Progression-free Survival Outcomes Research Articles

Novel Somay’s GLUCAR Index Efficiently Predicts Survival Outcomes in Locally Advanced Pancreas Cancer Patients Receiving Definitive Chemoradiotherapy: A Propensity-Score-Matched Cohort Analysis

Background: Propensity score matching (PSM) was used to investigate the prognostic value of a novel GLUCAR index [Glucose × (C-reactive protein ÷ albumin)] in unresectable locally advanced pancreatic cancer (LA-NPC) patients who received definitive concurrent chemoradiotherapy (CCRT). Methods: The PSM analysis comprised 142 LA-PAC patients subjected to definitive CCRT. Receiver operating characteristic (ROC) curve analysis was utilized to identify relevant pre-CCRT cutoffs that could effectively stratify survival results. The primary and secondary objectives were the correlations between the pre-CCRT GLUCAR measures and overall survival (OS) and progression-free survival (PFS). Results: The ROC analysis revealed significance at 43.3 for PFS [area under the curve (AUC): 85.1%; sensitivity: 76.8%; specificity: 74.2%; J-index: 0.510)] and 42.8 for OS (AUC: 81.8%; sensitivity: 74.2%; specificity: 71.7%; J-index: 0.459). Given that these cutoff points were close, the standard cutoff point, 42.8, was selected for further analysis. Comparative survival analyses showed that pre-CCRT GLUCAR ≥ 42.8 (n = 71) measures were associated with significantly shorter median PFS (4.7 vs. 15.8 months; p < 0.001) and OS (10.1 vs. 25.4 months; p < 0.001) durations compared to GLUCAR < 42.8 measures (n = 71). The multivariate analysis results confirmed the independent significance of the GLUCAR index on PFS (p < 0.001) and OS (p < 0.001) outcomes. Conclusions: Elevated pre-CCRT GLUCAR levels are robustly and independently linked to significantly poorer PFS and OS outcomes in unresectable LA-PAC patients treated with definitive CCRT.

Long-term outcomes of CNS WHO grade 2 oligodendroglioma in adult patients: a single-institution experience

PurposeOligodendrogliomas (ODGs) are a subtype of diffuse lower-grade gliomas with overall survival of > 10 years. This study aims to analyze long-term outcomes and identify prognostic factors in patients with WHO grade 2 ODG.MethodsWe retrospectively reviewed 138 adult patients diagnosed with 1p/19q co-deleted ODG who underwent surgical resection or biopsy between 1994 and 2021, analyzing clinical data, treatment details, and outcomes. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier analysis. Univariate and multivariate Cox regression analyses were utilized to identify significant prognostic factors.ResultsIn the gross total resection (GTR) group, 63 (45.7%) underwent observation and 5 (3.6%) received postoperative treatment; in the non-GTR group, 37 (26.8%) were observed and 33 (23.9%) received postoperative treatment. The median PFS and OS were 6.8 and 18.4 years, respectively. Between adjuvant treatment and observation, there was no significant difference in PFS or OS. However, GTR or STR with less than 10% residual tumor exhibited significantly better PFS and OS compared to PR or biopsy (p = 0.022 and 0.032, respectively). Multivariate analysis revealed that contrast enhancement on MRI was associated with worse PFS (HR = 2.36, p < 0.001) and OS (HR = 5.89, p = 0.001). And the presence of seizures at presentation was associated with improved OS (HR = 0.28, p = 0.006).ConclusionThis study underscores favorable long-term outcomes for patients with 1p/19q co-deleted ODG WHO grade 2. Our findings indicate that the EOR plays a crucial role as a significant prognostic factor in enhancing PFS and OS outcomes in WHO grade 2 ODG.

Long-term outcomes of CNS WHO grade 2 oligodendroglioma in adult patients: a single-institution experience

PurposeOligodendrogliomas (ODGs) are a subtype of diffuse lower-grade gliomas with overall survival of > 10 years. This study aims to analyze long-term outcomes and identify prognostic factors in patients with WHO grade 2 ODG.MethodsWe retrospectively reviewed 138 adult patients diagnosed with 1p/19q co-deleted ODG who underwent surgical resection or biopsy between 1994 and 2021, analyzing clinical data, treatment details, and outcomes. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier analysis. Univariate and multivariate Cox regression analyses were utilized to identify significant prognostic factors.ResultsIn the gross total resection (GTR) group, 63 (45.7%) underwent observation and 5 (3.6%) received postoperative treatment; in the non-GTR group, 37 (26.8%) were observed and 33 (23.9%) received postoperative treatment. The median PFS and OS were 6.8 and 18.4 years, respectively. Between adjuvant treatment and observation, there was no significant difference in PFS or OS. However, GTR or STR with less than 10% residual tumor exhibited significantly better PFS and OS compared to PR or biopsy (p = 0.022 and 0.032, respectively). Multivariate analysis revealed that contrast enhancement on MRI was associated with worse PFS (HR = 2.36, p < 0.001) and OS (HR = 5.89, p = 0.001). And the presence of seizures at presentation was associated with improved OS (HR = 0.28, p = 0.006).ConclusionThis study underscores favorable long-term outcomes for patients with 1p/19q co-deleted ODG WHO grade 2. Our findings indicate that the EOR plays a crucial role as a significant prognostic factor in enhancing PFS and OS outcomes in WHO grade 2 ODG.

Unmet needs in relapsed/refractory mantle cell lymphoma (r/r MCL) post-covalent Bruton tyrosine kinase inhibitor (BTKi): a systematic literature review and meta-analysis

To quantify the clinical unmet need of r/r MCL patients who progress on a covalent Bruton tyrosine kinase inhibitor (BTKi), we conducted a systematic review to identify studies that reported overall survival (OS), progression-free survival (PFS), or response outcomes of patients who received a chemo(immunotherapy) ± targeted agent standard therapy (STx) or brexucabtagene autoleucel (brexu-cel) in the post-BTKi setting. Twenty-six studies (23 observational; three trials) reporting outcomes from 2005 to 2022 were included. Using two-stage frequentist meta-analyses, the estimated median PFS/OS for patients treated with an STx was 7.6 months (95% CI: 3.9–14.6) and 9.1 months (95% CI: 7.3–11.3), respectively. The estimated objective response rate (ORR) was 45% (95% CI: 34–57%). For patients treated with brexu-cel, the estimated median PFS/OS was 14.9 months (95% CI: 10.5–21.0) and 32.1 months (95% CI: 25.2–41.2), with a pooled ORR of 89% (95% CI: 86–91%). Our findings highlight a significant unmet need for patients whose disease progresses on a covalent BTKi.

Unmet needs in relapsed/refractory mantle cell lymphoma (r/r MCL) post-covalent Bruton tyrosine kinase inhibitor (BTKi): a systematic literature review and meta-analysis

To quantify the clinical unmet need of r/r MCL patients who progress on a covalent Bruton tyrosine kinase inhibitor (BTKi), we conducted a systematic review to identify studies that reported overall survival (OS), progression-free survival (PFS), or response outcomes of patients who received a chemo(immunotherapy) ± targeted agent standard therapy (STx) or brexucabtagene autoleucel (brexu-cel) in the post-BTKi setting. Twenty-six studies (23 observational; three trials) reporting outcomes from 2005 to 2022 were included. Using two-stage frequentist meta-analyses, the estimated median PFS/OS for patients treated with an STx was 7.6 months (95% CI: 3.9–14.6) and 9.1 months (95% CI: 7.3–11.3), respectively. The estimated objective response rate (ORR) was 45% (95% CI: 34–57%). For patients treated with brexu-cel, the estimated median PFS/OS was 14.9 months (95% CI: 10.5–21.0) and 32.1 months (95% CI: 25.2–41.2), with a pooled ORR of 89% (95% CI: 86–91%). Our findings highlight a significant unmet need for patients whose disease progresses on a covalent BTKi.

Longitudinal circulating tumor DNA kinetics and correlation with patient outcomes in metastatic melanoma.

e21538 Background: Previous studies have shown circulating tumor DNA (ctDNA) to be an accurate noninvasive method for detecting minimal residual disease and predicting therapeutic response. This study aims to investigate if positive ctDNA and subsequent clearance kinetics may be used as a predictive and prognostic tool in patients with stage IV metastatic melanoma. Non-clearance of ctDNA may be associated with poorer outcomes for progression-free survival (PFS) and overall survival (OS). Methods: In this retrospective analysis of preexisting data from a cohort of 27 patients with stage IV melanoma treated at Rush University, longitudinal ctDNA plasma samples collected between 05/01/2020 and 01/01/2024 were analyzed. A tumor-informed ctDNA assay (SignateraTM, reported in mean tumor molecules per mL (MTM/ml), low limit of detection of 0.01% variant allele frequency) was used for detection and quantification of ctDNA in plasma samples. Progression was determined based off of radiographic studies, overall survival was determined by time from stage IV diagnosis to patient death. Results: A total of 192 ctDNA timepoints were analyzed. The median number of ctDNA timepoints per patient was 5 (range 1-26). 8 patients were identified whose initial ctDNA result was negative and remained negative throughout their treatment course; 5/8 of these patients had baseline negative values available prior to the initiation of treatment. 19 patients had at least 1 positive ctDNA result at any given time; 1/19 of these patients was ctDNA-negative at baseline, 7/19 were positive at baseline, and 11/19 did not have baseline values available. The PFS rate was higher for ctDNA-negative patients compared to ctDNA-positive patients (62.5% vs. 57.9%). The OS rate was also higher for ctDNA-negative patients compared to ctDNA-positive patients (75% vs. 52.6%). Of the ctDNA-positive patients, those who achieved persistent clearance or had decreasing values of ctDNA had higher PFS rates when compared to ctDNA-positive patients who neither downtrended nor achieved clearance (71.4% and 66.7% vs. 22.9%). Patients who achieved persistent clearance or had decreasing values of ctDNA also had higher OS rates when compared to ctDNA-positive patients who neither downtrended nor achieved clearance (71.4% and 100% vs. 33.3%). Conclusions: Within the limitations of a small sample size, our data suggests that for patients with stage IV melanoma, a positive ctDNA result is associated with poorer outcomes for PFS and OS, when compared to patients with negative ctDNA results. Additionally, ctDNA-positive patients who achieved persistent clearance or downtrending ctDNA values showed more favorable outcomes for PFS and OS than ctDNA-positive patients who did not. [Table: see text]

Development of a novel granulocyte scoring system for use as a predictive/prognostic biomarker in patients with advanced melanoma undergoing treatment with combination immunotherapy.

9551 Background: Despite the implementation of immune checkpoint inhibition (ICI) for patients with metastatic melanoma, there remains an unmet clinical need for predictive/prognostic biomarkers to determine, from outset, which patients will derive benefit. Recent literature has suggested a significant role for granulocyte subsets in the development of resistance to systemic therapies, with an associated role in adaptive immunity. Methods: We sought to establish a novel immunological scoring system to use as a predictive/prognostic biomarker in patients with advanced melanoma being treated with ICI. In this retrospective, single centre study evaluating patients with advanced melanoma treated with combination ipilimumab and nivolumab, progression free survival (PFS) and overall survival (OS) were compared between groups defined by neutrophil, lymphocyte, eosinophil, monocyte and basophil counts. Data from 226 patients was collected at baseline, week 3, week 6, first response scan and at progression. Baseline and week 3 data was the focus of this primary analysis. Kaplan-Meier estimation and Cox regression analysis were performed. Results: Univariate analysis demonstrated that absolute neutrophil, eosinophil and basophil count strongly associates with PFS and OS outcomes at week 3. Combination of these counts into a novel neutrophil to eosinophil + basophil ratio (NEBR, (N/(E+B)) was assessed as a scoring system. High NEBR was associated with poorer PFS and OS at baseline and week 3 with consistently superior predictive/prognostic value than the well-established neutrophil to lymphocyte ratio (NLR). After accounting for covariates including concurrent steroids, infection and LDH, high NEBR remained significantly associated with worse PFS at baseline and poorer PFS and OS at week 3. Conclusions: Our findings highlight NEBR as a novel immunotherapeutic predictive/prognostic biomarker with potential clinical utility that warrants further investigation in patients with advanced melanoma and across other tumour groups. Further validation will be required through independent external datasets. [Table: see text]

A systematic literature review and indirect treatment comparison of PARP inhibitors in combination with next-generation hormonal agents in BRCA-mutated metastatic castration-resistant prostate cancer.

e17029 Background: In the USA, several poly(ADP-ribose) polymerase inhibitors (PARPi) are approved in combination with next-generation hormonal agents (NHAs) for metastatic castration resistant-prostate cancer (mCRPC), including olaparib plus abiraterone acetate with prednisone/prednisolone (OLA+AA/P) and niraparib plus AA/P (NIRA+AA/P) for mCRPC with BRCA1 and/or BRCA2 mutations (BRCAm), and talazoparib plus enzalutamide (TALA+ENZ) for mCRPC with homologous recombination repair mutations, including BRCAm. All approvals were based on placebo (PBO)-controlled Phase III trials. To support clinical decision-making, we performed a systematic literature review and indirect treatment comparison (ITC) to assess the comparative efficacy and safety of regimens. Methods: Published clinical trials were identified by searching Embase, MEDLINE, Evidence-Based Medicine Reviews database, conferences and registries up to September 2023. Studies reporting radiographic progression-free survival (rPFS), overall survival (OS), and/or safety outcomes for mCRPC were included. The feasibility of performing anchored or unanchored ITCs using BRCAm subgroup data was assessed. Where feasible, Bayesian ITCs were performed using BRCAm subgroup hazard ratios (HRs) for investigator-assessed rPFS, blinded independent central review (BICR) rPFS, and OS. Safety ITCs were performed using overall study data and reported as risk differences (RD) for adverse events (AEs). Results: Thirty-nine studies were identified, of which three reported BRCAm-specific data, including PBO-controlled studies for OLA+AA/P, NIRA+AA/P, and TALA+ENZ. An anchored ITC was feasible for OLA+AA/P and NIRA+AA/P using PBO+AA/P as a common comparator. ITC results showed a significant improvement in rPFS and OS, and a numerical reduction in AE risk for OLA+AA/P vs NIRA+AA/P (Table). TALA+ENZ was excluded from the ITC as it was not possible to form a network with OLA+AA/P or NIRA+AA/P due to differences in NHA use (ENZ vs AA/P) in PBO-control arms, whilst data limitations prevented unanchored ITCs. Conclusions: In BRCAm mCRPC, ITC results suggest that OLA+AA/P has improved efficacy and a favorable safety profile vs NIRA+AA/P. Current evidence does not allow for a robust comparison of OLA+AA/P or NIRA+AA/P with TALA+ENZ in BRCAm mCRPC. [Table: see text]

A systematic literature review and indirect treatment comparison of PARP inhibitors in combination with next-generation hormonal agents in BRCA-mutated metastatic castration-resistant prostate cancer.

e17029 Background: In the USA, several poly(ADP-ribose) polymerase inhibitors (PARPi) are approved in combination with next-generation hormonal agents (NHAs) for metastatic castration resistant-prostate cancer (mCRPC), including olaparib plus abiraterone acetate with prednisone/prednisolone (OLA+AA/P) and niraparib plus AA/P (NIRA+AA/P) for mCRPC with BRCA1 and/or BRCA2 mutations (BRCAm), and talazoparib plus enzalutamide (TALA+ENZ) for mCRPC with homologous recombination repair mutations, including BRCAm. All approvals were based on placebo (PBO)-controlled Phase III trials. To support clinical decision-making, we performed a systematic literature review and indirect treatment comparison (ITC) to assess the comparative efficacy and safety of regimens. Methods: Published clinical trials were identified by searching Embase, MEDLINE, Evidence-Based Medicine Reviews database, conferences and registries up to September 2023. Studies reporting radiographic progression-free survival (rPFS), overall survival (OS), and/or safety outcomes for mCRPC were included. The feasibility of performing anchored or unanchored ITCs using BRCAm subgroup data was assessed. Where feasible, Bayesian ITCs were performed using BRCAm subgroup hazard ratios (HRs) for investigator-assessed rPFS, blinded independent central review (BICR) rPFS, and OS. Safety ITCs were performed using overall study data and reported as risk differences (RD) for adverse events (AEs). Results: Thirty-nine studies were identified, of which three reported BRCAm-specific data, including PBO-controlled studies for OLA+AA/P, NIRA+AA/P, and TALA+ENZ. An anchored ITC was feasible for OLA+AA/P and NIRA+AA/P using PBO+AA/P as a common comparator. ITC results showed a significant improvement in rPFS and OS, and a numerical reduction in AE risk for OLA+AA/P vs NIRA+AA/P (Table). TALA+ENZ was excluded from the ITC as it was not possible to form a network with OLA+AA/P or NIRA+AA/P due to differences in NHA use (ENZ vs AA/P) in PBO-control arms, whilst data limitations prevented unanchored ITCs. Conclusions: In BRCAm mCRPC, ITC results suggest that OLA+AA/P has improved efficacy and a favorable safety profile vs NIRA+AA/P. Current evidence does not allow for a robust comparison of OLA+AA/P or NIRA+AA/P with TALA+ENZ in BRCAm mCRPC. [Table: see text]

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in &gt;1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in &gt;50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

68Ga]Pentixafor PET/CT for staging and prognostic assessment of newly diagnosed multiple myeloma: comparison to [18F]FDG PET/CT.

To evaluate the prognostic performance of [68Ga]Pentixafor PET/CT at baseline for staging of patients with newly diagnosed multiple myeloma (MM) and to compare it with [18F]FDG PET/CT and the Revised-International Staging System (R-ISS). Patients who underwent [68Ga]Pentixafor and [18F]FDG PET/CT imaging were retrospectively included. Patient staging was performed according to the Durie-Salmon PLUS staging system based on [68Ga]Pentixafor PET/CT and [18F]FDG PET/CT images, and the R-ISS. Progression-free survival (PFS) at patient follow-up was estimated using the Kaplan-Meier estimator and compared using the log-rank test. Area under the receiver operating characteristic curve (AUC) was calculated to assess predictive performance. Fifty-five MM patients were evaluated. Compared with [18F]FDG PET, [68Ga]Pentixafor PET detected 25 patients as the same stage, while 26 patients were upstaged and 4 patients were downstaged (P = 0.001). After considering the low-dose CT data, there was no statistically significant difference in the number of patients classified in each stage using [68Ga]Pentixafor PET/CT and [18F]FDG PET/CT (P = 0.091). [68Ga]Pentixafor PET/CT-based staging discriminated PFS outcomes in patients with different disease stages (stage I vs. stage II, stage I vs. stage III, and stage II vs. stage III; all P < 0.05), whereas for [18F]FDG PET/CT, there was only a difference in median PFS between stage I and III (P = 0.021). When staged by R-ISS, the median PFS for stage III was significantly lower than that for stage I and II (P = 0.008 and 0.035, respectively). When predicting 2-year PFS based on staging, the AUC of [68Ga]Pentixafor PET/CT was significantly higher than that of [68Ga]Pentixafor PET (0.923 vs. 0.821, P = 0.002), [18F]FDG PET (0.923 vs. 0.752 P = 0.002), and R-ISS (0.923 vs. 0.776, P = 0.005). [68Ga]Pentixafor PET/CT-based staging possesses substantial potential to predict disease progression in newly diagnosed MM patients.

Randomized Bendamustine-Rituximab(R) + Bortezomib Induction and R + Lenalidomide Maintenance for Mantle Cell Lymphoma

While initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine-rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance following induction is often utilized. Thus, the open-label, randomized phase II ECOG-ACRIN Cancer Research Group E1411 trial was designed to test two questions: 1) Does addition of bortezomib to BR induction (BVR) and/or 2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012-2016, 373 previously untreated patients, 87% ≥ 60 years old, were enrolled in this trial. At a median follow up of 7.5 years, there is no difference in the median PFS of BR compared to BVR (5.5 yrs vs. 6.4 yrs, HR 0.90, 90% CI 0.70, 1.16). There were no unexpected additional toxicities with BVR treatment compared to BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide to rituximab did not significantly improve PFS, with median PFS in R vs LR (5.9 yrs vs 7.2 yrs, HR 0.84 90% CI 0.62, 1.15). The majority of patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with rituximab alone following BR. Nonetheless, the > 5 year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by rituximab maintenance as highly effective initial therapy for older MCL patients. (NCT01415752)

Radiotherapy for pediatric low-grade glioma.

Radiotherapy is a highly effective treatment for pediatric low-grade glioma, serving as the standard for evaluating progression-free and overall survival, as well as vision preservation. Despite its proven efficacy, concerns about treatment complications have led to increased use of chemotherapy and targeted therapy, which are associated with poorer progression-free survival outcomes. This review by Indu Bansal and Thomas E. Merchant examines the indications, timing, and results of radiotherapy for pediatric low-grade glioma. The authors provide a comprehensive analysis of clinical management strategies, addressing the controversies surrounding the use and timing of radiotherapy compared to other therapies. The review highlights that while radiotherapy is essential for certain patients, particularly those who are not candidates for complete resection due to the tumor's infiltrative nature or location, it is often deferred in favor of systemic therapies. This deferral can lead to significant morbidity, including poor visual outcomes. Reports indicate that systemic therapy negatively impacts progression-free survival in patients who eventually undergo radiotherapy. Newer radiotherapy techniques have been developed to minimize complications, offering potential benefits over traditional methods. The evolving clinical management of pediatric low-grade glioma involves balancing the benefits of radiotherapy with concerns about its side effects. Although systemic therapies are increasingly favored, their associated inferior progression-free survival and potential for significant morbidity underscore the need for careful consideration of radiotherapy, particularly in older children, adolescents, or those with progressive disease post-systemic therapy. The emerging role of targeted therapy presents additional challenges, including uncertainties about long-term side effects and its interaction with radiotherapy. Further research is needed to optimize treatment strategies and improve outcomes for pediatric patients with low-grade glioma.

A longer time to relapse is associated with a larger increase in differences between paired primary and recurrent IDH wild-type glioblastomas at both the transcriptomic and genomic levels

Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have been dedicated to uncover genomic/transcriptomic alternations associated with the recurrence of GBMs, the evolutionary trajectories of matched pairs of primary and recurrent (P-R) GBMs remain largely elusive. It remains challenging to identify genes associated with time to relapse (TTR) and construct a stable and effective prognostic model for predicting TTR of primary GBM patients. By integrating RNA-sequencing and genomic data from multiple datasets of patient-matched longitudinal GBMs of isocitrate dehydrogenase wild-type (IDH-wt), here we examined the associations of TTR with heterogeneities between paired P-R GBMs in gene expression profiles, tumor mutation burden (TMB), and microenvironment. Our results revealed a positive correlation between TTR and transcriptomic/genomic differences between paired P-R GBMs, higher percentages of non-mesenchymal-to-mesenchymal transition and mesenchymal subtype for patients with a short TTR than for those with a long TTR, a high correlation between paired P-R GBMs in gene expression profiles and TMB, and a negative correlation between the fitting level of such a paired P-R GBM correlation and TTR. According to these observations, we identified 55 TTR-associated genes and thereby constructed a seven-gene (ZSCAN10, SIGLEC14, GHRHR, TBX15, TAS2R1, CDKL1, and CD101) prognostic model for predicting TTR of primary IDH-wt GBM patients using univariate/multivariate Cox regression analyses. The risk scores estimated by the model were significantly negatively correlated with TTR in the training set and two independent testing sets. The model also segregated IDH-wt GBM patients into two groups with significantly divergent progression-free survival outcomes and showed promising performance for predicting 1-, 2-, and 3-year progression-free survival rates in all training and testing sets. Our findings provide new insights into the molecular understanding of GBM progression at recurrence and potential targets for therapeutic treatments.

The Effect of Thyrotropin Suppression on Survival Outcomes in Patients with Differentiated Thyroid Cancer: A Systematic Review and Meta-Analysis.

Background: Long-term management of intermediate- and high-risk differentiated thyroid cancer (DTC) involves thyrotropin (TSH) suppression with thyroid hormone to prevent potential stimulation of TSH receptors on DTC cells, leading to tumor growth. However, the current guidelines recommending TSH suppression are based on low- to moderate-quality evidence. Methods: We performed a systematic review and meta-analysis of studies evaluating the role of TSH suppression in intermediate- and high-risk DTC patients (≥18 years) treated as per regional guideline-based therapy with a follow-up duration of 5 years (PROSPERO #252396). TSH suppression was defined as "below normal reference range" or, when known, <0.5 mIU/L. Primary outcome measures included (i) composite of progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RLFS), and (ii) composite of disease-specific survival (DSS), and overall survival (OS). Secondary outcome included a composite of cardiac or skeletal adverse events. All outcomes and comparisons were represented as TSH suppression versus TSH nonsuppression. Randomized controlled trials, cohort studies, and case-control studies were included for analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effects model. Results: Abstract screening was performed on 6,369 studies. After the exclusion of irrelevant studies and full-text screening, nine studies were selected for the final meta-analysis. Based on seven studies (3,591 patients), the composite outcome of PFS, DFS, and RLFS was not significantly different between TSH suppression and nonsuppression groups (HR: 0.75; 95% CI: 0.48-1.17; I2 = 76%). Similarly, a DSS and OS composite outcome assessment based on four studies (3,616 patients) did not favor TSH suppression (HR: 0.69; 95% CI: 0.31-1.52; I2 = 88%). Even after excluding studies of lower quality, the primary outcomes were not significantly different between the TSH suppression and nonsuppression cohorts. The secondary outcome, obtained from two studies (1,294 patients), was significantly higher in the TSH-suppressed groups (HR: 1.82; 95% CI: 1.30-2.55; I2 = 0%). Significant study heterogeneity was noted for primary outcomes. Conclusion: TSH suppression in intermediate- and high-risk DTC may not improve survival outcomes but may increase the risk of secondary complications. However, the limited evidence and study heterogeneity warrant cautious interpretation of our findings. Registration: PROSPERO #252396.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-09.

Abstract PO4-13-12: PIK3CA mutational status in tissue &amp; plasma as a prognostic tool in HR+/HER2- breast cancer (BC)

Abstract Background: Activating mutations of PIK3CA gene are described in about 30-40% of BC. They confer overall worse prognosis and resistance to endocrine and chemotherapeutic therapy. Concordance between testing methods (tissue &amp; plasma) are not widely studied. We aim to correlate tissue &amp; plasma assays and to analyze the discordant cases and prognostic value of PIK3CA mutations (PIK3CAm) in HR+/HER2- BC. Methods: We performed a retrospective and unicentric analysis of PIK3CA mutational status in tissue &amp; plasma samples in patients (pts) with HR+/HER2- BC from February/21 to April/23. PIK3CA test: Cobas®PIK3CA Mutation Kit. We correlated both diagnostic methods. Kaplan-Meier and Cox models were used to analyze progression-free survival (PFS) and comparison outcomes in PIK3CAm vs wild-type (wt). Results: We analyzed 225 samples from 161pts with HR+/HER2- BC (149 in tissue &amp; 76 in plasma). PIK3CA mutations were detected in 62pts (38.5%), of which 39.6% (59pts) were detected in tissue and 11.8% (9pts) in plasma. Hotspot mutations: H1047X (45.7%), E545X (20%) and E542K (12.8%). In advanced disease, metastatic BC (mBC), tissue &amp; plasma concordance was conducted in 64 cases, with overall correlation rate of 70.3%. We found PIK3CAm in 28pts: by both methods in 9pts (32.1%) and exclusively tissue detection in 19 cases (67.8%). Plasma detection was correlated with the presence of ≥3 metastatic sites (66.7% vs 31.6%; p=0.08) and with collection of samples during disease progression (66.7% vs 47.4%; p=0.43). 80pts received treatment with CDK4/6 inhibitors + endocrine therapy. PFS was slightly shorter in PIK3CAm vs wt (24m vs 30m; HR=1.39 [95%CI,0.7-2.4], p=0.26). A sub-analysis was performed based on exons 9 &amp; 20, showing a significantly lower PFS in PIK3CAm exon 9 vs 20 population (9.7m vs 30.3m; HR=2.84 [95%CI,1.1-7.4], p=0.02). In addition, plasma detection of PIK3CAm was associated with worse PFS compared with PIK3CAm detected only in tissue (12.4m vs 29.3; HR=2.4 [95%CI,0.8-6.5], p=0.08). Although we observed a trend towards a poorer PFS in pts with visceral involvement in PIK3CAm (21.9m vs 30.1m; HR=2.82 [95%CI,0.6-12.3], p=0.14), in a multivariate analysis, mutations in exon 9 were an independent poor prognostic factor regardless visceral involvement and detection in plasma; p=0.05. Conclusions: Our results support the PIK3CA determination in tissue as the diagnostic method of choice, although further studies could better define the role of liquid biopsy in the detection of PIK3CAm. In our population, the presence of PIK3CAm confers poorer prognosis in luminal BC, being significantly worse in mutation carriers in exon 9 regardless visceral involvement and plasma mutation detection. Table. Tissue &amp; plasma correlation in patients with PIK3CA mutational status tested in our population (mBC). Citation Format: Eduardo Terán Brage, Rebeca Lozano Mejorada, Aline Rodrigues Françoso, José Antonio Muñóz Leon, Álvaro López Gutiérrez, Luis Figuero-Pérez, Daniel Morchón Araujo, María Garijo Martínez, Jonnathan Roldán Ruiz, María Mar Abad Hernández, Magdalena Sancho de Salas, Emilio Fonseca Sánchez, César Augusto Rodríguez Sánchez. PIK3CA mutational status in tissue &amp; plasma as a prognostic tool in HR+/HER2- breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-12.

The efficacy of immune checkpoint inhibitors on low PD-L1 cervical cancer: A meta-analysis.

The effectiveness of immune checkpoint inhibitors (ICIs) in low programmed death ligand 1 (PD-L1) expression in cervical cancer (CC) patients remains unknown. We aimed to evaluate the efficacy of ICIs in low PD-L1 expression CCpatients. The study is an individual patient data (IPD)-based meta-analysis. IPD were compiled through KMSubtraction and IPDfromKM methodologies from high-quality randomized clinical trials and single-arm studies which reported overall survival (OS) or progression-free survival (PFS) stratified by PD-L1 expression. Kaplan-Meier curves and Cox regression analysis were employed to evaluate the survival benefits of ICIs. A total of eightstudies and 1110 cases were included in the analysis. Within the low PD-L1 expression subgroup, ICI combination therapy, but not ICI monotherapy, demonstrated significant OS benefits over non-ICI treatment (hazard ratio [HR] = 0.61, 95% confidence interval [CI]:0.36-1.04, p = 0.06). Concerning PFS, ICI monotherapy was associated with a negative effect compared to non-ICI treatment (HR = 4.59, 95% CI:2.32-9.07, p < 0.001). Notably, both OS and PFS outcomes were unfavorable for ICI monotherapy compared to both non-ICI and ICI combination therapy in the combined positive score <1 subgroup (OS: HR = 2.60, 95% CI:1.31-5.16, p = 0.008; PFS: HR = 7.59, 95% CI:3.53-16.31, p < 0.001). In patients with CCand low PD-L1 expression, ICI monotherapy may not be considered as the optimal treatment strategy when compared to non-ICI treatment or ICI combination therapy. CRD42023395103.

Nivolumab, Pomalidomide, and Elotuzumab Combination Regimens for Treatment of Relapsed and Refractory Multiple Myeloma: Results from the Phase 3 CheckMate 602 Study

BackgroundPreclinical studies suggest that combining nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, with pomalidomide/dexamethasone (Pd) with or without elotuzumab, an antisignaling lymphocytic activation molecule F7 monoclonal antibody, may improve multiple myeloma (MM) treatment efficacy. Patients and MethodsThe phase 3 CheckMate 602 study (NCT02726581) assessed the efficacy and safety of nivolumab plus pomalidomide/dexamethasone (NPd) and NPd plus elotuzumab (NE-Pd). Eligible patients (aged ≥ 18 years) had measurable MM after ≥ 2 prior lines of therapy, that included an immunomodulatory drug (IMiD) and proteasome inhibitor (PI), each for ≥ 2 consecutive cycles, alone or combined, and were refractory to their last line of therapy. Patients were randomized 3:3:1 to receive NPd, Pd, or NE-Pd. The primary endpoint was progression-free survival (PFS); overall response rate (ORR) was a key secondary endpoint. ResultsAt a median follow-up of 16.8 months, PFS was similar between treatment arms (Pd, 7.3 months [95% CI, 6.5-8.4]; NPd, 8.4 months [95% CI, 5.8-12.1]; NE-Pd, 6.3 months [95% CI, 2.4-11.1]). ORR was similar in the Pd (55%), NPd (48%), and NE-Pd (42%) arms. Nivolumab-containing arms were associated with a less favorable safety profile versus Pd, including a higher rate of thrombocytopenia (NPd, 25.0%; NE-Pd, 16.7%; Pd, 15.7%), any-grade immune-mediated adverse events (NPd, 13.9%; NE-Pd, 16.7%; Pd, 2.9%), and adverse events leading to discontinuation (NPd, 25.0%; NE-Pd, 33.3%; Pd, 18.6%). No new safety signals were identified. ConclusionCheckMate 602 did not demonstrate clinical benefit of nivolumab (+/- elotuzumab) plus Pd versus Pd for patients with relapsed/refractory MM (RRMM).

Impact of the presence and number of chromosomal abnormalities on the clinical outcome in Waldenström Macroglobulinemia: a monocentric experience.

The prognostic and predictive role of specific gene mutations in Waldenström Macroglobulinemia (WM) is well-ascertained whereas the clinical impact of chromosome aberrations is far less known. Recent work has provided initial evidence for an adverse prognostic impact of some aberrations, such as del(6q), while other studies suggest a possible relationship between some clinical features (e.g. advanced age and/or inflammatory status) and specific cytogenetic abnormalities. To add to the still limited knowledge on WM cytogenetics and its clinical implications, we herein report our experience in a cohort of WM patients across 23years. Based on our retrospective study, we found that abnormal karyotype was more represented in older patients and maintained a statistically significant independence from other molecular, clinical, and biological features related to WM. The presence and number of cytogenetic aberrations correlated with inferior overall and progression-free survival outcomes regardless of the type of single chromosome aberration. Our data suggests that the role of the altered karyotype deserves to be further clarified especially in elderly WM patients, in whom cytogenetic abnormalities and disease biology appear to be characterized by a higher degree of complexity.