tbuckley/cabot-search huggingface dataset:
A phase Ib study of xentuzumab plus abemaciclib and fulvestrant in patients (pts) with advanced hormone receptor-positive (HR+), HER2-negative breast cancer (BC) with visceral or non-visceral disease.
Authors: Douglas Yee, Patricia LoRusso, Marie Paule Sablin, Aleix Prat, Agostina Stradella, Meri Utriainen, Mafalda Oliveira, Kan Yonemori, Yoichi Naito, Molly Catherine Hardebeck, Marta Puig, Joy Hu, Tsvetan Nikolov Biyukov, Hiroji Iwata
Journal: Journal of Clinical Oncology (2021)

1057 Background: Cyclin-dependent kinase (CDK) 4 &amp; 6 inhibitors plus endocrine therapy (ET) are standard of care for advanced HR+ BC. Combining xentuzumab, an insulin-like growth factor (IGF) ligand-neutralizing antibody, with ET and everolimus, suggested progression-free survival (PFS) benefit in pts with advanced HR+ BC and non-visceral disease. Activation of the IGF pathway leads to an increase in cyclin D1, providing a rationale for combining IGF and CDK4 &amp; 6 inhibition. This prospective, open-label study is investigating xentuzumab plus abemaciclib, a CDK4 &amp; 6 inhibitor, with fulvestrant. In dose-finding cohorts, the recommended phase II dose (RP2D) was determined as xentuzumab 1000 mg weekly intravenously plus abemaciclib 150 mg every 12h orally (Q12h). Here, we report preliminary data on disease control rate (DCR) from two expansion cohorts in pts with advanced HR+ BC with visceral (D1) or non-visceral disease (D2). Methods: Postmenopausal women with advanced/metastatic HR+ BC that had progressed on or after ET (including adjuvant ET) were enrolled. Pts could not have received &gt;1 line of ET or any chemotherapy for metastatic disease. No prior CDK4 &amp; 6 inhibitor therapy was permitted. Pts had to have ≥1 documented visceral metastasis in D1 and no visceral metastases in D2. Pts received xentuzumab weekly plus abemaciclib Q12h (at RP2D) plus fulvestrant 500 mg per label. Protocol primary endpoint was PFS rate at 18 months (mos). Secondary endpoints included DCR (complete response [CR], partial response [PR] and non-CR/non-progressive disease [PD] or stable disease [SD] lasting ≥24 weeks [wks]). Results: In D1/D2, 33/31 pts were treated: median age 60/53 years. 19 pts in D2 had bone-only, non-measurable disease. At data cut-off (Jan 2021), median treatment duration was 7.5/9.2 mos in D1/D2; 40 pts remain on treatment. In D1, DCR was 64%: 17 (52%) pts had PR and 4 (12%) had SD lasting ≥24 wks. In D2, DCR was 55%: 5 (16%) pts had PR, 10 (32%) had non-CR/non-PD lasting ≥24 wks and 2 (7%) had SD lasting ≥24 wks. Median duration of disease control was 10.9 mos in each cohort. Some pts had not reached 24 wks; full DCR data will be presented. Most common AEs are shown in the table (≥33% all-grade in either cohort). No hypo/hyperglycemia was reported. Conclusions: Xentuzumab plus abemaciclib and fulvestrant demonstrated encouraging disease control in pts with advanced HR+ BC with visceral and non-visceral disease. The safety profile was manageable, and consistent with the known profiles of the three agents. Clinical trial information: NCT03099174 .[Table: see text]
Breathlessness across generations: results from the RHINESSA generation study
Authors: Magnus Ekström, Ane Johannessen, Michael J Abramson, Bryndis Benediktsdottir, Karl Franklin, Thorarinn Gislason, Francisco Gómez Real, Mathias Holm, Christer Janson, Rain Jogi, Adrian Lowe, Andrei Malinovschi, Jesús Martínez-Moratalla, Anna Oudin, José Luis Sánchez-Ramos, Vivi Schlünssen, Cecilie Svanes
Journal: Thorax (2021)

Background Breathlessness is a major cause of suffering and disability globally. The symptom relates to multiple factors including asthma and lung function, which are influenced by hereditary factors. No study has evaluated potential inheritance of breathlessness itself across generations. Methods We analysed the association between breathlessness in parents and their offspring in the Respiratory Health in Northern Europe, Spain and Australia generation study. Data on parents and offspring aged ≥18 years across 10 study centres in seven countries included demographics, self-reported breathlessness, asthma, depression, smoking, physical activity level, measured Body Mass Index and spirometry. Data were analysed using multivariable logistic regression accounting for clustering within centres and between siblings. Results A total of 1720 parents (mean age at assessment 36 years, 55% mothers) and 2476 offspring (mean 30 years, 55% daughters) were included. Breathlessness was reported by 809 (32.7%) parents and 363 (14.7%) offspring. Factors independently associated with breathlessness in parents and offspring included obesity, current smoking, asthma, depression, lower lung function and female sex. After adjusting for potential confounders, parents with breathlessness were more likely to have offspring with breathlessness, adjusted OR 1.8 (95% CI 1.1 to 2.9). The association was not modified by sex of the parent or offspring. Conclusion Parents with breathlessness were more likely to have children who developed breathlessness, after adjusting for asthma, lung function, obesity, smoking, depression and female sex in both generations. The hereditary components of breathlessness need to be further explored.
Repurposing drugs for treatment of COVID-19
Authors: Priya Venkatesan
Journal: The Lancet Respiratory Medicine (2021)

Although the COVID-19 vaccine programme continues to be rolled out globally, there is still a need to identify effective treatments, particularly in countries where vaccine uptake is slow, and with the insidious threat of mutations resulting in vaccine escape. With the urgency of the pandemic making the timely discovery of new drugs almost impossible, the idea of repurposing existing drugs to treat COVID-19 is an attractive strategy, especially if they are already approved (for other indications) and have well established safety profiles.
Does pathological complete remission after neoadjuvant chemotherapy translate to longer relapse-free survival in patients with triple-negative breast cancer in the Indian population?
Authors: Rakesh Kumar Sharma, Ajay Gogia, SVS Deo, Dayanand Sharma, Sandeep Mathur, Hari Krishna Raju Sagiraju
Journal: Journal of Clinical Oncology (2021)

e12618 Background: Attainment of pathological complete remission (pCR) with neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) is associated with improved survival outcomes. However, data corroborating this fact is lacking from the Indian subcontinent. Methods: We evaluated 179 cases of TNBC, registered at Dr. B.R.A., I.R.C.H., AIIMS, New Delhi, from a period of May 2013 to July 2020, who were treated with neo-adjuvant chemotherapy (NACT) followed by surgery. Patients with oligometastatic disease who were treated with NACT with curative intent were also included in the analysis. Multivariate logistic regression analysis was done to explore the factors associated with the achievement of pCR. Survival analysis was done to study the correlation of pCR with relapse-free survival (RFS) and overall survival (OS). Results: The median age of our cohort was 43 (18-67) years. Study population comprised 104 (58.1%) pre-menopausal, 67 (37.4%) post-menopausal and 8(4.5%) peri-menopausal patients respectively. Twenty-three patients (12.9%) presented with early breast cancer, 144 (80.5%) were locally advanced and 12 (6.7%) were oligo-metastatic. Forty (22.4%), 127 (71.0%) and 12 (6.7%) patients were at clinical stages-II, III, and IV respectively at the time of presentation as per AJCC 7th edition. The median duration of symptoms was 4 (0.25-36) months. Forty-seven (26.3%) patients underwent breast conservation surgery and 128 (71.5%) patients had modified radical mastectomy. Overall pCR was attained in 29.6%(n=53) of the patients, with rates of 55%(n=22) and 23.6%(n=30) in patients with stage-II and stage-III respectively. Stage-II patients were more likely to achieve pCR after NACT [OR (95% CI: 4.3 (2.0-8.9)] when adjusted for other clinical covariates. Three-year RFS in patients achieving pCR was 94.7%, whereas in patients not achieving pCR was 43.9%, with a hazard of relapse or death significantly less in patients attaining pCR [HR (95% CI): 0.14 (0.06-0.37), p &lt;0.0001]. Similarly, three-year OS was 97.4 % vs 73.8% in patients attaining pCR vs not attaining pCR, with a hazard of death significantly less in patients with pCR [HR (95% CI): 0.06 (0.01-0.45) p&lt;0.006]. Conclusions: Our results confirm that attainment of pCR following NACT leads to better survival outcomes in TNBC. Factors associated with improved pCR rates in the Indian population needs further evaluation.
Clinical outcomes and efficacy of endoscopic ultrasound guided ablation of pancreatic cancer a systematic review and a meta-analysis.
Authors: Hamid Ehsan, Muhammad Nadeem Yousaf, Ahsan Wahab, Karun Neupane, Muhammad Khawar Sana, Abdul Rafae, Adeel Masood, Zahoor Ahmed, Ahmed Muneeb, Muhammad Tayyeb
Journal: Journal of Clinical Oncology (2021)

e16261 Background: Endoscopic ultrasound-guided ablation therapy (EUS-A) is a minimally invasive technique increasingly used for the management of surgically unresectable pancreatic cancer. The data on the efficacy and clinical outcome of EUS-A for unresectable pancreatic cancer is lacking. We conducted this systematic review and meta-analysis to evaluate the safety, technical and clinical success of EUS-A therapies specifically for unresectable pancreatic cancer. Methods: Studies were identified with a comprehensive search for EUS-A and pancreatic cancer on PubMed, Google Scholar, Web of Science and Embase data search as of October 2020. The technical and clinical success rates of EUS-A were primary outcomes while adverse events (AEs) rate was secondary outcome. We defined technical success as successful placement of probe within tumor and able to perform ablation regardless of tumor outcome. Clinical success was defined as symptomatic improvement and/or any reduction in tumor size or evidence of necrosis on radiological imaging after EUS-A. A compute pooled analysis was performed using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.0.2) using random effect model. Results: Nineteen studies including 192 patients (54% females) were included. Common pancreatic tumors were nonfunctional neuroendocrine tumor (NNET) 43.5% (97), followed by locally advanced pancreatic ductal adenocarcinoma (LAPDAC) 27.3% (61), insulinoma 17.9% (40), cystic neoplastic lesions 8.5% (19). The pancreatic head was the most common site of tumor 49.8% (111), followed by body, neck and tail 44.8% (100). EUS-RFA was the most commonly used ablative therapy 63% (12/19 studies), followed by EUS-EA (ethanol ablation) 26% (5/19 studies) while EUS-A using laser and lauromacrogol injection was used in one study each. The mean number of ablation sessions per patient was 1.4 based on the total 243 sessions in 176 patients. The pooled technical success rate of EUS-A was 99.5% [95% CI = 0.90-0.97, I 2 = 0%]. The pooled clinical success rate calculated out of total number of pancreatic lesions was 91.1% [95% CI = 0.79-0.92, I 2 = 16%]. Clinical improvement in symptoms was reported in 11 studies and a complete resolution or decrease in tumor size was reported in 16 studies. The pooled AEs rate was 22.9% [95% CI = 0.17-0.37, I 2 = 43%]. Common AEs were abdominal pain 7.8% (15), pancreatitis 5.2% (10) and pancreatic pseudocyst 2.1% (4). The median follow-up was 9.5 months. Conclusions: EUS-A is a safe and promising modality in the management of unresectable pancreatic cancer with a high technical and clinical success rate. Large prospective studies and clinical trials are required for comparison of clinical outcome of different EUS-A therapies and its widespread application for unresectable pancreatic cancer.
Multi-gene prognostic assays and age-related differences in prediction of pathologic complete response to neoadjuvant chemotherapy and survival in breast cancer.
Authors: Kent Hanson, Kent Hoskins, Naomi Yu Ko, Gregory Sampang Calip
Journal: Journal of Clinical Oncology (2021)

591 Background: Multi-gene testing of primary breast tumors in early-stage breast cancer is used to classify the risk of developing distant metastases and predict the benefit of adjuvant chemotherapy. The association between the tumor genomic prognostic score (GPS) and response to neoadjuvant chemotherapy (NACT) and survival is not well characterized. Our objective was to describe the association between GPS and rates of pathologic complete response (PCR) and subsequent overall survival among women with or without PCR. Methods: We utilized the National Cancer Database to perform a hospital-based, retrospective cohort study of breast cancer patients ages 18 years and older. We included women diagnosed with first primary stages I-III hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer who received NACT and surgery between 2010 and 2017. Women were categorized as having low (0-10 or 200), intermediate (11-25 or 300), or high-risk (25-199 or 400) GPS based on OncotypeDX or MammaPrint scores. Multivariable modified Poisson regression models with robust error variance were used to estimate the crude and adjusted relative risk and 95% confidence intervals (CI) for PCR associated with GPS groups. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% CI for associations between the GPS and overall survival (OS) in women who did and did not have PCR. Results: A cohort of 3,446 women (mean [SD] age, 56.7 [12.0] years; median [interquartile range] follow-up of 47 [31-68] months) who received genomic testing and neoadjuvant chemotherapy were included in our analysis, of which 935 (27%) were low risk, 1,357 (39%) intermediate risk, and 1,154 (34%) high risk GPS. The relative risk of PCR for all women with high GPS was 1.81 (95% CI, 1.47-2.22; p &lt; 0.001) in crude models and 1.49 (95% CI, 1.16-1.92; p = 0.002) after full adjustment compared to low GPS. Across all models, having a high GPS was significantly associated with achieving PCR in younger women ( &lt; 65 years). In women ages ≥65 years, the association between GPS and PCR was not predictive nor statistically significantly. Among women with no response or partial response to NACT, high GPS was associated with a significantly increased risk of overall mortality (HR 2.41; 95% CI, 1.61-3.60; p &lt; 0.001) compared to low GPS. Conversely, in women who did achieve PCR, GPS was not predictive of overall mortality across all age groups. Conclusions: In women with HR+/HER2- breast cancer, high risk GPS was predictive of PCR following NACT, primarily in younger women ( &lt; 65 years). Our findings also indicated GPS was associated with lower OS in high-risk patients who do not achieve PCR and unpredictive of OS in those without PCR. The utility of tumor genomic testing in the neoadjuvant setting needs further investigation.
Abstract 12825: Trends in the Incidence of Inpatient Complications After Transcatheter Aortic Valve Replacement
Authors: Sameer Arora, Paula D Strassle, Arman Qamar, Dhaval Kolte, Avirup Guha, Cassandra J Ramm, Madhu Paladugu, Mahesh Borhade, John P Vavalle
Journal: Circulation (2018)

Background: There has been rapid and widespread dissemination of transcatheter aortic valve replacement (TAVR) throughout the US, now with more annual procedures than surgical aortic valve replacem...
Patient human leukocyte antigen (HLA) genotype may predict response to anti-programmed death receptor 1 (anti-PD1) in advanced melanoma.
Authors: Oliver Oey, Muhammad Adnan Khattak, Afaf Abed, Tarek Meniawy, Anna Reid, Leslie Calapre, Michael Millward, Elin Gray
Journal: Journal of Clinical Oncology (2021)

e21512 Background: Anti-PD-1 therapy has improved the outcome of advanced melanoma patients with a 5-year survival rate of about 40-45%. However, biomarkers predictive of response to immune checkpoint blockade therapy are lacking. There is limited data on the utility of host germline human leucocyte antigen (HLA) genotype as a predictor of response to anti-PD-1 therapy in advanced melanoma. Here, we investigate the prognostic value of HLA in predicting survival outcomes of patients with unresectable locally advanced, metastatic melanoma on anti-PD-1 therapy. Methods: Blood was collected from 113 metastatic melanoma patients who were treated with anti-PD-1 therapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and subsequently HLA-I and HLA-II typed using clinically validated assay. Univariate analyses were conducted using Cox regression model correlating homozygosity at HLA-I and HLA-II loci with overall survival (OS). HLA-A and HLA-B were classified into 12 supertypes and correlated with OS. Multivariate analyses were performed while controlling for age, gender, prior therapy, BRAF mutation status, ECOG performance status and presence of liver and brain metastases. Results: Homozygosity at HLA-I or HLA-II loci was not associated with OS. However, the absence of HLA-B62 supertype was associated with a trend towards improved OS (HR: 0.53 [95% CI:0.25-1.10]; P = 0.09) as reported previously. Notably, the absence of HLA-B27 supertype was associated with improved OS which was statistically significant (HR: 0.45 [95% CI:0.24-0.85]; P = 0.01). In multivariate analyses, the prognostic value of HLA-B27 supertype (HR: 0.38 [95% CI:0.19-0.76]; P = 0.006) was maintained, whereas the prognostic value of HLA-B62 supertype significantly improved (HR: 0.42 [95% CI:0.19-0.94]; P = 0.03). Conclusions: Our results suggest a limited role of HLA homozygosity in predicting survival of melanoma patients treated with anti-PD-1 therapy. However, we identified that the absence of HLA-B62 and HLA-B27 supertype is associated with improved survival benefit. Therefore, HLA-B27 and HLA-B62 supertype may be used as adjunct biomarkers of response to anti-PD-1 therapy in patients with melanoma in addition to PD-L1 status, pending validation in prospective randomised clinical trials.
Mutation profile of DNA damage response genes in Chinese colorectal cancer patients and its association with TMB and MSI.
Authors: Meiling Yang, Jianfei Yao, Danni Liu, Tanxiao Huang, Zhizheng Wang, Shifu Chen, Haifu Huang
Journal: Journal of Clinical Oncology (2021)

e15608 Background: DNA damage response (DDR) genes are essential to maintain genomic integrity. Increasing evidence showed that mutations in DDR genes were related to tumor mutation load (TMB), microsatellite instability (MSI) and clinical benefit from immunotherapy. TMB and MSI are predictive biomarkers for immunotherapy. However, the mutation spectrum of genes involved in the DDR pathways and its association with TMB and MSI in Chinese colorectal cancer patients are still ambiguous. Methods: The genomic information of 728 Chinese colorectal cancer patients without germline mutation of Lynch syndrome related genes was obtained from HapLab database. HaploX WESPlus gene panel (an upgraded version of the standard WES) was performed to analyze the genomic data of patients. Results: 630 out of 728 patients (86.54%) had at least one mutation of the DDR genes. The frequently mutated DDR genes included TP53 (54.95%), BRCA2 (18.27%), PARP4 (13.46%), MSH2 (9.62%), XPC (7.55%), RAD54L2 (7.28%), ATM (6.73%), HMGB1 (5.77%), REV3L (5.49%) and POLD3 (5.36%). The TMB in patients with one, two, three and more than three mutations of DDR genes increased sequentially. The proportion of MSI-H in patients with more than three mutations of DDR genes (20.9%) was significantly higher than that in patients with less than 3 mutations of DDR genes (0.38%). Among the frequently mutated DDR genes, mutations of BRCA2, PARP4, MSH2, XPC, RAD54L2, ATM, REV3L or POLD3 were associated with higher TMB, mutations of MSH2, RAD54L2, ATM, REV3L or POLD3 were associated with higher proportion of MSI-H. The patients with mutation in each of eight DDR pathways showed significantly higher TMB and proportion of MSI-H than who without mutation of DDR genes. Conclusions: This study revealed the mutation profile of DDR genes in Chinese colorectal cancer patients. The mutation of DDR genes was closely related to TMB and MSI status. This result indicated the mutation of DDR genes may be a promising biomarker for immunotherapy in Chinese colorectal cancer patients.
Total neoadjuvant FOLFIRINOX or gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2): A nationwide multicenter randomized controlled trial.
Authors: Quisette Janssen, Jacob L. van Dam, Marc G.H. Besselink, Marjolein Y.V. Homs, Geertjan van Tienhoven, Johanna W. Wilmink, Bas Groot Koerkamp
Journal: Journal of Clinical Oncology (2021)

TPS4171 Background: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials (including the Dutch PREOPANC trial) have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including gemcitabine-based chemoradiotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether total neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine (i.e. the intervention arm of the PREOPANC trial) in patients with resectable or borderline resectable pancreatic cancer. Methods: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) added during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients, assuming an accrual period of 3 years and 1.5 years follow-up. Between June 2018 and January 2021, 375 patients were enrolled in 20 centers in the Netherlands and accrual is complete. Final analyses are expected at the end of 2022. Netherlands Trial Register: NL7094. Clinical trial information: NL7094.