PURPOSE Chromosome 1 (chr1) copy number abnormalities (CNAs) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and associate with a heterogeneous impact on outcome the drivers of which are largely unknown. EXPERIMENTAL DESIGN A multiomic approach comprising CRISPR, gene mapping of CNA and SV, methylation, expression, and mutational analysis was used to document the

PURPOSE PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small-cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. PATIENTS AND METHODS We integrated clinical, genomic and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase 3 trials (CameL and CameL-sq)

PURPOSE Postpartum breast cancer patients diagnosed after cessation of breastfeeding (post-weaning, PP-BCPW), have a particularly poor prognosis compared to patients diagnosed during lactation (PP-BCDL), or to pregnant (Pr-BC) and nulliparous (NP-BC) patients, irrespective of standard prognostic characteristics. Animal studies point to a role of the involution process in stimulation of tumor growth

Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined

PURPOSE Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN We collected 460 CHEK2 missense

PURPOSE The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of glioblastoma stem

PURPOSE Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGF-β, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, down-regulates

PURPOSE Early treatment intensification with neoadjuvant therapy may improve outcomes in high-risk, localized prostate cancer (PCa) patients treated with radical prostatectomy (RP). Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to RP in localized, high-risk PCa patients. PATIENTS AND

PURPOSE Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was to evaluate somatic mutations in urine to accurately discriminate endometrial cancer patients from controls. EXPERIMENTAL DESIGN Overall, 72 samples were analyzed using next-generation sequencing with molecular identifiers targeting 47 genes. We

PURPOSE Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma (UC) and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk. EXPERIMENTAL DESIGN This is a multicenter case-control study utilizing banked urine specimens collected

A phase 1 trial of the novel combination of the ATR inhibitor, berzosertib, plus the antibody-drug conjugate, sacituzumab govitecan, in patients with heavily pre-treatment tumors demonstrated some anti-tumor activity and no dose-limiting toxicities. This represents a new treatment paradigm which will be further explored in a phase 2 setting.

CD49d, the alpha chain of the VLA-4 integrin, has a negative prognostic impact in CLL treated with the BTK-inhibitors ibrutinib and acalabrutinib. Despite BTK inhibition, VLA-4 remains inside-out activated via BCR, an activation dampened by PI3K-inhibitors. Evaluation of CD49d expression in patients starting BTK-inhibitor therapy may improve their prognostic stratification.

In the evolving molecular treatment landscape of metastatic colorectal cancer (mCRC), the identification of druggable alterations is pivotal to achieve the best therapeutic opportunity for each patient. Since the number of actionable targets is expanding, there is the need to timely detect their presence or emergence to guide the choice of different available treatment options. Liquid biopsy, through

PURPOSE Despite the significant association of molecular subtypes with poor prognosis in pancreatic ductal adenocarcinoma (PDAC) patients, little effort has been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes. EXPERIMENTAL DESIGN We analyzed the transcriptomic profiles

PURPOSE We sought to identify features of patients with advanced non-small cell lung cancer (NSCLC) who achieve long-term response (LTR) to immune checkpoint inhibitors (ICIs), and how these might differ from features predictive of short-term response (STR). EXPERIMENTAL DESIGN We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with ICIs over ten years. LTR and

BACKGROUND Caveolin-1 and -2 (CAV1/2) dysregulation are implicated in driving cancer progression and may predict response to nab-paclitaxel. We explored the prognostic and predictive potential of CAV1/2 expression for early-stage HER2-negative (HER-) breast cancer (BC) patients receiving neoadjuvant paclitaxel-based chemotherapy regimens. PATIENTS AND METHODS We correlated tumor CAV1/2 RNA expression

A vaccine targeting HER2, a non-mutated but overexpressed tumor antigen, readily primed T-cells for ex vivo expansion and adoptive transfer with minimal toxicity. This regimen led to intramolecular epitope spreading in a majority of patients and offers a treatment modality that may improve outcomes for patients with metastatic breast cancer expressing HER2.

