tbuckley/cabot-search huggingface dataset:
Effect of <i>P. gingivalis</i> on osimertinib resistance in EGFR-mutant lung cancer.
Authors: Wendong Li, Aviva Rotter-Maskowitz, Keqiang Zhang, Erminia Massarelli, Jan Potempa, Ravid Straussman, Dan Raz
Journal: Journal of Clinical Oncology (2024)

e20511 Background: While most patients with EGFR-mutant lung cancers respond to osimertinib, resistance inevitably develops. Mechanisms of osimertinib resistance remain inadequately understood. Recent studies suggest a potential link between intra-tumoral bacteria and therapy resistance in cancer. Our previous studies found that the pre-conditioned medium (PCM) of certain bacteria in the Bacteroidetes phylum conferred resistance of all EGFR-TKIs tested. In this study, we specifically investigate the effect of Porphyromonas gingivalis, a common component of the human oral microbiome and the main pathogen responsible for periodontal disease, on osimertinib sensitivity in EGFR mutant lung cancer. Methods: P. gingivalis PCM (P-CM) was applied to EGFR-mutant lung cancer cell lines for 3 days and cell viability was measured. Western blot and receptor tyrosine kinase (RTKs) assay were used to analyze the changes of cell signaling pathways, and the contribution of identified signaling pathway to P. gingivalis-mediated resistance to osimertinib were further validated by rescue experiments. To investigate the existence of P. gingivalis in human lung cancer tissues, we used Fluorescence In Situ Hybridization (FISH) probes specific to P. gingivalis and hybridized probes to a tissue microarray (TMA) containing 3 mm punches of lung adenocarcinoma tissue from 30 patients in duplicate. The underlying mechanisms of osimertinib resistance conferred by P. gingivalis were explored by a combination of bacterial genomic and cellular proteomic approaches. Results: P-PCM led to osimertinib resistance in all EGFR-mutant lung cancer cell lines tested. Both Western blot and RTKs assay showed that phosphorylated insulin-like growth factor 1 receptor (pIGF1R) level significantly increased when P-PCM was applied to PC9 EGFR mutant lung cancer cells. We found that both IGF1R inhibitor (linsitinib) and IGF1R knockdown with siRNA eliminated the effect of P-PCM-mediated osimertinib resistance. We found that two cysteine proteases secreted by P. gingivalis, lysine-specific gingipain (Kgp) and arginine-specific gingipain A (RgpA) led to osimertinib, whereas arginine-specific gingipain B (RgpB), which lacks haemagglutinin/adhesin (HA) region of RgpA had no effect on osimertinib response. We also found that gingipains-mediated osimertinib resistance is independent of enzymatic activity. We detected intra-tumoral P. gingivalis in tumor tissue of 9 (30%) patients by using FISH probes specific to P. gingivalis. Conclusions: Our studies demonstrate that P. gingivalis can induce osimertinib resistance in EGFR-mutant lung cancer cells through secreted gingipains that activate the IGF1R pathway through an enzymatic- independent mechanism. P. gingivalis is frequently detected in human lung cancer tissues , suggesting that therapies targeting P. gingivalis may improve EGFR-TKI response in certain patients with EGFR-mutant lung cancer.
Neoadjuvant adebrelimab plus dalpiciclib in HPV-negative locally advanced head and neck squamous cell carcinoma: A phase II clinical trial.
Authors: Lei Liu, Yi Li, Fei Chen, Chunjie Li, Huixu Xie, Zhuoyuan Zhang, Xiang Xz, Yuanyuan Zeng, Jun Wang, Bowen Zhang, Chenfeng Tan, Zelei Dai
Journal: Journal of Clinical Oncology (2024)

TPS6129 Background: The efficacy and safety of neoadjuvant immunotherapy (NAI) for treating resectable locally advanced head and neck squamous cell carcinoma (LAHNSCC) remain uncertain, and the comprehensive protocol of NAI needs further explored. The tumor suppressor gene CDKN2A plays a pivotal role in cell cycle regulation by modulating cyclin-dependent kinase (CDK) activity. Mutations in CDKN2A lead to continuous activation of CDK4/6, resulting in uncontrolled cell proliferation and tumor growth. Approximately 35.7% of HNSCC patients exhibit CDKN2A mutations, with the incidence rising to 58% among HPV-negative LAHNSCC patients. Studies have shown that combining immunotherapy with a CDK4/6 inhibitor produces a synergistic anti-tumor effect. This study aims to assess the efficacy and safety of combining anti-PD-L1 (adebrelimab) with a CDK4/6 inhibitor (dalpiciclib) as NAI in resectable LAHNSCC patients. Methods: This open-label, single-arm, prospective phase II trial will enroll LAHNSCC patients eligible for surgery. Inclusion criteria include: being 18 to 75 years old at study entry; pathologically confirmed HPV-negative HNSCC (oral, laryngeal, hypopharyngeal, and HPV-negative oropharyngeal carcinoma), determined via p16 immunohistochemistry or HPV DNA tests; with CDKN2A mutation; resectable LAHNSCC, staged III-IVB according to the UICC/AJCC 8th edition TNM system; an ECOG Performance Status score of 0 or 1; no prior relevant anti-tumor treatments; intent for curative treatment; and adequate organ function. Key exclusion criteria are active autoimmune diseases, use of immunosuppressive drugs, or systemic corticosteroids. Eligible patients receive 3 cycles of adebrelimab (1200 mg intravenously every 3 weeks, Day 1, 22 and 43) and 2 cycles of dalpiciclib (150 mg, po, every 4 weeks, day 1-21 and 29-49) before surgery. Dose adjustments are allowed based on toxicity. Surgery will follow 2-4 weeks post-NAI, with subsequent adjuvant radiotherapy or chemoradiotherapy based on risk factors after surgery. The primary endpoints are 1-year disease-free survival (defined as the time from surgical resection to local recurrence) and major pathological response (MPR, defined as ≤10% residual viable tumor cells), with secondary endpoints focusing on safety and predictive biomarkers. Clinical trial information: NCT06199271 .
Comparing patient profiles and treatment outcomes with radium-223 (<sup>223</sup>Ra) in real-world settings: Academic vs. community practice in the US—Insights from the REASSURE study.
Authors: Celestia S. Higano, Robert K. Brookland, Peter S. Conti, Saby George, Robert Given, Constantine Mantz, John Sylvester, Mary-Ellen Taplin, Svetlana Babajanyan, Matthew J. Korn, Jeffrey Meltzer, Jacqueline Parkin, Jeffrey Tomaszewski, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2024)

e17040 Background: Our aim was to evaluate two distinct clinical settings catering to US patients with metastatic castration-resistant prostate cancer (mCRPC): academic (A) and community (C) practice. We used data from a real-world non-interventional study (REASSURE; NCT02141438) examining the use of 223 Ra. Methods: Patients with mCRPC who received at least one dose of 223 Ra in the US were included. Enrolment occurred between 2014 and 2017; median follow-up was nearly 12 months. Our analysis included patient disease characteristics, treatment history, short- and long-term safety of 223 Ra, patient overall survival (OS), and patient-reported pain (Brief Pain Inventory – Short Form [BPI–SF] scores). A clinically meaningful pain response was a ≥2-point decrease from a baseline score of ≥2 in the BPI-SF worst pain item during treatment until last dose. Results: Analysis included 498 patients (A: 147; C: 351). Comparing A with C, the median ages were 70 and 76 years, respectively, and the majority of patients (74% and 84%) had bone-only metastases. A higher percentage of patients in A (69%) than in C (49%) had completed at least one life-prolonging therapy (LPT) prior to 223 Ra; these included abiraterone (A: 38%; C: 19%), enzalutamide (A: 32%; C:17%), docetaxel (A: 38%; C: 19%), and sipuleucel-T (A: 18%; C: 25%). Most patients received 5–6 223 Ra injections in both settings (A: 65%; C: 71%). 223 Ra was used concomitantly with LPTs in 48% of patients in A and 57% in C, predominantly with abiraterone (A: 25%; C: 25%) or enzalutamide (A: 25%; C: 36%); fewer patients in A (35%) received concomitant bone health agents than in C (52%). For safety outcomes, refer to the table. During treatment, 47% and 62% of patients with a baseline BPI-SF ≥2 had a clinically meaningful pain response in A and C, respectively. The median OS was 17.2 months (95% CI 14.0–19.4) in A and 18.4 months (14.8–21.0) in C. More patients in A (42%) than in C (26%) received a LPT after 223 Ra, most commonly docetaxel (A: 25%; C: 12%). Conclusions: Patients treated in A tended to be younger and more heavily treated, as evidenced by a higher number of patients receiving LPTs prior to and following 223Ra treatment. Bone health agents were more frequently used in C. Additionally, more patients in C had a clinically meaningful pain response and more drug-related AEs were reported in A. Despite the observed differences, overall survival was comparable for both practice settings. Clinical trial information: NCT02141438 . [Table: see text]
Brain metastases in testicular cancer: A single-institution experience in Guatemala.
Authors: Allan Keithel Molina Estrada, Diana Beatriz Marroquin Flores
Journal: Journal of Clinical Oncology (2024)

e17019 Background: Brain metastases secondary to germ cell tumors develop in 2 to 3% of patients, in addition to implying a poor prognosis, its incidence in advanced stages increases to 10-15%. The European Urology Association guidelines recommend performing imaging studies using MRI or brain contrasted tomography to rule out metastases in patients with multiple lung metastases, or high beta subunit of human Chorionic Gonadotropin (β-HCG) values, or those in the poor-prognosis International Germ Cell Cancer Collaborative Group (IGCCCG) risk group. Methods: Retrospective descriptive study in patients with brain metastasis for testicular cancer at the Liga Nacional Contra el Cáncer – INCAN Guatemala, from 2018 to 2022. From medical records, we obtained: demographic, clinico-pathological and treatment data. Median was calculated for age, while frequencies and percentages were computed for the categorical variables. Results: Of the 238 patients diagnosed with testicular cancer, 22% (52) presented a β-HCG above 5,000 IU/L, of which 27% (14) developed brain metastases with a mean age of 28 years. Corresponding to 6% of the total cases studied. Among histological subtypes the most common was choriocarcinoma (43%), follow by mixed germ cell cancer (36%), embrionary carcinoma (14%) and classic seminoma (7%). All of the patients belonged to prognostic group S2. Most patients reported first symptom was headache (42%), followed by seizures (21%), cognitive dysfunction (15%), motor dysfunction (10%) and others (12%). Management of these patients included: orchidectomy in all of them, 57% (8) of patients died, of them 50% (4) of patients died before any other therapy. The rest of them, received chemotherapy and none received radiotherapy or surgery for the brain metastases. Conclusions: The presence of brain metastases in testicular cancer increases the mortality produced by the disease as previously reported in other regions of the world, reason why the early suspicion of it, should prompt the evaluation with a brain MRI or computed tomography.
A phase 2, open-label, single-arm, prospective, multicenter study of <i>nab</i>-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer.
Authors: Lauren E. Dockery, Brian M. Slomovitz, Fernanda Musa, Cara Amanda Mathews, Anna M. Priebe, Angela Green, Allison Puechl, Michael J. Birrer, Nicola M. Spirtos, Li Ding, Anita N. Schmid, Willis H. Navarro, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2024)

TPS5640 Background: This clinical trial is designed to evaluate the antitumor activity of nab-sirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma (EEC). Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative nonchemotherapy-based treatment options for patients with advanced or recurrent EEC remain necessary. Dysregulation of mTOR signaling is implicated in the pathology of EEC, in which &gt;80% harbor PTEN or PI3K/Akt/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine therapy resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORis) and endocrine therapy provides clinical benefit in patients with EEC. nab-Sirolimus is an mTOR inhibitor that uses albumin-bound sirolimus nanoparticles given by IV and is approved by the US FDA for malignant perivascular epithelioid cell tumor. Preclinical data of nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORis. We hypothesize that the simultaneous inhibition of mTOR and ER with nab-sirolimus and letrozole, respectively, may provide a signal of synergistic antitumor activity in patients with recurrent EEC. Methods: In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m 2 , intravenous, on days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned, Simon’s 2-stage design) with clinically confirmed, advanced, or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemotherapy-based regimen in the advanced, metastatic, or recurrent setting, prior adjuvant chemotherapy is permitted, Eastern Cooperative Oncology Group performance status score 0 or 1, naive to mTORi, and measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). The primary endpoint is best overall response rate by RECIST v1.1. Key secondary endpoints include duration of response, disease control rate (defined as complete response plus partial response plus stable disease of ≥12 weeks after start of treatment), progression-free survival, overall survival, and safety. Exploratory endpoints include correlation of baseline molecular biomarkers with clinical outcomes. The trial is open for enrollment. Clinical trial information: NCT05997017 .
Prognostic factors and survival in men with testicular germ cell tumors (GCT).
Authors: Valentina Zagoruiko, Anna Semenova, Sheyda Abdullaeva, Mureiko Ekaterina, Khidishyan Karina, Gulfiya Teletaeva, Alexey Novik, Dilorom Latipova, Alexandr Nosov, Tatiana Semiglazova, Svetlana Protsenko
Journal: Journal of Clinical Oncology (2024)

e17018 Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) has recently discovered new factors for GCT in 2021. We have estimated previously known and new prognostic factors in patients with nonseminomatous germ cell tumors (NSGCT) and seminoma treated at N.N. Petrov NMRC of Oncology. Methods: From 2011 to 2021, the study included 273 adult patients receiving standard cisplatin-based chemotherapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival was estimated using the Kaplan-Meier and Cox methods. Results: 5-year OS rates were 94%, 85% and 70% in the good, intermediate, and poor prognosis groups, respectively for NSGCT and 95% and 86% in good and intermediate prognosis groups for seminoma (p&lt;0.05). 5-year PFS rates were 74%, 51%, and 41% for NSGCT and 76% and 62% for seminoma of the above-mentioned prognostic groups, respectively (p&lt;0,05). Presence of pulmonary metastases (mts) (HR 0.177; 95% CI: 0.051-0.612; p=0.006), non-pulmonary visceral mts (HR 4.636; 95% CI: 1.710-12.570; p= 0.003), elevated LDH of ≥ 2.5 limit of normal (≥ 2.5 × ULN) (HR 4.107; 95% CI: 1.614-10.451; p= 0.003), treatment in high-experienced clinic (HR 0.37; 95% CI: 0.147-0.919; p=0.0032), and non-compliance with guidelines (HR 3.731; 95% CI: 1.456-9.564; p= 0.006) was significantly associated with OS in NSGCT. The presence of pulmonary mts (HR 0.15; 95% CI: 0.024-0.877; p=0.035) and elevated LDH ≥ 2.5 × ULN (HR 0.109; 95% CI: 0.015-0.775; p=0.027) were the only factors associated with poor OS in seminoma. The presence of pulmonary mts (HR 0.446; 95% CI: 0.247-0,804; p=0.007), non-pulmonary visceral mts (HR 2.668; 95% CI: 1.390-5,120; p=0.003) and treatment in high-experienced clinic (HR 1.852; 95% CI: 1.059-3.238; p=0.031), were significantly associated with inferior PFS in NSGCT. Pulmonary mts were the only significant (HR 0.301; 95% CI: 0.100-0.910; p=0.033) factor in the multivariate OS analysis for all testicular GCT. The absence of non-pulmonary visceral mts (HR 0.522: 95% CI: 0.265-0.963; p=0.019) and compliance with guidelines (HR 0.565; 95% CI: 0.309-0.910; p=0.038) were significant factors in the multivariate PFS model for all patients with testicular GCT. Conclusions: The original IGCCCG classification remains the reference for treatment decisions for testicular GCT in daily practice. Non-compliance with guidelines and treatment in high-experienced clinic could become additional poor prognostic factors.
Differences in clinical features between CA-125 and RECIST progression in patients with ovarian cancer treated with PARP inhibitors.
Authors: Yana Ma, Weiwei Lv, Hualei Bu, Beihua Kong, Kun Song
Journal: Journal of Clinical Oncology (2024)

e17568 Background: The clinical features of disease progression (PD) based on Response Evaluation Criteria in Solid Tumors (RECIST) and carbohydrate antigen (CA)-125 criteria, and the impact on prognosis in ovarian cancer patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi) were ambiguous. Methods: All ovarian cancer patients included in this retrospective analysis were treated with PARPi monotherapy and regularly assessed with RECIST and CA-125 criteria until disease progression was confirmed by RECIST criteria. According to the presence or absence of CA-125 PD within a 28-day period before and after RECIST PD, patients were categorized into two groups: RECIST PD group (no CA-125 PD within 28 days) and CA-125 PD group (CA-125 PD present within 28 days). Subsequently, the differences in clinical features and progression-free survival (PFS) of subsequent treatment after PARPi resistance between the two groups were analyzed. Results: A total of 139 patients were included, with 71 (51.1%) in RECIST PD group and 68 (48.9%) in CA-125 PD group. Patients in RECIST PD group had a lower proportion of lymph nodes progression (22.5% vs. 52.9%, p=0.000), and multi-sites progression (28.2% vs. 45.6%, p=0.033). Patients in CA-125 PD group had poorer benefit to subsequent chemotherapy after progression of PARPi, with a median PFS of 5.5 and 7.9 months, respectively (HR=1.44, p=0.019). The multivariate analysis showed that PARPi treatment time less than 6 months (HR=2.218, p=0.001) and RECIST PD accompanied by CA-125 PD (HR=1.766, p=0.024) were the main risk factors for PFS of subsequent treatment. Conclusions: Patients with RECIST PD but without CA125 PD have a reduced likelihood of experiencing lymph nodes progression or multi-sites progression. Conversely, patients with RECIST PD and CA125 PD simultaneously demonstrate poorer outcomes in subsequent treatment after PARPi resistance.
Long term sequelae of testicular cancer and treatment: A point prevalence observational study.
Authors: M Raheel Khan, Patrice Kearney Sheehan, Ashley Bazin, Christine Leonard, Umair Aleem, Sebastian Trainor, Lynda Corrigan, Raymond S. McDermott
Journal: Journal of Clinical Oncology (2024)

e17015 Background: Testicular cancer (TC) is a highly curable solid organ tumour, which usually occurs in the early years of life. Recent studies have observed an increase in the incidence of TC coupled with improvement in cure rates all around the world, especially in Western Europe and North America. Consequently, we have a growing population living in the survivorship phase. Many researchers have highlighted the late complications in TC survivors, linked with the different treatment modalities used for treatment. In this study, we aim to determine the point prevalence of morbidity and mortality in TC survivors at a tertiary care cancer centre in Ireland. Methods: Participants were assessed in a purpose built survivorship clinic and informed consent was obtained. All participants were 18 years or more of age at the time of assessment with a histologically confirmed diagnosis of testicular cancer over 5 years ago. Assessments included a thorough symptom review, clinical examination, blood tests and other investigations (e.g., X-ray, ECG) if required. Results: A total of 81 patients were recruited in the study from March 2023 to January 2024, with a median follow up of more than a 10 years (129 months). Chemotherapy had been given to 85% of patients and radiotherapy to 5%. All except one patient underwent orchiectomy while RPLND was performed in 17% of patients. There were 3 deaths in the survivorship phase, all related to second malignant neoplasms (SMNs). Hyperlipidaemia was the most common condition found in 55% of TC survivors, followed by raised gonadotropins (47%), low testosterone (34%) and hypertension (40%). Other conditions prevalent in our cohort were hearing impairment (26%), abnormal high glucose (8%) and renal impairment(7%). The majority of these co-morbidities were previously undiagnosed before assessment in our survivorship clinic, including 2 cases of coronary artery disease. Over 70% of hypogonadism, hyperlipidaemia, hypertension, renal impairment and high abnormal glucose were initially diagnosed in our clinic. Conclusions: Results from our study are comparable to the studies conducted in other cancer centres across Europe and the US. Second malignant neoplasms remain the major cause of mortality in this cohort but many modifiable risk factors can be diagnosed early and potentially treated to prevent morbidity. Our data strongly supports the need for specialised survivorship clinics to improve the prognosis and quality of life in TC survivors. [Table: see text]