tbuckley/cabot-search huggingface dataset:
Complete responders to checkpoint inhibitors in advanced melanoma: Relapse risk factors, and patients' outcomes.
Authors: Amelie Dutheil, Djaouida Belkadi, Marine Antigny, Severine Roy, Jeremy Lupu, Anaïs Vallet, Emilie Routier, Caroline Robert
Journal: Journal of Clinical Oncology (2021)

9550 Background: Since the development of immune checkpoint inhibitors (ICI) for advanced melanoma, a small group of patients with an excellent and durable response has emerged. Complete response (CR) is achievable in about 10-20% of the patients and seem to have an excellent prognosis. However, 10 to 15% of them might relapse eventually. Our main objective was to determine factors associated with relapse after a CR to ICI in advanced melanoma. The second objective was to describe relapse modalities and tumor response to subsequent treatments. Methods: We performed a single-center, retrospective study, in 141 patients with a CR to ICI for advanced melanoma, treated at Gustave Roussy (France) from January 2010 to June 2020. CR was confirmed on two consecutive CT-scanner or PET-CT at least 3 months apart. Characteristics of the patients at diagnosis, during and after treatment were compared in both groups: CR with relapse and CR without relapse. The LASSO analysis, a statistical analysis using lambda penalization coefficient for prognostic studies, was performed regarding the many statistical variables analysed. Results: At data analysis, immunotherapy was interrupted in 94.3% of the patients and the median follow-up was 3.5 years since immunotherapy discontinuation. Eventually, 18 of 141 patients (12.8%) had relapsed and 126 (87.2%) had not. The statistical analysis identified three factors associated with melanoma recurrence: prior lines of therapy, the type of melanoma and the mutation status. Indeed, relapse risk was higher in patients with wild type melanoma (as opposed to BRAF or NRAS mutant melanoma), with a mucosal, acral or unknown primitive melanoma and who received prior lines of treatment. Other factors such as demographical characteristics, tumor burden, metastasis localization, type or grade of toxicity, pseudo progression, type of ICI, treatment duration, use of a complementary local treatment and pursuit/discontinuation of immunotherapy were not statistically associated with the duration of the complete response. In case of melanoma recurrence, reintroduction of immunotherapy provided tumor response in half of our patients: 13 of the 18 relapsing patients received immunotherapy after melanoma recurrence; allowing 3 CR, 2 partial responses and 1 stable disease. One third of the relapsing patients eventually died of disease progression. Conclusions: This study confirmed the excellent prognosis of CR to ICI in advanced melanoma, even after treatment discontinuation and identified 3 baseline factors associated with a risk of relapse: absence of BRAF or NRAS mutation, primary of acral, mucosal or unknown origin, and previous lines of therapy. Rechallenge with ICI was effective in 50% of the patients.
Are National Cancer Institute Cancer Centers (NCI-CC) providing adolescents and young adults (AYA) with cancer focused clinical services? A national survey.
Authors: Katherine Daunov, Michael Daunov, Kara Noskoff, Hilary Gan, Simon Davies, Olivia Larbi, Megan Farrell, Whitney Hadley, Amelia Renee Baffa, Jennifer Giesel, Rachel A. Egler, Alex Yee-Chen Huang, John J. Letterio, Richard T. Lee
Journal: Journal of Clinical Oncology (2021)

1534 Background: AYA patients with cancer have inferior outcomes compared to their pediatric and adult counterparts. The NCI recommends they be treated by AYA focused healthcare professionals within an AYA oncology program. This survey captures the current landscape of AYA oncology care in the United States. Methods: An online survey was sent to 272 cancer centers in September 2020, in coordination with Teen Cancer America and included all clinically designated NCI-CC. The survey asked about the presence of an AYA program, types of patients, dedicated resources, clinical space, type of providers, associated support services, educational efforts, importance of AYA oncology care, and how well these services are provided. Results: In total, we received 93 responses, a 34% response rate, including 50 NCI centers, a 72% response rate. Only half (49%) of NCI-CC reported having an AYA program, and 70% were started in the past 5 years. One-third (32%) of centers reported plans to start an AYA program. Most programs included patient ages from ≥15 (56%) to ≤39 (63%) with a variety of cancers – most commonly hematologic (49%) and sarcoma (49%) and least commonly lung (36%), breast (38%), and head and neck cancer (38%). AYA programs are generally embedded in both adult and pediatric oncology services (63%). On average, cancer centers reported seeing 25-50 new AYA patients/month and 100-200 follow-up visits/month. Few programs reported a dedicated inpatient space (4%) or outpatient space (9%). Most NCI-CC have supportive services available for all oncology patients, but fewer of these services were dedicated specifically to AYA patients: navigators (92% vs. 71%), social work (98% vs. 57%), psycho-oncology (96% vs. 54%), dietician (98% vs. 24%), physical therapy (98% vs. 18%), chaplaincy (98% vs. 18%), and child life (83% vs. 26%). Other services available to the AYA population included sexual health (62%), academic support (62%), and career resources (36%). A minority of centers (30%) provided AYA training to their staff. A majority of NCI-CC felt AYA programs were important-very important (60%). They reported providing good-excellent overall AYA care (59%), but this dropped to 22% for sexual health and education of staff, which was relatively consistent across centers (Table). Conclusions: This survey is the first ever national survey to assess AYA oncology programs. Despite greater emphasis on the AYA cancer population, only half of NCI-CC report having a dedicated program, and areas of improvement include education of staff and sexual health services for patients. Self-report of providing good to excellent AYA care in specific areas.[Table: see text]
COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart
Authors: Maurizio Pesce, Piergiuseppe Agostoni, Hans-Erik Bøtker, Bianca Brundel, Sean M Davidson, Raffaele De Caterina, Peter Ferdinandy, Henrique Girao, Mariann Gyöngyösi, Jean-Sebastien Hulot, Sandrine Lecour, Cinzia Perrino, Rainer Schulz, Joost Pg Sluijter, Sabine Steffens, Ivan Tancevski, Can Gollmann-Tepeköylü, Carsten Tschöpe, Sophie van Linthout, Rosalinda Madonna
Journal: Cardiovascular Research (2021)

Abstract The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.
Racial disparities in genetic testing of breast cancer patients.
Authors: Solange Bayard, Yalei Chen, Genevieve A. Fasano, Melissa Davis, Eleanor M. Walker, Jessica Miley Bensenhaver, Lindsay Petersen, Jennifer Marti, Rache M. Simmons, Alexander J. Swistel, Lisa A. Newman
Journal: Journal of Clinical Oncology (2021)

10591 Background: TNBC is disproportionately prevalent in African American (AA) populations and in women with BRCA-1 germline mutations. BRCA mutation carriers are candidates for targeted therapy with PARP-inhibitors, and testing results may influence risk-reducing surgery choice. Methods: We evaluated genetic testing patterns and outcomes for TNBC patients treated in the prospectively maintained databases of academic cancer programs in two metropolitan cities in the Northeast (New York City, NYC) and Midwest (Detroit, Det), 1998-2018. Median follow up was 3.73 years. Testing patterns were also analyzed by time, comparing pts diagnosed before versus after the mid-2013 Supreme Court ruling that expanded testing availability by banning gene patenting. Results: Of 810 pts, 600 were from NYC and 200 from Det; 202 were AA and 488 WA. Pts undergoing genetic testing were younger (median age 50 vs 62; p &lt; 0.0001). Compared to WA, AA pts were less likely to undergo genetic testing overall (23.8% vs 42.0%; p &lt; 0.0001) and within site (NYC: 25.6% vs 42.8%, p = 0.008; Det: 22.3% vs 38.6%, p = 0.025). No significant differences were seen in frequency of pathogenic BRCA mutations (AA-14.6%; WA-29.3%) or VUSs (AA-6.3%; WA- 4.9%); p = 0.20. Genetic testing disparities were reduced among pts diagnosed after mid-2013 (AA-31.4% vs WA-44.0%; p = 0.01) compared to pre-mid-2013 (AA-18.3% vs WA-40.7%; p &lt; 0.0001). No differences were seen in local or distant recurrence free survival between patients with BRCA, BRCA variants of uncertain significance, non-BRCA mutations, and patients without genetic mutations (local recurrence p = 0.827; distant recurrence p = 0.574). This outcome equivalence was consistent when stratified by WA vs AA identity. Conclusions: Genetic testing has increased for TNBC pts following the mid-2013 Supreme Court ban on gene patenting, but race-associated disparities persist. Pts undergoing genetic testing are more likely to undergo risk-reducing mastectomy, but testing results do not affect survival outcomes, regardless of race. Addressing genetic testing disparities will become increasingly important as mutation-associated targeted therapies are identified through advances in precision medicine.
Clinical significance of next-generation sequencing in Chinese patients with relapsed/refractory Wilm’s tumor.
Authors: Juan Wang, Fei-fei Sun, Wanming Hu, Lian Zhang, Qing WANG, Zijun Zhen, Jia Zhu, Suying Lu, Junting Huang, Yi Que, Xiaofei Sun, Yizhuo Zhang
Journal: Journal of Clinical Oncology (2021)

e22003 Background: Medical advances have been greatly improved in the survival rate for Wilms’ tumor, but the survival is still dismal for relapsed/refractory (R/R) patients. In the present study, we aimed to investigated the genomic profiling and the incidence of germline cancer susceptibility mutations of Chinese patients with R/R WT. Methods: From Jun 18, 2020 to Dec 22, 2020, the tumor specimens with matched blood samples obtained from R/R pediatric WT in Sun Yat-Sen University Cancer Center were performed next-generation sequencing (NGS) using a 539 cancer-related gene panel in a CAP-certified laboratory (Simcere Diagnostic Co, Ltd). Clinical information including age, gender and tumor histology were collected. Somatic and germline variations including single nucleotide variants (SNV), insertion-deletion variants (Indels), copy number variations (CNVs) and fusion, as well as tumor mutational burden (TMB)/microsatellite instability (MSI) were analyzed. IHC staining for PD-L1 expression was performed by FDA-approved VENTANA PD-L1(SP263) assay. Results: Eight patients with R/R WT were enrolled in this study, including 5 males and 3 females, with a median age of 6 years old (range, 3-14). All of the pathology was identified as favorable histology WT (FHWT). Of the specimens, 8 were from pulmonary and 1from peritoneum. We identified 152 reportable molecular aberrations, with a median of 19 (0-24). CNVs accounted for the majority of the total somatic aberrations, followed by SNVs, the percentage was 77% and 22%, respectively. Genes with either CNVs or SNVs were detected in FGFR1 (n=4), ERBB2(n=3), MYCN(n=4), MET(n=2), CDK4/6(n=2), TP53(n=2), CTNNB1(n=2), MYC(n=2), NF1(n=2), MDM4(n=2), CHEK2(n=1), FBXW7(n=1), EGFR(n=1). Notable cancer driver mutations were also characterized, such as the amplifications of ERBB2/MET/EGFR/FGFR1, and the point variations of CHEK2/FBXW7/NF1. Besides, a novel ASB12 intergenic region- AMER1 fusion was identified. Both of the patients available for PD-L1 evaluation showed negative PD-L1 expression on tumor cells. The median TMB was 1.47 (range, 0-7.8). All patients were microsatellite stabilization (MSS). A 4-year-old patient suffering peritoneal relapse harbored a germline pathogenic mutation in FANCA (c.1777-1G&gt;C, intron 19), this locus has never been reported in WT before. Conclusions: We discovered some driver genes mutations which potentially sensitive to the corresponding targeted drugs in Chinese R/R WT patients. Large sample size was needed to provide a better understanding of molecular features in R/R WT patients to achieve precision medicine.
Rate of incidental germline findings detected by tumor-normal matched sequencing in cancer types lacking hereditary cancer testing guidelines.
Authors: Timothy A. Yap, Arya Ashok, Jessica Stoll, Anna Ewa Schwarzbach, Kimberly L. Blackwell, Tianhong Li, Hyunseok Kang, Judy Ellen Garber, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2021)

10582 Background: Up to 10% of all cancers are associated with hereditary cancer syndromes; however, guidelines for germline testing are currently limited to patients and families with specific cancer types (ovarian, breast, prostate, pancreatic, etc.). Although germline alterations have been shown in genes associated with cancers such as bile-duct, head &amp; neck, brain, bladder, esophageal, and lung cancers, genetic testing is not routinely offered (PMID: 28873162). In such cancers, a guidelines-based approach may fail to detect cancer risk variants found by tumor-normal (T/N) matched sequencing. Here, we report the prevalence of incidental germline findings in patients with the aforementioned 6 cancer types and highlight frequently mutated genes by cancer type. Methods: We retrospectively analyzed next-generation sequencing data from de-identified records of 19,630 patients tested using Tempus|xT T/N matched assay. Incidental germline findings (i.e., single nucleotide variants and small insertions/deletions) detected in 50 hereditary cancer genes were determined for: bile duct (n = 466), head &amp; neck (n = 673), esophageal (n = 395), brain (n = 1,391), bladder (n = 810), and lung (n = 5,544), where n = total patients. For comparison, we also included 4 cancer types that frequently undergo germline testing: ovarian (n = 2,042), breast (n = 3,542), prostate (n = 2,146), and pancreatic (n = 2,621). Results: We detected incidental pathogenic/likely pathogenic germline variants (P/LPV) in 6.5% (601/9,279) of patients diagnosed with the 6 selected cancer types lacking hereditary cancer testing guidelines. The highest prevalence of P/LPV was identified in patients with bladder (8%), brain (6.9%), and lung (6.5%) cancers. Frequently mutated genes (Table) include ATM (n = 62), BRCA2 (n = 60), BRCA1 (n = 33), APC (n = 27), and CHEK2 (n = 21). Of note, the Ashkenazi Jewish variant (p.I1307K) was the most frequent mutation in APC. For cancer types where patients frequently undergo germline testing, the rates of incidental germline findings in descending order were ovarian (15%), breast (12%), prostate (9.4%), and pancreatic (8.5%) cancers. Conclusions: In addition to enhanced variant calling, T/N matched sequencing may identify germline variants missed by a guidelines-based approach to testing. The identification of such germline findings may have clinical implications for the patient, as well as at-risk family members, thereby resulting in the opportunity for genetic counseling and risk-stratified intervention.[Table: see text]
Comparing FOLFOX delivery in trial and real-world populations using longitudinal cumulative dose.
Authors: Michael Webster-Clark, Hanna Kelly Sanoff, Alexander P. Keil, Til Sturmer, Daniel Westreich, Jennifer Leigh Lund
Journal: Journal of Clinical Oncology (2021)

1521 Background: Patterns of chemotherapy delivery are likely to differ between trial and real-world populations. Typical measures used to compare these patterns are calculated at treatment completion, potentially missing key differences in the timing and trajectory of delays and dose reductions. We used a new measure, longitudinal cumulative dose (LCD), to compare treatment delivery over time in trial and real-world populations. Methods: We compared chemotherapy delivery in patients with stage II-III colon cancer enrolled in the MOSAIC trial of 5-fluorouracil (5FU) vs oxaliplatin + 5FU (FOLFOX4) to patients treated from 2008-2019 in the US Oncology Network with FOLFOX4, FOLFOX6, or mFOLFOX6. For each patient, we computed oxaliplatin LCD as the cumulative oxaliplatin dose received at a given timepoint (t) divided by the final standard oxaliplatin dose. We then estimated the median and 25th and 75th percentiles for oxaliplatin LCD within each regimen at day 68 (before the standard timing of the 7th dose), 168 (two weeks after the standard end of treatment), and 250. Results: The table shows the number of patients receiving each treatment regimen and the median and interquartile range for oxaliplatin LCD at each time. Higher LCDs in the trial show delivery closer to standard treatment, meaning fewer delays, dose reductions, and discontinuations. Differences between the medians, 25th percentiles, and 75th percentiles of LCD in each regimen were small at day 68 but grew considerably by days 168 and 250. Conclusions: Divergence from the standard dosing schedule was larger in real-world versus trial settings and varied by oxaliplatin regimen. LCD, as a longitudinal measure, showed that differences in delivery between trial and real-world populations grew substantially over time (even after 168 days and the standard end of treatment) possibly as real-world patients experienced more side effects and barriers to treatment than trial participants. These discrepancies in LCD may cause poorer outcomes in real-world settings than expected based on randomized trials.[Table: see text]
PP26. MULTIMODAL MOLECULAR IMAGING IN THE EVALUATION OF EARLY RESPONSE BIOMARKERS IN A GLIOMA MODEL
Authors: Dico D, Diceglie D, Valtorta D, Raccagni D, Martelli D, Belloli D, Lucignani P, Politi D, Fiorini P, Moresco P, ottobrini D
Journal: Neuro-Oncology (2017)
A phase II trial of trastuzumab plus modified-FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer (BTC): Multi-institutional study of the Korean Cancer Study Group (KCSG-HB19-14).
Authors: Choong-kun Lee, Jaekyung Cheon, Hong Jae Chon, Min Hwan Kim, Jin Won Kim, Myung Ah Lee, Hyung Soon Park, Myoung Joo Kang, Joung-Soon Jang, Hye Jin Choi
Journal: Journal of Clinical Oncology (2021)

TPS4161 Background: Biliary tract cancer (BTC), one of the most fatal cancers with limited treatment options, is generally rare in most high-income countries, but is relatively prevalent in South Korea. Recent genomic profilings have provided druggable molecular targets including HER2 amplification, which accounts for about 15% of total BTC patients. Trastuzumab is a humanized monoclonal antibody against HER2 with known efficacy in patients with HER2-positive breast and gastric cancer, and has not been tested prospectively in patients with HER2-positive BTC. The modified-FOLFOX regimen is currently being tested as a second-line therapy of BTC in phase III ABC-06 trial. This phase II study is investigating the combination of trastuzumab and modified-FOLFOX as second- or third-line treatment in HER2-postivie BTC. Methods: This study (KCSG-HB19-14; NCT04722133) is a phase II, multi-institutional, single arm trial to evaluate the efficacy and safety of trastuzumab plus modified-FOLFOX in gemcitabine/cisplatin refractory patients with HER2-positive BTC. The main inclusion criteria are HER2-positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/CEP17 ≥2.0, or ERBB2 gene copy number ≥ 6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (one or two previous cytotoxic chemotherapy lines permitted), ECOG 0 or 1, and adequate organ function. Patients receive trastuzumab-pkrb 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m 2 D1, leucovorin 200mg/m 2 D1, 5-FU 400mg/m 2 bolus D1, and 5-FU 2400mg/m 2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The study has a Simon's two-stage design, with objective response rate (ORR) per RECIST v1.1 as primary endpoint. Secondary endpoints included progression-free survival, disease control rate, overall survival, safety, quality of life and correlative biomarker exploration. Additional patients were to be recruited if pre-specified thresholds for ORR are met at the first stage. The study will enroll up to 34 patients and is currently recruiting at eight sites in South Korea. As of February 2021, 16 patients have been enrolled. The pre-specified activity goal for the first stage of accrual was met; second stage accrual began in February 2021. Clinical trial information: NCT04722133.