tbuckley/cabot-search huggingface dataset:
Target trial emulation with real-world data to determine the population-level cost-effectiveness of multi-gene panel sequencing in advanced melanoma.
Authors: Emanuel Krebs, Deirdre Weymann, Cheryl Ho, Samantha Pollard, Dean A Regier
Journal: Journal of Clinical Oncology (2024)

e21508 Background: Compared to single-gene BRAF testing to guide targeted treatment for advanced melanoma, multi-gene panels can identify additional gene mutations with known therapeutic or prognostic relevance. No randomized control trials of multi-gene panel sequencing have been completed in advanced melanoma. This study determined the population-level cost-effectiveness of multi-gene panel sequencing compared to single-gene BRAF testing for advanced melanoma. Methods: Our population-based retrospective study emulated a hypothetical pragmatic trial using comprehensive patient-level clinical and health administrative data between September 2016 and December 2018 from British Columbia, Canada. To emulate random treatment assignment, we 1:1 matched multi-gene panel patients to contemporaneous controls using a machine learning approach that maximized balance on 15 covariates. Following matching, we estimated mean three-year survival time and costs (2021 CAD), and calculated incremental net monetary benefit (INMB) for life-years gained (LYG) at $100,000/LYG using inverse probability of censoring weighted linear regression and nonparametric bootstrapping. Besides an intention-to-treat (ITT) effect, we also estimated the per-protocol (PP) effect of initiating treatment within 90 days of receiving test results additionally using inverse probability of treatment weights. We also estimated overall survival using Weibull regression and Kaplan-Meier (KM) survival analysis. Results: We matched 147 patients receiving multi-gene panel sequencing to controls, achieving good balance for all included covariates. ITT mean incremental costs were $19,541 (95%CI: -$18,939, $77,396) and mean incremental LYG were 0.22 (95%CI: -0.06, 0.50). We did not find statistically significant different differences in overall survival using the KM (P = 0.11) and Weibull regression (HR: 0.73 [95%CI: 0.51-1.03]) survival analysis in the ITT analysis. PP incremental costs were $36,367 (95%CI: -$6,653, $120,216) and incremental LYG were 0.56 (95%CI: 0.39, 1.24), with corresponding differences in overall survival using KM (P = 0.02) and Weibull regression (HR: 0.56 [95%CI: 0.36-0.87]) survival analysis. The probability of multi-gene panel sequencing being cost-effective at $100,000/LYG was 54.9% in the ITT analysis and 64.5% in the PP analysis. Conclusions: We found the cost-effectiveness of multi-gene panel sequencing to be evenly poised, with estimates favouring multi-gene panel sequencing with respect to overall survival and cost-effectiveness when accounting for probability of treatment initiation. This real-world evidence generated using randomized trial design principles can support jurisdictions’ deliberations on the reimbursement of precision oncology interventions.
Clinical outcomes after adjuvant anti-PD1 therapy for high-risk resectable melanoma and predictors of response.
Authors: John Marsiglio, Feng Bingjian, Magdalena Kovacsovics, Berit Gibson, Qin Zhou, Umang Swami, Jeffery Scott Russell, Alyssa Erickson-Wayman, Elliot Amponsah Asare, Marcus Monroe, Tawnya Lynn Bowles, David Nix, Matthew Williams, Aik-choon Tan, John Robert Hyngstrom, Siwen Hu-Lieskovan
Journal: Journal of Clinical Oncology (2024)

e21502 Background: Adjuvant anti-PD1 is the standard of care for high-risk resectable melanoma but many still suffer recurrence. We report a single institution observational study of patients who received adjuvant anti-PD1 with a particular focus on those who recurred. Methods: Through an approved protocol by Huntsman Cancer Institute IRB, patients with resected high-risk melanoma who first received anti-PD1 in the adjuvant setting were consented and followed. Clinical outcomes were assessed per RECIST 1.1, progression free survival (PFS), and overall survival (OS). Results: 186 eligible patients were included, 105 male and 81 females, median age at C1D1 58 (22-93), 12/161/7 at stage II/III/IV and 5 unstageable. Subtypes included 79 (43%) superficial spreading, 50 (27%) nodular, 16 (9%) lentigo/nevoid, 13 (7%) non-acral skin (NOS), 10 (5%) acral, 4 (2%) mucosal, and 14 (7%) others. With median follow up of 708 days (23-9599), 66 (35.5%) had progressive disease (PD), including 33 (50%) early PD and 33 (50%) late PD. Statistically significant predictors of worse outcome included age &gt; 50 (OS p = 0.043), acral subtype (PFS p = 0.023), PD-L1 IHC &lt; = 1% (OS p = 0.052, PFS p = 0.002), duration of treatment &lt; 3 months (OS p = 0.005, PFS p = 1.8E-07), early PD (OS p = 0.003, PFS p = 1.5E-6) and distant recurrence (OS p = 0.002). Trends that were not significant included: male gender (worse OS), BRAF mutation (better PFS), NF1 mutation (better PFS). No correlation between outcomes and TMB, NRAS, TERT mutation, and primary location. In the early/late PD groups, median age was 57/55 (range 28-79 / 25-84), 64/61% male, 1/0, 29/31, 3/2 stage II, III, IV. 17/13 were superficial spreading, 6/10 nodular, 2/5 acral, 2/2 lentigo, 1/0 mucosal and 4/3 other non-acral skin. Primary site was 12/12 head/neck, 9/5 trunk, 4/7 upper limb, 8/9 lower limb. BRAF was 9/11 wildtype, 15/9 mutant and 9/13 unknown. PD-L1 &gt; = 1% by IHC was 4/2. TMB mut/mb &gt; 10 was 6/5. Sites of recurrence included 6/12 local, 7/7 regional LN, 20/14 distal (3/1 in brain) relapses. For unresectable PD (13/13 early/late) response to next line systemic therapy is shown in Table 1. Conclusions: One third of patients developed PD after adjuvant anti-PD1 for high-risk melanoma. PD-L1 negativity and short duration of treatment was associated with worse outcome. Early PD corresponded to more distant metastasis, poorer OS and response to subsequent systemic therapy. Importantly most late PD can still have a favorable response by resuming anti-PD1 therapy. Further molecular study is ongoing to investigate mechanisms of resistance. [Table: see text]
Survival in de novo metastatic merkel cell carcinoma according to sites of metastases.
Authors: Karam Khaddour, Mofei Liu, Anita Giobbie-Hurder, Emily Kim, Manisha Thakuria, Ann W. Silk
Journal: Journal of Clinical Oncology (2024)

e21511 Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a propensity to form regional and distant metastases. Due to the low incidence of MCC, there is a dearth of studies evaluating the impact of the sites of metastases on clinical outcomes. Recently, we found that liver and bone metastases were associated with shorter overall survival (OS) in patients with recurrent metastatic MCC. Herein, we report on the prognostic impact associated with specific metastatic sites in patients who presented with de novo Stage IV MCC at Dana-Farber Cancer Institute. Methods: Patients were included if they consented to participate in a biobanking study (DF/HCC #09-156) and presented with one or more distant sites of metastases on imaging at the time of diagnosis due to MCC. The following data were collected: age at diagnosis, gender, race, metastatic site(s) at the time of diagnosis, date of diagnosis, first-line treatment, treatment type, best response on imaging, progression, and vital status. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Fisher’s exact test was used for response rate analysis. Results were considered statically significant if p &lt; 0.05. Results: 34 participants presented with one or more distant metastatic sites of MCC between the years 2010 and 2022. There was no association between the number of metastatic sites at presentation and OS (p= 0.58), PFS (p= 0.79), or response rates (p= 0.53). Among the organ sites we examined, bone metastases were associated with shorter OS (8.2 versus 25.2 months, HR = 2.4; 95% CI 1.01 – 5.7, p= 0.04). There were non-significant associations between OS and metastases in lymph nodes (p= 0.07) and in liver (p= 0.16). The location of metastases was not associated with the response rate to first-line treatment. There was no statistically significant association between any site of metastases and PFS. Conclusions: In this cohort of patients with de novo metastatic MCC, the presence of bone metastases, but not the number of overall organs involved, was associated with significantly worse overall survival. If bone involvement is confirmed to be a negative prognostic factor in an independent dataset, it would warrant mechanistic studies to further our understanding of this interplay and a re-examination of the AJCC staging for metastatic disease.
Efficacy and safety of combined anti-angiogenic chemoradiotherapy with PD-1 monoclonal antibody in advanced melanoma: A retrospective study.
Authors: Zhengyun Zou, Yu Ren, Lianjun Zhao
Journal: Journal of Clinical Oncology (2024)

e21516 Background: Malignant melanoma, characterized by its aggressiveness and early metastasis, poses significant challenges in terms of treatment efficacy. This retrospective study aimed to assess the efficacy and safety of the integrated treatment regimen in patients (pts) with advanced melanoma. Methods: 42 pts with histologically confirmed inoperable stage III or IV melanoma and ECOG PS 0 or 1 were included in this retrospective study conducted from September 2020 to August 2023. Pts received combination therapy with albumin-bound paclitaxel, bevacizumab (bev), and toripalimab (tor) (Q3W). Maintenance therapy with bev and tor was given after 6-8 cycles without disease progression or intolerable adverse reactions. Personalized radiotherapy was delivered. Radiological evaluations were performed every 2 cycles during combination therapy and every 3 cycles during maintenance therapy using RECIST 1.1 criteria. Adverse events were graded according to NCI-CTCAE version 4.03. Results: All pts underwent at least one efficacy evaluation. The male-to-female ratio was 1:1, with a median age of 61.5 years (range: 34-80 years). Treatment-naïve pts accounted for 47.6% (n = 20), second-line pts for 35.7% (n = 15), third-line pts for 11.9% (n = 5), and fourth-line pts for 4.8% (n = 2). There were 25 cases (59.5%) of acral melanoma, 4 cases (9.5%) of cutaneous melanoma, 12 cases (28.6%) of mucosal melanoma, and 1 case (2.4%) with an unknown primary site. During the treatment period, 66.7% (n = 28) of pts received radiotherapy. As of December 2023, 26 out of 43 pts showed tumor shrinkage, including 2.4% (n = 1) achieving CR through conversion surgery following PR, maintaining it for 30 months. The ORR was 61.9%, with a confirmed ORR of 57.1%, and a DCR) of 92.9%. The median PFS was 14.4 months, and the median OS has not yet been attained. Common adverse events included alopecia (100%), hypertriglyceridemia (61.9%), elevated transaminases (59.5%), anemia (59.5%), leukopenia (52.4%), hypercholesterolemia (52.4%), peripheral neuropathy (50%). No treatment-related deaths were reported. Conclusions: This study demonstrates that PD-1 monoclonal antibody in combination with chemotherapy, anti-angiogenic therapy and radiotherapy offers a promising therapeutic option for advanced melanoma. Keywords:Malignant melanoma; Albumin-bound paclitaxel; Bevacizumab; PD-1 monoclonal antibody; Radiotherapy.
Real-world effectiveness and safety of dabrafenib-trametinib as first-line of treatment for BRAF mutated metastatic melanoma: Results of the study GEM1801.
Authors: Miguel-Ángel Berciano-Guerrero, Elisabeth Perez-Ruiz, Eva Muñoz Couselo, Jose Luis Manzano, Pablo Cerezuela-Fuentes, Pablo Ayala de Miguel, Ainara Soria, Almudena García Castaño, Guillermo Crespo, Teresa Puértolas, Carlos Aguado De La Rosa, Lourdes Gutiérrez Sanz, Rafael López Castro, Enrique Espinosa, Maria José Lecumberri, Margarita Majem, Javier Medina Martinez, Lorena Bellido, Luis Antonio Fernández-Morales, Salvador Martin-Algarra
Journal: Journal of Clinical Oncology (2024)

e21515 Background: Dabrafenib-Trametinib (DT) is included in the therapeutic arsenal for BRAFV600-mutant metastatic melanoma. However, detailed effectiveness results for dabrafenib and trametinib depending on patient prognostic profile in the real-world are limited. Methods: GEM1801 is a prospective observational study that analyzes the clinical and pathological disease presentation patterns, the different lines of treatment choices and the health outcomes derived from treatments in patients with melanoma in Spain. Here we focus on patients receiving DT as first-line treatment in the metastatic melanoma. Based on previous studies, we defined 3 subgroups: good prognosis (normal LDH and &lt; 3 metastatic sites), poor prognosis (high LDH and ≥3 metastatic sites), and intermediate prognosis (neither of good or poor prognosis). Results: From August 2018 to December 2022, 140 patients receiving DT were enrolled; 45 (32.1%) with good, 42 (30%) with intermediate and 34 (24.3%) with poor prognosis. Subgroup allocation was not possible for 19 patients due to missing info on LDH or metastatic sites. Overall survival (OS) was longer in patients with good versus poor prognosis (median 26.2 vs 10 months; p = 0.024), while those with intermediate prognosis showed a mixed profile with a median OS of 17.4 months. Response to treatment also showed correlation with OS (3-years OS rate: 57.1% vs 23% vs 46.9% vs 26.8% for CR, PR, SD and PD, respectively; p &lt; 0.001). In patients who had a complete response, the 5-year OS rate was 58.3% (95% CI: 31.3-100) while the median overall survival was not reached. In patients with intermediate prognosis, the ECOG-PS was the main prognostic factor in multivariate analysis (hazard ratio: 4.6; 95% CI: 1.8-1.7; p = 0.002). The reported grade 3-5 toxicity was less than 5%. Treatment-related adverse events were reported in 5 (3.6%) patients, consisting of fever, mucositis, pneumonitis, neutropenia, ocular toxicity and retinal detachment. There were no differences across prognostic subgroups ( p = 0.741). Conclusions: DT in the Real-World has an acceptable effectiveness and safety profile. Prognostic groups could help in the selection of patients who could achieve a complete response, since it is the most important prognostic biomarker. Clinical trial information: NCT03605771 . [Table: see text]
Personalized starting age of gastric cancer screening based on individuals’ risk profiles: a population-based, prospective study
Authors: Siyi He, Zhiyi Zhang, Guohui Song, Zhenhai Wang, He Li, Maomao Cao, Fan Yang, Dianqin Sun, Xinxin Yan, Shaoli Zhang, Yi Teng, Qianru Li, Changfa Xia, Wanqing Chen
Journal: JNCI Journal of the National Cancer Institute (2024)

The current recommended starting age for gastric cancer screening lacks unified guideline and individualized criteria. We aimed to determine the risk-stratified starting age for gastric cancer screening in China based on individuals' risk profiles and to develop an online calculator for clinical application.
Ischemia Severity, Coronary Artery Disease Extent, and Exercise Capacity in ISCHEMIA
Authors: Jerome L. Fleg, Zhen Huang, Harmony R. Reynolds, Leslee J. Shaw, Bernard R. Chaitman, Sean M. O’Brien, Leonid Berstein, Jesus Peteiro, Paola E.P. Smanio, Gurpreet S. Wander, Jeffrey S. Berger, Daniel S. Berman, Michael H. Picard, Raymond Y. Kwong, James K. Min, Lawrence M. Phillips, Sripal Bangalore, David J. Maron, Judith S. Hochman
Journal: Circulation (2024)
Letter by Kohsaka et al Regarding Article, “Safety of Switching From a Vitamin K Antagonist to a Non-Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial”
Authors: Shun Kohsaka, Shiori Nishimura, Hiraku Kumamaru
Journal: Circulation (2024)
Predictors of immediate and delayed cutaneous hypersensitivity reactions to paclitaxel.
Authors: Megan Hannah Trager, Alyce Mei-Shiuan Kuo, Stephen W. Dusza, Vivian Park, Larisa J. Geskin, Autumn Guyer, Nour Abuhadra, Ayca Gucalp, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2024)

e24101 Background: Paclitaxel is one of the first-line treatments for breast, ovarian, and lung cancers. However, its use is limited by the high frequency of hypersensitivity reactions. The purpose of the current study was to assess clinical factors associated with immediate and delayed hypersensitivity reactions to paclitaxel and characterize delayed hypersensitivity reactions to paclitaxel in patients with breast cancer. Methods: We conducted a retrospective chart review of patients who received paclitaxel (Taxol) or nab-paclitaxel (Abraxane) between 1/1/2017 and 1/1/2022 at Memorial Sloan Kettering Cancer Center. Results: In total, 12,274 patients were identified who were treated with paclitaxel. Of these, 6,165 had breast cancer and 1,233 were seen by a dermatologist. 734 patients (11.9%) developed an immediate hypersensitivity reaction to paclitaxel. Age (p &lt; 0.001), race (p &lt; 0.001), and prior history of allergy based on prior ICD-10 code (p = 0.05) were significantly associated with immediate hypersensitivity reactions. Patients who developed an immediate HSR (mean 52.5 ± 12.5 years versus 54.8 ± 12.9 years) tended to be younger, on average, than those who did not experience a reaction. Compared to White patients, Black patients were 37% less likely (OR = 0.63; 95% 0.48 – 0.83) and Asian patients were 70% more likely (OR = 1.70; 95% 1.37 – 2.12) to experience a hypersensitivity reaction. 147 patients (4.0%) had a delayed hypersensitivity reaction (cutaneous rash). Delayed hypersensitivity reaction included toxic erythema of chemotherapy, urticaria, morbilliform, maculopapular, and pruritus phenotypes. The most common phenotypes were maculopapular (52%) and urticaria (36%). The majority had not been treated with nab-paclitaxel prior to rash (86%). Race (p &lt; 0.001) and history of allergy (p &lt; 0.001) were associated with development of a cutaneous reaction. Asian patients were almost twice as likely (OR = 1.99; 95% CI: 1.51 - 2.61, P &lt; 0.001) as White patients to present with a delayed HSR to paclitaxel. Patients with an immediate hypersensitivity reaction were more likely to develop a delayed cutaneous reaction (OR = 1.80; 95% confidence interval: 1.27-2.55) than those who did not get an immediate HSR, controlling for breast cancer stage and patient race. Conclusions: In conclusion, risk factors identified for development of immediate hypersensitivity reactions in this study were younger age, Asian race, and history of allergy. Patients who developed an immediate hypersensitivity reaction were more likely to develop a delayed hypersensitivity reaction. Risk factors for development of the rash included Asian race and history of allergy. Awareness of these clinical factors which are associated with development of a rash could guide providers in choosing treatment with paclitaxel or nab-paclitaxel.
Acute pancreatitis secondary to tamoxifen-induced hypertriglyceridemia: A systematic review.
Authors: Ali Hussain, Sumaira Zareef, Sangeetha Isaac, Aakriti Arora, Srijan Valasapalli, Munizay Paracha, Azka Tasleem, Nayan Mainkar, Mahvish Muzaffar
Journal: Journal of Clinical Oncology (2024)

e24105 Background: Tamoxifen can cause paradoxical effects on lipid metabolism and increase triglyceride levels. Acute pancreatitis (AP) can culminate in increased severity and morbidity. A multitude of secondary etiologies may lead to hypertriglyceridemia (HTG), including alcohol, pregnancy, diabetes mellitus, or medications. Tamoxifen is known to cause HTG, but AP as a sequel to this complication remains exceedingly rare. Methods: We performed a systematic search of MEDLINE, Cochrane, Embase, and Google Scholar by using MeSH terms and keywords "tamoxifen," "acute pancreatitis," and "hypertriglyceridemia" from tamoxifen approval in 1977 to December 2023. A total of 26 cases were identified. The diagnosis of AP was established on meeting two of the three Revised Atlanta Classification criteria. Results: A total of 17 case reports fulfilled our inclusion criteria. The mean age of included patients was 35.84 ± 5.99 years. Clinical presentation was mainly related to vomiting (65%), abdominal pain (59%), nausea (47%), and epigastric discomfort (18%). HTG (55%), diabetes mellitus (27%), and hypertension (18%) were major comorbid conditions. The mean onset delay was 11.81 ± 14.75 months, and the tamoxifen dose was 20 mg per day. AP was categorized into mild (35%), moderate (35%), or severe (30%) forms. Treatment mainly consisted of conservative measures, but intravenous insulin (24%) and plasmapheresis (6%) were used in severe cases. The overall mortality rate was 6%. Conclusions: Tamoxifen-induced hypertriglyceridemic pancreatitis is a potential complication of tamoxifen therapy. The findings underscore the need for regular monitoring of serum lipids in these patient patients, especially those with pre-existing HTG or other comorbid conditions that increase their risk of developing hypertriglyceridemic pancreatitis. By implementing these recommendations, clinicians can help reduce morbidity and mortality associated with this condition. [Table: see text]
Letter by Millis et al Regarding Article, “Safety of Switching From a Vitamin K Antagonist to a Non–Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial”
Authors: Christopher E. Millis, Denise F. Feradov, Xavier E. Prida
Journal: Circulation (2024)
Letter by Suwa et al Regarding Article, “Safety of Switching From a Vitamin K Antagonist to a Non–Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial”
Authors: Michihiro Suwa, Isao Morii, Masaya Kino
Journal: Circulation (2024)