bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective analysis of efficacy of immune checkpoint inhibitors in BRCA-mutant non-small cell lung cancer.
Authors: Chen Shaomu , Li Si , Chen Dongsheng , Xiao Mingzhe
Published: June 2021

e21067

Background: Efficacy of BRCA1/2 inhibitor in non-small cell lung cancer (NSCLC) is under investigation in serval clinical trials. Meanwhile immune checkpoint inhibitor (ICI) has become one of the standard therapies for advanced NSCLC, while its efficacy in BRCA mutant NSCLC is not clear. This study assessed the efficacy of anti-PD-(L)1/CTLA-4 in advanced BRCA-mutant NSCLC. Methods: Data of cohort OAK, POPLAR and Rizvi et al.,2018 was downloaded. Efficacy including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were reviewed for BRCA1/2 mutant and wild-type group. The impact of mutant gene ( BRCA1, BRCA2), histological types (adenocarcinoma, squamous) and tumor mutation burden ranges (TMB, > 10 SNVs/Mb, < 10 SNVs/Mb) was analyzed if information was available. Results: A total of 809 ICI-treated advanced NSCLC patients, including 53 (6.6%) with BRCA1/2 mutation, were identified. In OAK/POPLAR cohort (atezolizumab monotherapy, 2nd line or more), TMB in BRCA1/2 mutant group was significant higher (19.2 vs. 10.24, P=0.008) than group of wild-type. The ORR of mutant group was 21.9% (Table), median PFS was 2.5 months, median OS was 9.5 months. The ORR and PFS were comparable between mutant and wild-type groups, while OS of the mutant group was significantly shorter than that in wild-type group (mOS, 9.5 months vs. 14.1 months, P= 0.02). Within mutant group, no significant difference of ORR, PFS and OS were found between mutant gene ( BRCA1 vs. BRCA2), histological type (adenocarcinoma vs. squamous) and TMB range (>10 vs. <10). In Rizvi’s cohort (anti-PD-(L)1 /CTLA-4 mono- or combination therapy, 1st line or more), TMB in mutant group was also significant higher (22.2 vs. 9.1, P=0.04) than wild-type group. ORR, PFS for mutant and wild-type groups were 25.0% vs. 20.1%, 3.2 months vs. 3.4 months, without significant difference. Within mutant group, superior PFS was found in adenocarcinoma subgroup (mPFS, 5.5 months vs. 1.2 months (squamous subgroup), P = 0.008) and BRCA2-mutant subgroup tend to have superior PFS (mPFS 5.5 months vs. 1.8 months, P=0.08) than BRCA1-mutant subgroup. Conclusions: This retrospective multicohort analysis showed a trend of worse survival in BRAC-mutant NSCLC patients after ICI treatment compared to those in wild-type group, in spite of higher TMB level. Analysis with more samples are needed to provide more precise treatment reference. [Table: see text]
MRI-based radiomics signature for the prediction of response of lung cancer brain metastases after whole-brain radiotherapy.
Authors: Xu Ruizhe , Tian Ye , Zhang Bo
Published: June 2021

e21096

MRI-based Radiomics signature for the Prediction of Response of Lung Cancer Brain Metastases After Whole-Brain Radiotherapy Background: Local response prediction for brain metastases (BMs) from lung cancer after Whole-Brain Radiotherapy (WBRT) is challenging, as existing criteria are based solely on unidimensional measurements. This study sought to determine whether radiomic features of lung cancer BMs derived from pre-treatment magnetic resonance imaging (MRI) could be used to predict local response following WBRT. Methods: A total of 88 Lung Cancer patients with BMs treated with WBRT were analyzed. After volumes of interest were drawn, 944 radiomic features including first-order, shape, Gray Level Co-occurrence Matrix (GLCM), Gray Level Dependence Matrix (GLDM), Gray Level Run Length Matrix (GLRLM), Gray Level Size Zone Matrix (GLSZM), Neighborhood Gray Tone Difference Matrix (NGTDM), and Laplacian of Gaussian (LoG) features were extracted, using the baseline pre-treatment post-contrast T1 (T1c) and T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences, respectively. Local response status was determined by contrasting the baseline and follow-up MRI according to the RANO-BM criteria. The independent samples t test or Mann-Whitney U test, and then least absolute shrinkage and selection operator (LASSO) were used for dimensionality reduction and feature selection. An adaboost classifier was trained using the selected radiomic features and evaluated using the area under the receiver operating characteristic curve (AUC) in both the training and testing sets. Other discrimination metrics, including classification accuracy, positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity, were also calculated. Results: The optimal radiomics signature was developed based on a multivariable logistic regression with 4, 5, 6 radiomic features on T1c, T2 FLAIR and T1c+T2 FLAIR, respectively. The radiomics model based on T1c features presented the AUC of (0.920 vs. 0.805, respectively) for both the training and testing sets, followed by T2 FLAIR features (0.893 vs. 0.701, respectively), and T1c+T2 FLAIR features (0.971 vs. 0.857, respectively). The classification accuracy of the radiomics model also well predicted the local response of BMs for both the the training and testing sets (T1c: 82.9% vs. 77.8%, T2 FLAIR: 82.9% vs. 77.8%, T1c+T2 FLAIR: 90.0% vs. 77.8%, respectively). Conclusions: Radiomics holds promise for predicting local tumor response following WBRT in patients with lung cancer and brain metastases. A predictive model built on radiomic features from an institutional cohort performed well on cross-validation testing. These results warrant further validation in independent datasets. Such work could prove invaluable for guiding management of individual patients and assessing outcomes of novel interventions.
KEAP1 mutations in squamous cell lung cancer.
Authors: Koleczko Sophia , Hillmer Axel , Bayarassou Abdel Hakim , Grohé Christian , Buchenroth Martin , Kaminsky Britta , Schulte Clemens , Michels Sebastian Yves Friedrich , Schaufler Diana , Kron Anna , Riedel Richard , Westphal Theresa , Weber Jan-Phillip , Fischer Rieke Nila , Merkelbach-Bruse Sabine , Nogova Lucia , Buettner Reinhard , Wolf Juergen , Scheffler Matthias
Published: June 2021

