Alternative statistical designs cannot fully mitigate the limitations of traditional clinical trials in rare cancers. Creative study designs that integrate early clinical data and correlative outcomes from concomitant translational and laboratory models to evaluate the efficacy of druggable targets can potentially expedite access to novel therapies for these patients.

Purpose: Immunotherapy efficacy data on appendiceal cancer from clinical trials does not exist, due to appendiceal cancer incidence of 0.97 per 100,000. The goal of this study was to preclinically explore the application of immunotherapy in treating appendiceal cancer in a personalized organoid model. Experimental Design: Patient tumor organoids (PTO) were fabricated using unsorted tumor cells with

Purpose: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). Experimental Design: In patients with non–small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University

Purpose: Enfortumab vedotin (EV) is an antibody–drug conjugate (ADC) targeting NECTIN4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In this study, we sought to (i) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and (ii) determine whether

Purpose: Systems biology approaches can identify critical targets in complex cancer signaling networks to inform new therapy combinations that may overcome conventional treatment resistance. Experimental Design: We performed integrated analysis of 1,046 childhood B-ALL cases and developed a data-driven network controllability-based approach to identify synergistic key regulator targets in Philadelphia

Purpose: To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab. Experimental Design: Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity

Purpose: Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all patients with cancer. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots. Discovering T-cell receptors (TCR) that recognize shared

Purpose: The Cancer Immune Monitoring and Analysis Centers – Cancer Immunologic Data Commons (CIMAC-CIDC) network supported by the NCI Cancer Moonshot initiative was established to provide correlative analyses for clinical trials in cancer immunotherapy, using state-of-the-art technology. Fundamental to this initiative is implementation of multiplex IHC assays to define the composition and distribution

Purpose: The Cancer Immune Monitoring and Analysis Centers – Cancer Immunologic Data Commons (CIMAC-CIDC) Network is supported by the NCI to identify biomarkers of response to cancer immunotherapies across clinical trials using state-of-the-art assays. A primary platform for CIMAC-CIDC studies is cytometry by time of flight (CyTOF), performed at all CIMAC laboratories. To ensure the ability to generate

Purpose: Whole-exome (WES) and RNA sequencing (RNA-seq) are key components of cancer immunogenomic analyses. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the Cancer Immune Monitoring and Analysis Centers (CIMAC) and the Cancer Immunologic Data Commons (CIDC) conducted a systematic harmonization study. Experimental Design: DNA and RNA were centrally

Purpose: Immunoprofiling to identify biomarkers and integration with clinical trial outcomes are critical to improving immunotherapy approaches for patients with cancer. However, the translational potential of individual studies is often limited by small sample size of trials and the complexity of immuno-oncology biomarkers. Variability in assay performance further limits comparison and interpretation

Purpose: M-protein is a well-established biomarker used for multiple myeloma monitoring. Current improvements in multiple myeloma treatment created the need to monitor minimal residual disease (MRD) with high sensitivity. Measuring residual levels of M-protein in serum by MS was established as a sensitive assay for disease monitoring. In this study we evaluated the performance of EasyM—a noninvasive

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and

Purpose: This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel. Patients and Methods: Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin

Purpose: Statin use is reportedly associated with the risk of prostate cancer, outcomes after treatment, and prostate cancer-specific mortality. We sought to determine the efficacy of adjuvant atorvastatin in prostate cancer after radical prostatectomy. Patients and Methods: In this randomized, double-blind trial, we assigned patients with pathologic high-risk prostate cancer to receive either low-dose

Purpose: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD)

Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (g BRCA )-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel. Patients and Methods: Eligible patients ( N = 513) were randomized

Chromosomal rearrangements of NTRK1–3 resulting in gene fusions ( NTRK gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers. Typically, NTRK gene fusions involve both inter- and intrachromosomal fusions of the 5′ regions of a variety of genes with the 3′ regions of NTRK genes leading to TRK fusion proteins with constitutive, ligand-independent activation

It is a sad fact that despite being almost completely preventable through human papillomavirus (HPV) vaccination and screening, cervical cancer remains the fourth most common cancer to affect women worldwide. Persistent high-risk HPV (hrHPV) infection is the primary etiologic factor for cervical cancer. Upward of 70% of cases are driven by HPV types 16 and 18, with a dozen other hrHPVs associated with

Nectin-4 is the target for enfortumab vedotin, a novel antibody–drug conjugate. NECTIN4 gene expression differs considerably across different molecular subtypes and is shown to be important for enfortumab vedotin efficacy. See related article by Chu et al., [p. 5123][1] [1]: /lookup/volpage/27/5123?iss=18

Statins have plausible biological effects against prostate cancer cells and are associated with improved disease-specific mortality. In current randomized placebo-controlled trial, low-dose atorvastatin caused no difference in relapses after radical prostatectomy in Asian men. Future trials should study higher statin doses at later disease stages with survival as the endpoint. See related article by

### [Puhalla et al. Page 4983][1] Advanced breast cancers associated with germline breast cancer susceptibility gene (g BRCA ) mutations are sensitive to platinum chemotherap. and poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi). However, shared mechanisms of acquired resistance to

PURPOSE Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. EXPERIMENTAL DESIGN Patients with R/R MZL were enrolled in the phase 2 MAGNOLIA

PURPOSE B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cells (CART-BCMA) are a promising treatment for relapsed/refractory multiple myeloma (r/rMM). We evaluated the safety and feasibility of bridging radiation (RT) in subjects treated on a phase 1 trial of CART-BCMA. EXPERIMENTAL DESIGN Twenty-five r/rMM subjects were treated in 3 cohorts with two doses of CART-BCMA cells

PURPOSE Pre-operative nodal staging is important for planning treatment in cervical cancer (CC) and endometrial cancer (EC) but remains challenging. We compare nodal staging accuracy of 18F-ethyl-choline-(FEC)-PET/CT, 18F-Fluoro-deoxy-glucose-(FDG)-PET/CT and diffusion-weighted-MRI (DW-MRI) with conventional morphological MRI. EXPERIMENTAL DESIGN A prospective, multicentre observational study of diagnostic

PURPOSE Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma(ICC). However, little is known about the intertumor heterogeneity(ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. EXPERIMENTAL

PURPOSE Bladder cancer (BC) treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of BC recurrence. EXPERIMENTAL DESIGN Here, we performed single-cell RNA-seq and ATAC-seq on tumors from 13 patients with low recurrence risk, high recurrence risk and recurrent BC. RESULTS Our study generated

PURPOSE Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from CRPC patients and investigate the clinical utility of detecting

BACKGROUND Cancer vaccines targeting nonmutated proteins elicit limited Type I T-cell responses and can generate T-regulatory and Type II T-cells. Class II epitopes that selectively elicit Type I or Type II cytokines can be identified in nonmutated cancer associated proteins. In mice, a T-helper I selective IGFBP-2 N-terminus vaccine generated high levels of IFN-Ɣ secreting T-cells, no regulatory T-cells

PURPOSE Multiple Myeloma (MM) is a biologically heterogenous plasma-cell disorder. In this study we aimed at dissecting the functional impact on transcriptome of gene mutations, copy-number abnormalities (CNAs), and chromosomal rearrangements (CRs). Moreover, we applied a geno-transcriptomic approach to identify specific biomarkers for personalized treatments. METHODS We analyzed 514 newly-diagnosed

PURPOSE Serum Thymidine Kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor-positive MBC treated on a prospective randomized trial of anastrozole (A) vs. A plus fulvestrant (A+F). EXPERIMENTAL DESIGN sTK1 was assessed in 1,726 serums [baseline (BL), cycles 2, 3, 4, and 7] using the

PURPOSE Based on strong preclinical rationale, we sought to confirm recommended phase 2 dose for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. EXPERIMENTAL DESIGN We performed a safety lead in followed by expansion in endometrial, triple negative breast, or ovarian cancers. Olaparib 300mg orally twice daily (BID) and

PURPOSE To evaluate the tissue distribution and clinical significance of OX40 and OX40L in human non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN Using multiplexed quantitative immunofluorescence (QIF), we conducted simultaneous and localized measurements of OX40 and OX40L proteins, major T-cell subsets and conventional type-1 dendritic cells (cDC1) in 614 primary NSCLCs from three independent

PURPOSE Natural Killer (NK) cells are type 1 innate lymphoid cells that are known to secrete cytokines and for their role in killing virally infected cells or cancer cells through cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although

PURPOSE MPS1 kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase 1 study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. EXPERIMENTAL DESIGN Patients with solid tumors were randomized to receive oral BAY (BID 2‑days‑on/5‑days‑off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy

PURPOSE Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF-mutated myeloma as a model for resistance to precision medicine we investigated if BRAF-mutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment. EXPERIMENTAL

