Independent Prognostic Factor For Survival Research Articles

Primary tumour category, site of metastasis, and baseline serum S100B and LDH are independent prognostic factors for survival in metastatic melanoma patients treated with anti-PD-1.

Prognostic classification of metastatic melanoma patients treated with anti-PD-1 is of great interest to clinicians. We aimed to determine the anti-PD-1 treatment related prognostic performance of demographics, clinical and histological prognostic markers and baseline serum S100B and LDH levels in advanced melanoma. A total of 200 patients with unresectable metastatic melanoma were included in this retrospective study. 34.5% had stage M1c disease and 11.5% had stage M1d disease at the start of therapy. 30% had pT4b primary melanoma. 55.5% had elevated baseline serum S100B levels and 62.5% had elevated baseline serum LDH levels. We analysed the risk of death using univariate and multivariate Cox proportional-hazards models and the median overall (OS) and progression-free (PFS) survival using the Kaplan-Meier estimator. The median follow-up time from the start of anti-PD-1 treatment in patients who were alive at the end of the study (N=81) was 37 months (range: 6.1-95.9). The multivariate Cox regression analysis showed that M1c stage (vs. M1a, p=0.005) or M1d stage at the start of therapy (vs. M1a, p=0.001), pT4b category (vs. pT1a, p=0.036), elevated baseline serum S100B levels (vs. normal S100B, p=0.008) and elevated LDH levels (vs. normal LDH, p=0.049) were independently associated with poor survival. The combination of M1d stage, elevated baseline serum S100B and LDH levels and pT4b category was associated with a very high risk of death (HR 4.72 [1.81; 12.33]). In the subgroup of patients with pT4b primary melanoma, the median OS of patients with normal serum S100B levels was 37.25 months [95% CI 11.04; 63.46]), while the median OS of patients with elevated serum S100B levels was 8.00 months [95% CI 3.49; 12.51]) (p<0.001); the median OS of patients with normal serum LDH levels was 41.82 months [95% CI 11.33; 72.32]), while the median OS of patients with elevated serum LDH levels was 12.29 months [95% CI 4.35; 20.23]) (p=0.002). Our real-world study indicates that the prognostic role of primary melanoma parameters is preserved in anti-PD-1 treated stage IV patients. Furthermore, there seems to be perspective in combining clinical, histological and serum prognostic markers in a prognostic model.

AI-based quantification of whole-body tumour burden on somatostatin receptor PET/CT

BackgroundSegmenting the whole-body somatostatin receptor-expressing tumour volume (SRETVwb) on positron emission tomography/computed tomography (PET/CT) images is highly time-consuming but has shown value as an independent prognostic factor for survival. An automatic method to measure SRETVwb could improve disease status assessment and provide a tool for prognostication. This study aimed to develop an artificial intelligence (AI)-based method to detect and quantify SRETVwb and total lesion somatostatin receptor expression (TLSREwb) from [68Ga]Ga-DOTA-TOC/TATE PET/CT images.MethodsA UNet3D convolutional neural network (CNN) was used to train an AI model with [68Ga]Ga-DOTA-TOC/TATE PET/CT images, where all tumours were manually segmented with a semi-automatic method. The training set consisted of 148 patients, of which 108 had PET-positive tumours. The test group consisted of 30 patients, of which 25 had PET-positive tumours. Two physicians segmented tumours in the test group for comparison with the AI model.ResultsThere were good correlations between the segmented SRETVwb and TLSREwb by the AI model and the physicians, with Spearman rank correlation coefficients of r = 0.78 and r = 0.73, respectively, for SRETVwb and r = 0.83 and r = 0.81, respectively, for TLSREwb. The sensitivity on a lesion detection level was 80% and 79%, and the positive predictive value was 83% and 84% when comparing the AI model with the two physicians.ConclusionIt was possible to develop an AI model to segment SRETVwb and TLSREwb with high performance. A fully automated method makes quantification of tumour burden achievable and has the potential to be more widely used when assessing PET/CT images.

KIF20A is a Prognostic Marker for Female Patients with Estrogen Receptor-Positive Breast Cancer and Receiving Tamoxifen as Adjuvant Endocrine Therapy.