In a recent study, the authors developed a nectin-4-targeting bicyclic peptide-based radiotracer, 68Ga-N188, for PET imaging of advanced urothelial cancer. Preclinical investigation and first-in-human study in 14 patients demonstrated excellent specificity and sensitivity of 68Ga-N188 in detecting metastases. These promising results support 68Ga-N188 as a companion diagnostic for future personalized

PURPOSE We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ breast cancer (BC) patients who failed to achieve pathologic-complete response (pCR) after anti-HER2+chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs

PURPOSE Malignant peripheral nerve sheath tumors (MPNSTs) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting CDK4/6, MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. EXPERIMENTAL DESIGN Patient-matched MPNSTs and precursor lesions were examined by FISH, RNAseq, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6

PURPOSE Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omic approach to quantitatively profile kinome enrichment in a mouse model that has predicted therapeutic responses in clinical trials

PURPOSE We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric (EG) cancer in conjunction with outcomes from an independent MSK cohort. EXPERIMENTAL DESIGN The significance of pre-treatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was

In April 2022, the U.S. FDA approved axicabtagene ciloleucel for adults with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. Approval was based on ZUMA-7, a randomized (1:1), open-label trial in 359 patients with primary refractory LBCL (74%) or early relapse who were transplant candidates. The study

PURPOSE Pancreatic ductal adenocarcinoma (PDA) resists immunotherapy of adoptive cell transfer (ACT) and immune checkpoint inhibitors. Understanding the mechanisms underlying this resistance will improve PDA immunotherapy. This study investigated therapeutic effects and underlying mechanisms of anticoagulants on immunotherapy in PDA. EXPERIMENTAL DESIGN The antitumor activity of immunotherapy was evaluated

PURPOSE Antibodies against IGF-1R have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF-1R antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase

PURPOSE Cancer drug development is currently limited by a paradigm of preclinical evaluation that does not adequately recapitulate the complexity of the intact human tumor microenvironment (TME). To overcome this, we combined trackable intratumor microdosing (CIVOTM) with spatial biology readouts to directly assess drug effects in patient tumors in situ. PATIENTS AND METHODS In a first-of-its-kind

PURPOSE The study evaluated safety and efficacy of olaratumab+pembrolizumab in patients with unresectable locally advanced/metastatic soft-tissue sarcoma with disease progression on standard treatment. PATIENTS AND METHODS This was open-label, multicenter, nonrandomized, phase 1a/1b dose-escalation study followed by cohort expansion (olaratumab+pembrolizumab intravenous infusion). Primary objectives

PURPOSE Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients and the overall survival of those who benefit from it remains very low (~9.3 months). This highlights the need to develop improved mechanistic

PURPOSE Isocitrate dehydrogenase (IDH) mutant gliomas are usually treated with radiotherapy and chemotherapy, which increases the risk for neurocognitive sequelae during patients' most productive years. We report our experience using off-label first-inclass IDH1mut-inhibitor ivosidenib and its impact on tumor volume in IDHmut gliomas. EXPERIMENTAL DESIGN We retrospectively analyzed patients aged ≥18

PURPOSE Target-dependent TCB activity can result in strong and systemic release of cytokines that may develop into Cytokine Release Syndrome (CRS), highlighting the need to understand and prevent this complex clinical syndrome. EXPERIMENTAL DESIGN We explored the cellular and molecular players involved in TCB-mediated cytokine release by single cell RNA sequencing of whole blood treated with CD20-TCB

PURPOSE Plasma circulating tumor DNA (ctDNA) analysis is used for genotyping advanced non-small cell lung cancer (NSCLC); monitoring dynamic ctDNA changes may be used to predict outcomes. EXPERIMENTAL DESIGN This was a retrospective, exploratory analysis of two phase III trials (AURA3 [NCT02151981], FLAURA [NCT02296125]). All patients had epidermal growth factor receptor mutation-positive (ex19del

The results of CheckMate-238 led to the original FDA approval of anti-PD1 therapy in high-risk, resectable melanoma. In this CCR Translations, we discuss the 5-year update of this pivotal trial and contextualize its results in the face of limited survival data, neoadjuvant therapy, next-generation biomarkers, and novel immunotherapy combinations.

PURPOSE Cancer vaccines represent a novel treatment modality with a complementary mode of action addressing a crucial bottleneck for checkpoint inhibitor (CPI) efficacy. CPIs are expected to release brakes in T-cell responses elicited by vaccination, leading to more robust immune responses. Increased anti-tumor T-cell responses may confer increased anti-tumor activity in patients with less immunogenic

In April 2022, the FDA issued draft guidance to help industry develop strategies to improve diversity in clinical trials. Historically, clinical trial sponsors have not systematically incorporated efforts to promote diversity, equity, and inclusion (DEI), particularly during the early design stages of clinical development plans and operational strategies. Unfortunately, a retrospective approach to

BACKGROUND Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL, but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. METHODS Final results

PURPOSE The androgen receptor axis inhibitors (ARPI) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown Experimental Design: In a prospective trial MATCH-R (NCT02517892), 59 mCRPC patients underwent

PURPOSE High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG immunohistochemistry (IHC) was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated

PURPOSE This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators. PATIENTS AND METHODS A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (

PURPOSE Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy, but it is associated with significant dose to normal organs-at-risk (OAR). In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN)

PURPOSE Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance to BH3 mimetics in T-ALL in order to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL. METHODS We used BH3 profiling as a predictive tool for BH3

PURPOSE To overcome resistance to anti-hormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor Tucatinib, aromatase inhibitor Letrozole, and CDK4/6 inhibitor Palbociclib (TLP) for treatment of HR+/HER2+ metastatic breast cancer (MBC). PATIENTS AND METHODS Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated

Accurately assessing homologous recombination deficiency to use as predictive biomarker is an area of intense research in ovarian cancer. Validated assays have demonstrated utility in determining maintenance therapy following platinum sensitive chemotherapy. Novel functional assays promise the potential to reflect HRD in real time and predict response to PARP inhibitors.

PURPOSE Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine

PURPOSE Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 re-expression. This study examines the role of ASS1 silencing on tumor growth and initiation and

PURPOSE Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas (EC) including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, though tumor initiating events remain elusive. There is

Purpose To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Patients and Methods We used targeted sequencing (TS) to analyse 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi)

PURPOSE Laser interstitial thermal therapy (LITT) is an effective minimally-invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT. EXPERIMENTAL DESIGN The impact of GNS on LITT coverage capacity was tested in ex vivo models utilizing clinical

PURPOSE We evaluated the efficacy of bavituximab - a monoclonal antibody with anti-angiogenic and immunomodulatory properties - in newly diagnosed glioblastoma (GBM) patients who also received radiation and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916)

PURPOSE Cemiplimab is approved for the treatment of locally advanced basal cell carcinomas (BCCs), however with mitigated results. We sought to interrogate the cellular and molecular transcriptional reprogramming underlying BCC resistance to immunotherapy. EXPERIMENTAL DESIGN Here, we combined spatial and single-cell transcriptomics to deconvolute the spatial heterogeneity of the tumor microenvironment

PURPOSE TGF-β1 and TGF-βR1 participate in regulation of the host's immune system and inflammatory responses and may serve as prognostic biomarkers for HPV-associated OPSCC. EXPERIMENTAL DESIGN This study included 1013 patients with incident OPSCC, of whom 489 had tumor HPV16 status determined. All patients were genotyped for two functional polymorphisms: TGF-β1 rs1800470 and TGF-βR1 rs334348. Univariate

Although a minority of colorectal cancers exhibit mismatch-repair deficiency and associated sensitivity to immune checkpoint inhibitors, the vast majority of colorectal cancers arise in a tolerogenic microenvironment with mismatch-repair proficiency, low tumor-intrinsic immunogenicity, and negligible immunotherapy responsiveness. Treatment strategies to augment tumor immunity with combination immune

On January 29, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab

PURPOSE Acquired mutations in Bruton's tyrosine kinase (BTK) or phospholipase C-γ2 (PLCG2) genes are associated with clinical progressive disease (PD) in patients with chronic lymphocytic leukemia (CLL) treated with BTK inhibitors. Data on mutation rates in patients without PD on ibrutinib treatment are limited. EXPERIMENTAL DESIGN We evaluated frequency and time to detection of BTK and PLCG2 mutations

RET fusions occur as a rare mechanism of acquired resistance to osimertinib in epidermal growth factor receptor mutation (EGFRm) positive non-small cell lung cancer (NSCLC) patients. Inhibiting RET alongside osimertinib shows promising clinical activity but innovative approaches are needed to seek regulatory approvals in these rare treatment resistance settings.

Hypoxia in head and neck tumors has proven to be predictive of outcomes. Current hypoxia signatures have failed for patient treatment selection. In a recent study, the authors identified a hypoxia methylation signature as a more robust biomarker in HNSCC and shed light into the mechanism of hypoxia-mediated treatment resistance.

Drug development can be associated with slow timelines, particularly for rare or difficult-to-treat solid tumors such as glioblastoma. The use of external data in the design and analysis of trials has attracted significant interest because it has the potential to improve the efficiency and precision of drug development. A recurring challenge in the use of external data for clinical trials, however

PURPOSE Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody-drug conjugates