bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase IIb study of selinexor in combination with carfilzomib, daratumumab, or pomalidomide in patients with multiple myeloma relapsing on current therapy.
Authors: Biran Noa , Vesole David H. , Parmar Harsh V. , Phull Pooja , Doucette Kimberley , Feinman Rena , Zenreich Joshua , Anand Palka , Ivanovski Kristin , Pace Monique , Breeze Genevieve , Amer Rania , Biamonte Lisa , Aleman Adolfo , Unawane Rashmi , Pendergrass Elizabeth , Della Pia Alexandra , Kumka Susan , Siegel David Samuel DiCapua
Published: June 2023

e20042

Background: Selinexor is an oral, selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1), leading to retention of tumor suppressor proteins and apoptosis in malignant cells. Preclinical studies suggest synergistic activity when selinexor is combined with other treatments for MM. We hypothesize the addition of selinexor can recapture response to patients relapsing or refractory on carfilzomib (CFZ), pomalidomide (POM) or daratumumab (DARA)-based regimens. Methods: This is an ongoing phase IIb, open-label, multicenter study to evaluate the safety and efficacy of selinexor plus CFZ, POM, or DARA in patients with MM. Patients were enrolled to each arm only if their disease was refractory to the specific drug of interest (CFZ for Arm 1, POM for Arm 2, and DARA for Arm 3). Arm 1 (n=1) consists of selinexor 80 mg orally on D1, 8, 15; CFZ 56 mg/m2 IV on D1, 8, 15; and dexamethasone (DEX) on D1, 8, 15, 22. Arm 2 (n=7) consists of selinexor 60 mg orally on D1, 8, 15; POM 4 mg orally on D1-21; and DEX on D1, 8, 15, 22. Arm 3 (n=7) consists of selinexor 100 mg orally on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ on D1, 8, 15, 22 for C1-2; D1 and 15 for C3-6; D1 for ≥C7; and DEX on D1, 8, 15, 22. The primary endpoint is ORR and secondary endpoints include PFS, OS, MRD negativity and TEAEs. Results: At data cutoff (Feb 6 2023), 15 patients were enrolled with a median age of 64 years (range 60-83), 27% with ISS stage III MM, 73% with high-risk cytogenetics, 93% refractory to the last LOT, 47% triple refractory, and 33% quadruple refractory (Table). The ORR was 33% (4/12; 4 PR) and the CBR was 92% (11/12; 7 SD); 3 patients are pending. The most common grade 3-4 TEAEs (n=34) were neutropenia (32%), hypophosphatemia (9%), pneumonia (6%), hyperglycemia (6%), and fatigue (6%). Ten patients discontinued treatment due to PD (n=5), withdrawal of consent (n=2), or TEAEs (n=3; fall, diarrhea, and RSV pneumonia), of whom 1 patient died while hospitalized for diarrhea and weakness. Conclusions: Preliminary results show selinexor plus CFZ, POM, or DARA is safe and restores sensitivity to therapy in relapsed/refractory MM patients. In this population of heavily pretreated MM patients, the ORR (33%) and CBR (92%) observed are higher compared to those seen with single-agent selinexor (ORR 4% and CBR 21%) (Chen C et al, Blood 2018). Clinical trial information: NCT04661137 . [Table: see text]
Efficacy of teclistamab in patients (pts) with heavily pretreated, relapsed/refractory multiple myeloma (RRMM), including those refractory to penta RRMM and BCMA (B-cell maturation antigen) directed therapy (BDT).
Authors: Venkatesh Priyanka , Atrash Shebli , Paul Barry , Alkharabsheh Omar , Afrough Aimaz , Mahmoudjafari Zahra , Mushtaq Muhammad Umair , Hashmi Hamza , Davis James A. , Abdallah Al-Ola A.
Published: June 2023

e20044

Background: Teclistamab is a B-cell maturation antigen (BCMA) targeting bispecific agent approved in 10/2022 for pts with relapsed refractory multiple myeloma (RRMM) based on the results of the MAJESTEC-1 study. This is the first report on the real-world safety and efficacy of teclistamab in pts with RRMM and highlights patterns of utilization and outcomes in pts, including those who would have been ineligible for enrollment on MAJESTEC-1. Methods: Twenty-two pts with RRMM who received teclistamab at the University of Kansas Health System as of 2/10/2023 had electronic medical records (EMR) reviewed retrospectively in collaboration with US Myeloma Innovations Research Collaborative (USMIRC). Baseline pt characteristics were outlined by descriptive analyses. Responses were evaluated using the International Myeloma Working group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. Results: Pts included in the analysis had received a median of 6 prior LOT and 64% had extramedullary disease (EMD). All of the pts were triple class exposed and 91% were triple class refractory, 77%/59% were penta-class exposed/refractory, while 72% were refractory to prior BCMA directed therapy (BDT). Median follow up was 3.1 (1.7-4.1) months. The most common grade III/IV hematological toxicities were lymphopenia (95%), neutropenia (36%), leukopenia (36%), thrombocytopenia (32%) and anemia (9%). Cytokine release syndrome (CRS) was observed in 9 (41%) pts, all o which were grade I/II events, while immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 5 (23%) pts, with 2 (9%) pts having grade III events. The overall response rate was 50%, and was 56%,46% and 28% for pts who were BDT refractory, penta- refractory, or had EMD, respectively. Of those that did respond, responses tended to be deep (73% ≥ VGPR; 55% ≥ CR). No treatment related mortality was observed, although5 (23%) pts died due to disease progression during follow up. Conclusions: Our study demonstrates the efficacy of teclistamab in heavily pre-treated RRMM, including those who were penta-refractory, BDT refractory, or had EMD. Overall, teclistamab was well tolerated with no major safety events. Keywords: Plasma cell disorders, relapsed multiple myeloma, Penta-class refractory myeloma, BCMA directed therapy. [Table: see text]
Belantamab mafodotin (belamaf) for relapsed/refractory multiple myeloma (RRMM): A real-world observational study update.
Authors: Hultcrantz Malin , Kleinman David , Vij Ravi , Escalante Fernando , Delforge Michel , Kotowsky Nirali , Bitetti Jacopo , Boytsov Natalie , Camadoo-O'Byrne Leena , Powers Happ Lindsey , Rohman Mujib , Germain Guillaume , Duh Mei Sheng , Laliberté François , Mahendran Malena , Urosevic Ana , Lee Hans C.
Published: June 2023

