Citations

Abstract The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. COVID-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The Food and Drug Administration currently allows outpatient CCP for the immunosuppressed. Viral-specific antibody levels in CCP can range 10- to 100-fold between donors, unlike the uniform viral-specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-δ/pre-ο donor units obtained before March 2021, 20 post-δ COVID-19/postvaccination units, and 1 pre-δ/pre-ο hyperimmunoglobulin preparation for variant-specific virus (vaccine-related isolate [WA-1], δ, and ο) neutralization correlated to Euroimmun S1 immunoglobulin G antibody levels. We observed a two- to fourfold and 20- to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to δ or ο, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-δ COVID-19/postvaccination units and the hyperimmunoglobulin effectively neutralized all 3 variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.

ObjectiveThe aim of this study was to determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity.MethodsThe prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012 to 2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together.ResultsOf 555 children, 324 (58%) were non‐Hispanic white, 55 (10%) non‐Hispanic Black, 24 (4%) non‐Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) other/unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, non‐Hispanic Black children had lower odds of receiving a standard treatment course compared with non‐Hispanic white children (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.20–0.89; p = 0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR, 0.42; CI, 0.21–0.84; p = 0.01).InterpretationNon‐Hispanic Black children were more often treated with non‐standard IS therapies than non‐Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. ANN NEUROL 2022;92:32–44

AbstractConvalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID‐19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID‐19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID‐19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody‐based therapies.

Background: Optimum management of carotid stenosis, both symptomatic (sx) and asymptomatic (asx), remains controversial despite clinical trials evaluating Carotid Endarterectomy (CEA) and Carotid Stenting (CAS). Objective: We compared attitudes in management of carotid stenosis between experts in Europe (EU), and North America (NA). Methods: From April 2011 to July 2012, a 3-round, email-Delphi survey was sent to members of the European Stroke Organisation (n=390) and to a list of NA stroke neurologists developed at the University of Texas at Houston Stroke Program (n=289). Those completing the survey were shown all responses broken down by EU/NA after each of the first 2 survey rounds. Continent specific consensus was defined a priori to be > 80% agreement. Results: 100 (15%, of which 73% EU) participated in all 3-Delphi rounds, 19% of all EU vs 9% NA (χ2=11.62, p=0.0007): 76% male; 69% treating between 1-8 new cases of carotid stenosis per month. In the final round, EU reached consensus in 7/11 statements (3 reached in phase-I), while NA did in 4/11 (1 reached in phase-I).Ninety-percent of EU vs 70% of NA (χ2=8.09, p=0.017) disagreed that CAS and CEA are equivalent treatments for sx carotid stenosis, and stated that CEA is superior. There remains a significant difference between EU and NA when considering ipsilateral stroke and death < 30 days as primary outcome (χ2=12.18, p=0.007). Sixty-nine-percent of NA agreed that there is a stronger indication for CAS over CEA in patients < 65 years for sx carotid stenosis whereas 55% of EU (χ2=11.39, p=0.023) disagreed with the statement. When asked how likely they would recommend CEA for an asx carotid stenosis, 81% of EU and 80% of NA said ‘sometimes’. When asked how likely they would recommend CAS for an asx carotid stenosis, 62% of NA said ‘sometimes’ vs 60% of EU said ‘never’(χ2=3.54, p=0.06). Conclusion: There are several clear differences in attitudes regarding the management of carotid stenosis between EU and NA: EU has a stronger attitude towards superiority of CEA while in NA there is more equipoise between the two treatments. Areas of lack of consensus may provide direction for future clinical trials.

Abstract Background Patients (pts) with ER+ HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after neoadjuvant chemotherapy with dual HER2 blockade than pts with ER- HER2+ BC. Endocrine therapy (ET) plus trastuzumab is effective in advanced ER+ HER2+ BC, but pCR rate is low in the neoadjuvant setting. Inhibition of CDK4/6 and HER2 results in synergistic reduction in cell proliferation in preclinical studies. We therefore combined ET with CDK4/6 inhibition and trastuzumab in ER+ HER2+ BC as a chemotherapy-sparing regimen. Methods We evaluated the efficacy of palbociclib, letrozole, trastuzumab (PLT) in the neoadjuvant setting for pts with stages II or III ER+ HER2+ BC. Primary endpoint was pCR after 16 weeks of therapy. We assumed null of 15% pCR and pCR ≥ 30% warrants further investigation. To achieve 80% power at 1-sided 0.05 significance, 48 pts were to be enrolled. Evaluable population included pts who completed Cycle (C) 1 unless discontinued due to treatment-emergent adverse events (TEAEs) prior to completing C1. All who received one dose on study were considered evaluable for toxicity. Biopsies were collected at baseline (BL), C1 day 15 (C1D15), and surgery for RNA sequencing and central Ki67 assessment, for PAM50 subtype distribution, complete cell cycle arrest (CCCA: Ki67 ≤2.7%) at C1D15 and surgery, and treatment induced signaling changes. Results Accrual stopped early due to futility. 26 pts accrued were evaluable for efficacy and toxicity. pCR (residual cancer burden- [RCB] 0) was 7.7% (95% CI 0.9 - 25.1%) and RCB 0/I was 38.5% (95% CI 20.2 - 59.4%). TEAEs (n= 337) were seen in all pts (71.5% grade [G] 1, 19.3% G2, 8.6% G3, 0.6% G4); the most common were leukopenia (7.7%), neutropenia (7.1%), anemia (5.9%). G3/4 TEAEs occurred in 19 pts (73.1%). Among the 19, incidence of G3/4 neutropenia was 50%, hypertension 26.9%, leucopenia 7.7%. TEAEs (hypertension, ventricular tachycardia, pulmonary edema) leading to treatment discontinuation were reported in 1 pt. Two pts had at least one SAE. No treatment-related deaths occurred. Pt reported outcomes using NCI PRO-CTCAE revealed no differences in appetite, nausea, respiratory symptoms, edema, palpitations, rashes and dry skin, or concentration from BL to end of C4. Pts had worsening hair loss from BL to end of C4. Ki67 analysis indicated CCCA in 78% at C1D15, compared to 18% at surgery after only P had been discontinued approximately 4 weeks prior to surgery. RNA sequencing was performed on available biopsies collected at BL (N=16), C1D15 (N=5), and surgery (N=2) from 16 pts. Among 16 BL samples, PAM50 subtyping identified 5 (31.3%) basal-like, 2 (12.5%) HER2-E, 6 (37.5%) Lum B, and 3 (18.8%) normal. Subtype switching to Lum A at C1D15 (N=3, 1 each with HER2-E, Lum B, and normal at BL) or normal (N=2, 1 basal and 1 HER2-E at BL) was observed. 161 genes were differentially expressed (FDR p&lt;0.05); 145 downregulated and 16 upregulated comparing C1D15 to BL. MKI67, TK1, CCNB1, AURKB, PLK1 were among the downregulated genes, consistent with CCCA for majority of the samples at C1D15 by Ki67. Analysis of the Molecular Signatures Database Hallmark gene-sets comparing C1D15 and BL samples demonstrated downregulated biological processes involved in proliferation (E2F targets, G2M checkpoint, MYC targets, mitotic spindle), signaling (Estrogen response, mTORC1 signaling), and DNA damage (DNA repair) at C1D15, consistent with the mechanisms of action of the study drugs. E2F targets were higher in BL samples of RCB II/III, compared to RCB I (FDR p=0.042). Conclusions PALTAN did not meet its primary endpoint of pCR. Neoadjuvant PLT showed a pCR of 7.7% but was well tolerated. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments, despite significant heterogeneity of intrinsic subtypes. Clinical trial information: NCT02907918. Citation Format: Foluso O Ademuyiwa, Donald Northfelt, Tracey O'Connor, Ellis Levine, Jingqin Luo, Yu Tao, Jeremy Hoog, Marie Laury, Tracy Summa, Trish Hammerschmidt, Zhanfang Guo, Ashley Frith, Katherine Weilbaecher, Mateusz Opyrchal, Rebecca Aft, Katherine Clifton, Rama Suresh, Nusayba Bagegni, Ian S Hagemann, Cynthia X Ma. Phase 2 study of neoadjuvant palbociclib, letrozole, and trastuzumab in patients with ER+ HER2+ breast cancer (PALTAN) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-01.

