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Background Our study was designed to determine the safety, efficacy, and immunological effects of perioperative pembrolizumab in early-stage NSCLC. Methods This is a single-arm phase II study of perioperative pembrolizumab in patients with untreated, clinical stage IB to IIIA NSCLC. Patients received two doses of 200 mg pembrolizumab, surgery, standard adjuvant chemotherapy, followed by four doses adjuvant pembrolizumab. The primary objective of this study was to determine surgical feasibility rate, and secondary objectives are pathological response rate, treatment adverse events, efficacy data, and exploratory analysis of biomarkers. Results 30 patients initiated perioperative pembrolizumab, and 25 completed tumor resection. At median follow-up of 59 months after surgical resection, seven patients had disease progression, while six had died representing. A 5-year progression-free survival (PFS) from time of surgery was 72.0% (56.4%–91.9%) and overall survival (OS) from time of surgery was 75.8% (60.7%–94.7%). Major pathological response (MPR) was found in seven tumors (28%) including two complete responses (4%). Across all treated patients, four receiving neoadjuvant and four receiving adjuvant pembrolizumab experienced treatment-related adverse events of grade 3 or higher with no grade 5 events. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels increased across our patient cohort over time from baseline until postsurgery and remained elevated at the end of treatment. There was a significant difference between mean plasma PCSK9 levels for patients with MPR versus all other patients on study when checked postoperatively. Conclusions Perioperative pembrolizumab was safe and effective with promising MPR rate, PFS, and OS.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Lung Cancer Screening provide criteria for selecting individuals for screening and offer recommendations for evaluating and managing lung nodules detected during initial and subsequent annual screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

Abstract Pharmacogenomics (PGx) is focused on the relationship between an individual's genetic makeup and their response to medications, with the overarching aim of guiding prescribing decisions to improve drug efficacy and reduce adverse events. The PGx and genomic medicine communities have worked independently for over 2 decades, developing separate standards and terminology, making implementation of PGx across all areas of genomic medicine difficult. To address this issue, the Clinical Genome Resource (ClinGen) Pharmacogenomics Working Group (PGxWG) was established by the National Institutes of Health (NIH)-funded ClinGen to initially create frameworks for evaluating gene–drug response clinical validity and actionability aligned with the ClinGen frameworks for evaluating monogenic gene–disease relationships, and a framework for classifying germline PGx variants similar to the American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) system for interpretation of disease-causing variants. These frameworks will leverage decades of work from well-established PGx resources facilitating buy-in among PGx stakeholders. In this report, we describe the background and major activities of the ClinGen PGxWG, and how this initiative will facilitate the critical inclusion of PGx into the larger context of genomic medicine.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel’s current recommendations regarding sexual health and fertility.

Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.

Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset autoinflammatory disorder defined by somatic UBA1 mutations in hematopoietic cells. VEXAS is associated with a high frequency of clonal hematopoiesis (CH- 60%); with the clonal landscape being dominated by DNMT3A mutations. In our prior study (Gutierrez-Rodrigues Blood 2023), we showed that DNMT3A mutations in VEXAS associated with increased mortality, but without a higher risk of MDS/AML. As DNMT3A is a critical epigenetic regulator, we conducted this study to define the epigenetic deregulation and impact on mortality of DNMT3Amt (mutant) CH in VEXAS. Methods: After IRB approval, 88 VEXAS patients from the Mayo Clinic and the NIH were retrospectively assessed, including 81 screened for CH by error-corrected DNA sequencing (ECS). DNA methylation changes were identified using the Illumina Infinium MethylationEPIC BeadChip on peripheral blood samples (PB). Cellular indexing of transcriptomes and epitopes (CITE)-seq was performed using the 10x Chromium 3' GEX platform; 16,600 pooled cells were subjected to UMAP dimensionality reduction, followed by Azimuth based cell identification. Genotyping of targeted loci with chromatin accessibility (GoTChA) was conducted on two PB DNMT3Amt samples from CCUS individuals (Izzo et al Nature 2024). Results: Patients' median age was 70 years (range: 56 - 89); 95% were white. Twelve out of 81 patients screened by ECS were found with a DNMT3Amt (15%), with a median variant allele fraction (VAF) of 42% (range: 6-46%). In this cohort, while the presence of any CH mutation did not impact survival, DNMT3Amt CH had an age-independent negative impact on mortality (5.5 years vs 8.7 years, p =0.005), without an increase in risk for MDS/AML. Changes in DNA methylation were profiled in 19 and 9 VEXAS patients without CH (Median Age: 68) or with DNMT3Amt CH (Median Age: 74), respectively. VEXAS samples with DNMT3Amt CH had >4,000 differentially methylated CpGs with 95% of the CpGs being hypomethylated compared to those without CH. Using the Roadmap Epigenomics project, we found that this hypomethylation was enriched at enhancer (Enh) sites and actively transcribed states (TxWk). Pathway analysis revealed that the hypomethylated sites were in or near genes involved in the development and differentiation of leukocytes, with IL-13 and IL-15 being identified as upstream regulators of the methylation changes. Bulk RNA-seq performed on PB of 2 and 3 VEXAS patients with and without DNMT3Amt, respectively, identified >1,500 differentially expressed genes in DNMT3Amt samples, 78% of these being overexpressed. Pathway analysis was enriched in gene pathways involved in the development of leukocytes, with IL-13 and IL-15 once again being identified as upstream regulators. Integration of methylation and transcriptomic data identified upregulation of several genes within the IL-13 and IL-15 pathways, with these regions correlating with a decrease in methylation. To assess if the epigenetic dysregulation is linked to DNMT3A mutations, we performed GoTChA-seq on two DNMT3Amt clonal cytopenia samples (CCUS). The comparison of the number of cutsites in DNMT3A wild type vs mt cells from the same individual demonstrated increased open chromatin within the IL-13 and IL-15 pathways in mt cells, both globally and in a genomic locus specific manner. CITE-seq performed on 3 VEXAS samples (2 DNMT3Amt CH vs 1 no CH) further showed that expression of genes involved in IL-13 and IL-15 pathway is significantly increased in CD4+ and CD8+ T cells from DNMT3Amt samples, suggesting a paracrine regulatory effect of T lymphocytes (mostly UBA1 and DNMT3A wild-type) in VEXAS. Pathway analysis of DEGs in these cells also revealed an enrichment of genes involved in inflammation and lymphocyte proliferation. Conclusions: Our study validates the age-independent, negative prognostic impact of DNMT3Amt CH on survival in VEXAS syndrome. DNMT3Amt mediates epigenetic and transcriptional priming associated with upregulation of IL-13/15 pathway in CD4/CD8 T cells, which are mostly DNMT3A and UBA1 wild-type, suggesting that the contribution of T lymphocytes to inflammation may be secondary to CH in the myeloid compartment.

Background The International Myeloma Working Group (IMWG) defines progression of disease (PD) in multiple myeloma by the increase in serum or urine paraprotein beyond a certain threshold. With more common use of serial bone marrow-based measurable residual disease (MRD) assessment, some patients will evolve with increase in MRD burden without meeting IMWG criteria for PD and no consensus exist on the best approach for this circumstance. Understanding the implication of increasing MRD burden is particularly relevant in patients with NDMM treated with quadruplet therapy (QUAD, consisting of a PI, an IMiD, an anti-CD38 mAb and dexamethasone) and autologous stem cell transplantation (ASCT), since most will reach MRD negativity. Methods We analyzed a large dataset of patients with NDMM patients treated with QUADs + ASCT +/- QUAD consolidation +/- single or dual-agent maintenance and monitored with serial MRD assessment by next-generation sequencing (clonoSEQ®) at end of induction, post ASCT, post consolidation and at least yearly thereafter. The dataset was built from clinical trial participants and from patients receiving standard care under an institutional guideline. MRD progression (MRD-P) was arbitrarily defined as quantitative increase in MRD burden by at least 1 log10 above the nadir. Treatment modification in the event of MRD-P without IMWG-defined PD was at discretion of treating physician. For patients with MRD-P without concomitant PD we describe cumulative incidence of PD after MRD-P. To contextualize the clinical implications of MRD-P, we describe survival free of failure of second line therapy (SFF2T), defined as time from progression event (MRD-P or PD not preceded by MRD-P) until occurrence of IMWG-defined PD or death on second line therapy, regardless of whether second line was initiated due to MRD-P or subsequent IMWG-defined PD. Results Among the 216 patients, 113 (52%) were clinical trial participants, median age was 61 years (IQR 56-68), 21% age 70 or older, 32% were non-White, 57% male, 38% had MM with 1 high risk chromosome abnormality [HRCA, gain/amp 1q, t(4;14), t(14:16), del(17p)], 15% had 2+HRCA. Median duration of follow up is 39.5 months, and 966 MRD datapoints were assessed. Overall, 83% of patients achieved sCR, 78% achieved MRD negativity at 10-5, 68% at the 10-6 threshold, and 56% ceased therapy after confirmed MRD negativity. Forty-nine patients had MRD-P(N=19) or PD not preceded by MRD-P (N=30). Patients with MRD-P or PD not preceded by MRD-P often had 1 or more HRCA (73.7% and 82.8%), International staging system III (36.8% and 30.0%), and high LDH at diagnosis (31.6% and 23.3%). Median time from onset of therapy to MRD-P was 24.4 mo (IQR 12.6-35.8) and to PD not preceded by MRD-P was 23.2 mo (IQR 18.4-29.4). Among the 19 patients with MRD-P, 12 (63%) were on observation at time of MRD-P, 2 were receiving single agent lenalidomide, 5 were receiving a QUAD, 17 (89%) had previously obtained MRD negativity at <10-5 including 10 (53%) who had also achieved MRD negativity at 10-6. Upon detection of MRD-P, 12 (63%) pts changed therapy, all to a monoclonal antibody-containing triplet or quadruplet regimen. Yet, median time from MRD-P to PD was 10.1 months. Patients with MRD-P had 1-year SFF2T of 55.6%, in contrast to 35.0% for patients with PD not preceded by MRD-P. OS 2-year from progression event was 78.0% for MRD-P and 53.9% for PD not preceded by MRD-P. Conclusions In the context of NDMM treated with QUAD + ASCT, MRD-P indicates imminent IMWG-defined PD, and is driven by a thriving plasma cell population unlikely to be controlled by reinstitution of anti-CD38 mAb-based combinations. Outcomes of patients with MRD-P are similar to those of patients with IMWG-defined PD. These findings challenge the paradigm of IMWG-defined PD and paraprotein measurability as minimal parameters for change in therapy and introduction of agents with new mechanisms of action.