Our aim was to verify whether KIF20A has the potential to serve as a prognostic marker for female patients with estrogen receptor (ER)-positive breast cancer (BC) and treated with tamoxifen (TAM). Online tools were used to investigate the potential correlation between KIF20A gene expression and survival of patients with ER-positive BC and TAM treatment. Furthermore, immunohistochemistry (IHC) was conducted to assess the expression levels of KIF20A in patients included from our center. The prognostic value of KIF20A for disease-free survival (DFS) and overall survival (OS) was further evaluated using Cox regression analysis. According to the results obtained from online tools, it was found that patients with low KIF20A expression exhibited significantly better survival outcomes in terms of relapse-free survival (RFS), distant metastasis-free survival (DMFS), and OS compared to those with high KIF20A expression (P < 0.001, P < 0.001, and P = 0.008, respectively). Additionally, significantly lower gene expression of KIF20A was found in patients who responded to TAM than in those who did not respond to TAM (P < 0.001). We further included 203 patients with adjuvant TAM therapy, and IHC for KIF20A was performed on sections from paraffin-embedded blocks. Patients with low KIF20A expression had significantly better DFS and OS (P = 0.001 and 0.002, respectively, log rank test), and the expression of KIF20A was identified as an independent factor for predicting both DFS and OS (P = 0.001 and 0.008, respectively). KIF20A expression is an independent prognostic factor for survival in patients with ER-positive BC who received adjuvant TAM therapy. In clinical practice, IHC evaluation of KIF20A expression in surgical samples before administering tamoxifen may assist in predicting the treatment outcomes of these patients.

Nodal response to primary systemic therapy predicts prognosis of cN3c breast cancer patients receiving multimodality therapy.

To investigate the survival outcomes, patterns and risks of recurrence in cN3c breast cancer patients after multimodality therapy, as well as the predictors of candidates for ipsilateral supraclavicular (SCV) area boosting. Consecutive cN3c breast cancer patients from January 2009 to December 2020 were retrospectively reviewed. Based on nodal response to primary systemic therapy (PST), patients were categorized into three groups: clinical complete response (cCR) not achieved in SCV lymph nodal (SCLN, Group A), SCLN cCR but axillary node (ALN) did not achieve pathological complete response (pCR, Group B), cCR in SCLN and pCR in ALN (Group C). The median follow-up time was 32.7 months. The 5-year overall survival (OS) and recurrence-free survival (RFS) were 64.6% and 43.7% respectively. Multivariate analysis showed cumulative SCV dose and ypT stage, ALN response and SCV response to PST were significantly associated with OS and RFS respectively. Compared with Group A or B, Group C showed significantly improved 3y-RFS (53.8% vs 73.6% vs 100%, p=0.003), and the lowest rate of DM as first failure (37.9% vs 23.5% vs 0%, p=0.010). In Group A, the 3y-OS for patients receiving the cumulative SCV dose of ≥60Gy versus <60Gy was 78.0% versus 57.3% (p=0.029). Nodal response to PST is an independent prognostic factor for survival and pattern of failure. A cumulative SCV dose of ≥60Gy is positively associated with improved OS, especially in Group A. Our data supports the perspective of optimizing radiotherapeutic strategy based on nodal response.

Primary microcephaly gene CENPE is a novel biomarker and potential therapeutic target for non-WNT/non-SHH medulloblastoma.

Non-WNT/non-SHH medulloblastoma (MB) is one of the subtypes with the highest genetic heterogeneity in MB, and its current treatment strategies have unsatisfactory results and significant side effects. As a member of the centromere protein (CENP) family, centromeric protein E (CENPE) is a microtubule plus-end-directed kinetochore protein. Heterozygous mutations in CENPE can leads to primary microcephaly syndrome. It has been reported that CENPE is upregulated in MB, but its role in MB development is still unknown. We downloaded the relevant RNA seq data and matched clinical information from the GEO database. Bioinformatics analysis includes differential gene expression analysis, Kaplan-Meier survival analysis, nomogram analysis, ROC curve analysis, immune cell infiltration analysis, and gene function enrichment analysis. Moreover, the effects of CENPE expression on cell proliferation, cell cycle, and p53 signaling pathway of non-WNT/non-SHH MB were validated using CENPE specific siRNA in vitro experiments. Compared with normal tissues, CENPE was highly expressed in MB tissues and served as an independent prognostic factor for survival in non-WNT/non-SHH MB patients. The nomogram analysis and ROC curve further confirmed these findings. At the same time, immune cell infiltration analysis showed that CENPE may participate in the immune response and tumor microenvironment (TME) of non-WNT/non-SHH MB. In addition, gene enrichment analysis showed that CENPE was closely related to the cell cycle and p53 pathway in non-WNT/non-SHH MB. In vitro experimental validation showed that knockdown of CENPE inhibited cell proliferation by activating the p53 signaling pathway and blocking the cell cycle. The expression of CENPE in non-WNT/non-SHH MB was positively correlated with poor prognosis. CENPE may affect tumor progression by regulating cell cycle, p53 pathway, and immune infiltration. Hence, CENPE is highly likely a novel biomarker and potential therapeutic target for non-WNT/non-SHH MB.

Brain metastasis resection: the impact of fluorescence guidance (MetResect study).

Maximal resection of brain metastases (BMs) improves both progression-free survival and overall survival (OS). Fluorescein sodium (FL) in combination with the YELLOW 560-nm filter is a safe and feasible method for visualizing residual tumor tissue during BM resection. The authors of this study aimed to show that use of FL would positively influence the volumetric extent of resection (EOR) and thus the survival outcome in patients undergoing BM resection. Analyzing their institution's prospective brain tumor registry, the authors identified 539 consecutive patients with BMs (247 women, mean age 62.8 years) by using preoperative high-quality MR images for volumetric analysis. BMs were resected under white light (WL) in 293 patients (54.4%; WL group) and under FL guidance in 246 patients (45.6%; FL group). Sex, age, presurgical Karnofsky Performance Status (KPS), recursive partitioning analysis class, and adjuvant treatment modalities were well balanced between the two groups. Volumetric analysis was performed in a blinded fashion by quantifying pre- and postoperative tumor volume based on gadolinium-enhanced T1-weighted sequences. In the FL group, the postoperative tumor volume was significantly smaller (p = 0.01), and hence the quantitative EOR was significantly larger (p = 0.024) and OS was significantly longer (p = 0.0001) (log-rank testing). Multivariate Cox regression modeling showed that age, presurgical KPS, metastasis status, and FL-guided resection are independent prognostic factors for survival. Compared with WL resection, FL-guided BM resection increased resection quality, significantly improved EOR, and prolonged OS.

Effects of iodine-125 seed brachytherapy on patients with heterochronous pulmonary metastasis from hepatocellular carcinoma: A propensity score matching study.

To investigate the effects of iodine-125 seed brachytherapy (ISB) on the overall survival (OS) of patients with heterochronous pulmonary metastasis (HPM) secondary to hepatocellular carcinoma (HCC). The clinical and imaging data of 123 patients with HPM secondary to HCC treated at a single center from July 2012 to July 2020 were analyzed retrospectively. The patients were divided into ISB and non-ISB groups based on ISB treatment. Propensity score matching yielded 46 pairs of patients. A total of 191 lesions were treated, and the data were evaluated for 6 months after ISB. The OS rates of the two groups were compared using the Kaplan-Meier method. Independent prognostic factors were determined using a Cox proportional hazards regression model. The percentages of lung lesions in complete remission, partial remission, disease stable, and disease progression stages were 49.2%, 32.8%, 9.6%, and 8.4%, respectively. The disease control rate was 91.6%. The median follow-up time from the initial diagnosis was 47 months and 33 months for the ISB and non-ISB groups, respectively. Patients in the ISB group had a longer OS than those in the non-ISB group (1-year: 95.7% vs. 80.3%; 3-year: 62.9% vs. 45.7%; 5-year: 37% vs. 20.9%; P < 0.05). Multivariate analysis demonstrated that ISB treatment, tumor differentiation, vascular invasion, and Child - Pugh score were independent prognostic factors for survival. ISB improves local control and OS rates of HPM secondary to HCC; thus, it is an effective and feasible option for patients with HPM secondary to HCC.

Persistent high levels of carcinoembryonic antigen after tumor resection are associated with poorer survival outcomes in patients with resected colon cancer