Abstract Background: Data supporting high tumor mutational burden (TMB-H) as a lone biomarker for an immune responsive tumor microenvironment (TME) or of response to immune checkpoint inhibition (ICI) in metastatic breast cancer (MBC) is weak; yet the tumor agnostic approval in TMB-H advanced tumors makes ICI an option in the clinic. PDL-1 positivity (PDL-1+) is the only consistent biomarker for ICI benefit in metastatic triple-negative BC (mTNBC). We sought to further evaluate concurrent predictors of an immune responsive or non-responsive TME within TMB-H MBC. Methods: Tumor samples (N=5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020) recommendations, with the TMB-H threshold set to ≥ 10 muts/Mb, were used. PDL-1+ (≥1% immune cells stained) assessed by IHC (Ventana SP142). Deficient-mismatch repair (dMMR) and high microsatellite instability (MSI-H) were determined by IHC and NGS, respectively. Gene expression profiling assessed 21 immune-related signatures and TMEs using MCP-counter (Betch et al., 2016) and quanTIseq (Finotello et al., 2019). Immune cell types were classified as immune-responsive (CD8+ and CD4+ T cells, B cells, myeloid dendritic cells, M1 macrophages, NK cells, and neutrophils) or non-responsive (Tregs, M2 macrophages, and monocytes). P-values adjusted by the Benjamini-Hochberg procedure. Exploratory p-values reported for sub-analyses of TMB-H responsive vs nonresponsive TME and PDL1+ vs PDL1- subgroups. Results: TMB-H was identified in 461/5621 (8.2%) MBC samples. TMB-H tumors exhibit significant enrichment of dMMR/MSI-H (7 vs 0%, p&lt;0.0001) and IHC-PDL1+ (36 vs 28%, p&lt;0.05) compared to TMB-L. TMB-H was not associated with increased abundance or proportion of immune responsive cell types or immune response gene signatures (e.g. antigen presentation), yet positive trends were observed. To identify predictive biomarkers of immune responsive (hot) or non-responsive (cold) TME profiles within TMB-H MBC, we generated a composite TME score representing the overall proportion of hot vs cold immune cell types. APOBEC mutagenesis was common in TMB-H tumors (72%) and was more frequently associated with an immune cold TME (77 vs 66% in hot TME subgroup, p=0.068). Within TMB-H tumors, cold TMEs were enriched with mutations (muts) in PIK3CA (61 vs 47%), CHEK2 (5 vs 0%), CBFB (4 vs 0%), amplifications (amp) of CCND1 (13 vs 4%), FGF19 (16 vs 5%), FGF4 (11 vs 4%), and MMLT6 (6 vs 0%), and expression of IHC-AR (75 vs 58%) compared to hot TMEs (all p&lt;0.05). Hot TMEs had increased frequency of MSI-H (12 vs 5%) and KMT2D muts (12 vs 3%) compared to cold TMEs (all p&lt;0.05). Amongst TMB-H and TMB-L tumors, PDL1+ was significantly associated with increased proportion of immune responsive cell types (ie CD8+) compared to PDL1- tumors (0.14 vs -0.08 TME score, p&lt;0.0001). Comparison of TMB-H tumors by PDL1 status revealed enrichment of TP53 (67 vs 53%) and B2M (8 vs 0%) muts in PDL1+ tumors, while IHC-ER positivity (68 vs 54%) and CDH1 muts (32 vs 16%) were increased in PDL1- tumors (all p&lt;0.05). Conclusions: High TMB alone does not strongly correlate with immune infiltrate or immune response gene signatures in MBC. Within TMB-H MBC, concurrent mutations in MSI-H and KMT2D are associated with an immune responsive TME while mutations in PIK3CA, CHEK2, CBFB, amplifications of CCND1, FGF19, FGF4, and MMLT6, and expression of IHC-AR are associated with an immune non-responsive TME. Co-occurring biomarkers within TMB-H breast cancer warrant evaluation in prospective cohorts for response or resistance to ICI to help develop composite biomarkers in breast cancer. Citation Format: Sarah Sammons, Andrew Elliott, Jeremy Force, Saranya Chumsri, Carey Anders, Antoinette R Tan, Daniel Magee, Jia Zeng, W. Michael Korn, Mustafa Kahsraw, Evanthia T Roussos Torres. Concurrent predictors of an immune responsive tumor microenvironment within tumor mutational burden-high breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-08.

PURPOSEAn ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors.CLINICAL CONTEXTAn increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection.PROVISIONAL CLINICAL OPINIONPatients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel–based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase ( NTRK) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker–linked options relative to other approved or investigational treatments. Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines .

Abstract Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logistic, technical, and financial implications, we provide points to consider for the global evolution of cytogenetic testing.