tbuckley/cabot-search huggingface dataset:
Fixed-duration (FD) first-line treatment (tx) with ibrutinib (I) plus venetoclax (V) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of the FD cohort of the phase 2 captivate study.
Authors: Paolo Ghia, John N. Allan, Tanya Siddiqi, Thomas J. Kipps, Ryan Jacobs, Stephen Opat, Paul M. Barr, Alessandra Tedeschi, Livio Trentin, Rajat Bannerji, Sharon Jackson, Byrone Kuss, Carol Moreno, Edith Szafer-Glusman, Kristin Russell, Cathy Zhou, Joi Suzuki Ninomoto, James P. Dean, William G. Wierda, Constantine Si Lun Tam
Journal: Journal of Clinical Oncology (2021)

7501 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line I+V in CLL. We previously reported results from the Minimal Residual Disease (MRD) cohort wherein undetectable MRD (uMRD) was achieved in over two-thirds of patients (pts) with 12 cycles of I+V, and 30-mo PFS rates were ≥95% irrespective of subsequent randomized treatment (Wierda, ASH 2020). We now present results from the FD cohort, evaluating fixed-duration tx with I+V. Methods: Pts aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Primary endpoint was CR rate, including CR with incomplete recovery (CRi); secondary endpoints were ORR, duration of response, uMRD rate (&lt;10 -4 by 8-color flow cytometry), PFS, OS, tumor lysis syndrome (TLS) risk reduction, and adverse events (AEs). Results: 159 pts were enrolled (median age 60 y). High-risk features included del(17p)/ TP53 mutation, 17%; del(11q), 18%; complex karyotype, 19%; and unmutated IGHV, 56%. 147 (92%) and 149 (94%) pts completed planned tx with I and V, respectively. Median time on study was 27.9 mo (range, 0.8–33.2). With fixed-duration I+V, CR rate was 55% (95% CI 48–63) in the overall population and was consistent across high-risk subgroups. Of the 88 pts who achieved CR, 78 (89%) had durable CR (duration ≥1 y); 1 died 7 mo after CR, and 9 with &lt;1 y follow-up were not evaluable. ORR was 96%. Best uMRD response was achieved in 77% of pts in peripheral blood (PB) and 60% of pts in bone marrow (BM). 24-mo PFS was 95%; 24-mo OS was 98%. Results were similar in pts without del(17p) (n=136) (Table). In pts with del(17p)/ TP53 mutation (n=27), CR rate was 56%, uMRD rate was 81% (PB) and 41% (BM), and 24-mo PFS was 84% (95% CI 63–94). Of 34 pts with high baseline TLS risk based on tumor burden, 32 (94%) shifted to medium or low risk after I lead-in; no TLS occurred. AEs were primarily grade 1/2. Most common grade 3/4 AEs were neutropenia (33%), hypertension (6%), and neutrophil count decreased (5%). AEs led to discontinuation of I in 4% and V in 2%. Conclusions: First-line I+V is an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that provides deep, durable responses in pts with CLL/SLL, including those with genomic high-risk features. CR, uMRD rates, PFS, and OS appear favorable. The safety profile of I+V was consistent with known AEs for each agent; no new safety signals were identified. Clinical trial information: NCT02910583. [Table: see text]
Gasdermin C as a potential prognostic biomarker and its correlation with immune infiltration in pancreatic ductal adenocarcinoma.
Authors: Xianghou Xia, Yang Yu, Hongjian Yang, Dehong Zou, Canming Wang, Jiejie Hu, Jiefei Mao, Xixi Cai, Wenjuan Yin
Journal: Journal of Clinical Oncology (2021)

e16256 Background: Although pyroptosis is critical for macrophages against pathogen infection, its role in cancer cells remains elusive. GSDMC is a pyroptosis executioner newly identified in cancer cells and have been shown to facilitate inflammatory tumor death. However, the expression of GSDMC in Pancreatic Ductal Adenocarcinoma (PDAC), its prognostic significance and possible impact on reshaping tumor immune microenviroment in PDAC is still unknown. Methods: We investigated the expression level of GSDMC using TNM plotter with TCGA and GTEx databases, the prognostic value of GSDMC in PDAC using Kaplan-Meier plotter with TCGA, GTEx and TCGA databases. The correlations between GSDMC and immune infiltration in PDAC were calculated using TIMER2.0 and TIDE with TCGA database. We further validated the prognostic value of GSDMC with immunohistochemistry(IHC) staining on a tissue microarray of 172 cases of PDAC patients receiving treatment in our institution. Correlations between expression of GSDMC and tumor infiltration lymphacytes(TILs) cells were also analyzed on tissue samples of those 172 PDAC patients. Results: TNM plotter analysis shows that the expression of GSDMC in PDAC tumor tissue is 10.49 folds higher than it is in pancreatic normal tissues (p = 8.86*e-56). Results from Kaplan-Meier plotter analysis shows high expression of GSDMC is significantly correlated with poorer overall survival(OS), HR = 1.8(1.19−2.71) logrank P = 0.004 and shorter relapse free survival (RFS), HR = 4.6(1.94−10.88), Logrank P = 0.00014 in PDAC. Analysis with TIMER2.0 and TIDE platform shows that expression of GSDMC is positively correlated with immunosuppressive cells, Cancer Associated Fiberblast (CAF) and Meyloid Derived Tumor Suprresso Cells(MDTSC). IHC staining analysis results is also consistent with aformentioned bioinformatic analysis, showing that high GSDMC expression correlated with shorter OS and reduced Tils infiltration. Conclusions: Our findings suggest that high expression of GSDMC is related to poor prognosis and compromised immune cell infiltration in PDAC. GSDMC holds promise for serving as a valuable prognostic marker and therapeutic target in PDAC.
Aphorisms, Definitions, Reflections, and Paradoxes, Medical, Surgical and Dietetic.
Journal: JAMA (1901)

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Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.
Authors: Sophie Cousin, Carine A. Bellera, Jean Philippe Guégan, Thibault Mazard, Carlos A. Gomez-Roca, Jean Philippe Metges, Coralie Cantarel, Antoine Adenis, Iphigenie Korakis, Pierre-guillaume Poureau, Mariella spalato-Ceruso, Kevin Bourcier, Michèle Kind, Isabelle Soubeyran, Alban Bessede, Antoine Italiano
Journal: Journal of Clinical Oncology (2021)

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.
Faecal immunochemical tests safely enhance rational use of resources during the assessment of suspected symptomatic colorectal cancer in primary care: systematic review and meta-analysis
Authors: Noel Pin-Vieito, Coral Tejido-Sandoval, Natalia de Vicente-Bielza, Cristina Sánchez-Gómez, Joaquín Cubiella
Journal: Gut (2021)

Objective Implementation of faecal immunochemical tests (FIT) as a triage test in primary healthcare may improve the efficiency of referrals without missing cases of colorectal cancer (CRC). We aim to summarise the performance characteristics of FITs for CRC in symptomatic patients presenting to primary healthcare. Design We performed a systematic literature review of Medline and EMBASE databases from May 2018 to November 2020. Previous related systematic searches were also adapted to this aim and completed with reference screening. We identified studies performed on adult patients consulting for abdominal symptoms in primary care which reported data such that the FIT diagnostic performance parameters for CRC could be obtained. Bivariate models were used to synthesise available evidence. Meta-regression analysis was performed to evaluate the causes of heterogeneity. Results Twenty-three studies (69 536 participants) were included (CRC prevalence 0.3%–6.2%). Six studies (n=34 691) assessed FIT as rule in test (threshold of ≥150 µg Hb/g faeces) showing a sensitivity of 64.1% (95% CI 57.8% to 69.9%) and a specificity of 95.0% (95% CI 91.2% to 97.2%). A threshold of 10 µg/g (15 studies; n=48 872) resulted in a sensitivity of 87.2% (95% CI 81.0% to 91.6%) and a specificity of 84.4% (95% CI 79.4% to 88.3%) for CRC. At a 20 µg Hb/g faeces threshold (five studies; n=24 187) less than one additional CRC would be missed per 1000 patients investigated compared with 10 µg Hb/g faeces threshold (CRC prevalence 2%). Conclusion FIT is the test of choice to evaluate patients with new-onset lower gastrointestinal symptoms in primary healthcare.
Complementary and alternative medicine use among cancer patients at two cancer centers in Brazil.
Authors: Eliza Dalsasso Ricardo, Denise Oishi, Angel Ayumi Tome Uchiyama, Catarina Marchon da Silva, Josué Bravo Espinoza, Frederico Rafael Moreira, Marcelo Oliveira Dos Santos, Rachel Pimenta Riechelmann, Renata D'Alpino D'Alpino
Journal: Journal of Clinical Oncology (2021)

12060 Background: Complementary and alternative medicine (CAM) use is relatively common among cancer patients. Data regarding CAM use in Brazil is scarce. We sought to define CAM use among cancer patients and investigate factors that might influence it. Methods: We conducted a cross-sectional survey of adults diagnosed with any cancer type who came to appointments at two cancer centers in Brazil from January 2020 to January 2021. Unadjusted and adjusted analyses were conducted by using Logistic Regression models to determine the association of covariates with binary outcome. Statistical analyses were performed with SAS 9.4 (SAS Institute Inc, Cary, NC). All tests were 2-sided, and P &lt; 0.05 was considered significant. Results: In total, 319 patients who consented to the face-to-face interview were included and all of them completed the questionnaires. Most patients (52.4%) were between 51 and 70 years-old, 59,6% were female, 85,2% were from the private service and 67% had college graduate/baccalaureate. Most cancer types were from gastrointestinal tract (31,4%), breast (20.4%), lung (12.3%) and genitourinary type. More than 85% of the participants were on any active cancer treatment. The prevalence of current CAM use was 34.2% and 50.2% of the patients did not believe CAM has anti-cancer properties. Two-thirds of the participants have never discussed about CAM with their oncologists. Only 4.1% of the respondents would abandon conventional cancer treatment in order to use just CAM. Among CAM users, 55% referred multiple therapies use. Of those therapies, spiritual surgery was the most prevalent one. There was a significant higher proportion of females reporting CAM use (p = 0,008) as well as a higher proportion of CAM use among private patients (p = 0,008). Conclusions: CAM use was common among our study population, especially spiritual surgery. Women and private patients were more prone to use CAM. Although most patients would not abandon conventional treatment, many of them have never discussed about CAM with their oncologists.
Genetic and immune divergence in pancreatic cancer lesions at the time of metastatic relapse compared to primary tumor.
Authors: Bereket Gebregziabher, Derek A. Oldridge, Emma E. Furth, Michael D. Feldman, Andrew J. Rech, Robert H. Vonderheide
Journal: Journal of Clinical Oncology (2021)

4140 Background: Relapse of pancreatic ductal adenocarcinoma (PDA) is common even after complete resection and adjuvant therapy. Compared to the resected tumor, the biological characteristics of metastatic tumors at the time of first relapse are poorly understood. Methods: Whole-exome sequencing (WES) (250x) and bulk RNA sequencing were performed on samples from 30 patients with PDA. Paired primary tumor samples were obtained after R0 or R1 resection, and metastatic tumor samples were obtained by biopsy at the time of first relapse. 74.1% of patients had received adjuvant chemotherapy and radiation therapy, 7.4% had received adjuvant chemotherapy only, and 3.7% had received adjuvant radiation therapy only. Most common metastatic sites were liver and lung. The cohort was 60% male with a median age at diagnosis of 64 years. The vast majority of patients had stage IIA or IIB disease at diagnosis. Median disease-free survival was 481 days. Analysis used Freebayes (somatic variant calling), Kallisto (transcript quantification), Danaher et al. (cell type deconvolution), and antigen.garnish (neoantigen prediction). Results: High-quality WES and/or RNA sequencing were available for 27/30 patients. Among these were 16 pairs of primary and metastatic samples for WES and 15 paired samples for RNA sequencing. Median tumor purity was 32% (primary) and 42% (metastatic). KRAS mutations were present in 43/48 evaluable samples, with conserved KRAS mutations in 14/16 primary-metastatic pairs. Tumors were otherwise highly variable, with 13/16 patients developing oncogenic mutations in metastatic tumors that were undetected in primary tumors (BRCA1 [3/16], AKT3 [3/16], TP53 [2/16], ROS1 [2/16]). Overall, primary and metastatic tumors had similar tumor mutation burden and neoantigen production rate. However, neoantigens were highly variable at the peptide and gene level, with conservation rates of 2.73% and 11.57%, respectively, across primary-metastatic pairs. PDA transcriptomic subtype also differed across primary-metastatic pairs in all cases. Furthermore, metastatic tumors contained lower immune suppressive signal by transcripts and deconvolution (CTLA4: p = 0.0012, FOXP3: p = 0.0026, PDCD11: p = 0.012, regulatory T cells: p = 0.012), while myeloid cells were higher (CD33: p = 0.0067). Conclusions: With the exception of KRAS, metastatic PDA tumors at relapse contain new oncogenes, distinct neoantigens, and lower immune-suppressive signal compared to primary PDA tumors. These data suggest a potential clinical utility for tumor biopsies at the time of first metastatic relapse and caution against clinical decisions for relapsed, metastatic patients based solely on sequencing of the originally resected tumor.
Enrollment disparities in cancer clinical trials leading to FDA approvals between 2008 and 2020.
Authors: Ryan Huu-Tuan Nguyen, Yomaira Silva, Vijayakrishna K. Gadi
Journal: Journal of Clinical Oncology (2021)

e18501 Background: Cancer clinical trials based in the United States (US) have lacked adequate representation of racial and ethnic minorities, the elderly, and women. Pivotal clinical trials leading to United States Food and Drug Administration (FDA) approval are often multi-national trials and may also lack generalizability to underrepresented populations in the United States. We determined the racial, ethnic, age, and sex enrollment in pivotal trials relative to the US cancer population. Methods: We reviewed the FDA’s Drug Approvals and Databases for novel and new use drug approvals for breast, colorectal, lung, and prostate cancer indications from 2008 through 2020. Drugs@FDA was searched for drug approval summaries and FDA labels to identify clinical trials used to justify clinical efficacy that led to FDA approval. For eligible trials, enrollment data were obtained from FDA approval summaries, FDA labels, ClinicalTrials.gov, and corresponding journal manuscripts. Enrollment Fraction (EF) was calculated as enrollment in identified clinical trials divided by 2017 SEER cancer prevalence. All data sources were publicly available. Results: From 2008 through 2020, 60 drugs received novel or new use drug approval for breast, colorectal, lung, or prostate cancer indications based on 66 clinical trials with a total enrollment of 36,830. North America accounted for 9,259 (31%) enrollees of the 73% of trials reporting location of enrollment. Racial demographics were reported in 78% of manuscripts, 66% of ClinicalTrials.gov pages, and 98% of FDA labels or approval summaries. Compared with a 0.4% enrollment fraction among White patients, lower enrollment fractions were noted in Hispanic (0.2%, odds ratio [OR] vs White, 0.46; 95% confidence interval [CI], 0.43 to 0.49, P&lt; 0.001) and Black (0.1%, OR 0.29; 95% CI 0.28 to 0.31, P&lt; 0.001) patients. Elderly patients (age ≥ 65 years) were less likely than younger patients to be enrollees (EF 0.3% vs 0.9%, OR 0.27; 95% CI 0.26 to 0.27, P&lt; 0.001) despite accounting for 61.3% of cancer prevalence. For colorectal and lung cancer trials, females were less likely than males (EF 0.7% vs 1.1%, OR 0.66; 95% CI 0.63 to 0.68, P&lt; 0.001) to be enrolled. Conclusions: Black, Hispanic, elderly, and female patients were less likely to enroll in cancer clinical trials leading to FDA approvals from 2008 to 2020. Race and geographic enrollment data were inconsistently reported in journal manuscripts and ClinicalTrials.gov. The lack of appropriate representation of specific patient populations in these key clinical trials limits their generalizability. Future efforts must be made to ensure equitable access, representation, and reporting of enrollees that adequately represent the US population of patients with cancer.
Recurrent disease in patients with stage III melanoma in the era of adjuvant immune and targeted therapy.
Authors: Victor Lo, Valerie Francescutti, Elaine McWhirter, Forough Farrokhyar, Linda May Lee
Journal: Journal of Clinical Oncology (2021)

e21570 Background: Advancements in systemic therapy have reduced recurrence, and the adoption of nodal surveillance in place of dissection has reduced morbidity for patients with Stage III melanoma. The objective of this study was to describe the timing and pattern of recurrence in stage III melanoma patients and evaluate the impact of adjuvant treatment and nodal surveillance. Methods: A multicenter retrospective chart review of patients with pathologically confirmed Stage III cutaneous melanoma seen at either the Juravinski Cancer Centre or Walker Family Cancer Centre in Ontario, Canada from January 1, 2017 to December 31, 2019. Results: There were 137 patients with Stage III melanoma: 18% IIIA, 22% IIIB, 52% IIIC, and 8% Stage IIID as per the 8 th American Joint Committee on Cancer (AJCC) 2018 staging system. 103 (75%) patients had sentinel lymph node biopsy (SLNB) only as part of initial surgical therapy, 6 (4%) had SLNB with completion dissection, and 25 (18%) had upfront radical nodal dissection. 67 (49%) patients received adjuvant therapy, of which 50 (74%) had immunotherapy, 17 (25%) received BRAF-targeted therapy, and 1 (1%) had interferon. 54 (39%) patients developed recurrent disease, with a median time to recurrence of 8.5 months (IQR: 4.3-14.9). The recurrence rates were 63% in patients who did not have adjuvant treatment and 37% in those who had adjuvant therapy, with a median time-to-recurrence of 7.5 and 9.0 months respectively. There were 30 (56%) loco-regional recurrences and 24 (44%) distant recurrences. Of the patients with loco-regional recurrence, 26 (87%) had SLNB only compared to 4 (13%) who had upfront or completion dissection. 12 (24%) patients recurred while on adjuvant treatment (7 distant recurrences and 5 loco-regional recurrences), and 8 (13%) patients recurred following completion of adjuvant treatment (5 distant recurrences and 3 loco-regional recurrences). Recurrences were detected by patients, clinicians, CT and nodal US surveillance in 43%, 20%, 28% and 9% of cases, respectively. The majority of loco-regional recurrence was detected clinically (67%) rather than by radiologic surveillance (33%). Of the 30 loco-regional recurrences, 24 underwent surgical resection of the recurrence, 4 had subsequent systemic therapy without surgery, 1 had intra-tumoral injections and 1 had no treatment. Conclusions: Recurrences in Stage III melanoma occur early, often within a year, with higher rates of loco-regional rather than distant disease. Recurrence rates were lower in those who received adjuvant therapy, but the majority of recurrences were detected by patients or clinicians, including loco-regional recurrences in patients who had SLNB only despite surveillance nodal US.