e21098

Background: KEAP1 mutations have been shown to decrease the efficacy of both chemotherapy (CTX) and immune-checkpoint inhibition (ICI) in lung adenocarcinoma. However, few is known about their impact on systemic treatment of squamous cell lung cancer (SqCC). The aim of this study was to assess the impact of KEAP1 mutations on systemic treatment outcome in SqCC. Methods: Tumor biopsies of SqCC patients were analyzed within the German Network Genomic Medicine (NGM) using a next-generation DNA sequencing (NGS) panel comprising 17 genes. In subsets, PD-L1 expression was tested with immunohistochemistry (IHC). MET amplification and FGFR1 amplification was tested with fluorescence in situ hybridization (FISH). Overall survival was estimated using Kaplan Meier statistics. For comparisons, we used log rank. A cohort with KEAP1 wild-type patients from the same panel served as control group. Results: Out of 1399 SqCC patients analyzed, 151 had a KEAP1 mutation (11%). The most common co-occurring mutations besides TP53 were PTEN, KRAS and NFE2L2. The median overall survival (OS) of stage IV KEAP1 mutated patients (n = 82) compared to stage IV control group patients (n = 82) was 7.3 vs. 11.4 months (hazard ratio (HR) 0.87 [95% confidence interval (CI) 0.62-1.23], p = 0.43). The addition of a second treatment line with ICI led to marked OS improvements in both KEAP1 mutant patient group (18.7 vs. 6.6 months, HR 0.11, [95% CI 0.04-0.25], p < 0.0001) and control group (20.3 vs. 5.0 months, HR 0.12 [95% CI 0.06-0.24], p < 0.0001). PD-L1 expression did not differ significantly in both groups. Conclusions: KEAP1 mutations occur commonly in SqCC patients and do not impact the efficacy of ICI in terms of OS. To identify prognostic markers for response to ICI further research is needed.
Efficacy and safety of afatinib in advanced non-small cell lung cancer with EGFR mutations: A real-world study based meta-analysis.
Authors: Zhang Lemeng
Published: June 2021

e21134

Background: This study aimed to explore the efficacy and safety of Afatinib in advanced EGFR mutation NSCLC patients based on real-world evidence. We also explore the effectiveness of tolerability-guided dose reduction on outcomes in the real-world setting. Methods: Eligible real-world studies from Pubmed, Emabse and Cochrane Library were included in this study. The quality assessment of the included studies was based on the guidelines of Cochrane. Then heterogeneity analysis was performed based on Cochran’s Q test and I2 statistics. Results: A total of twenty-five studies were enrolled for this meta-analysis. Meanwhile, nine studies were included in qualitative descriptive analysis. The efficacy of DCR and ORR were 87.6 % (81.5, 92.7) and 58.9 % (48.8, 68.7). The pooled medium PFS was 12.45 months (10.36, 14.54), medium TTF was 15.42 months (13.62, 17.22) and medium OS was 31.67 (26.78, 36.56) months. The efficacy of afatinib in first-line only group was superior than those in second-line. The total incidence of adverse events for diarrhea, mucositis and skin rashes were 70.4 (60.1, 79.8)%, 36.5 (29.5, 43.8)% and 71.4 (64.4, 77.9)%, respectively. Meanwhile, the serious adverse reactions (Grade ≥3) for diarrhea, mucositis and skin rashes were 9.7 (6.8, 13.1)%, 2.1 (1.0, 3.6)% and 5.8 (4.5, 7.2)%, respectively. Furthermore, the different for PFS and OS between afatinib non-full dose group ( < 40mg) and full dose group ( > 40mg) was not significant (P < 0.05). however, the ORR in full dose group was 78.5 % (66.7, 88.4), which was significantly higher in the non-full dose group 67.8 % (56.8, 77.9). Conclusions: Afatinib was a safe and effective TKI for real-world EGFR-mutated NSCLC patients, which was consistent with the results of RCT. Tolerability-guided dose adjustment might affect the efficacy of afatinib in real-world setting.
Retrospective validation of a pretreatment serum protein profile in metastatic non-small cell lung cancer patients treated with a pembrolizumab containing regime as first line of treatment.
Authors: Mellema Wouter W. , Basak Edwin A. , Roder Heinrich , Roder Joanna , Georgantas Robert W. , Smit Egbert F. , Aerts Joachim
Published: June 2021

e21135

Background: There is an unmet need for reliable biomarkers predictive of treatment outcome with immunotherapy in patients with non-small cell lung cancer (NSCLC). The aim of our study is to examine, in front-line patients, the potential utility of a proteomic signature, PIR (primary immune response), developed and validated in 2nd line patients (M. Muller Clin Cancer Res. 2020 Oct 1;26(19):5188-5197. doi: 10.1158/1078-0432.CCR-20-0538. Epub 2020 Jul 6) as a predictive biomarker of response to treatment with pembrolizumab in a first-line setting. Methods: Pretreatment serum samples were collected from stage IV NSCLC patients treated with a pembrolizumab-containing regimen in first-line at the Netherlands Cancer Institute and Erasmus Medical Center between 2016 and 2020. Data on demographics, ECOG performance status (PS), PD-L1 expression, treatment, progression free survival (PFS) and overall survival (OS) were collected. The PIR test was performed and classified in two groups: resistant vs. intermediate/sensitive (not-resistant). Results: Serum samples of 119 patients were available for analysis. Median age was 65 (36-82) years; 49% female; PS 0-1 80%. 45 samples failed QC and were excluded allowing for the analysis of 74 patients: 24 receiving pembrolizumab monotherapy, and 50 receiving a combination of chemotherapy and pembrolizumab. Overall, median PFS was 5.3 months in the resistant group vs. 9.0 months in the not-resistant group (HR 0.60 (95%CI 0.33-1.08; p = 0.09). In patients receiving pembrolizumab monotherapy, the resistant group had a trend toward shorter PFS (median PFS 3.4 months vs. 10.3 months) then the non-resistant group, (HR 0.42 (95% CI 0.15-1.21; p = 0.11))). No difference was observed in patients treated with a combination of chemotherapy and pembrolizumab (median PFS 5.8 months vs. 9.0 months, respectively; HR = 0.65 (95% CI 0.31-1.36; p = 0.25). Median OS was not reached vs 17.0 months, respectively (HR 0.90 (95% CI 0.34-2.36; p = 0.83)). We did not observe any significant association between performance score and PD-L1 expression, and the PIR test. Conclusions: These data encourage further study of PIR as a predictive biomarker for first-line treatment with pembrolizumab in NSCLC patients.
Identification of predictive biomarker for immunotherapy by associating with CD8+T cell Infiltration in lung adenocarcinoma.
Authors: Xing Puyuan , Li Teng , Wang Han , Yang Lin , Wang Guoqiang , Cai Shangli , Junling Li
Published: June 2021

e21177

Background: Tumor immune microenvironment (TIME) has been proved associated with response to immunotherapy(I/O). We hypothesized that screening potential mutation pattern which could significantly impact the tumor infiltrating lymphocytes(TILs) can help us to identify predictive biomarkers for I/O in Lung adenocarcinoma(LUAD). Methods: Multiple-dimensional data from The Cancer Genome Atlas LUAD cohort (n = 514) was used for building a mathematical model beween mutation signature and CD8+TIL score (based on MCP-counter). An independent public validation cohort (cohort 1: LUAD, n = 598) were used to assess the immunotherapeutic predictive performance of the potential mutation patterns. Results: Top 100 gene associated with CD8+TIL score were selected based on MC+ model which can provides the minimum non-convexity of the penalized loss given the level of bias. Seven TIME genes (SPTA1 coef 0.09; MET coef 0.02; HSD3B1 coef -0.00; STAT4 coef -0.01; EGFR coef -0.08; PIK3CB coef -0.08; KEAP1 coef -0.24) were generated by taking the intersection of the top 100 mutant genes and FoundationOne (F1) CDx NGS 315 genes panel and verified in cohort 1. Survival analysis showed that SPTA1mt was the only one that associated with both significantly longer PFS (median PFS 3.15 vs 2.89 months; HR 0.65; 95% CI 0.45 to 0.93; p = 0.02) and OS (median PFS 15.08 vs 7.36 months; HR 0.59; 95% CI 0.40 to 0.88; p = 0.01) for patients who received I/O compared with chemotherapy(CT) among seven TIME genes. In order to test our hypothesis fully, a pooled analysis of SPTA1mt (a core positive predictors of CD8+TILs) and KEAP1mt (a core negative predictors for CD8+TILs ) were conducted and yielded that co occurrence of SPTA1mt and KEAP1mt had a compound effects for TIME. The validation showed that co mutation with SPTA1mt was accompanied by an decrease HR for I/O vs. CT in both PFS (HR S+K vs. K only 0.59 vs 1.56) and OS (HR S+K vs. K only 0.39 vs 0.80) for KEAP1mt patients. Conclusions: Our data show that it is feasible to identify individuals or groups of individual with specific mutations to immunotherapy responses from TIME view. SPTA1mt was a core predictors for higher CD8+ TILs and can be identified as a predictive biomarker for benefit from I/O compared with CT. Prospective studies are warranted for further investigation.
Real-world data of osimertinib in the management of leptomeningeal metastases in EGFR mutant NSCLC: Light at the end of the tunnel?
Authors: Sharma Mansi , Nathany Shrinidhi , Narayan Satya , Redhu Pallavi , Jain Parveen , Batra Ullas
Published: June 2021

e21197

Background: Presence of leptomeningeal metastases (LM) in NSCLC is indicative of aggressive disease and the incidence is as high as 9%-16% in the EGFR mutant subgroup. Traditionally, these patients had a dismal outcome with WBRT and intrathecal chemotherapy. Osimertinib crosses the blood brain barrier and is efficacious in the second line setting, as seen in BLOOM trial (LM ORR of 62%) and AURA program (LM ORR 55%). Osimertinib has also demonstrated CNS efficacy in the first line (FLAURA trial). This study is a retrospective review of cases with LM treated with osimertinib, and their response outcomes. Methods: 16 patients of EGFR mutant NSCLC developed LM at some point in their disease course and were treated with osimertinib. Clinical features and response outcomes were retrieved from medical record archives. Descriptive statistics were done using SPSS v23 software. LM PFS was defined as the time between 1st dose of osimertinib and date of progression in LM. LM OS was defined as the time between the first dose of osimertinib to the date of last follow up/death. ORR was defined as the percentage of cases showing CR/PR to osimertinib. Results: Median age was 61 years (range: 33-79) with 9 males and 7 females. Del19 mutations were seen in 9 patients and L858R in 7 patients. Only one patient was given WBRT prior to TKI. 6 patients with LM at diagnosis were given 1st line osimertinib. 3 (50%) progressed in LM and 3 (50%) showed partial response. Median LM PFS and median LM OS was not reached. ORR for osimertinib in the first line was 83.3%. 10 patients developed LM later in the course of the disease and median time to onset of LM was 12.47 months. Median LM PFS for osimertinib was 7.9 months (95% CI:3.2-8.3). Median LM OS was 8.2 months (95% CI: 2.6-19.8 months). ORR for osimertinib in the later line was 60%. Conclusions: This early experience reveals superior efficacy of osimertinib in LM with an excellent LM ORR in the first line setting and concordant results with second line BLOOM Study. Despite the small numbers in this study, this report becomes clinically relevant owing to the rarity of LM occurrence and paucity of available data. Efficacy of osimertinib in EGFR treatment-naive patients with LM requires further investigation and a larger prospective trial with a longer follow up may help confirm our preliminary findings.
Duration of pemetrexed maintenance therapy with or without pembrolizumab is associated with risk of renal toxicity in patients with metastatic nonsquamous NSCLC.
Authors: Patil Tejas , Nie Yunan , Hu Junxiao , Schenk Erin Lynn , Pacheco Jose Maria , Purcell William T. , Bunn Paul A. , Camidge D. Ross
Published: June 2021