PURPOSE Our team previously defined six quantitative transcriptomic components, and a classification in five subtypes by association of these components. In this study, we compared the robustness of quantitative components and qualitative classifications from different transcriptomic profiling techniques, investigated their clinical relevance and proposed a new prognostic model. EXPERIMENTAL DESIGN

PURPOSE Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKIs). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase 3 INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients

PURPOSE Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a pre-activated nucleoside released. 3'-deoxyadenosine (3'-dA) is a naturally-occurring

PURPOSE Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to-date. Greater than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion. However

PURPOSE To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histological tumor type. PATIENTS AND METHODS Patients with treatment-refractory BRCA1/2 mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In DRUP, patients with treatment-refractory

PURPOSE Here we describe a combination chimeric antigen receptor (CAR) T cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. EXPERIMENTAL DESIGN We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T cell receptor (TCR) specific for gp100. As gp100 is

PURPOSE Doxorubicin is standard therapy for advanced soft tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings

PURPOSE Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain. We describe the development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)

PURPOSE Abnormal notch signaling promotes cancer cell growth and tumor progression in various cancers. Targeting γ-secretase, a pivotal regulator in the Notch pathway, has yielded numerous GSIs for clinical investigation in the last two decades. However, GSIs have demonstrated minimal success in clinical trials in part due to the lack of specific and precise tools to assess γ-secretase activity and

The editors are publishing this note to alert readers to a concern about [this article][1] ([1][2]): in Fig. 3D, the p21 and Noxa Western blots for SKN-DZ were accidentally duplicated as the PUMA and Noxa Western blots for SKN-BE(2). The SKN-DZ blots were correct, and the authors have additional SKN

In the original version of [this article][1] ([1][2]), the authors found five images that were published in error: Fig. 2B, colony formation assay of KYSE-140/miR-644a; Fig. 2C, migration assay of KYSE-140/control (0h); Fig. 2D, invasion assay of KYSE-140/miR-644a; Fig. 4C, “Scramble” proportion

In the original version of [this article][1] ([1][2]), Supplementary Table S1 is incorrect. A subset of the whole exome sequencing sample IDs was incorrectly labeled with the RNA-sequencing IDs from the same tumors. Supplementary Table S1 has been replaced with a corrected version in the latest

In the original version of [this article][1] ([1][2]), the name of the thirty-third author, F. Stephen Hodi, is incorrect. The name has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error. 1. 1.[↵][3]1. Monjazeb AM, 2. Giobbie-Hurder A

In earlier versions of [this article][1] ([1][2]) that were published online on February 3, 2021 and February 25, 2021, one of the paired cell line models (T47D P/PalboR) failed authentication. The authors replaced the original T47D P and its PalboR cell derivative with a parallel T47D model (T47D P

We thank Kossatz and Notni for their interest in our article about the use of fluorescent cRGD-ZW800-1 for visualization of tumor tissue in humans during surgery ([1][1]). Their concern seems the specificity of the tracer for integrin αvβ6, which is lower than for αvβ3, and the relation with our

A recent article by de Valk and colleagues reported the use of the fluorescent agent cRGD-ZW800–1 for visualization of tumor tissue in humans during surgery ([1][1]). The authors hypothesize that their compound, which “consists of a cyclic pentapeptide (cRGD) conjugated to the 800 nm

Purpose: Lineage plasticity in prostate cancer—most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program—is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover

Purpose: Bcl-2 has been effectively targeted in lymphoid malignancies. However, resistance is inevitable, and novel approaches to target mitochondrial apoptosis are necessary. AZD5991, a selective BH3-mimetic in clinical trials, inhibits Mcl-1 with high potency. Experimental Design: We explored the preclinical activity of AZD5991 in diffuse large B-cell lymphoma (DLBCL) and ibrutinib-resistant mantle

Purpose: Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid

Purpose: While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens. Experimental Design: We performed transcriptional profiling of tumors from

Purpose: Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor–positive (ER+)/HER2− breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient

Purpose: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell–refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics

Purpose: In REFLECT, lenvatinib demonstrated an effect on overall survival (OS) by confirmation of noninferiority to sorafenib in unresectable hepatocellular carcinoma. This analysis assessed correlations between serum or tissue biomarkers and efficacy outcomes from REFLECT. Experimental Design: Serum biomarkers (VEGF, ANG2, FGF19, FGF21, and FGF23) were measured by ELISA. Gene expression in tumor

Purpose: A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear. Experimental Design: We selected PD-L1–positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in