A plain language summary of the ASCENT study: Sacituzumab Govitecan for metastatic triple-negative breast cancer

Sacituzumab Govitecan (also known by the brand name TRODELVY®) is a new and available treatment for metastatic triple-negative breast cancer, or mTNBC for short. Metastatic breast cancer means the breast cancer has spread to other parts of the body. Triple negative means the breast cancer does not have 3 common proteins on the cell surface called receptors. This is a summary of the ASCENT study, published in the New England Journal of Medicine in April 2021. This study compared Sacituzumab Govitecan with standard chemotherapy. Chemotherapy is a treatment that kills cancer cells or stops them from dividing. 529 people with mTNBC took part in the study across 7 countries. All who took part had already received 2 previous chemotherapies, which stopped working for their cancer. The study showed that patients who took Sacituzumab Govitecan lived longer than those who took a different chemotherapy while on the study. Tumors shrank in more patients who took Sacituzumab Govitecan than in patients who took chemotherapy. In general, patients who took Sacituzumab Govitecan experienced more side effects. This included low levels of a type of white blood cell known as neutrophils (neutropenia) and loose or watery stool (diarrhea). Use of supportive care lessened these side effects. This summary also includes insights and perspectives from 2 breast cancer patient advocates. ClinicalTrials.gov NCT number: NCT02574455. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here.</italic.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer

Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Sacituzumab govitecan as second-line treatment for metastatic triple-negative breast cancer—phase 3 ASCENT study subanalysis

Patients with triple-negative breast cancer (TNBC) who relapse early after (neo)adjuvant chemotherapy have more aggressive disease. In the ASCENT trial, sacituzumab govitecan (SG), an antibody-drug conjugate composed of an anti-Trop–2 antibody coupled to SN-38 via a hydrolyzable linker, improved outcomes over single-agent chemotherapy of physician’s choice (TPC) in metastatic TNBC (mTNBC). Of 468 patients without known baseline brain metastases, 33/235 vs 32/233 patients (both 14%) in the SG vs TPC arms, respectively, received one line of therapy in the metastatic setting and experienced disease recurrence ≤12 months after (neo)adjuvant chemotherapy. SG prolonged progression-free survival (median 5.7 vs 1.5 months [HR, 0.41; 95% CI, 0.22–0.76]) and overall survival (median 10.9 vs 4.9 months [HR, 0.51; 95% CI, 0.28–0.91]) vs TPC, with a manageable safety profile in this subgroup consistent with the overall population. In this second-line setting, as with later-line therapy, SG improved survival over conventional chemotherapy for patients with mTNBC.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Health-related quality of life in the phase III ASCENT trial of sacituzumab govitecan versus standard chemotherapy in metastatic triple-negative breast cancer

Background: The antibody–drug conjugate sacituzumab govitecan (SG) prolongs progression-free survival and overall survival in patients with refractory/relapsed metastatic triple-negative breast cancer (mTNBC). Here, we investigated its effect on health-related quality of life (HRQoL). Methods: This analysis was based on the open-label phase III ASCENT trial (NCT02574455). Adults with refractory/relapsed mTNBC who had received ≥2 prior systemic therapies (≥1 in the metastatic setting) were randomised 1:1 to SG or treatment of physician's choice (TPC; capecitabine, eribulin, vinorelbine, or gemcitabine). HRQoL was assessed on day 1 of each treatment cycle using the EORTC QLQ-C30. Score changes from baseline were analysed using linear mixed-effect models for repeated measures. Stratified Cox regressions evaluated time to first clinically meaningful change of HRQoL. Results: The analysis population comprised 236 patients randomised to SG and 183 to TPC. For global health status (GHS)/QoL, physical functioning, fatigue, and pain, changes from baseline were superior for SG versus TPC. Compared with TPC, SG was inferior regarding changes from baseline for nausea/vomiting and diarrhoea but non-inferior for other QLQ-C30 domains. Median time to first clinically meaningful worsening was longer for SG than for TPC for physical functioning (22.1 versus 12.1 weeks, P < 0.001), role functioning (11.4 versus 7.1 weeks, P < 0.001), fatigue (7.7 versus 6.0 weeks, P < 0.05), and pain (21.6 versus 9.9 weeks, P < 0.001). Conclusions: SG was generally associated with greater improvements and delayed worsening of HRQoL scores compared with TPC. This supports the favourable profile of SG as an mTNBC treatment.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2 -Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials

Importance: Biologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC). Objective: To define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41. Design, Setting, and Participants: In this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023. Main Outcomes and Measures: The association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses. Results: In the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P <.001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P =.03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P =.009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94. Conclusions and relevance: In patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates..SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease