Reduced Progression Free Survival Research Articles

Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia

ObjectivesIn this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. Materials and methodsThe efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. ResultsOf the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35–3.46]; ICIs vs docetaxel, 1.49 [1.21–1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07–0.64]). ConclusionsAfter platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

A cross-sectional study of the association of dental health factors with progression and all-cause mortality in men diagnosed with HPV-associated oropharyngeal cancer

BackgroundHuman Papillomavirus-associated oropharyngeal cancer (HPV-OPC) incidence is increasing among men in the United States. Poor dental health has previously been associated with risk of head and neck cancers, oral HPV infection, and persistence but it is not understood whether dental health is associated with outcomes. We sought to determine the association of dental health with progression free survival and overall mortality among men with an HPV-OPC.MethodsA cross sectional study of men diagnosed with HPV-OPC between 2014–2020 at Moffitt Cancer Center in Tampa, FL was conducted. Dental records were abstracted for assessment of dental fitness prior to cancer treatment. Five dental factors including number of teeth lost, pocket depth, gingival score, loss of attachment, and bone loss were individually examined. Risk factor and outcome data were collected from a patient risk questionnaire and medical record. Using item response theory, an overall dental fitness score from five dental factors was developed in which missing data were multiply imputed. Cox proportional hazards model was used to assess whether dental factors were associated with progression-free survival or overall mortality.ResultsAmong 206 HPV-OPC cases, median follow-up was 3.4 years (IQR: 2.4–4.4) during which 40 cases involved progression or mortality and 25 deaths occurred. Overall dentition was significantly associated with progression free survival (p = 0.04) and with overall survival (p = 0.03) though findings were not significant after adjustment for age at diagnosis, stage, and smoking history (p = 0.146 and p = 0.120, respectively). A pocket depth of 7 mm or more was associated with overall survival (HR: 5.21; 95% CI: 1.43—19.11) and this remained significant after adjustment for confounding (aHR: 4.14; 95% CI: 1.72—16.26).ConclusionsAmong men diagnosed with an HPV-associated OPC in the US, worse dental health was associated with reduced progression free survival and overall survival, but not after adjustment for confounders. Further studies are needed to examine whether dental health is associated with other prognostic factors and subsequent treatment-related outcomes.

1237 The Mutational Landscape of Molecularly Defined Oligodendrogliomas

INTRODUCTION: Oligodendrogliomas are molecularly defined by IDH1/2 mutation and codeletion of chromosome arms 1p/19q. Prior studies identified capicua transcriptional repressor (CIC), far upstream binding protein (FUBP1), and the promoter region of telomerase reverse transcriptase (TERTp) as commonly mutated in oligodendrogliomas. However, prognostically relevant molecular signatures have yet to be identified. METHODS: A retrospective single-center study evaluated adults with pathologically confirmed IDH-mutant and 1p/19q co-deleted oligodendrogliomas that underwent surgery between 2005 and 2021. Genetic data from formalin-fixed, paraffin-embedded specimens were analyzed with the NGS Solid Tumor Panel at the Johns Hopkins Medical Laboratories, which tested over 400 genes. Kaplan-Meier curves and log-rank tests were used to compare progression-free survival (PFS) and overall survival (OS). Chi-squared tests compared clinical characteristics between mutation status in the ten most frequently mutated genes. RESULTS: From 277 patients with IDH-mutated, 1p/19q co-deleted oligodendrogliomas, 95 patients with NGS were included. Ten genes had 9 or more patients with a mutation, with CIC and FUBP1 being the most frequently mutated genes (n = 60 and n = 23, respectively). Kaplan-Meier curves showed that most genes were not associated with differences in PFS or OS. CIC conferred a reduction in PFS in patients with a PFS <100 months (p = 0.038), though this significance was lost when including all PFS durations (p = 0.52). While no biomarkers had sufficient statistical power, our analysis showed trends in shortened survival in patients with TP53 (p = 0.01) and PIK3CA (p = 0.03) mutations. CONCLUSIONS: Oligodendrogliomas harbor frequent mutations in CIC, FUBP1, and TERTp, but most patients typically have minimal additional alterations. As NGS becomes routine, understanding these mutations may inform therapeutic and prognostic recommendations or the development of novel targeted therapies. Additional molecular assays beyond mutation analysis with NGS may reveal prognostically relevant biologic subgroups of oligodendrogliomas.

