of early recurrence before surgery will contribute to the selection of treatment strategies. We examined the value of preoperative dual time point (DTP) 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (FDG PET/CT) as a predictor of early recurrence in or the outcomes of patients with pancreatic cancer. The results showed that DTP FDG PET/CT may effectively predict relapse in patients, and the combination of SUVmax1 and ΔSUVmax% identified early recurrent patient groups more precisely than SUVmax1 alone.We examined the value of preoperative dual time point (DTP) 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (FDG PET/CT) as a predictor of early recurrence or the outcomes in patients with pancreatic cancer. Standardized uptake values (SUVs) in DTP FDG PET/CT were performed as preoperative staging. SUVmax1 and SUVmax2 were obtained in 60 min and 120 min, respectively. ΔSUVmax% was defined as (SUVmax2 − SUVmax1)/SUVmax1 × 100. The optimal cut-off values for SUVmax parameters were selected based on tumor relapse within 1 year of surgery. Optimal cut-off values for SUVmax1 and ΔSUVmax% were 7.18 and 24.25, respectively. The combination of SUVmax1 and ΔSUVmax% showed higher specificity and sensitivity, and higher positive and negative predictive values for tumor relapse within 1 year than SUVmax1 alone. Relapse-free survival (RFS) was significantly worse in the subgroups of high SUVmax1 and high ΔSUVmax% (median 7.0 months) than in the other subgroups (p < 0.0001). The multivariate Cox analysis of RFS identified high SUVmax1 and high ΔSUVmax% as independent prognostic factors (p = 0.0060). DTP FDG PET/CT may effectively predict relapse in patients with pancreatic cancer. The combination of SUVmax1 and ΔSUVmax% identified early recurrent patient groups more precisely than SUVmax1 alone.

Abstract P1-07-08: Endoxifen predicts early recurrence in breast cancer: A Brazilian prospective study

Abstract Tamoxifen is widely used in adjuvant therapy for breast cancer patients, but up to one-third of patients recur within 15 years after surgery even with its regular use. Low plasma levels of (Z)-endoxifen, the most active tamoxifen metabolite, have been studied as a possible predictor of treatment failure. Here, we evaluated plasma (Z)-endoxifen as a predictor of response to adjuvant treatment in breast cancer patients. Methods: One hundred forty nine patients were selected from a prospective cohort of consecutive newly diagnosed breast cancer patients recruited at a national referral center for treatment of cancer in Curitiba, Southern Brazil. Inclusion criteria were breast cancer women on stage I - III, positive hormone receptor tumors, operable, undergoing or not (neo)adjuvant chemotherapy, and signed for adjuvant tamoxifen for at least five years. At diagnosis, peripheral blood samples were collected for CYP2D6 genotyping for *1 *2, *3, *4, *5, *6, *7, *8, *9, *10, *17, *29 and *41 and subsequent metabolic activity scores according to phenotypes assigned for each allele (poor metabolizer PM; intermediate, IM; extensive, EM and ultrarapid metabolizer, UM). After the tamoxifen initiation, patients were evaluated at months 3, 6, and 12 for adherence and drug interactions, and plasma (Z)-endoxifen quantification. They were followed from April 2014 to April 2019. The study's primary objective was to evaluate whether (Z)-endoxifen plasma levels predict early recurrence in patients on adjuvant tamoxifen. The secondary aim was to evaluate an association between (Z)-endoxifen levels and clinical and phenotypic CYP2D6 metabolism variables. A Cox model estimated hazard ratios (HR) comparing recurrence free survival (RFS) according to (Z)-endoxifen plasma levels. The survival was compared using the Kaplan-Meier method and the log-rank test. Results: The median follow-up period was 52.3 months and at that point, there were 20 recurrences of 149 patients. At 3 months there were no cases of low adherence to tamoxifen. The (Z)-endoxifen levels were established by quartiles, with the first lower quartile being used as a cutoff (14.72nM). High (Z)-endoxifen levels at 3 months (&amp;gt;14.72nM) were detected in 75.8% (n = 113) of cases and low levels (≤14.72nM) in 24.2% (n = 36). There was no statistically significant difference between the groups with low or high (Z)-endoxifen levels regarding clinical and pathological variables, but there was a higher CYP2D6 PM/IM frequency in the low (Z)-endoxifen levels group (p&amp;lt;0.001). High (Z)-endoxifen levels were associated with lower RFS compared to low (Z)-endoxifen levels (HR 2.5, 95% CI 1.00-6.22, p=0.041). Low (Z)-endoxifen levels increased the recurrence risk even when adjusted for staging and molecular subtypes (HR 2.55, 95% CI 1.00-6.48, p&amp;lt;0.001) or staging and CYP2D6 phenotype (UM/EM vs IM/PM; HR 4.38, 95% CI 1.66-11.59, p=0.003), or prior chemotherapy exposure (HR 2.65, 95% CI 1.06-6.61, p=0.036). Conclusion: This is the first Brazilian prospective trial evaluating the association of plasma (Z)-endoxifen levels, with the clinical outcome in breast cancer women treated with adjuvant tamoxifen, controlled by predictable confounding factors of plasma (Z)-endoxifen levels, such as tamoxifen adherence, and drug interaction with CYP2D6 inhibitors. In our study, a low plasma level of (Z)-endoxifen (≤ 14.72nM) after 3 months of tamoxifen treatment was a predictor of early recurrence in patients under adjuvant tamoxifen (p=0.041). A longer follow-up and a larger cohort may be needed to confirm the (Z)-endoxifen cutoff value that is a predictor of long-term recurrence. Citation Format: Thais Almeida, Werner Schroth, Jeanine Marie Nardin, Thomas Mürdter, Solane Picolotto, Reiner Hoppe, Jenifer Primon Kogin, Elisa Daniele Gaio, Angela Dasenbrock, Raquel Cristina Skrsypcsak, Lucia Noronha, Hiltrud Brauch, José Claudio Casali-da-Rocha. Endoxifen predicts early recurrence in breast cancer: A Brazilian prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-08.