BackgroundInterindividual survival and recurrence rates in cases of locoregional colon cancer following surgical resection are highly variable. The aim of the present study was to determine whether elevated pre-operative and post-operative CEA values are useful prognostic biomarkers for patients with stage I-III colon cancer who underwent surgery with curative intent.MethodsWe conducted a retrospective study in patients with histologically confirmed stage I-III primary colonic adenocarcinoma who underwent radical surgical resection at Mexico’s National Cancer Institute, between January 2008 and January 2020. We determined pre-operative and post-operative CEA and analyzed the association of scores with poorer survival outcomes in patients with resected colon cancer, considering overall survival (OS) and disease-free survival (DFS).ResultsWe included 640 patients with stage I-III colon cancer. Pre-operative CEA levels were in the normal range in 460 patients (group A) and above the reference value in the other 180. Of the latter, 134 presented normalized CEA levels after surgery, but 46 (group C) continued to show CEA levels above the reference values after surgery. Therefore, propensity score matching (PSM) was carried out to reduce the bias. Patients were adjusted at a 1:1:1 ratio with 46 in each group, to match the number in the smallest group. Median follow- up was 46.4 months (range, 4.9–147.4 months). Median DFS was significantly shorter in Group C: 55.5 months (95% CI 39.6–71.3) than in the other two groups [Group A: 77.1 months (95% CI 72.6–81.6). Group B: 75.7 months (95% CI 66.8–84.5) (p-value < 0.001)]. Overall survival was also significantly worse in group C [57.1 (95% CI 37.8–76.3) months] than in group A [82.8 (95% CI 78.6–86.9 months] and group B [87.1 (95% CI 79.6–94.5 months] (p-value = 0.002). To identify whether change in CEA levels operative and post-surgery was an independent prognostic factor for survival outcomes, a Cox proportional hazard model was applied. In multivariate analysis, change in CEA level was a statistically significant, independent prognostic factor for overall survival (p-value = 0.031).ConclusionsWhen assessed collectively, pre-operative and post-operative CEA values are useful biomarkers for predicting survival outcomes in patients with resected colon cancer. Prognoses are worse for patients with elevated pre-operative and post-surgical CEA values, but similar in patients with normal post-surgical values, regardless of their pre-surgery values.

Survival of small-cell lung cancer patients after surgery: a single-center retrospective cohort study.

This study summarized and analyzed the clinical characteristics and prognosis of small-cell lung cancer (SCLC) patients after surgical treatment. The clinical data of 130 patients (99 males and 31 females) with SCLC treated by surgery and confirmed by postoperative pathological examination at Peking Union Medical College Hospital from April 2004 to April 2019 were retrospectively analyzed. Clinical characteristics, surgery, pathological stage, and perioperative treatment were summarized. Kaplan-Meier survival curve and Cox regression analysis were performed. Pathological examination revealed that 36 (27.69%) patients had stage I SCLC, 22 (16.92%) patients had stage II SCLC, 65 (50.00%) patients had stage III SCLC, and 7 (5.39%) patients had stage IV SCLC. The overall median survival time was 50 months (95% confidence interval, 10.8-89.2 months). The median survival time of stage I, II, III and IV SCLC patients was 148, 42, 32, and 10 months, respectively. In patients who underwent surgical treatment, postoperative adjuvant therapy and tumor stage were independent prognostic factors for survival (p < 0.05).Lobectomy and lymph nodes resection combined with adjuvant therapy were cautiously recommended for stage I-IIIa SCLC patients.

Arterial Blood Gas Analysis for Survival Prediction in Pediatric Patients with Out-of-Hospital Cardiac Arrest.

Arterial blood gas analysis (ABGA) is one of the few tests performed during cardiopulmonary resuscitation (CPR). There have been some studies on the prediction of survival outcomes in adult out-of-hospital cardiac arrest (OHCA) patients during CPR using ABGA results. However, in pediatric OHCA patients, the prognosis of survival outcome based on ABGA results during CPR remains unclear. We retrospectively analyzed prospectively collected data from the Korean Cardiac Arrest Resuscitation Consortium (KoCARC) registry, a multicenter OHCA registry of Republic of Korea. We analyzed 108 pediatric (age < 19 years) OHCA patients between October 2015 and June 2022. Using multivariable logistic regression, an adjusted odds ratio (aOR) was obtained to validate the ABGA results of survival to hospital admission and survival to discharge. The variables associated with survival to hospital admission were non-comorbidities (aOR 3.03, 95% confidence interval (CI) 1.22-7.53, p = 0.017) and PaO2 > 45.750 mmHg (aOR 2.69, 95% CI 1.13-6.42, p = 0.026). There was no variable that was statistically significant association with survival to discharge. PaO2 > 47.750 mmHg and non-comorbidities may serve as an independent prognostic factor for survival to hospital admission in pediatric OHCA patients. However, the number of cases analyzed in our study was relatively small, and there have been few studies investigating the association between ABGA results during CPR and the survival outcome of pediatric OHCA patients. Therefore, further large-scale studies are needed.