e20046

Background: A prior retrospective analysis of US patients (pts) with RRMM suggested that pts treated with belamaf, a BCMA-targeting antibody-drug conjugate, experienced similar outcomes to those who received belamaf in the pivotal DREAMM-2 study. This updated analysis aimed to characterize pts, assess occurrence and management of ocular adverse events (AEs), and evaluate belamaf effectiveness in a real-world setting. Methods: This retrospective, longitudinal, observational study used data sourced from the US EHR-derived Flatiron Health de-identified database (01/01/2011–06/30/2022). Eligible pts had a confirmed MM diagnosis, initiated belamaf after FDA approval (08/05/2020; first administration=index date), were ≥18 years old at index, and had chart abstraction data for ocular safety and treatment effectiveness. Data on ocular AEs were reported separately for all pts and pts with ≥4 months (mo) of follow-up to allow for sufficient follow-up to evaluate incidence of ocular AEs and their mitigations. Tumor response was assessed in all pts, along with Kaplan-Meier estimates of duration of response (DoR), overall survival (OS), and progression-free survival (PFS). Results: Of the 184 pts included in the study, mean age was 68.7 years; 64% were White and 47% were female. Eastern Cooperative Oncology Group (ECOG) status was ≥2 in 28% patients, 62% had received ≥5 prior lines of therapy, and 82% were triple-class refractory. Median (IQR) follow-up was 4.1 (1.9–8.5) mo. Among pts with ≥4 months of follow-up (n=94) 75% had ≥1 ocular AE, with keratopathy and blurred vision being the most frequent. Mean (SD) time to first ocular AE was 39 (34) days. Most ocular AEs were managed by therapy hold (69%; of which 73% restarted belamaf) and/or AE treatment (63%). The median dose hold due to ocular AEs was 43 days (physician-reported keratopathy: mild, 21 days; moderate/severe, 56 days). In all pts, 39 (21%) had a derived tumor response based on serum free light chain levels, (partial response: 74%, very good partial response: 51%). For all pts, the estimated median DoR was 9.1 mo, PFS 4.5 mo, and OS 7.9 mo, while the 6-month DoR rate was 57%, PFS rate was 46%, and OS rate was 58%. Conclusions: Overall, belamaf was effective in the real world setting in heavily pre-treated pts with RRMM and limited therapy options. The AE profile was consistent with DREAMM-2. Ocular AEs were manageable and despite their occurrence, a high percentage of pts remained on treatment, suggesting belamaf may fill an unmet need for triple-class refractory pts with RRMM. [Table: see text]
Sequencing bispecific antibodies and CAR T cell therapy in multiple myeloma with prior exposure to BCMA-targeted therapies.
Authors: Patel Urvi , Oluwole Olalekan O. , Kassim Adetola , Jayani Reena , Belliveau Paul , Savani Bipin , Dholaria Bhagirathbhai R.
Published: June 2023

e20049

Background: In patients with heavily pretreated relapse and refractory multiple myeloma (MM), novel approaches such as immunotherapies and B-cell maturation antigen (BCMA) targeted therapies have been utilized to show favorable responses Despite these therapies however, patients continue to have disease progression leaving them with fewer options. A need exists to investigate the optimal sequencing strategies in the treatment approach for MM with novel bispecific antibodies (BsAbs) and CAR T cell therapy in patients previously exposed to BCMA-directed therapies. Methods: A comprehensive review of active clinical trials, published primary literature, and meeting abstracts was performed to gather efficacy endpoints and overall response rates (ORR) in patients receiving BsAbs or CAR T therapy with previous exposure to BCMA directed therapy. Results: A variety of BCMA and non-BCMA directed BsAbs along with CAR T cell therapy have been evaluated for ORR in patients who received previous BCMA-targeted therapies. Teclistamab, a BCMA BsAb induced an adequate response of 40% in patients who received previous BCMA directed antibody drug conjugate (ADC) or CAR-T- cell therapy, with a deepening of response observed in 28%. Elranatamab, an investigational BCMA-targeted BsAb demonstrated a preliminary ORR of 54% in a cohort of 13 pts. Talquetamab, a first in class GPRC5D BsAb induced an ORR of 50% in pts with previous BCMA-directed therapy as monotherapy and resulted in an ORR of 72% in combination with daratumumab. Cevostamab, an investigational FcRH5 directed BsAb demonstrated an adequate ORR of 47% in 20 pts who received previous BCMA-directed therapy. In parallel to evaluating responses for BsAbs, CAR T cell therapies including cilta-cel and ida-cel have also induced favorable and durable responses in their prior BCMA therapy exposed cohorts with an ORR of 60.0% and 74% respectively. Comparable safety profiles across both BCMA treatment exposed and BCMA treatment-naive cohorts were observed among all studies. Additional endpoints including minimal residual disease and incidence of infections are to be included in final results. Conclusions: This analysis indicates that sequencing BsAbs and CAR -T cell therapy after previous BCMA-targeted treatments offers meaningful clinical benefit with durable response rates in patients who have few other options. Longer follow up and larger studies are needed to further evaluate their enhanced benefit and generate greater insight for optimal sequencing strategies in heavily pretreated MM patients who have exhausted other options. [Table: see text]
Bendamustine-bortezomib-dexamethasone in relapsed/refractory multiple myeloma.
Authors: Cerchione Claudio , Nappi Davide , Cangini Delia , Ronconi Sonia , Ceccolini Michela , Musuraca Gerardo , Martinelli Giovanni
Published: June 2023

e20051

Background: Bendamustine is an old bi-functional alkylating agent which has proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM). Thus, aiming to provide further insights in this field, also in novel agents’era, we present here a retrospective, real-life analysis of patients with relapsed/refractory MM (rrMM), who had received salvage therapy with bendamustine in combination with bortezomib and dexamethasone (BVD). Methods: 81 patients (44 M/37 F), with rrMM, median age at diagnosis 59.4 years (r. 36-82), median age at start of treatment 63.6 years (r.37-86) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (B 90 mg/sqm days 1,2; V 1.3 mg/sqm days 1,4,8,11, D 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression. Setting and Patients: All patients had previously received bortezomib-based and IMIDs-based treatments, and 32% (26/81) had also received radiotherapy. 69% (56/81) had undergone single or double autologous and three (2%) allogeneic stem cell transplant. Results: Bendamustine was well tolerated, with grade 3-4 transfusion-dependent anemia in 56% (46/81) of patients, and 43% (35/81) grade 3-4 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs. ORR was 63% (51/81: 7 CR, 18 VGPR, 15 PR, 11 MR) with 11 PD and 19 patients in SD, impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Eight patients have surprisingly achieved a notable PR after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Median time to response was 1.3 months (r.1-3), median OS from diagnosis was 67.3 months (r.6-151), median OS from start of Bendamustine was 9.6 months (r.2-36). Conclusions: BVD has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to SCT, also after failure of novel agents. Clinical trial information: FEDII 2022000378 .
FISH abnormalities in Agent Orange–associated multiple myeloma.
Authors: Kort Jeries , O'Brien Timothy
Published: June 2023

e20056

Background: Multiple myeloma (MM) is a plasma cell neoplasm that accounts for approximately 10% of all hematologic malignancies. Molecular investigations have identified a wide heterogeneity in MM at the genomic and epigenomic levels, often with IgH translocations and trisomies seen early in the pathogenesis. Etiological factors, though, are still not well characterized. Agent Orange (AO) was a herbicide widely used as a defoliant by the U.S. military during the Vietnam War. Studies have indicated a probable causative link between exposure to AO and the development of multiple myeloma; in fact, MM is now recognized by the VA as a service-connected diagnosis. However, there have been few small studies addressing whether there are any unique molecular findings in AO associated MM. We sought to determine if there were any specific myeloma FISH abnormalities seen in AO associated MM and if there were any differences in their respective survival. Methods: We included all patients diagnosed with MM from 2010-2022 at Louis Stokes VA Medical Center (Cleveland, OH). Data collected included: age, sex, race, year of diagnosis, AO exposure, bone marrow biopsy results and myeloma FISH panel results. We defined high risk MM based on the presence of t(14;16), t(14;20), del 17p/TP53 or gain 1q. Overall survival (OS) was calculated from date of diagnosis to death. Results: We included 162 patients with MM, among them 32 had AO exposure. There was no significant difference in age or race between exposed and non-exposed patients. MM FISH results were available for 137 patients. Overall, 20% of patients had high risk group cytogenetics and there was no significant difference based on AO exposure. However, there was a trend for increased TP53 mutations in those exposed to AO, although this did not reach statistical significance (8% vs. 3.6%, p = 0.3). Median OS was 72 months for non-exposed patients and 98 months for exposed patients, with no significant difference observed (p = 0.18). Conclusions: In this single institution, retrospective study, AO exposure was not associated with a higher incidence of high-risk cytogenetics by FISH in MM. There was a trend for increased TP53 mutation with AO exposure, but the cohort was small and did not reach statistical significance. In addition, AO exposure was not associated with a worse survival. Further studies are needed to clarify the effects of AO on the development of MM, including genomic and transcriptomic analysis to elucidate the pathobiology of this disease. [Table: see text]
Estimating the impact of adjuvant atezolizumab in preventing recurrences and reducing costs in resectable early PD-L1 high non-small cell lung cancer in Europe.
Authors: Arnold Melina , Jovanoski Nick , Tomar Akanksha , Dubey Akansha , Yim Yeun Mi , Napalkov Pavel
Published: June 2023

e20501

Background: Recurrences of non-small cell lung cancer (NSCLC) after surgery remain common and are associated with significant morbidity and mortality. Loco-regional or metastatic disease recurrence can lead to a substantial health care resource use and economic burden. The aim of this study was to estimate the effect of treating patients with early-stage NSCLC with adjuvant atezolizumab (ATZ) on the number of recurrences and direct healthcare costs in Germany, Spain, France Italy and the UK, together referred to as EU5. Methods: Using an epidemiological model, we estimated the reduction in loco-regional (LR) recurrences or distant metastases (DM) after adjuvant ATZ treatment following chemotherapy in operable NSCLC patients with PDL-1 expression of ≥ 50% on tumor cells (PD-L1 high), stage II-IIIA (AJCC 7th edition staging), without EFGR or ALK alterations. We used data from cancer registries, published literature sources, and market research to obtain incidence rates, staging distribution, biomarker status data, and adjuvant treatment rates. Moreover, we used evidence on the disease-free survival (DFS) of patients on adjuvant ATZ from the IMpower010 (NCT02486718) clinical trial to calculate the projected reduction in the number of LR recurrences or DM over a 10-year period post-ATZ launch relative to best supportive care (BSC). The model considers the costs associated with treatment, management of adverse events, monitoring of the disease, and follow-up healthcare. Results: We project that between 2023 and 2033, 20,483 patients with resected PD-L1 high stage II-IIIA NSCLC would experience recurrence (LR, or DM, or both) in the EU5 if they were treated with BSC (adjuvant platinum-based chemotherapy) alone (Table 1). Assuming peak ATZ uptake of 75%, the model estimates that following adjuvant ATZ and chemotherapy, a total of 4,665 recurrences would be prevented in this patient population in the EU5 over 10 years, representing a 23% decrease in recurrence relative to BSC. These avoided recurrences in EU5 could translate into a considerable reduction in direct healthcare costs. Conclusions: Adjuvant ATZ following chemotherapy results in a considerable population-level reduction of loco-regional recurrence or distant metastasis in resected PD-L1 high stage II-IIIA NSCLC patients. This could translate into a substantial decrease in the economic and societal burden caused by the disease. [Table: see text]
A survey on the detection of HPD-related genes by liquid biopsy in patients with lung cancer in China.
Authors: Zhang Peng , Peng Bo , Jing Zhang , Cheng Shaochen
Published: June 2023

e20502

Background: he prognosis for lung cancer patients receiving immunotherapy is impacted by hyper-progression disease (HPD). Assays for HPD-associated gene mutations were anticipated to be crucial for immunotherapy. Although easy and non-invasive, the liquid biopsy technique is not widely employed in immunotherapy. Here, we want to study details of HPD-related gene mutations in the detection of tissue and liquid biopsy and dig out some relevant information from Chinese Lung Cancer (CLC) patients. Methods: 10 genes with HPD-associated mutation were collected by literature, like SNV ( EGFR, KEAP1, STK11, DNMT3A, PTEN), CNV ( ALK fusion, amplification of MDM2, MDM4, FGF3, FGF4). 3540 cell-free DNA (cfDNA) samples and 6553 tumor tissue samples of LC patients download from Haplab database (HaploX, Shenzhen, China). Genetic alterations were sequenced by NGS platform and microsatellite instability status was calculated through msisensor analysis. The chi-square test was used for statistical hypothesis test. Results: In general, all mutation genes tested except EGFR were detected significantly differently between tissue and cfDNA samples (p < 0.05). 193 samples (156 tDNA, 37cfDNA) with microsatellite instability (MSI) were screened to test HPD-related gene consistency. Results showed no significant difference in 10 HPD-related genes between MSI tissue and blood samples (p > 0.05). Microsatellite stable (MSS) samples of 4499 tumor DNA and 1173 cfDNA were also performed on consistency test. EGFR and the other 4 genes ( FGF3, FGF4, KEAP1, PTEN) were found consistency in tDNA and cfDNA, and ALK (p 0.0051), MDM2 (p 0.0004), MDM4 (p 0.0052), STK11 (p 0.0344), DNMT3A (p < 0.0001) showed significant difference of two type of samples. Conclusions: In overall samples and subtypes tested, only EGFR had no significant differences between tissue and cfDNA, which might make EGFR a perfect biomarker candidate in HPD detection and prognosis. Our outcomes also proved that liquid biopsy has some limitations in monitoring HPD-related genes of CLC compared with tissue biopsy. MSS patients presented more reliable results than MSI patients. When monitoring HPD-related genes except for EGFR using cfDNA, appropriate patients should be considered.
Comparison of gene alterations detected with tumor tissue and plasma in a Chinese population with advanced lung adenocarcinoma.
Authors: Zhang Yong , Li Si , Xi Wenjing , Zhu Chan , Song Yunjie , Deng Wanglong , Qi Chuang
Published: June 2023

e20511

Background: Currently, plasma cell-free DNA has been recommended as an alternative biomarker for guiding precision treatment in lung cancer. In this study, we retrospectively reviewed gene alterations detected by matched plasma and tumor tissue to investigate the concordance and sample-specific observations. Methods: The inclusion criterions included 1) samples collected between January and October 2022, 2) clinical stage IV, lung adenocarcinoma, 3) plasma taken within 4 weeks of tumor biopsy, 4) cell-free DNA and tumor DNA were extracted for next-generation sequencing (sequencing depth, 4000X for tissue and 10000X for plasma), with a pan-cancer 539-gene panel in a CAP-certificated laboratory. Alterations including mutations (SNV, indel), fusion and CNV of driver genes, including EGFR, ALK, ROS1, RET, MET, NTRK, BRAF, ERBB2, KRAS (9-gene), were emphatically reviewed and compared. Concordance was defined as tissue and plasma reported alterations within the same gene, or both negative. Tumor mutation burden (TMB) was calculated as ratio between total number of non-synonymous variants and total size of coding region. Results: After reviewing 630 patients with matched plasma and tumor samples, 121 patients diagnosed with stage IV lung adenocarcinoma were included. The top five altered genes in tissue were TP53 (71.07%), EGFR (57.86%), MYC (33.88%), MUC16 (23.97%), CDK6(23.97%), those in plasma were TP53 (52.89%), EGFR (40.5%), DNMT3A (28.93%%), MUC16 (18.18%), LRP1B (15.7%). The detection rates of driver gene (9-gene) alterations were 92.56% (112/121) for tissue and 69.42% (84/121) for plasma. The overall concordance of 9-gene alteration was 69.42%, it increased to 74.38% excluding fusions and CNVs. Among mutations, EGFR (61/121), KRAS (14/121), ERBB2 (9/121) and BRAF (3/121) were more often reported in tissue or plasma. The concordances were 71.13% ( EGFR), 66.67% ( BRAF), 55.56% ( ERBB2) and 42.86% ( KRAS) respectively. We also observed five mutations ( EGFR G719A/S768I, KRAS G12A/Q61L/A146P) that were only detected in plasma in four patients. One patient was detected with STRN-ALK only in plasma. These plasma-only mutations might provide extra efficacy predicting (sensitive or resistance) for EGFR/KRAS/ALK inhibitors. TMB of plasma and tissue showed strong correlation (Pearson’s Correlation Coefficient of 0.74). 14 and 13 patients were divided into TMB-H ( > 10 mutations/Mb) in tissue and plasma respectively, the concordance rate was 94.21% (114/121). Among qualified samples for MSI evaluations, non MSI-H was detected, the concordance rate was 100%. Conclusions: The sequencing results of matched plasma and tissue presented good concordance of driver gene alterations (especially for EGFR mutations), TMB-H and MSI-H. These suggested ctDNA testing might be a reliable commentary approach to tissue to guide target and immunotherapy in advanced lung adenocarcinoma.
High frequency of germline mutations in DDR associated genes SLX4, MSH6, CDK4, TSC2, and BRCA2 might contribute to the occurrence of MPLC.
Authors: Gu Weiquan , Zhao Ning , Ye Jun , Wang Fei , Xiao Ye , Xiao Mingzhe
Published: June 2023

e20514

Background: Multiple primary lung cancer (MPLC) is the presence of two or more distinct and separate lung tumors in a single patient. Each is considered a primary tumor rather than a metastasis from another site. This phenomenon has been the subject of several studies in recent years due to its increasing incidence and potential implications for patient management and prognosis. The underlying causes of MPLCs are not fully understood. Still, several factors have been proposed to contribute, including the genetic predisposition of carcinogens, such as those in the TP53, BRCA1, and BRCA2 genes, which are associated with an increased risk of developing MPLCs, as well as other cancers. Whether the presence of germline genetic mutations can increase an individual's susceptibility and contribute to the development of MPLCs is not clear yet. Here we reported the landscape of germline mutations of 77 MPLC patients. Methods: We retrospectively analyzed the somatic and germline mutations from 77 MPLC patients by NGS analysis. The GO and KEGG analyses were performed based on the top 30 most frequent germline mutations. Results: Among the 77 patients, 21 (27.27%) were male, and 56 (72.73%) were female. The median age was 60 (26-82) years old. The top 5 frequent germline mutated genes were SLX4 (34.92%), MSH6 (39.68%), CDK4 (26.98%), TSC2 (25.4%), and BRCA2 (25.4%). The top 5 frequent somatic mutated genes were EGFR (80.95%), CDK4 (26.98%), MCL1 (23.81%), SOCS1 (19.05%), and TP53 (19.05%). GO analysis of germline mutations revealed enrichment in ontologies such as response to radiation and UV, cell cycle regulation, a series of DNA damage repair associated ontologies, and telomere organization. KEGG analysis indicated that these germline mutations were enriched in the PI3K-Akt pathway, microRNAs in cancer, TP53 pathway, Fanconi anemia pathway, cellular senescence, and many other cancer-associated pathways. Conclusions: Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. In our analysis, the MPLC patients contained widespread germline mutations in SLX4, MSH6, CDK4, TSC2, and BRCA2, which were all associated with DNA damage repair. Besides, GO analysis and KEGG analysis also revealed enrichment in DDR-associated ontologies or pathways (e.g., TP53 pathway, Fanconi anemia pathway, cellular senescence pathways). To our knowledge, an underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. The widespread of germline mutations in DDR-associated genes, including SLX4, MSH6, CDK4, TSC2, and BRCA2, might contribute to the gene instability and promote the development of MPLC.
Multicenter evaluation of AI-based CT radiomics for EGFR mutation prediction in NSCLC.
Authors: Liu Yan , Bodard Sylvain , Felfli Mehdi , Zerka Fadila , Voyton Charles , Thinnes Alexandre , Jacques Sebastien , Iannessi Antoine
Published: June 2023

e20515

Background: Tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) were the first targeted therapy to enter clinical use for non-small cell lung cancer (NSCLC), thanks to its significant improvement on treatment response and patient survival. Today, tissue sampling is the standard to collect material for testing EGFR mutation status in advanced NSCLC, but has known sampling limitations due to intra-tumoral heterogeneity leading to false negative results. Computed tomography (CT) image based radiomics models offer a non-invasive solution, allowing comprehensive analysis of the entire tumor and surrounding tissue. Radiomics could provide insights during patient longitudinal follow up, or when tissue sample is not accessible is suboptimal. During the past decade, predicting EGFR mutation status using CT radiomics was widely investigated, with promising results. Nevertheless, most studies were single center retrospective studies, without external validation. Therefore, our study aims to investigate the performance of a CT radiomics EGFR mutation prediction model in a multicentral setting with an external cohort. Methods: CT images were collected from multicenter institutions and open source databases (https://www.cancerimagingarchive.net/), including a total of 1047 patients with advanced stage NSCLC with at least one measurable lung lesion (≥10mm). Each lung lesions was segmented semi-automatically followed by the validation of an experienced radiologist with > 20 years of experience. The dataset was divided to 2:1 for training and testing, with the test set originating from centers unique from the training cohort. A total of 1246 radiomics features were extracted using the Pyradiomics package. The 10 most robust features were selected first, by removing all features with variances near zero, then by applying Maximum Relevance — Minimum Redundancy (MRMR) to the remaining features. All selected features were standardized before modelling. A support vector machines (SVM) classifier was trained using a five-fold cross validation to classify EGFR mutations status (Wild type vs Mutant). Results: The SVM model trained with the radiomics features achieved mean area under curve (AUC) of 0.83 (95% CI, ±0.03) on the cross validation and an AUC of 0.76 (95% CI, ±0.03) on the test set. Conclusions: Our multicentric study demonstrated the potential of CT radiomics models in predicting EGFR mutation status in advanced NSCLC, with results similar to those found in current literature. We are optimizing the radiomics model by combining deep learning and clinical features, to improve the accurate, reliable and reproducible performance. AI powered medical image analysis has a bright future as an non-invasive and easy-to-use alternative to identify the expression status of common oncologic genes, serving as predictive biomarker for guiding the targeted therapies of the future.
Impact of CLEC3B mRNA expression on genetic landscape and immune tumor-microenvironment in NSCLC.
Authors: Zimmer Kai , Kocher Florian , Tymoszuk Piotr , Martowicz Agnieszka , Daum Sophia , Pircher Andreas , Horvath Lena , Baca Yasmine , Puri Sonam , Owonikoko Taofeek K. , Oliver Trudy G. , Uprety Dipesh , Kulkarni Amit , Lopes Gilberto , Halmos Balazs , Borghaei Hossein , Liu Stephen V. , Ma Patrick C. , Wolf Dominik , Seeber Andreas
Published: June 2023

e20517

Background: Downregulation of C-type lectin domain family 3 member B (CLEC3B) is observed in non-small cell lung cancer (NSCLC), but its role remains largely unclear. Thus, we conducted this large scale genomic and transcriptomic analysis to gain novel insights into molecular and immunological functions of CLEC3B mRNA expression in NSCLC. Methods: Five publicly available WTS/WES NSCLC datasets (TCGA LUAD/LUSC, GSE41271, GSE66863, GSE81089, BATTLE) and the lung cancer single-cell atlas (Salcher, Cancer Cell 2022) were re-analyzed to decipher various molecular and biological aspects of CLEC3B in NSCLC. Findings were validated in a cohort of 19,982 NSCLC samples, which were centrally profiled (Caris Life Sciences, Phoenix, AZ) using WES/WTS. The cohort was stratified in quartiles according to CLEC3B mRNA expression status, with CLEC3Bhigh ( CLEC3BH) and CLEC3Blow ( CLEC3BL) expression defined as top and bottom quartile of transcripts per million (TPM) for further comparison. Immune cell fractions were calculated using QuantiSeq. Real-world overall survival (OS) was calculated using data from insurance claims. Results: CLEC3B mRNA expression was diminished in NSCLC compared to matched normal tissue (p < 0.001). Adenomatous histology was associated with higher CLEC3B expression compared to squamous/large-cell carcinomas (p < 0.005). In CLEC3B H tumors we observed lower rates of somatic mutations in TP53 (44.1 vs 81.7%), TTN (54.1 vs 79%), CDKN2A (5.2 vs 15%), but higher rates in KRAS (24 vs 7.8%) and STK11 (15.8 vs 2.69%) (all, q < 0.01), which we corroborated in our validation cohort (TP53 (52.4 vs 74.7%), CDKN2A (8.3 vs 13%), RB1 (9.2 vs 13.5%), KMT2D (3.8 vs 7.3%), KRAS (31.8 vs 25.6%), EGFR (17.2 vs 8.1%) and STK11 (15.9 vs 11.3%, all q < 0.05)). Further, CLEC3BH tumors were characterized by an immunosuppressive phenotype reflected by lower TMB and lower rates of MSI-H/dMMR, lower PD-L1 IHC expression and abundance of M2 macrophages and regulatory T-cells. Analysis of bulk and single cell transcriptomic datasets revealed that CLEC3BH was linked to endothelium-specific signaling and higher expression levels in endothelial cells. Finally, increased CLEC3B expression was associated with improved OS in the exploratory and validation cohorts. Conclusions: We herein described the molecular landscape of NSCLCs according to CLEC3B mRNA expression. We speculate that CLEC3B is mainly expressed by endothelial cells, and observed that CLEC3BH was associated with a distinct genetic profile and an immunosuppressive tumor-microenvironment. Thus, CLEC3B expression warrants further investigation as a stratification marker for NSCLC patients undergoing immune checkpoint therapy.
Clinical characteristics of patients with non-small cell lung cancer eligible for biology-guided radiotherapy.
Authors: Olaechea Santiago , Song Tidie , Gilmore Linda , Infante Rodney E. , Westover Kenneth D. , Zhang Yuanyuan , Desai Neil B. , Dan Tu , Timmerman Robert D. , Oz Orhan K. , Iyengar Puneeth , Garant Aurelie
Published: June 2023

e20523

Background: Biology-guided radiotherapy (BgRT) is a novel radiotherapy modality that uses real-time positron emission tomography (PET) to guide radiotherapy beamlets. BgRT recently received FDA clearance for clinical use using the 18F FDG radiotracer for the treatment of tumors in lung and bone. We sought to identify non-small cell lung cancer (NSCLC) patients who may be candidates for BgRT based on diagnostic FDG PET/CT imaging. Methods: We conducted an IRB-approved retrospective assessment of NSCLC patients diagnosed between 01/01/2006 and 12/31/2013 at a tertiary care center in the United States. Patient and tumor characteristics were verified by an institutional data repository team and through electronic medical record review. Patients were excluded from analysis when documentation of clinical/ imaging findings was insufficient. Frequency of characteristics were interpreted with and without tumor diameter and maximum standardized uptake value (SUVMax) parameters, to confirm eligibility for BgRT on this novel radiotherapy device. Results: Of the 686 patients eligible for analysis, 523 presented with tumor SUVMax of ≥6 on diagnostic PET imaging and 360 presented with tumor diameters of at least 2 cm and below 5 cm. Of the 277 patients who met both SUVMax and size parameters, respectively, 75 (27.1%), 145 (52.3%), and 57 (20.6%) presented with squamous, adenocarcinoma, or other/unknown histology, and 77 (27.9%), 29 (10.5%), 92 (33.3%), and 78 (28.3%) presented with stage I, II, III, or IV tumors (AJCC 7th edition). Conclusions: Theoretical applicability of biology-guided radiotherapy was observed in our NSCLC patient cohort. Therefore, despite current limitations of radiotracer uptake thresholds and tumor size restrictions, there is broad potential applicability of this treatment modality, either as a single modality treatment or in conjunction with active systemic therapy. [Table: see text]
Postoperative prognosis in patients with NSCLC with different EGFR mutation sites.
Authors: Dong Chao , Zhang Hushan , Liu Weiqing , Kong Deyu , Chen Xiao , Mo Fei , Deng Jun , Qian Ying
Published: June 2023

e20528

Background: Lung cancer can be divided into small cell lung cancer and non-small cell lung cancer. At the same time, non-small cell lung cancer can be divided into non-small cell lung cancer with different molecular mutations. Among them, the EGFR mutation accounts for about 50% of the patients with non-small cell lung cancer in China, which is a large group of patients. The EGFR mutation has many sites and many forms of mutational subtypes, including common mutations such as L858R, and rare mutations. Although the proportion of rare mutations is small, it is still different from common mutations in patients with TKI treatment and immunity. Methods: This study collected and analyzed the data from Formalin-Fixed Paraffin-Embedded (FFPE) tissues of 330 NSCLC patients which received surgery and underwent a targeted next-generation sequencing (NGS) assay performed by 3DMed Clinical Laboratory Inc., a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory of 3D Medicines Inc. between January, 2019 and June, 2022 in China, to obtain a comprehensive molecular profile of EGFR mutations. genomic alterations, tumor mutational burden (TMB) and PD-L1 expression were analyzed. Gene mutation and TMB level were analyzed by NGS, detected PD-L1 expression by using Dako PD-L1 IHC 22C3 pharmDx, Tumor Proportion Score (TPS) was used to determine expression of PD-L1. Finally, the postoperative follow-up data were also collected and analyzed in this study. Results: Therefore, we retrospectively analyzed the tissue samples of patients with non-small cell lung cancer who received surgical treatment, and carried out NGS detection and analysis, as well as postoperative follow-up. Among them, patients with EGFR mutations accounted for 51.2%. We further analyzed the TMB and PD-L1 expression levels of different EGFR mutation subtypes. First, we found that different EGFR mutation sites, whether common mutations such as L859R, 19del or unusual mutations such as S768I, There is no difference in the prognosis after operation, but it is very significant that our results show that there are two or more EGFR mutations at the same time. Conclusions: NSCLC with EGFR mutation is a very large group of patients, which should be further subdivided into different subtypes according to different EGFR mutation sites, and should perform individualized management. This study found that patients with two or more EGFR mutations and patients with EGFR single site mutations are different types of NSCLC, with different postoperative prognosis, and it may be related to the differences in the expression levels of TMB and PD-L1, which is a direction worthy of further exploration in the future.
Association of TP53 mutations with the expression of PD-L1 expression and TMB, and R175H could be the predictor of neoantigen.
Authors: Wang Lucas , Yang Yaxian , Wang Heran , Fan WenTao , Lian Bin , Jin Ying , Luo Weiquan , Long Zhongming , Huang Mingming , Wang Yongsi , Wen Yunjie , Huang Jian
Published: June 2023

e20530

Background: Lung cancer (LC) is the second leading causes of cancer-related mortality and composed of diverse molecular types. PD-L1 expression and tumor mutation burden (TMB) are important biomarkers of tumor immunotherapy. TP53 mutation is associated with neoantigen productions which is also involved in tumor immunotherapy. The relationship between PD-L1 expression, TMB and TP53 mutations have not yet been fully studied, and the neoantigens derived from TP53 mutations need to be explored. Methods: The total 1932 LC tissue samples (from same number of patients) in formalin fixed and paraffin embedded were collected from Guangzhou Huayin Health Medical Group Co.,Ltd. By targeting next generation sequencing (NGS) of 600 genes, the mutations of TP53 and TMB were obtained. PD-L1 expression was determined according to the tumor proportion score (TPS) evaluated by immunohistonchemistry (the cutoff of PD-L1 is greater than 1% TPS). Neoantigen predictions based on binding affinity data (https://services.healthtech.dtu.dk/service.php?NetMHCcons-1.1). In this data set, mutated peptides of TP53 with a binding affinity of IC50≤50 nM was regarded as candidate neoantigens. Results: Among 1932 samples, 890 (46%) were TP53 mutated. The positive rate of PD-L1 in TP53 mutant type (MT) group was higher than that in TP53 wide type (WT) group(p < 0.01). The WT group had a lower TMB compared with MT group (p = 0.002). The intersection of 49 candidate neoantigens and TP53 high-frequency mutation sites was R175H, which could predicate a neoantigen. Conclusions: This study determined the connection between TP53 mutations and PD-L1 expression and TMB, also made neoantigen prediction of R175H mutation. This study may provide theoretical insights for drug developments of treating lung cancer.
Incidence of additional primary malignancies in patients with malignant peritoneal mesothelioma.
Authors: Pandav Vivek , Patel Jaydeepbhai , Inampudi Jyothik Varun , Li Shenduo , Mahadevia Himil , Koshiya Hiren , Lou Yanyan , Manochakian Rami , Bagaria Sanjay Prakash , Zhao Yujie
Published: June 2023

e20535

Background: Malignant peritoneal mesothelioma (MPM) is a rare disease with about 600 new cases per million people diagnosed annually in the U.S. High incidence of germline mutations has been reported in MPM patients (pts) without asbestos exposure. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in MPM pts. Methods: Using the Mayo Clinic Cancer Registry, we identified 64 pts who were treated for MPM from January 2002-December 2022 with updated follow-up data until 01/15/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 25 pts were male, and 39 pts were female. 14/64 (22%) pts were found to have at least one additional malignancy, including breast cancer (4/14, 29%), colon cancer (3/14, 21%), lymphoma (3/14, 21%), ovarian cancer (2/14, 14%), melanoma (2/14, 14%), anal squamous cell carcinoma (1/14, 7%), papillary thyroid cancer (1/14, 7%), Chronic lymphocytic leukemia (1/14, 7%), renal cell carcinoma (1/14, 7%), squamous cell carcinoma of tongue (1/14, 7%), hepatocellular carcinoma (1/14, 7%) and pituitary macroadenoma (1/14, 7%). 4/14 (29%) pts had more than one (2-4) non-MPM malignancies. The median age at diagnosis of MPM was 65 years (44-82). The median age at diagnosis of non-MPM malignancies was 66 years (18-81). Most of the patients (11/14) were diagnosed with non-MPM malignancy within 12 months of diagnosis of MPM. Most pts (11/14, 78%) were diagnosed with non-MPM malignancy first, among which 5 pts (45%) were found to have MPM on surveillance scans. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and Li-Fraumeni syndrome. FH was available in 29 pts, out of which 28 pts had FH of cancer identified in first-degree relatives. Among the 14 pts with additional malignancies, 9 pts had FH of cancer in first-degree relatives. Among all pts, 15 (18%) pts had a history of asbestos exposure. Among pts who also had non-MPM malignancies, 3/14 (21%) pts had a history of asbestos exposure. Among the 21 non-MPM cancers, 1/21 (5%), 11/21(52%), 1/21(5%), 3/21(14%), and 5/21(24%) non-MPM malignancies were stage 0, stage I, II, and III, or unknown at the diagnosis respectively. All except 1 pt underwent curative treatment for their non-MPM malignancies, and 12 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of multiple primary malignancies in pts with MPM is high, indicating possible genetic predisposition associated with this disease. Early genetic consultation and evaluation for germline mutations may need to be considered for these pts to improve long-term outcomes.
Impact of BAP1 mutational status on immunotherapy outcomes in advanced malignant pleural mesothelioma: A single institution experience.
Authors: Ogbue Olisaemeka , Unlu Serhan , Sorathia Sharmeen , Nanah Abdel Rahman , Abdeljaleel Fatima , Haddad Abdo S. , Daw Hamed
Published: June 2023

e20537

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor of mesothelial cells usually diagnosed at advanced stages with dismal prognosis. Most patients progress after 1st line systemic chemotherapy. In the last decade, single or dual agent immune checkpoint inhibitor (ICI) therapy has emerged as a therapeutic option. BAP1 is a commonly mutated tumor suppressor gene in MPM that has been shown to correlate negatively with survival in other solid tumors. We sought to determine the impact of BAP1 mutation on outcomes with ICIs when used as second line systemic therapy. Methods: We retrospectively reviewed a cohort of MPM patients who received ICIs at the Cleveland Clinic foundation between 2017-2022. Patients must have progressed after 1st line systemic chemotherapy prior to ICI. We then compared oncologic outcomes of ICI therapy based on BAP1 mutational status on Next-Generation Sequencing (NGS). End points of interest were overall response rate (ORR) and progression free survival (PFS) while on ICIs. Results: There were a total of 43 MPM patients who received ICIs following progression on pemetrexed/carboplatin (Median age 74 years, IQR 66-81, range 57-92) with a male predominance (M:F ratio 39:4). Histologies included- 58% epithelioid, 28% sarcomatoid and 14% mixed/biphasic histology. Single agent ICI therapy with nivolumab or pembrolizumab was used in 65%. Median follow up was 3 months. BAP1 mutation on NGS was detected in 16%. Other mutated genes included CDKN2A- 7%, BRAF- 5%, MTAP 2% and PTEN 2%. We compared baseline characteristics and outcomes between BAP1 wild type (WT) and BAP1 mutated (MT) groups. Median age at mesothelioma diagnosis were similar 74 vs 70 years (0.3347) with no significant differences in either asbestos or smoking exposure (Table 1). An analysis of outcomes revealed an ORR to ICI of 33% (36% vs 29% respectively [p = 0.9]). PFS was similar between both groups - 4 months [95% CI, 3-NA] for BAP1 WT vs 4 months [95% CI, 2-18] for BAP1 MT group. Conclusions: BAP1 mutation had no prognostic significance on either response rates or disease progression while on ICI therapy in our cohort of advanced MPM patients. The identification of predictive biomarkers for immunotherapy of MPM is an area of unmet clinical need. [Table: see text]