SUVmax to tumor perimeter distance: a robust radiomics prognostic biomarker in resectable non-small cell lung cancer patients.

The purpose of this study was to evaluate the prognostic value of novel geometric variables obtained from pre-treatment [18F]FDG PET/CT with respect to classical ones in patients with non-small cell lung cancer (NSCLC). Retrospective study including stage I-III NSCLC patients with baseline [18F]FDG PET/CT. Clinical, histopathologic, and metabolic parameters were obtained. After tumor segmentation, SUV and volume-based variables, global texture, sphericity, and two novel parameters, normalized SUVpeak to centroid distance (nSCD) and normalized SUVmax to perimeter distance (nSPD), were obtained. Early recurrence (ER) and short-term mortality (STM) were used as end points. Univariate logistic regression and multivariate logistic regression with respect to ER and STM were performed. A cohort of 173 patients was selected. ER was detected in 49/104 of patients with recurrent disease. Additionally, 100 patients died and 53 had STM. Age, pathologic lymphovascular invasion, lymph nodal infiltration, TNM stage, nSCD, and nSPD were associated with ER, although only age (aOR = 1.06, p = 0.002), pathologic lymphovascular invasion (aOR = 3.40, p = 0.022), and nSPD (aOR = 0.02, p = 0.018) were significant independent predictors of ER in multivariate analysis. Age, lymph nodal infiltration, TNM stage, nSCD, and nSPD were predictors of STM. Age (aOR = 1.05, p = 0.006), lymph nodal infiltration (aOR = 2.72, p = 0.005), and nSPD (aOR = 0.03, p = 0.022) were significantly associated with STM in multivariate analysis. Coefficient of variation (COV) and SUVmean/SUVmax ratio did not show significant predictive value with respect to ER or STM. The geometric variables, nSCD and nSPD, are robust biomarkers of the poorest outcome prediction of patients with NSCLC with respect to classical PET variables. • In NSCLC patients, it is crucial to find prognostic parameters sinceTNM system alone cannot explain the variation in lung cancer survival. • Age, lymphovascular invasion, lymph nodal infiltration, and metabolic geometrical parameters were useful as prognostic parameters. • The displacement grade of the highest point of metabolic activity towards the periphery assessed by geometric variables obtained from [18F]FDGPET/CT was a robust biomarker of the poorest outcome prediction of patients with NSCLC.

Maximum standardized uptake value change rate before and after neoadjuvant chemotherapy can predict early recurrence in patients with locally advanced esophageal cancer: a multi-institutional cohort study of 220 patients in Japan.

Neoadjuvant chemotherapy (NAC) followed by esophagectomy can improve the prognosis of locally advanced esophageal cancer (LAEC). However, LAEC reportedly recurred in 17-21% of patients within 6 months post surgery. Thus, current treatment strategies may be inadequate for LAECs with poor prognosis. Preoperative identification of patients with poor prognosis might aid in modification of treatment strategies. This study aimed to evaluate the usefulness of the maximum standardized uptake value change rate (ΔSUVmax) in predicting treatment effects on the primary lesion, prognosis, and LAEC recurrence. This study involved 220 esophageal cancer patients who underwent esophagectomy after NAC at three facilities in Japan. The optimal cut-off point for ΔSUVmax in predicting tumor regression grade (TRG) was calculated and used to assess the correlation between ΔSUVmax and postoperative survival. The optimal cut-off point for ΔSUVmax was 0.5. The 5-year overall survival rate in patients with ΔSUVmax ≥ 0.5 was significantly higher than that in patients with ΔSUVmax < 0.5 (71.5% vs. 50.5%, P = 0.001). Multivariate analysis identified ΔSUVmax (hazards ratio, 0.496; P = 0.004) as an independent prognostic factor. Among 199 patients evaluated for recurrence, 24 (12.1%) showed recurrence within 6 months post surgery. Univariate analysis revealed ΔSUVmax as the only predictor for early recurrence (odds ratio, 0.222; P = 0.004). ΔSUVmax before and after NAC is clinically useful as it could help predict TRG, survival outcome, and early recurrence within 6 months post esophagectomy and is easily obtainable in general clinical practice. We believe that it may also help determine suitable treatment strategies for LAEC.