A risk score model based on endoplasmic reticulum stress related genes for predicting prognostic value of osteosarcoma

BackgroundWe aimed to establish an osteosarcoma prognosis prediction model based on a signature of endoplasmic reticulum stress-related genes.MethodsDifferentially expressed genes (DEGs) between osteosarcoma with and without metastasis from The Cancer Genome Atlas (TCGA) database were mapped to ERS genes retrieved from Gene Set Enrichment Analysis to select endoplasmic reticulum stress-related DEGs. Subsequently, we constructed a risk score model based on survival-related endoplasmic reticulum stress DEGs and a nomogram of independent survival prognostic factors. Based on the median risk score, we stratified the samples into high- and low-risk groups. The ability of the model was assessed by Kaplan–Meier, receiver operating characteristic curve, and functional analyses. Additionally, the expression of the identified prognostic endoplasmic reticulum stress-related DEGs was verified using real-time quantitative PCR (RT-qPCR).ResultsIn total, 41 endoplasmic reticulum stress-related DEGs were identified in patients with osteosarcoma with metastasis. A risk score model consisting of six prognostic endoplasmic reticulum stress-related DEGs (ATP2A3, ERMP1, FBXO6, ITPR1, NFE2L2, and USP13) was established, and the Kaplan–Meier and receiver operating characteristic curves validated their performance in the training and validation datasets. Age, tumor metastasis, and the risk score model were demonstrated to be independent prognostic clinical factors for osteosarcoma and were used to establish a nomogram survival model. The nomogram model showed similar performance of one, three, and five year-survival rate to the actual survival rates. Nine immune cell types in the high-risk group were found to be significantly different from those in the low-risk group. These survival-related genes were significantly enriched in nine Kyoto Encyclopedia of Genes and Genomes pathways, including cell adhesion molecule cascades, and chemokine signaling pathways. Further, RT-qPCR results demonstrated that the consistency rate of bioinformatics analysis was approximately 83.33%, suggesting the relatively high reliability of the bioinformatics analysis.ConclusionWe established an osteosarcoma prediction model based on six prognostic endoplasmic reticulum stress-related DEGs that could be helpful in directing personalized treatment.

Prognostic value of Lynch syndrome, BRAFV600E , and RAS mutational status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts.

Current knowledge on prognostic biomarkers (especially BRAFV600E /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors. This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017). All mCRC patients with a histologically proven dMMR tumor were included. In our real-world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line palliative systemic chemotherapy. Mean age of first-line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAFV600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66-1.72), BRAFV600E mutational status (HR: 1.02, 95% CI: 0.67-1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64-1.59), with similar results for PFS. BRAFV600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision-making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.

LAG3 in gastric cancer: it’s complicated

PurposeLymphocyte activation gene 3 (LAG3) is thought to contribute to T cell exhaustion within the tumor microenvironment of solid tumors. This study aimed to analyze the spatial distribution of LAG3 + cells in relation to clinicopathological and survival data in a large set of 580 primary resected and neoadjuvantly treated gastric cancers (GC).MethodsLAG3 expression was evaluated in tumor center and invasive margin using immunohistochemistry and whole-slide digital image analysis. Cases were divided into LAG3-low and LAG3-high expression groups based on (1) median LAG3 + cell density, (2) cut-off values adapted to cancer-specific survival using Cutoff Finder application.ResultsSignificant differences in spatial distribution of LAG3 + cells were observed in primarily resected GC, but not in neoadjuvantly treated GC. LAG3 + cell density showed evident prognostic value at following cut-offs: in primarily resected GC, 21.45 cells/mm2 in tumor center (17.9 vs. 10.1 months, p = 0.008) and 208.50 cells/mm2 in invasive margin (33.8 vs. 14.7 months, p = 0.006); and in neoadjuvantly treated GC, 12.62 cells/mm2 (27.3 vs. 13.2 months, p = 0.003) and 123.00 cells/mm2 (28.0 vs. 22.4 months, p = 0.136), respectively. Significant associations were found between LAG3 + cell distribution patterns and various clinicopathological factors in both cohorts. In neoadjuvantly treated GC, LAG3 + immune cell density was found to be an independent prognostic factor of survival (HR = 0.312, 95% CI 0.162–0.599, p < 0.001).ConclusionIn this study, a higher density of LAG3 + cells was associated with favorable prognosis. Current results support the need for extended analysis of LAG3. Differences in the distribution of LAG3 + cells should be considered, as they could influence clinical outcomes and treatment responses.Graphical abstract

Outcomes and Prognostic Factors of Extensive Stage Small Cell Lung Cancer: A Retrospective Study

Introduction Small cell lung cancer (SCLC) represents about 15% of all lung cancers. Extensive stage (ES) SCLC represents around 60% of diagnosed SCLC cancers. The median survival in untreated ES SCLC is 2 to 4 months and that of treated cases is 8 to 13 months. Aim and Objectives This retrospective analysis aims to find out the clinical outcome of patients with ES SCLC and the prognostic factors affecting their survival. Methods Details of patients registered in the department of radiation oncology from January 1, 2010 to September 30, 2019 were retrieved from the hospital records. This includes the demographic characteristics, treatment received, toxicity, and follow-up details. Results Two-hundred eighty-three patients were included. Median age of presentation was 62 years. Around 97.5% of patients were men. Smokers constitute 94% of all cases. About 86.9% (246 patients) of cases were not alive at the end of the study period. The median estimated overall survival (OS) was 7 months ± 0.47 (95% confidence interval [CI]: 6.026–7.974) and progression-free survival (PFS) was 5 months ± 0.535 (95% CI: 3.952–6.048). Multivariate analysis showed that Eastern Cooperative Oncology Group performance status (ECOG PS), hyponatremia, number of chemotherapy cycles, consolidative radiotherapy (RT) and prophylactic cranial irradiation (PCI) were found to have prognostic effect on OS. Smoking, ECOG PS, number of chemotherapy cycles, consolidative RT, and PCI were found to have prognostic effects on PFS. Conclusion There is a difference in OS and PFS patterns of ES SCLC patients among various Indian studies even though the available data is scarce. Our study shows that the OS and PFS of our study population are comparable to other South Indian studies available. PS, serum sodium level, number of chemotherapy cycles, consolidative RT, and PCI were found to be independent prognostic factors for survival of ES SCLC. The identification of these factors will help physicians to tailor treatment.

Simultaneous and Sequential Use of Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Real-World Practice in China.

Molecular targeted agents (MTAs) plus immune checkpoint inhibitors (ICIs) treatment for advanced hepatocellular carcinoma (HCC) has shown an exciting prospect. This study aimed to report the efficacy of the Simultaneous and Sequential use of them in a real-world practice. From April 2019 to December 2020, patients with advanced HCC in three Chinese medical centers receiving MTAs and ICIs as their initial systemic therapy were enrolled. Participants were classified into the Simultaneous group (treated with them simultaneously) and the Sequential group (treated with MTAs initially and added ICIs after tumor progression). Toxicity, tumor response, survival outcomes and prognostic factors were investigated. One hundred and ten consecutive patients participated in the study (64 in the Simultaneous group and 46 in the Sequential group). A total of 93 (84.5%) patients experienced treatment-related adverse events (AEs), of which 55 (85.9%) in the Simultaneous group and 38 (82.6%) in the Sequential group (P=0.19). Grade 3/4 AEs were observed in 9 (8.2%) patients. Patients in the Simultaneous group achieved a higher objective response rate than those in the Sequential group (25.0% vs 4.3%, p=0.04). The median overall survival (OS) of the entire cohort was 14.8 [95% confidence interval (CI): 4.6-25.5] months and the OS rates at 6 and 12 months were 80.6% and 60.9%, respectively. Patients in the Simultaneous group achieved better survival outcomes than those in the Sequential group, but without statistically significant differences. Child-Pugh 6 scores (HR: 2.97, 95% CI: 1.33-6.61, P=0.008), tumor number ≤3 (HR: 0.18, 95% CI: 0.04-0.78, P=0.022), extrahepatic metastasis (HR: 3.05, 95% CI: 1.35-6.87, P=0.007) were independent prognostic factors for survival. The combined treatment of MTAs and ICIs shows good tumor response and survival outcomes with acceptable toxicity for advanced HCC in the real-world practice, in particular when they are applied simultaneously.

Observational prospective study of physical activity in patients with cancer to define an objective performance status (OPS).

1506 Background: Clinical trials in patients with advanced cancer rely on a good selection of candidates based on their functional status. The Eastern Cooperative Oncology Group (ECOG) Performance Status is the most frequently used in adult patients and is based on the subjective impression of the clinician during the interview with the patient. The current use of wearable devices will allow clinicians to assess the functional status of candidates for a clinical trial in a more objective way. We aim to define an “Objective Performance Status” (OPS) by measuring the daily physical activity of patients with metastatic cancer and correlating it with the classical prognostic variables. Methods: We prospectively measured daily physical activity with a wearable device in 111 patients with metastatic cancer during the screening period for a phase 1 clinical trial to avoid treatment interference with the functional status. Daily steps/distance and sleeping hours were measured and correlated with overall survival (OS) to define the OPS. Results: Full data was available for 70 patients. Median survival was gradually shorter as physical activity decreases (HR 5.76 (95% CI 2.98-11.1) P &lt; 0001). The cut off selected to define the OPS was determined by univariate survival analysis and showed that patients who walk less than 1200 meters per day have 5 times the risk of mortality (poor OPS). Median OS was 3.2 months (95% CI 2.5-5.8) P &lt; 0001) for patients with poor OPS and 11.2 months for patients with good OPS (95% CI 7.2-31.3 P &lt; 0001). Conclusions: The objective assessment of performance status (OPS) using a wearable device to monitor the physical activity in patients with cancer is an independent prognostic factor for survival and is an objective predictor of mortality.[Table: see text]

Prognostic significance of estrogen receptor status in de novo metastatic breast cancer.

e13049 Background: The clinical behaviors of de novo metastatic breast cancer (dnMBC) differ according to hormone receptor (HR) status, but an association between estrogen receptor (ER) expression and clinical outcomes has not been established. Our study aimed to investigate the influence of different ER status on survival outcomes for patients with dnMBC. This study was the Medical Science Research Project of Hebei Province and approved by the Ethics Committee of the Ethics Committee of Cangzhou Clinical College of Integrated Traditional Chinese and Western Medicine of Hebei Medical University (NO. 2017-AF29-058). Methods: Using hospital-based database, we identified patients with dnMBC diagnosed between 2010 and 2017, retrospectively collecting demographic data, tumor characteristics, treatment types and survival data. According to ER status, the patients were divided into ER-negative and ER-positive groups, and the propensity score matching (PSM) was used to balance the mixed bias. Overall survival (OS) was estimated by Kaplan-Meier method and log rank test. Univariable and multivariable analyses were performed using the Cox proportional hazard model to identify statistically significant prognostic factors. Results: A total of 322 patients were included. The median age was 53 (21-82) years, and the median follow-up was 8.5 years. The median OS for the PSM cohort was 29 months (95% confidence interval [CI], 26-35 months), and 5-year OS was 18.9%. OS differed significantly between the two groups (p = 0.0012), with a median OS of 36 months (95% CI, 32-41 months) in ER-positive group and 24 months (95% CI, 19-27 months) in ER-negative group. Multivariate analysis showed that clinical T-stage and initial metastatic sites were independent prognostic factors for survival in patients focused on ER status, with Ki-67 index, endocrine therapy and radiotherapy added to the ER-positive group, while initial and advanced chemotherapy added to the ER-negative group. Conclusions: For patients with dnMBC, there were substantial differences in OS according to ER status. ER-negative subtype is clinically different from ER-positive subtype, showing unfavorable tumor characteristics and poorer OS. We identified several prognostic factors that could guide therapy selection in this patient population. Clinical trial information: 20210957 .

MINIMAL RESIDUAL DISEASE STATUS IMPROVED THE RESPONSE EVALUATION IN PATIENTS WITH WALDENSTRöM’S MACROGLOBULINEMIA

Minimal residual disease (MRD) has been recognized as an important prognostic factor for survival in hematological malignancies. However, the prognostic value of MRD in Waldenström’s macroglobulinemia (WM) remains largely unexplored. We analyzed 108 newly diagnosed WM patients receiving systematic therapy and assessed MRD by multiparameter flow cytometry (MFC) in the bone marrow. At best response, 34 patients (31.5%) achieved undetectable MRD (uMRD). Hemoglobin > 115 g/L (p = 0.03), serum albumin >35 g/L (p = 0.01), β2-MG ≤ 3 mg/L (p = 0.03), and low-risk International Prognostic Scoring System for WM (IPSSWM) stage (p < 0.01) were associated with a higher rate of uMRD. Improvements in IgM (p < 0.01) and hemoglobin (p = 0.03) were more evident in uMRD patients compared with MRD-positive patients. The 3-year progression-free survival (PFS) was better for uMRD patients compared with those MRD-positive patients (96.2% vs. 52.8%; p = 0.0012). Landmark analysis also showed that uMRD patients had a better PFS than MRD-positive patients after 6 and 12 months. Patients who achieved partial response (PR) and uMRD had a 3-year PFS of 100%, which was significantly higher than that patients with MRD-positive PR (62.6%, p = 0.029). Multivariate analysis showed that MRD positivity was an independent factor for PFS (HR 2.55, p = 0.03). Moreover, the combination of the 6th International Workshop on WM assessment (IWWM-6 Criteria) and MRD had a higher 3-year AUC compared with the IWWM-6 criteria only (0.71 vs. 0.67). MRD based on MFC was an independent prognostic factor for survival in WM, which could improve the precision of response evaluation, especially for patients who had obtained PR. Keywords: diagnostic and prognostic biomarkers, indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

RAF-inhibitor rechallenge therapy in BRAF aberrated pan-cancers: RE-RAFFLE study.