Introduction QUADs with an anti-CD38 mAb, an IMiD, a proteasome inhibitor and dexamethasone followed by autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed multiple myeloma (NDMM) led to substantial improvements in depth of response, including minimal residual disease (MRD) negativity, and progression-free survival. The therapeutic success of QUAD + ASCT has reinvigorated an interest in fixed-duration therapy, yet optimal short term efficacy endpoint for treatment cessation is unknown. We used a large dataset of patients (pts) treated with QUAD + ASCT, monitored with serial MRD assessment and managed with MRD-adapted treatment duration to determine the best short term efficacy endpoint to identify pts at low risk of treatment failure. Methods We analyzed 221 pts with NDMM treated with QUAD + ASCT and monitored with serial marrow-based MRD by next-generation sequencing. Based on trial design (N=116) and institutional practice (N=105) most pts received post ASCT QUAD consolidation followed by treatment cessation if MRD<10-5 in two consecutive datapoints. Pts were monitored with MRD post induction, ASCT and consolidation, and at least yearly thereafter. We utilized Cox regression to build parallel models of predictors of disease progression or MRD resurgence utilizing the same patient and disease features and one distinct short term efficacy endpoint per model, inputted as time-varying covariate. Efficacy endpoints tested were IMWG-defined stringent complete response (sCR), MRD<10-5 (single datapoint), MRD<10-6, sustained MRD (S-MRD, two consecutive assessments at least 1 year apart) <10-5and S-MRD<10-6. Best fitting models were determined using Akaike's information criterion (AIC, lower value indicates better fitting model), an information theory approach, and Heagerty & Zheng C index. Results Median age of the 221 pts. was 61 years (IQR 55-68), 21% age 70 or older, 37% had MM with 1 high risk chromosome abnormality [HRCA, gain/amp 1q, t(4;14), t(14:16), del(17p)], 16% had 2+HRCA, 30% were non-White and 58% male. We followed pts for a median of 40.6 mo. and performed 979 MRD assessments. One hundred and eighty-three pts (83%) achieved sCR, 170(77%) MRD<10-5, 146 (66%) MRD<10-6 , 110 (50%) S-MRD<10-5 and 90 (41%) S-MRD<10-6. Average time to achieve the endpoint was 7.8 mo for sCR, 7.1 mo. for MRD <10-5, 9.4 mo. for MRD<10-6, 19.3 mo. for S-MRD<10-5 and 20.5 mo. for S-MRD<10-6. We first tested models to predict PFS among all 221 pts. Predictive models included same covariates (ISS, high LDH and number of HRCA) other than the efficacy endpoint. The best fitting model (AIC 417.2, C-stat 0.757) was based on S-MRD<10-5 (HR=0.23, 95% C.I. 0.11-0.47) and included presence of 1 HRCA (HR=2.93, 95% C.I. 1.31-6.52), 2+ HRCA (HR=7.60, 95% C.I. 3.31-17.43), high LDH (HR=1.64, 95% C.I. 0.81-3.33), ISS2 (HR 1.31, 95% C.I. 0.62-2.77) and ISS3 (HR 1.96, 95% C.I. 0.90-4.28). The model with S-MRD<10-6 had similar, but not better performance (AIC 419.4, C-stats 0.752). We subsequently analyzed the 121 (55%) pts who reached MRD-guided treatment cessation for the best fitting model to predict progression or MRD resurgence in absence of continuous therapy. Among these pts, 117(97%) achieved sCR, all (by definition) MRD<10-5, 116 (96%) MRD<10-6 , 95 (79%) S-MRD<10-5 and 81 (67%) S-MRD<10-6. The best fitting model (AIC 197.2, C-stat 0.766) was based on S-MRD<10-5 (HR 0.01, 95% C.I. 0.002-0.05) and included presence of 1 HRCA (HR=1.41, 95% C.I. 0.49-4.07), 2+ HRCA (HR=5.43, 95% C.I. 1.75-16.84), high LDH (HR=3.19, 95% C.I. 0.98-10.40), ISS2 (HR 1.25, 95% C.I. 0.53-2.96) and ISS3 (HR 0.73, 95% C.I. 0.23-2.37). The model with S-MRD<10-6 did not perform better (AIC 232.4, C-stat 0.727). Among the 94 pts who achieved S-MRD<10-5 and were monitored off therapy, the risk of MRD resurgence or progression 2.5 years after cessation of therapy was 6.1%, 15.0% and 22.2% and risk of progression was 3.0 %, 12.0% and 11.1% for patients with 0, 1 and 2+ HRCA, respectively Conclusion In the setting of QUAD therapy + ASCT, no short term conventional or MRD-based efficacy parameter negates the cumulative impact of HRCA on prognosis. S-MRD<10-5 is the best predictor of PFS and yields the best predictive models for risk of MRD resurgence or progression in the setting of fixed duration therapy. This analysis validates S-MRD<10-5 as efficacy parameter for treatment cessation in trials exploring fixed duration therapy in NDMM.