e21205

Background: Use of maintenance pemetrexed with pembrolizumab is the standard of care among patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations treated with the KEYNOTE-189 regimen. Whether the addition of pembrolizumab to pemetrexed maintenance alters the risk of renal toxicity is not well characterized. Methods: A single center retrospective study was performed. The frequency of acute kidney injury as well as the rates of discontinuation due to renal injury was assessed. Acute renal injury was defined as ≥ 0.3 increase in serum creatinine (sCr) above the upper limit of normal or a rise in sCr ≥ 1.5 times baseline per KDIGO criteria. A Fisher exact test was conducted to compare the rate of renal injury between the two groups. Logistic regression adjusting for performance status, prior lines of treatment, and number of maintenance cycles was performed. Results: We identified 114 patients who received either maintenance pemetrexed or pemetrexed + pembrolizumab. The median number of cycles for the maintenance pemetrexed and pemetrexed + pembrolizumab groups was 5 and 7 cycles respectively. Of these, 41% (47/114) patients developed acute renal injury during their treatment course. Renal injury was seen in 14.3% (5/35) patients who received single agent pemetrexed maintenance and 25% (3/12) who received maintenance pemetrexed + pembrolizumab with no significant difference in the rates of renal injury between both arms (p = 0.403). Among patients who developed acute renal injury, 9% (4/47) permanently discontinued maintenance due to nephrotoxicity. All patients who permanently discontinued therapy received maintenance pemetrexed alone. When adjusting for covariates, ECOG performance status and number of prior lines of therapy did not increase the risk of renal toxicity. Logistic regression analysis identified that the rate of renal injury was significantly associated with the number of maintenance cycles received (p-value = 0.017, OR = 1.14, 95% CI 1.03 - 1.29). The odds of developing renal injury were 1.14 times higher with each additional cycle of maintenance therapy received. Conclusions: Renal injury is common among patients treated with patients receiving maintenance therapy. The addition of pembrolizumab to maintenance pemetrexed did not significantly increase the rate of renal injury. The risk of renal injury appears to correlate with the total number of maintenance cycles received suggesting a cumulative risk of nephrotoxicity over time.
Combination of pembrolizumab (PEMBRO) plus temozolomide (TMZ) therapy in Chinese patients (pts) with advanced acral and mucosal melanoma.
Authors: Hu Tu , Sun Wei , Xu Yu , Luo Zhiguo , Chen Yong
Published: June 2021

e21505

Background: Acral and mucosal melanoma are rare in Caucasians but have higher incidence in Asians and have poor prognosis. However, it has been reported that monotherapy seems to have limited efficacy in these population. Therefore, new treatments especially novel combination therapy are needed to further improve the outcome for these two subtypes. Here, we present the efficacy and safety of PEMBRO combined with TMZ in previously untreated pts with advanced acral and mucosal melanoma in China. Methods: The records of pts in Fudan University Shanghai Cancer Center with metastatic and unresectable acral and mucosal melanoma firstly treated with PEMBRO plus TMZ, PEMBRO alone or TMZ/DTIC based chemotherapy (CHEMO) were reviewed. Data regarding to best objective response rate (ORR), progression free survival (PFS) and toxicities were estimated. Response to treatment was assessed based on direct review of scan images and radiology reports according to the RECIST 1.1 criteria. Safety and tolerability were assessed per NCI-CTCAE v 4.0. Results: From May 2018 to February 2020, 49 pts were identified, including 28 (57.1%) with acral melanoma, 21 (42.9%) with mucosal melanoma. 32 (65.3%) pts had prior received adjuvant treatment, of which most (15, 30.6%) were interferon-α (IFN-α) or interleukin-2 (IL-2). Among these pts, PEMBRO alone was received by 18 (36.7%) pts with standard dosing of 2 mg/kg every 3 weeks. 20 (40.8%) pts received CHEMO at standard recommended dosing schedule, of which TMZ was given at 200 mg/m2 orally days 1–5, every 4 weeks. PEMBRO plus TMZ was given to 11 (22.4%) pts with the same dosing of each treatment alone. The ORR of PEMBRO plus TMZ (6/11, 54.5%) was significantly higher than PEMBRO alone (2/18, 11.1%; p = 0.011) or CHEMO(1/20, 5.0%; p = 0.002), however, the difference of ORR between PEMBRO alone and CHEMO was not statistically significant ( p = 0.485). The disease control rate of the three groups were 81.8%, 72.2% and 70.0% respectively (not significant). The median PFS of PEMBRO plus TMZ in the front-line therapy was 9.8 months (95% CI, 3.2 -16.4), as compared with 6.2 months (95% CI, 1.8 - 10.3) in PEMBRO alone and 4.2 months (95% CI, 2.8 - 5.6) in CHEMO ( p = 0.258). Grade 3 treatment-related adverse events (TRAEs) occurred in one acral melanoma patient (rash) in PEMBRO plus TMZ and two pts in CHEMO (one thrombocytopenia and one anemia, both were mucosal melanoma). No grade 3 TRAEs was reported in PEMBRO alone. There were no significant differences in grade 1/2 toxicity, with the common TRAEs including nausea, vomiting, fatigue, elevated transaminase and leukocytopenia. Conclusions: These results suggest that the combination of PEMBRO plus TMZ as first line therapy for advanced acral and mucosal melanoma could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. Need to be further evaluated in a large prospective study.
18F-FDG-PET/CT response assessment in patients with advanced melanoma treated with combination of low-dose ipilimumab and anti-PD1: A real-world experience.
Authors: Liz Caio Dabbous , Teixeira Marcos Rezende , Mendes Gomes Siqueira Luciana Beatriz , Rinck Jose A. , Lima Joao Paulo S. N. , Tavares Monique Celeste , Garcia Daniel , Oliveira Thiago Bueno , Cavicchioli Marcelo , Lima Eduardo , Duprat Joao , De Barros E. Silva Milton Jose
Published: June 2021

e21533

Background: Combination therapy with anti-PD1 and low-dose ipilimumab has shown reduced rate of immune-related adverse effects compared with standard dose used in the Checkmates studies 067 and 204. However, the discussion whether low-dose ipilimumab may hamper the response rate in advanced melanoma is still open. Methods: We conducted a retrospective analysis of response evaluation based on 18F-FDG PET/CT for patients with advanced melanoma treated with combination of nivolumab 3mg/kg plus ipilimumab 1mg/kg for 4 cycles (N3+I1) followed by anti-PD1 maintenance therapy and compared the results to RECIST 1.1 response criteria in the same population. Results: Between December 2017 and August 2020, 45 patients with advanced melanoma treated with N3+I1 in first-line setting were identified. Unresectable stage III/stage IV were 2/43 patients, respectively. Among stage IV patients, 60.5% were M1c, 23.3% had elevated LDH and 28% had brain metastasis (3 or more brain lesions: 58%). At a median follow-up of 16.7 months, 11 patients (24.4%) had G3/G4 toxicity. During induction phase, three patients (6.6%) discontinued all drugs and 2 other patients (4.4%) interrupted only ipilimumab. Review of response evaluation by RECIST was possible in 36 patients and showed an objective response of 50%. Complete response (CR): 11% and partial response (PR): 39%. Eight percent presented progressive disease (PD). In 37 patients, review of response evaluation using 18F-FDG PET/CT was possible. Twenty-four patients (65%) achieved metabolic CR, 5 (13.5%) PD and 8 (21.5%) were classified as non-CR non-PD. Median progression-free survival (PFS) and overall survival(OS) were not reached. 12-month PFS and OS were: 72.5 and 89%, respectively. During the study follow-up, only 1 patient with metabolic complete response relapsed and 3 out of 8 with non-CR non-PD progressed. Conclusions: Using low-dose ipilimumab combination does not hamper the response rates and, possibly due to fewer protocol interruptions, these patients may achieve more complete responses as showed by 18F-FDG PET/CT evaluation.
Organic iodine-based preparation inhibits growth of B16/F10 melanoma in C57BL6 mice with thyroid disorders.
Authors: Kaplieva Irina V. , Frantsiyants Elena M. , Bandovkina Valeria A. , Surikova Ekaterina I. , Neskubina Irina V. , Trepitaki Lidia K. , Cheryarina Natalia D. , Nemashkalova Ludmila A. , Pozdnyakova Viktoria V. , Przhedetskiy Yuriy V. , Przhedetskaya Viktoria Yu. , Maksimova Natalia A. , Ilchenko Maria G. , Khokhlova Olga , Zakharova Natalia A. , Kit Oleg I. , Engibaryan Marina A. , Gvaramiya Astanda K.
Published: June 2021

e21580

Background: The thyroid gland is the most important regulator of the body's response to stressful influences, including malignant growth. Iodine is a constituent of thyroid hormones, and it plays an important role in anti-tumor protection. The purpose of the study was to analyze the levels of thyroid hormones in the thyroid gland of male and female mice with B16/F10 melanoma, as well as the effect of an organic iodine-based preparation on the survival of animals with transplanted melanoma. Methods: Levels of total (T3, T4) and free (FT3, FT4) thyroid hormones were measured by RIA in the thyroid of male and female С57ВL/6 mice (n = 80) with transplantable B16/F10 melanoma. The effect of an organic iodine-based preparation on the dynamics of the melanoma growth was studied in the main group of animals (n = 42) receiving per os 1,3-diethylbenzimidazolium triiodide in a single dose of 0.4 mg/kg throughout the experiment; the control group (n = 20) received distilled water. The tumor volume and survival of mice were measured. Results: The lowT3/lowT4 syndrome developed in females with transplantable B16/F10 melanoma starting from week 2 of the experiment, diagnosed by decreasing levels of FТ3 and FТ4 by 3 times and lower and normal levels of T3 and T4. In males, melanoma growth caused the thyroid hypofunction expressed in a decrease in the levels of T3 and T4 by 2 times, and FT3 and FT4 by 1.5 times. The latent period prior to the tumor onset was 10-12 days in females and 5-7 days in males. The survival of females was 5-6 weeks, males – 3-4 weeks. The administration of the organic iodine-based preparation extended the latent period in females up to 14-18 days, in males up to 10-14 days; the survival of females increased by 1.8 times, males by 1.5 times. 9% of females in the main group showed complete tumor resorption without relapses throughout their lives. Conclusions: The growth of transplantable B16/F10 melanoma in male and female С57ВL/6 mice was accompanied by suppression of the thyroid function with the development of uncontrolled hypothyroidism in males and the lowT3/lowT4 syndrome in females, which correlates with the survival of animals.
Association of PTPN11 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors.
Authors: Long De , Fan Dandan
Published: June 2021

e21596

Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Mutations of PTPN11 (Protein Tyrosine Phosphatase, Non-receptor type11) have been reported to be associated with higher response rate and prolonged survival in advanced Renal Cell Carcinoma, Glioblastoma. The association between PTPN11 mutation and the efficacy of ICIs for melanoma is unknown. Methods: Genomic and survival data of melanoma patients administrated with ICIs were retrieved from publicly accessible data (Melanoma.Allen2015.WES.110) and the association between PTPN11 mutation and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between PTPN11 mutation with TMB was also analyzed in this public immunotherapy-treated cohort(Melanoma.Allen2015.WES.110), Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 466 patients with Skin Cutaneous Melanoma (SKCM) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and PTPN11 mutation status was further analyzed by CIBERSORT. Statistical significance was set at p = 0.05. Results: 3.6% (4/110) patients in the clinical cohort harbored PTPN11 mutation. Survival analysis in the public cohort demonstrated that PTPN11 mutation resulted in significantly longer OS (33.6 vs 8.5 months; HR, 0.16; p = 0.037) and an increasing trend on PFS without significantly difference (9.1 vs 2.8 months; HR, 0.3; P = 0.078) in melanoma patients treated with ICIs. Moreover, PTPN11 mutation is associated with higher TMB in public cohort (p = 0.01). Furthermore, the correlation analysis between immune infiltration and PTPN11 mutation status in melanoma shows that M1 macrophages increased significantly (p = 0.0014), CD8 T cells, plasma B cells and activated NK cells also show an upward trend (p = 0.17, p = 0.17 and p = 0.19) while the resting NK cells decreased significantly (p = 0.016)in melanoma patients with PTPN11 mutation. Conclusions: This study shows that PTPN11 mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages and the down regulation of resting NK cells may be a potential mechanism for the better efficacy of ICIs in patients with PTPN11 mutation.
Analysis of epigenomic signatures in cell-free DNA (cfDNA) from cancer patients and high-risk controls: A blinded test cohort of THUNDER-II study.
Authors: Gao Qiang , Li Bingsi , Xu Jiayue , Fang Shuai , Qiu Fujun , Su Jing , Wang Guoqiang , Cai Shangli , Zhao Heng , Zhang Wei , Li Ning , Wang Weilin , Qiao Gui-Bin , Liu Hao , Zhang Zhihong , Fan Jia
Published: June 2021

e22518

Background: Early detection of cancer has the potential to provide a clinical benefit to patients, especially for those with hard-to-treat diseases like ovarian and pancreatic cancer. The THUNDER (the unintrusive detection of early-stage cancers) program was designed to develop and validate a multicancer detection blood test (ELSA-seq) through a series of prospective, observational case-control studies. The second sub-study of THUNDER program (THUNDER-II) includes a discovery, training/validation, and single-blind test (SBT) phase. This new analysis, comprising data from the SBT set of THUNDER-II, evaluated performance of ELSA-seq in an independent group of participants, including individuals at high risk of certain cancer types for the first time. Methods: In the SBT group reported here, all participants were recruited from sites that were not represented in training or validation. The cancer group focused on six deadly cancer types (lung, colorectal, liver, pancreatic, esophageal, and ovarian cancer), and the non-cancer controls were stratified to ‘healthy’ and ‘high-risk’ subgroups based on examination results of low-dose spiral chest CT scan (LDCT), abdominal ultrasound, and Hepatitis B serologic test (HBsAg). 10ml of blood from each participant was collected and methylation-sequencing libraries were prepared by ELSA-seq as described previously. The detection results were automatically reported by a locked computational pipeline to mimic a real-world test scenario (Burning Rock Biotech, China). All samples were delinked from the donors’ cancer status and experiments were performed by blinded personnel. Results: In general, the cancer and non-cancer groups were comparable with respect to age, sex, and tobacco/alcohol-consumption history. The assessment is still in progress, and we have studied 360 eligible participants including 202 cancer cases and 158 non-cancer controls (76 ‘healthy’; 82 ‘high-risk’). Overall, ELSA-seq achieved a specificity of 98.1% (95%CI: 94.1-99.5%) and a sensitivity of 74.8% (95%CI: 68.1-80.5%), consistent with the performance in training and validation1. Among six pre-specified cancer types, sensitivity was 53.0% (95%CI: 40.4-76.3%) in stage I, 73.3% (95%CI: 57.8-84.9%) in stage II, 90.4% (95%CI: 78.2-96.4%) in stage III, and 92.3% (95%CI: 78.0-98.0%) in stage IV. In terms of identifying the diseased organ(s), 80.8% (95%CI: 73.4-86.6%) of the predications matched the true TOO status. Conclusions: ELSA-seq demonstrated consistent results in sites that did not contribute to training, supporting that performance was not subject to sample-/site-dependent bias. It also showed a very low false positive rate in asymptomatic individuals with or without certain cancer-prone conditions, suggesting a potential applicability to broad populations.
The impact of live education on the competence and performance of oncology practitioners who care for patients with ovarian cancer.
Authors: Carranza Vanessa , Taylor Bryan Carson , Gitzinger Susan H. , Fowler Joan B. , Hall Jessica
Published: June 2021

e23010

Background: About a third of ovarian cancer patients in the US have limited access to a gynecologic oncologist (GO) due to geographic disparities. A survey by The Society of Gynecologic Oncology (SGO) found that the majority of GOs found it was vital to coordinate local access to care, from diagnosis to survivorship, for patients living in areas of disparity. This allows rural/underserved patients broader access to novel therapies, as they increasingly become standard of care. It is critical for not only GOs to be current on the latest ovarian cancer data, but all clinicians who care for these patients. Methods: CEC Oncology developed two educational initiatives focused on PARP inhibitor therapy in ovarian cancer, which was targeted to all US healthcare professionals caring for ovarian cancer patients. Evaluations were collected from attendees attending an SGO Symposium and Ground Round (GR) series to assess impact on practice, increased competency, and intent to make a change in practice. Learning, knowledge, and competence was objectively assessed by analyzing pre-test, post-test, and follow-up survey data (sent 4-6 weeks post-activity). Chi-square analysis was conducted with a priori significance set at 0.05. Results: A total of 830 clinicians were educated, with SGO attendees primarily practicing in academic settings and GR attendees mostly from community practices. SGO attendees were asked case questions at baseline, immediately after the activity, and 4-6 weeks after the activity. Knowledge increased from pre- to post-test regarding current genetic testing recommendations (23% increase; P= .004) and appropriate selection of PARP inhibitor therapy (25% increase; P= .017). Knowledge was sustained at follow-up analysis. At follow-up, 90% of SGO and 84% of GR attendees made a change as a result of attending the activities. More attendees were able to incorporate germline multigene testing into practice, than originally intended; increase of 29% for SGO and 7% for GR audiences. All attendees experienced the barrier lack of patient education about the importance of genetic testing/counseling more than anticipated; increase of 7% for SGO and 13% for GR audiences. At follow-up, there was a 9% increase in GR attendees listing staying current with trial data and practice guidelines as a barrier. Conclusions: There were some notable differences seen in competence/performance among attendees of the two ovarian cancer educational initiatives. Differences may be attributed to practice setting (SGO primarily academic; GR primarily community.) Overall, GR attendees were more likely to face barriers, suggesting that community-based clinicians have fewer resources and experience more barriers to implementing best practices. Thus, it is vital to offer education for clinicians in community-based practices, particularly in areas that are considered ‘geographically disparate’.
Impact of the azoximer bromide concomitant therapy on outcomes in patients with soft tissue sarcoma.
Authors: Novik Aleksei Viktorovich , Shendaleva Natalya , Zozulya Anton , Nekhaeva Tatyana Leonidovna , Semenova Anna , Teletaeva Gulfiya Midhatovna , Latipova Dilorom Khamidovna , Semiglazova Tatiana , Protsenko Svetlana , Baldueva Irina Alexandrovna
Published: June 2021

e23534

Background: Immunomodulators are used in the management of patients with soft tissue sarcoma, (STS). However, the precise mechanism behind their benefits in anticancer therapy effects have yet to be determined. We assessed the impact of the immunomodulator azoximer bromide (AB) as a prognostic factor for survival when used concomitant with standard therapy in patients with STS. Methods: We reviewed medical history and disease outcomes in STS patients attending the Petrov National Medical Research Centre of Oncology (St Petersburg, Russia). Data were collected per protocol on treatments and patient outcomes. A Cox proportional-hazards model for time-to-progression (TTP) was constructed in SPSS v19. Known prognostic factors (TNM stage and substage, sex, age, therapy by type, and by immunologic action, as well as treatment modality), setting and AB therapy extracted from patient records were included in the model. The model employed a ‘step-forward’ method with AB therapy identified as the ‘unknown’ variable. Results: Complete patient records were available on 243 clinic attendees (from 2010 to 2020), 25 had received treatment with AB. The median follow-up was 20.9 months. Patients received single- and multi-agent chemotherapy, vaccines, cytokines, radiation therapy and/or surgery in the adjuvant or metastatic setting. Significant factors in the TTP model were current therapy type (Hazards ratios: 0.59 for surgery, 0.533 per added method for complex therapy and HR 1.689 for single-agent chemotherapy), previous systemic chemotherapy (HR: 1.451) and AB therapy (HR 0.547). Conclusions: Use of AB with standard therapy in STS emerged as an independent favorable prognostic factor. Appropriately controlled, well-designed prospective trials are needed to investigate this finding further. [Table: see text]
Mindfulness based stress reduction (MBSR) to improve cardiovascular (CV) function and psychosocial outcomes in breast cancer survivors.
Authors: Blaes Anne Hudson , Jewett Patricia , Nijjar Prabhjot , Everson-Rose Susan
Published: June 2021

e24058

Background: Breast cancer survivors on aromatase inhibitors (AIs) can develop endothelial dysfunction, a measure of increased CV risk. Stress modifying techniques such as MBSR may improve CV function and quality of life (QOL). We present data of a pilot study assessing the impact of MBSR on endothelial dysfunction and psychosocial outcomes. Methods: 31 women with locally advanced breast cancer and taking an AI were randomized 1:1 to 8 weekly MBSR classes or wait-list control. Subjects with tobacco use, known hypertension or hyperlipidemia were excluded. Participants completed surveys and vascular testing at baseline and 10 weeks. With the COVID-19 pandemic, MBSR classes were held on a virtual platform. Endothelial function was measured using the Endo-PAT2000 system; reductions in EndoPAT ratio (<1.6) are indicative of worsening endothelial function and increased CV risk. Questionnaires included the CDC’s 4-item Healthy Days Core Module (HRQOL), Patient Health Questionnaire (PHQ)-8 for depression, the Perceived Stress Scale, and the Generalized Anxiety Disorder Scale (GAD-7). Functional test markers were compared between groups using t-tests. Results: Baseline mean age was 59 years, body mass index was 28.4 kg/m2, mean systolic blood pressure was 128.1 mmHg and cholesterol was 226.9 mg/dL. These measures did not differ between groups. Baseline EndoPAT ratio (0.60) and follow up (0.52) were low in all participants. As statewide COVID-19 cases spiked, 3/31 participants did not return for a second assessment, and for another 5 participants, one EndoPAT ratio measurement was not interpretable. Both groups showed a decline in EndoPat ratio pre-to-post, but the decline among MBSR participants (all of whom completed the intervention) was five times less than that observed among controls [Table]. Groups did not differ on QOL or psychosocial outcomes. Conclusions: Breast cancer survivors on AIs have endothelial dysfunction, a measure of increased CV risk. Stress reduction techniques, using virtual platforms, are feasible and acceptable to this patient population, and may help improve endothelial function. Further research and longer follow up is warranted in understanding the long-term impact of these interventions on CV risk and psychosocial well-being. [Table: see text]
Incidence of neutropenia in breast cancer patients with administration of mecapegfilgrastim.
Authors: Fu Peifen , Wang Yongsheng , Li Yongqing , Yao Yumin , Li Huiping , Shi Yanxia , Yu Zhiyong , Song Lihua , Zhang Guifang , Ren Zhangxia , Cheng Gang , Ding Lifang , Yan Jun , Zhang Jing , Bie Jun , Yuan Chao , Wang Zhanggui , Ma Jun
Published: June 2021

e24070

Background: Neutropenia is the frequently observed adverse events for breast cancer patients under chemotherapy. Prophylactic administration of mecapegfilgrastim could reduce the incidence of grade 3/4 neutropenia/febril neutropenia(FN). The effectiveness of mecapegfilgrastim in breast cancer patients and different subgroups were explored. Methods: Patients with breast cancer and tolerable of mecapegfilgrastim were prospectively enrolled in a real-world study. All the patients received mecapegfilgrastim prophylacticly at least in chemotherapy cycle one. The incidence of grade 3/4 neutropenia/febril neutropenia in all patients and subgroups were presented. Results: 322 eligible patients were enrolled. The median age was fifty one years. The ECOG performace score was 0 – 1. In total, 752 chemothrapy cycles were conducted. Grade 3/4 neutropenia occurred in 44 (5.9 %) cycles, grade 4 neutropenia occurred in 16 (2.1 %) cycles. FN were reported in 4 (1.2 %) patients. The incidence of grade 3/4 neutropenia were stratificated by age group (≥65, ＜65), chemotherapy history, radiotherapy history, baseline absolute white blood cell count (≥4.0 ×109/L, ＜4.0 ×109/L), baseline absolute neutrophil count (≥2.0 ×109/L, ＜2.0 ×109/L), baseline hemoglobin level (≥110 g/L, ＜110 g/L) and chemotherapy regimens (High risk of FN, intermediate risk of FN). The results showed that patients with baseline hemoglobin of ≥110 g/L and ＜110 g/L had grade 3/4 neutropenia of 5% and 14.8 % respectively (P = 0.017). Patients treated with high FN risk chemotherapy and intermediate FN risk chemotherapy had grade 3/4 neutropenia of 0.9 % and 8.9 % respectively (P = 0.003). No significant difference of incidence of grade 3/4 neutropenia between other subgroups were found. Patients treated with cyclophosphamide and epirubicin (AC, classified as intermediate risk of FN by investigator) had grade 3/4 neutropenia of 15.4 %; Patients treated with cyclophosphamide, docetaxel and epirubicin (TAC, classified as high risk of FN by investigator) had grade 3/4 neutropenia of 14.3 %; Patients treated with docetaxel monotherapy (classified as intermediate risk of FN by investigator) had grade 3/4 neutropenia of 4.9 %. Conclusions: Prophylactic administration of mecapegfilgratim reduced the incidence of grade 3/4 neutropenia/febril neutropenia. Baseline hemoglobin level and specific chemotherapy regimen could be a useful prognostic facots for neutropenic events after administered mecapegfilgrastim.
Outcomes of radiotherapy combined with systemic therapy for stage IV NSCLC: A real-world study.
Authors: Jia Hongyuan , Lv Jiahua , Liang Long
Published: June 2021

e24084

Background: Although systemic therapy is standard treatment for stage IV NSCLC, radiation therapy can also play an important role. In the practice of our institute, radiotherapy to local diseases has been extensively used. In this study, we observed and analyzed the outcomes of systemic therapy combined with radiotherapy in stage IV non-small cell lung cancer. Methods: Patients with stage IV non-small cell lung cancer treated with combination of systemic therapy and radiotherapy were enrolled in this study. Radiotherapy was delivered using sIMRT or VMAT technique with CBCT image guidance. SBRT or hypofractionated radiation was used according to lesion site and patients general condition. For patients with driving gene mutations TKIs were used, and for these without chemotherapy of cisplatin/carboplatin plus paclitaxel or pemetrexed was given. Results: From 2016 to 2018, 105 patients were included in this study. Sites mostly irradiated included pulmonary lesions or mediastinal lymph nodes(48%), intracranial metastatic lesions(33%), bone metastatic lesions (20%). 42% of all patients received one course of radiotherapy to a single lesion site and others received multiple courses of radiation to different sites. Median follow-up was 39.1 months. Median OS for whole cohort was 18.6 months. In subgroup analysis, the survival of TKIs+radiotherapy group as significantly better than that of chemotherapy+radiotherapy group (median OS: 35.2 months vs 11.1 months, p < 0.001). The survival of patients with oligometastasis was also significantly better than these with extensive diseases( median OS 25.3 months vs 7.9 months, p < 0.001). The local control rate of irradiated sites was 82%. The incidence of ≥Grade 2 radiation esophagitis and pneumonitis were 33.2% and 24.2% for thoracic radiotherapy. Conclusions: Radiotherapy combined with systemic therapy is feasible and well tolerated for stage IV NSCLC, especially for patients with driving gene mutations and oligometastasis. It needs to be further confirmed by large randomized controlled clinical studies.