Circulating tumour mutation detection in triple-negative breast cancer as an adjunct to tissue response assessment

Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

Increased pretreatment triglyceride glucose-body mass index associated with poor prognosis in patients with advanced non-small cell lung cancer

The association between the triglyceride glucose-body mass index (TyG-BMI) and various health outcomes has been postulated. Nonetheless, the application of TyG-BMI in predicting the prognosis of non-small cell lung cancer (NSCLC) remains poorly understood. Our objective was to explore the association between TyG-BMI and both progression-free survival (PFS) and overall survival (OS) in patients with advanced NSCLC. A retrospective study was conducted on the data of 426 patients diagnosed with advanced NSCLC between 2018 and 2022. The TyG-BMI values were derived from the serum triglyceride, fasting plasma glucose, and BMI measurements obtained at the time of diagnosis. Cox proportional hazards regression models were applied to examine the impact of TyG-BMI on both progression-free survival (PFS) and overall survival (OS) in advanced NSCLC. The median duration of follow-up was 899 days, with an interquartile range of 256-1486 days. In comparison to the lowest tertile of TyG-BMI, the highest tertile model demonstrated a significant association with worse OS (hazard ratio [HR]: 1.85; 95% confidence interval [CI]: 1.21-2.80; P=0.001) and PFS (HR: 2.10; 95% CI: 1.40-3.10; P<0.001). Each standard deviation increase in TyG-BMI corresponded to a 10% reduction in OS (95% CI: 1%-24%) and a 14% reduction in PFS (95% CI: 2%-27%). Subgroup analyses indicated that cigarette smokers and individuals with elevated C-reactive protein (CRP) levels exhibited a notably unfavorable prognosis in relation to TyG-BMI-associated advanced NSCLC, as evident in both OS (P for interaction: 0.046 for smoking) and PFS (P for interaction: 0.033 for smoking and 0.049 for CRP). Our data revealed a causal relationship between TyG-BMI and an unfavorable prognosis in patients with advanced NSCLC. Furthermore, this independent association exhibits greater significance in individuals who are smokers and exhibit higher levels of CRP.

Baseline C-reactive protein predicts efficacy of the first-line immune checkpoint inhibitors plus chemotherapy in advanced lung squamous cell carcinoma: a retrospective, multicenter study

AimsTo investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC).Materials and methodsIn this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups.ResultsOf the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12–2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13–4.44; p = 0.033).ConclusionIn patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma

IntroductionHigh-dose methotrexate (HDMTX)-based regimens are the treatment of choice in primary central nervous system lymphoma (PCNSL). Folinic acid (FA) rescue is used to mitigate the toxic effects of MTX on normal cells. However, the optimal dosing of FA in PCNSL remains uncertain. MethodsWe analyzed the relationship between FA dosing and treatment efficacy and toxicity in a cohort of 36 PCNSL patients treated at our institute between the years 2014 and 2022. A combination of univariate and multivariate analyses using known prognostic factors were used to determine the association between FA dosing and treatment outcomes. ResultsWe found that higher per-treatment cumulative FA doses were associated with inferior progression-free survival (PFS), with a hazard ratio (HR) of 2.2 for each 100 mg/m2 increase in FA dose. We identified a threshold of 350 mg/m2/treatment, above which there was a significant reduction in PFS. Notably, lower FA doses did not result in increased toxicity. ConclusionOur findings suggest that optimizing FA dosing to avoid very high rescue doses may improve treatment outcomes in PCNSL patients receiving HDMTX. Further prospective studies are warranted to validate these findings.

Toxicity Profile According to Etoposide and Cytarabine Dosing in Patients with Lymphoma Receiving Autologous Stem Cell Transplantation Following BEAM Conditioning.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is part of the treatment strategy for some patients with high-risk lymphoma by improving survival with an acceptable toxicity profile. Although the BEAM (BCNU, etoposide, cytarabine, and melphalan) intensification regimen is the most used, the optimal dosing for each drug is unclear. Here, we retrospectively compared the outcome of 110 patients receiving higher (400mg/m2, n = 69) or lower (200mg/m2, n = 41) etoposide and cytarabine doses in our institution between 2012 and 2019. Patients in the BEAM 200 group experienced less toxicity with reduced fever duration (P < 0.001), number of platelet transfusions (P = 0.008), antibiotic duration (P < 0.001), antifungal therapy (P < 0.001), and mucositis (P < 0.001) whereas length of stay, admission to the intensive care unit, and in-hospital mortality were not different between groups. Progression-free survival (PFS) was non-significantly lower in the BEAM 200 group (36-month PFS, 68% vs. 80%, P = 0.053) whereas OS was similar between the two groups (36-month OS, 87% vs. 91%, respectively, P = 0.12). Albeit a non-significant reduction in PFS, BEAM 200 conditioning intensity was associated with a reduced toxicity profile.

Progression-free survival as a surrogate endpoint of overall survival in advanced biliary tract cancer: A meta-analysis of randomized trials and individual-patient level correlation.

4101 Background: Biliary tract cancer (BTC) is a heterogeneous group of diseases commonly diagnosed at advanced stages. Overall survival (OS) is the gold-standard primary endpoint in randomized controlled trials (RCT). However, the increasing use of subsequent lines of therapies and cross-over designs may confound the treatment effect. We therefore explored the use of progression free survival (PFS) as a surrogate endpoint of OS both at the trial-level and at the patient-level. Methods: For the trial-level correlation, we conducted a systematic review of RCTs in advanced BTC following the PRISMA guidelines. We searched PubMed, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from database inception to June 2022 and identified all randomized phase II/III trials testing systemic therapies for advanced BTC. We used a weighted linear regression to measure the correlation of log-transformed hazard ratios (HR) of OS and PFS based on trial size and calculated the surrogate threshold effect (STE). We used the IQWiG framework to define the strength of evidence. For the individual-level analysis, we included patients with advanced BTC treated with first and second line chemotherapy in the real-world RETUD registry. We estimated the correlation via the iterative multiple imputation method. Results: From a total of 1992 studies, we identified 32 RCTs including 70 treatment arms and 5140 patients that fulfilled the inclusion criteria. Twenty-three trials were performed in the first line setting and most were phase II RCTs (N = 23). We found a moderate correlation between OS and PFS ( R= 0.79, 95% CI 0.61-0.89). The slope of the regression line was 0.62±0.08, indicating that a 10% risk reduction in PFS will result in a 6.2%±0.8% improvement in OS. The STE was 0.69, suggesting that in a hypothetical trial of 400 patients, a PFS HR of 0.69 will likely result in a significant improvement on OS. Regarding the individual-level correlation, a total of 593 patients with advanced BTC were included. The median age of patients was 68y (IQR 59-74), most were males (54%) and received platinum-based chemotherapy (73.1%). In the first line setting, the median OS was 9.7 months (95% CI 8.7-10.5) and median PFS was 5 months (95% CI 4.5-5.5). We observed a strong correlation between PFS and OS ( r= 0.84, 95% CI 0.81-0.86). In the second line setting (N = 259), a similar correlation was observed to the first-line setting ( r= 0.76, 95% CI 0.72-0.8). Conclusions: At the trial-level, in this analysis treatment effects on PFS were moderately correlated with OS. A HR &lt; 0.69 in PFS suggested that it would likely lead to a significant OS benefit in a hypothetical trial including 400 patients. At the individual-level, PFS and OS were strongly correlated in a real-world cohort. Future validation in patients treated in the context of randomized trials is warranted.

Effect of Concurrent Proton Pump Inhibitors With Palbociclib Tablets for Metastatic Breast Cancer

BackgroundPalbociclib is indicated for the treatment of hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant. Two retrospective studies found that concurrent proton pump inhibitor (PPI) use with palbociclib capsules significantly reduced progression free survival (PFS) versus patients without a PPI. Palbociclib tablets were released in 2020 without restriction on PPI use. No study to date has evaluated the combination of palbociclib tablets with concurrent PPI use. MethodsPatients were retrospectively evaluated after they received palbociclib tablets for the treatment of HR+ HER2- MBC in the first line setting with or without a PPI. Patients were assigned to the no PPI use arm if they never used a PPI and the PPI use arm if they used a PPI for >50% of the duration of palbocicib therapy. The primary endpoint was PFS. The secondary endpoints included overall survival (OS) and adverse events. ResultsEighty-two patients were identified; 50 in the no PPI use group and 32 in the PPI use group. The median PFS was 20.6 months (95% confidence interval [CI], 16.07 to not estimable) in the no PPI use arm versus 21.0 months (95% CI, 15.15 to not estimable) in the PPI use arm (P = 0.95). Median OS was not reached in either arm. Adverse effects did not differ between arms. ConclusionUse of a concurrent PPI with palbociclib tablets does not significantly reduce PFS in patients treated for HR+ HER2- MBC.

Abstract 335: Ubiquitin Specific Peptidase 37promotes Osteosarcoma oncogenesis by interacting with PCNA and impacting constitutive replication fork movement.

Abstract Osteosarcoma is the heterogeneous primary malignancy of bone which is most commonly found among children and adolescents. Recent data related to treatment of osteosarcoma indicates the lack information about the progression of the disease. Osteosarcoma has been a challenge for the oncologist because even after surgical removal of primary tumors many patients go on to develop pulmonary metastasis. Protein deubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. Ubiquitin specific peptidases (USPs) remove ubiquitin tags from target proteins to alter protein configuration and function. Recent studies have revealed that Ubiquitin specific peptidase 37 (UPS37) regulates replication stress by regulating important protein involved in several important cellular functions. Analysis of TCGA data indicated that overexpression of USP37 correlated with reduced progression free survival (PFS) in osteosarcoma patients. Next generation sequencing (NGS) analysis of osteosarcoma cells indicated that distinct set of genes were altered on overexpression or knockdown of USP37. Our data indicate that USP37 overexpression confers survival advantage while its depletion enhances sensitivity for cell killing in osteosarcoma cells due to replication stress. USP37 overexpressing cells were able to resolve DNA damage foci much more rapidly than the control cells or cells in which USP37 was depleted in response to genotoxic stress. USP37 depletion results in reduced resolution of γ H2AX and 53BP1 DNA damage foci and increase in number of collapsed replication fork which indicates the reduced ability of cells to carry out constitutive DNA replication. USP37 was found to interact with PCNA (Proliferative cell nuclear antigen). Interestingly docking studies indicated that USP37 and PCNA interacted with stronger affinity in presence of double stranded DNA through different residues. We further correlated our data with archived tissue blocks of osteosarcoma patients by analyzing if USP37 and PCNA expression colocalized. Present data suggests that USP37 is required for tolerance of replication stress as it interacts with PCNA which is required to dock additional replication factors and stabilize DNA replication fork. The current data provides new mechanistic details for the regulation of replication stress by USP37 which merits the development of targeting strategies to explore its therapeutic potential in osteosarcoma by inducing synthetic lethality. Citation Format: Ravi Chauhan, Lakshay Malhotra, Ashna Gupta, Ajaz Bhat, Gunjan Dagar, Tariq Masoodi, Muzafar A. Macha, Ethayathulla Abdul Samath, Atul Batra, Mehar Chand Sharma, Mohammad Haris, Ammira Al-Shabeeb Akil, Tej K. Pandita, Shahab Uddin, Mayank Singh. Ubiquitin Specific Peptidase 37promotes Osteosarcoma oncogenesis by interacting with PCNA and impacting constitutive replication fork movement. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 335.

Polatuzumab vedotin in previously untreated DLBCL: an Asia subpopulation analysis from the phase 3 POLARIX trial

AbstractIn the phase 3 POLARIX study in previously untreated diffuse large B-cell lymphoma, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intention-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cutoff (28 June 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population, and was superior with Pola-R-CHP vs R-CHOP (hazard ratio, 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3 to 4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations in POLARIX. This trial was registered at https://clinicaltrials.gov/ct2/home as # NCT03274492.

LncRNA HOTAIR impairs the prognosis of papillary thyroid cancer via regulating cellular malignancy and epigenetically suppressing DLX1.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy with a fast-growing incidence in recent decades. HOTAIR as a long non-coding RNA has been shown to be highly expressed in papillary thyroid cancer tissues with only a limited understanding of its functional roles and downstream regulatory mechanisms in papillary thyroid cancer cells. We applied three thyroid cancer cell lines (MDA-T32, MDA-T41 and K1) to investigate the phenotypic influence after gain or loss of HOTAIR. The Cancer Genome Atlas (TCGA) database were utilised to select candidate genes possibly regulated by HOTAIR with validation in the cellular system and immunohistochemical (IHC) staining of PTC tissues. We observed HOTAIR was highly expressed in MDA-T32 cells but presents significantly decreased levels in MDA-T41 and K1 cells. HOTAIR knockdown in MDA-T32 cells significantly suppressed proliferation, colony formation, migration with cell cycle retardation at G1 phase. On the contrary, HOTAIR overexpression in MDA-T41 cells dramatically enhanced proliferation, colony formation, migration with cell cycle driven toward S and G2/M phases. Similar phenotypic effects were also observed as overexpressing HOTAIR in K1 cells. To explore novel HOTAIR downstream mechanisms, we analyzed TCGA transcriptome in PTC tissues and found DLX1 negatively correlated to HOTAIR, and its lower expression associated with reduced progression free survival. We further validated DLX1 gene was epigenetically suppressed by HOTAIR via performing chromatin immunoprecipitation. Moreover, IHC staining shows a significantly stepwise decrease of DLX1 protein from normal thyroid tissues to stage III PTC tissues. Our study pointed out that HOTAIR is a key regulator of cellular malignancy and its epigenetic suppression on DLX1 serves as a novel biomarker to evaluate the PTC disease progression.

Variable Frailty Categorization Among Real-World Patient with Multiple Myeloma: A Prospective Cohort Study (MFRAIL)

Introduction Multiple Myeloma (MM) is a non-curable cancer of older adults. Frailty has emerged as one important high-risk factor which confers a poor prognosis with reduced progression free survival, increased toxicity, higher rates of drug discontinuation and worse overall survival. Several tools have emerged for evaluation of frailty in MM in recent years. These include non-cancer specific geriatric assessment tools such as the Fried frailty index or more specific MM tools such as the International Myeloma Working Group (IMWG) frailty index, simplified frailty index or the Mayo frailty index. Uptake of these measures across clinical settings has been variable, leading to a gap in knowledge about the prevalence of geriatric impairments among MM patients as well as the proportion of patients classified as frail using these different scoring systems. The MFRAIL study is an ongoing prospective, multicentre study evaluating the association of different frailty assessment tools at baseline and longitudinally over time with clinical outcomes. In this abstract we present an interim analysis after at least 50% of patients have been enrolled. We describe baseline characteristics from the initial 57 patients enrolled into the study with the specific objective of 1) to report the prevalence of geriatric impairments among MM patients prior to therapy initiation 2) characterize the proportion of patients classified as frail using different frailty assessment tools. Methods The MFRAIL is an ongoing, prospective pilot cohort study being conducted at three sites within Ontario, Canada which was initiated in August 2021. Multiple myeloma patients aged >18 initiating a new line of therapy are enrolled in the preceding six weeks. Demographic and MM-specific factors are collected at baseline and at 12 months following treatment along with MM response criteria, toxicity and health care utilization. Additional collected measures include: comorbidities, physical performance measures (NIH 4 meter walk test and grip strength), cognition, patient reported outcome of quality of life and depression. Frailty assessment tools measured include the IMWG frailty index (Palumbo et al. Blood 2015), simplified frailty index (Facon et al. Leukemia 2020), Mayo frailty index (Milani et al. AJH 2016) and the Fried frailty index (modified from Fried et al. J Gerontol A Biol Sci Med Sci 2001). Results A total of 57 patients were enrolled in the study (data cut off June 1/2022) with baseline characteristics summarized in Table 1. The median age of the patients was 71 (range 47-93) with 61% males. A total of 26% and 35% of the patients had an ECOG and CCI status of 2 or higher, respectively. Polypharmacy was common with over 50% of the patients being prescribed five or more medications at baseline. Geriatric impairments were common with over 1/3 of the patients reporting at least one deficit in ADLs or IADLs. Additionally, cognitive impairment was present in 19.3% of the patients. With regards to treatment details, 61.4% of the enrolled patients received first line treatment (ASCT eligible 34.3%, ASCT ineligible 65.7%), 26.3% second line and the remainder third line and beyond. Immunomodulatory-based treatments were the most common with 57.8% of the patients utilizing these agents. Empiric dose reduction outside the product monograph was observed in 17.5% of the patients with the majority of dose reductions (80%) done for agents other than dexamethasone alone among those patients. The prevalence of frailty in our cohort ranged from 12.3% (Fried frailty index), 17.5% (Mayo frailty index), 38.6% (IMWG frailty index) to 52.6% (simplified frailty score). Similarly, the number of patients classified as fit/robust also varied ranging from 15.8% (Mayo frailty index), 25.3% (fried frailty index), 33.3% (IMWG frailty index) and 47.3% (simplified frailty score). Conclusion Impairments in geriatric domain are common among real-world patients with MM emphasizing the need to incorporate these assessments in routine clinical practise. Additionally, prevalence of patients classified as frail versus fit varies depending upon the assessment tool utilized with no uniform definition of frailty in routine clinical practise. Further work is needed in both evaluating and standardizing frailty assessment tools in different clinical settings and with different therapeutic modalities to further optimize outcomes in this high-risk patient subgroup. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PGAM1 Promotes Glycolytic Metabolism and Paclitaxel Resistance via Pyruvic Acid Production in Ovarian Cancer Cells.