3105 Background: Prior studies have demonstrated clinical benefit with rechallenging the RAF pathway in melanoma with prior exposure to BRAF inhibitors. Purpose of this study was to explore antitumor activity and outcomes of BRAF aberrated solid tumors retreated with RAF inhibitors (RAFi). Methods: Between January 2010 and November 2022, 44 pts with BRAF alterations [ V600E (42); V600K (1); K601Q (1)] who received RAFi as monotherapy or in combination were rechallenged with a second RAFi with or without other therapies at a single tertiary cancer center. All received therapy as part of standard of care or investigational (INV) regimens. Primary objectives: objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) on rechallenge. Results: Median age: 54.5 (25-76) with predominantly Caucasian pts (36; 82%) and males (26; 59%). Tumor types: melanoma (16; 36%), colon (10; 23%), thyroid (4; 9%); brain (4; 9%) and others (10; 23%). Median treatment duration was 7 months (m) for first RAFi (RAF1i) and 2.8m with second RAFi (RAF2i) while median time to RAF2i was 3.3m. Best ORR to rechallenge with RAF2i was partial response (PR) (8; 18.1%), stable disease (SD) (16; 36%) and progressive disease (PD) (20; 45.4%) with 5 PR + 6 SD &gt;6m. PRs were seen in thyroid (1 anaplastic; 2 papillary), 1 ovarian, 2 melanoma, 1 cholangiocarcinoma and 1 anaplastic astrocytoma with median duration of response for 2.5m. Of the 36 pts who discontinued RAF1i due to PD, 14% responded (6 PR) to RAF2i. Among 16 pts who had CR or PR on RAF1i, 5 pts had PR with RAF2i. In RAF2i group, of all pts achieving PR ( n = 8), 5 pts had other intervening therapies prior to RAF2i (immunotherapy [IO]; kinase inhibitors; chemotherapy; INV) while 3 had no interim therapies and both factors did not have significant impact on survival for RAF2i ( p=0.2). 5 responders received combination with MEKi, while 1 had MEKi + IO and 2 had monotherapy. ORR did not significantly differ between combination and monotherapy group in RAF 2i ( p=0.056). At median follow up of 20m, median OS and PFS from rechallenge was 15.5m and 2.7m. 9 pts had genomic testing post RAF1i (3 tumor;7 blood) with no new acquired aberrations and persistence of BRAF V600E mutation. Independent prognostic factors for survival at rechallenge compared to RAF1i included inferior outcomes with male gender (HR: 3.05; p=0.0089), presence of metastatic sites (HR: 3.12; p=0.036), ECOG (1 vs. 0 or 2; HR: 3.50; p&lt;0.001) while rechallenge with combination RAF2i had a worse survival impact compared to RAF2i monotherapy (PFS: 11.6m vs 2.7m; HR: 3.6; p=0.00145). These findings need to be cautiously inferenced due to small sample size. Conclusions: Rechallenge with RAFi(s) resulted in a clinically meaningful benefit in &gt;50% pts on efficacy (&gt;6m in 25%) and survival outcomes. Further prospective studies are warranted to validate these findings and expand re-challenging targeted therapy options in tumor-agnostic BRAF-aberrated cancers.

Clinical implications of Cytokeratin 19 expression in patients with oral squamous cell carcinoma.

This study was done to quantify the prevalence of high cytokeratin (CK) 19 expression in Indonesian oral squamous cell carcinoma (OSCC) patients and explore the prognostic role of CK19 in OSCC. Clinical data and samples from 61 patients diagnosed with OSCC at a tertiary national referral hospital in Jakarta, Indonesia were analyzed in this retrospective cohort study. Immunohistochemical staining of CK19 was performed on all patients and its expression was scored using the H system. All patients were followed up for a minimum of 36 months after diagnosis. Comparative and survival analyses were performed. Twenty six point two percent of Indonesian OSCC patients had high CK19 expression. There were no differences in clinicopathological characteristics between patients with low and high CK19 expression. The 3-year overall survival (OS) of our cohort was 11.5%. Patients with high CK19 expression had lower 3-year OS compared to patients with low CK19 expression, even if the difference in OS was not statistically significant. Keratinization was an independent prognostic factor for survival in multivariate regression analysis. Data obtained here indicate a possible prognostic role of CK19 in OSCC. This prognostic role should be confirmed in larger series.