Enhanced glycolysis occurs in most human cancer cells and is related to chemoresistance. However, detailed mechanisms remain vague. Using proteinomics analysis, we found that the glycolytic enzyme Phosphoglycerate mutase 1 (PGAM1) was highly expressed in the paclitaxel-resistant ovarian cancer cell line SKOV3-TR30, as compared to its parental cell line SKOV3. Cell Counting Kit-8 proliferation experiment, plasmids and siRNA transfection, pyruvic acid and lactic acid production detection, immunofluorescence staining of functional mitochondria and oxygen consumption rate and extracellular acidification rate measurement were uesd to assess the glycolytic metabolism and paclitaxel resistance in ovarian cancer cells. The expression and prognostic effect of PGAM1 in 180 ovarian cancer patients were analyzed. SKOV3-TR30 cells display higher glycolytic flux and lower mitochondrial function than SKOV3 cells. Down-regulation of PGAM1 in SKOV3-TR30 cells resulted in decreased paclitaxel resistance. Up-regulation of PGAM1 in SKOV3 cells led to enhanced paclitaxel resistance. Analysis of the glycolytic flux revealed that PGAM1-mediated pyruvic acid or lactic acid production could modulate the capabilities of ovarian cancer cell resistance to paclitaxel. Our data also show high expression of PGAM1 as significantly correlated with reduced overall survival and reduced progression free survival in ovarian cancer patients. PGAM1 acts to promote paclitaxel resistance via pyruvic acid and/or lactate production in ovarian cancer cells. Inhibiting PGAM1 may provide a new approach to favorably alter paclitaxel resistance in ovarian cancer.

Asia subpopulation analysis from the phase III POLARIX trial.

7558 Background: In the pivotal Phase III POLARIX trial, Pola-R-CHP demonstrated significantly improved progression-free survival (PFS) compared with R-CHOP, with a similar safety profile in patients with previously untreated DLBCL (Tilly et al. 2022). An Asia subpopulation analysis was included as part of the trial design; patients enrolled in Asia were analyzed for the purpose of registration in China of POLARIX (NCT03274492). Methods: Patients from mainland China, Hong Kong, Japan, South Korea, and Taiwan (enrolled during the global phase), and from the China extension cohort were included in the Asia subpopulation. POLARIX methods were previously described (Tilly et al. 2022). Briefly, patients with untreated DLBCL were randomized 1:1 using the same stratification factors to receive six cycles of Pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The purpose of this analysis was to evaluate consistency of PFS (defined as ≥50% risk reduction in PFS) in the Asia subpopulation with the global population. Results: Overall, 281 patients (intent-to-treat population; 150, 85, 31 and 15 patients in mainland China, Japan, South Korea and Taiwan, respectively) were analyzed (141 received Pola-R-CHP and 140 received R-CHOP); 160 patients from the global population and 121 from the China extension cohort. Median age was 63 (range 19–79) years, and most patients had an International Prognostic Index of 3–5 (61.9%). At the data cut-off of June 28, 2021, (median follow-up of 24.2 months) PFS was superior with Pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.40–1.03) and met the consistency definition with the global population. The 2-year PFS rate was 74.2% (95% CI: 65.7–82.7) with Pola-R-CHP vs 66.5% (95% CI: 57.3–75.6) with R-CHOP. Other key efficacy results were similar to the global study results (Table). The safety profile was generally comparable for Pola-R-CHP vs R-CHOP, including rates of grade 3–4 adverse events (AEs; 72.9% vs 66.2%), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to discontinuation of any study treatment (5.0% vs 7.2%), and incidence of peripheral neuropathy (all grades, 44.3% vs 50.4%), respectively. Key efficacy results. CR, complete response. Conclusions: The results from the Asia subpopulation of POLARIX were consistent with the global study, with a clinically meaningful improvement in PFS (risk of disease progression, relapse or death reduced by 36%) following treatment with Pola-R-CHP vs R-CHOP, and a comparable safety profile in Asian patients with previously untreated DLBCL. Clinical trial information: NCT03274492. [Table: see text]

150P Monitoring of PD-L1 expression on circulating immune cells of patients with small cell lung cancer (SCLC) receiving first-line treatment: Prognostic implications

PD-L1 expression has been reported on tumor-infiltrating immune cells in SCLC tissue, however its prognostic role is not clear as yet. We herein assessed the incidence and clinical value of PD-L1 expression on immune cells circulating in the peripheral blood (PB) of SCLC patients receiving first-line treatment. PB was obtained from 34 SCLC patients (limited-stage: n=7; extensive-stage: n=27) at baseline and at the end of first-line treatment, consisting of chemotherapy alone (n=18) or in combination with atezolizumab (n=16). Peripheral blood mononuclear cell (PBMC) cytospins were immunofluorescently stained for dapi/PD-L1 (Clone: E1L3N) and PD-L1 expression was quantified on 1.000 randomly selected intact PBMCs/per sample via the Ariol microscopy system. PD-L1positive PBMCs were identified in 70.6% and 73.5% of patients at baseline and post treatment, respectively, while PD-L1high PBMCs in 17.6% and 26.5%, respectively. In 23.5% of patients, PD-L1high PBMCs were detected in the post-treatment sample only (in 31.3% and 16.7% of patients treated with chemoimmunotherapy as compared to chemotherapy alone, respectively; p=0.429). The detection of PD-L1high PBMCs in the post-treatment sample only was associated with disease progression in the brain (in 38.5% versus 0% of patients with and without brain progression, respectively; p=0.009). Kaplan Meier analysis showed that patients harboring PD-L1high PBMCs post-treatment only, had numerically reduced progression free survival (median PFS: 5.3 versus 6.7 months; p=0.089) and overall survival (median OS: 8.4 versus 15.8 months; p=0.152). In addition, patients treated with chemoimmunotherapy and post-treatment only PD-L1high PBMCs, had significantly shorter OS (8.4 versus 15.7 months; p=0.007). PD-L1 is frequently expressed on PBMCs of SCLC patients receiving first-line treatment. The detection of PD-L1high PBMCs post-treatment might be associated with disease progression in the brain and worse survival measures. To further delineate its role, PD-L1 expression on PBMCs is currently being investigated in a larger SCLC patient cohort.

Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival.

The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.

Circulating Serum MiRNA-8074 as a Novel Prognostic Biomarker for Multiple Myeloma.

MiRNA-8074 is a molecule with the potential to regulate the expression of key genes related to the pathogenesis of multiple myeloma (MM), i.e., TP53, MYC, MAPK1, and KIAA. We analyzed the predictive and prognostic value of miRNA-8074 expression in MM patients. In total, 105 newly diagnosed MM patients treated with thalidomide (n = 27), bortezomib (n = 41) and bortezomib with thalidomide (n = 37) were studied. For miRNA analysis, the column method and the Real-Time PCR technique with specific TaqMan Fast Advanced Master Mix and TaqMan probes were used. Factors that were associated with a significant reduction in progression-free survival (PFS) included: ECOG > 1, ISS stage III, low hemoglobin, thrombocytopenia, hypoalbuminemia, abnormal renal function, elevated creatinine, GFR < 60 mL/min/1.73 m2, elevated LDH, del(17p), t(11;14), the use of a single drug regimen (thalidomide or bortezomib) and high miRNA-8074 expression (HR = 2.01, 95% CI: 1.16–3.49; p = 0.0233). In addition to the known prognostic factors, such as ECOG > 1, Durie–Salmon stage III, diagnosis of light chain disease or non-secreting MM, renal failure, hypoalbuminemia, hypercalcemia, high β2-microglobulin, elevated LDH, and t(14;16), a high expression of miRNA-8074 was significantly associated with a higher risk of death (HR = 4.12, 95% CI: 2.20–7.70; p = 0.0009). In summary, miRNA-8074 may be a useful diagnostic tool to assess the prognosis in MM patients.

Carfilzomib-Lenalidomide-Dexamethasone Consolidation in Myeloma Patients with a Positive FDG PET/CT after Upfront Autologous Stem Cell Transplantation: A Phase II Study (CONPET)

Background:[18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) positivity after first line treatment with autologous stem cell transplantation (ASCT), is strongly correlated with reduced progression free survival and overall survival (Moreau et al., JCO, 2017). However, FDG PET/CT positive patients who obtain FDG PET/CT negativity after treatment seem to have comparable outcomes to patients who were FDG PET/CT negative at baseline (Davies et al., Haematologica 2018). Aiming for FDG PET/CT negativity may therefore be an important goal in myeloma treatment. The use of FDG PET/CT positivity as an indication for consolidation therapy after ASCT has not been studied before.Methods:This is an ongoing, multicenter phase II study. Patients with multiple myeloma who have received standard first line treatment including ASCT and achieved very good partial response (VGPR) or better, are eligible for the study and examined by FDG PET/CT. Patients who are FDG PET/CT positive defined by the Italian Myeloma criteria for PET USe (IMPETUS) (Nanni C et al., EJNMMI 2016 and 2018) are included in the treatment phase of the study and are assessed for minimal residual disease (MRD) by Euroflow (sensitivity: 10 -5) before treatment. FDG PET/CT examinations are centrally read by two experienced nuclear medicine radiologists. The treatment consists of four 28-day cycles of KRd (carfilzomib 36 mg/m 2 day 1,2,8,9,15 and 16 (except 20 mg/m 2 day 1 and 2 first cycle), lenalidomide 25 mg day 1-21 all cycles and dexamethasone 40 mg day 1,8,15 and 22 all cycles). After 4 cycles, FDG PET/CT and Euroflow for MRD are repeated for response evaluation. Both patients with FDG PET/CT negativity and patients with FDG PET/CT positivity at baseline are followed for progression free survival and overall survival.Results:As of the 1st of July 2021, 149 patients have been screened in the study. Fifty-one patients (34%) had a positive FDG PET/CT post-ASCT. Twenty-eight of 50 (56%) patients with positive FDG PET/CT were MRD negative. Forty-four patients have completed four cycles of KRd consolidation; Twelve (27%) patients converted into FDG PET/CT negativity. Nine of them were MRD negative both before and after consolidation; two were MRD positive both before and after consolidation and one turned MRD negative after consolidation. In all patients who were FDG-PET positive before treatment, the rate of MRD negativity after consolidation treatment was 78%. Eleven of twenty (55%) patients who were MRD positive before consolidation treatment turned MRD negative after treatment.Conclusion:A significant proportion (34%) of patients treated with standard first line treatment including ASCT with achieved very good partial response or better was FDG PET/CT positive post-ASCT. Fifty-six percent of them were MRD negative by Euroflow, confirming the complementary features of these two methods. Treatment with four cycles of KRd converted 12 of 44 (27%) patients to FDG PET/CT negativity, and 78% of all patients were MRD negative after treatment. The study is ongoing and we will follow up on data for progression free (PFS) and overall survival (OS). At the congress, complete post-consolidation data for all patients (n=50) will be presented. [Display omitted] DisclosuresNørgaard: Bayer: Honoraria; AstraZeneca: Honoraria; Ultimovacs: Current holder of individual stocks in a privately-held company; Targovax: Current holder of individual stocks in a privately-held company; Photocure: Current holder of individual stocks in a privately-held company. Tsykunova: Sobi: Consultancy; Ablynx: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Sanofi: Consultancy. João: Janssen: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding. Schjesvold: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Nordics Nanovector: Current holder of individual stocks in a privately-held company; Sanofi: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; SkyliteDX: Honoraria; AbbVie: Honoraria; Bayer: Consultancy; Adaptive Biotechnologies: Consultancy; Schain: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria.