Crabtreehayden8416

In



metastatic melanoma, cyclin D-CDK4/6-INK4-Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of cyclin-dependent kinase 4 (CDK4) inhibitors. Vorapaxar cost In this phase I-II study, we aimed to establish the MTD of palbociclib when added to vemurafenib.

Patients with



metastatic melanoma harboring

loss and

expression were included and stratified into two groups according to previous BRAF inhibitor treatment (nostrata 1; yesstrata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics, and tumor molecular profiling.

Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were American Joint Committee on Cancer stage IVM1c (

= 16; 88.9%), high lactate dehydrogenase (

= 9; 50.0%), and median number of pre was highlighted.

Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent

mutations or specific gene fusions, most commonly involving

. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.

A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT;

= 136) or hotspot 8-oncogene genotyping (

= 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS).

Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including

mutations (76%),

fusions (7%),

alterations (6%), and other less common events. In addition, WTS identified a novel

fusion (

-

). Overall, targetable gene fusioBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.

Poly (ADP ribose)-polymerase (PARP) inhibitors are approved for use in breast, ovarian, prostate, and pancreatic cancers, which are the solid tumor types that most frequently have alterations in key homologous recombination (HR) genes, such as

. However, the frequency of HR deficiency (HRD) in other solid tumor types, including bladder cancer, is less well characterized.

Specific DNA aberration profiles (mutational signatures) are induced by HRD, and the presence of these "genomic scars" can be used to assess the presence or absence of HRD in a given tumor biopsy even in the absence of an observed alteration of an HR gene. Using whole-exome and whole-genome data, we measured various HRD-associated mutational signatures in bladder cancer.

We found that a subset of bladder tumors have evidence of HRD. In addition to a small number of tumors with biallelic

events, approximately 10% of bladder tumors had significant evidence of HRD-associated mutational signatures. Increased levels of HRD signatures were associated with promoter methylation of

, which encodes CtIP, a key protein involved in HR.

A subset of bladder tumors have genomic features suggestive of HRD and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HRD.

A subset of bladder tumors have genomic features suggestive of HRD and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HRD.

Intratumoral hepatitis B virus (HBV) integrations and mutations are related to hepatocellular carcinoma (HCC) progression. Circulating cell-free DNA (cfDNA) has shown itself as a powerful noninvasive biomarker for cancer. However, the HBV integration and mutation landscape on cfDNA remains unclear.

A cSMART (Circulating Single-Molecule Amplification and Resequencing Technology)-based method (SIM) was developed to simultaneously investigate HBV integration and mutation landscapes on cfDNA with HBV-specific primers covering the whole HBV genome. Patients with HCC (

= 481) and liver cirrhosis (LC;

= 517) were recruited in the study.

A total of 6,861 integration breakpoints including

and

were discovered in HCC cfDNA, more than in LC. The concentration of circulating tumor DNA (ctDNA) was positively correlated with the detection rate of these integration hotspots and total HBV integration events in cfDNA. To track the origin of HBV integrations in cfDNA, whole-genome sequencing (WGS) was performed on their paired tumor tissues. The paired comparison of WGS data from tumor tissues and SIM data from cfDNA confirmed most recurrent integration events in cfDNA originated from tumor tissue. The mutational landscape across the whole HBV genome was first generated for both HBV genotype C and B. A region from nt1100 to nt1500 containing multiple HCC risk mutation sites (OR > 1) was identified as a potential HCC-related mutational hot zone.

Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of noninvasive detection of virus insertion/mutation.

Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of noninvasive detection of virus insertion/mutation.

Activating mutations in

promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically.

This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with

-mutant HER2-positive (HER2

) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies.

Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea (

= 6), hypokalemia (

= 3), abnormal liver enzymes (

= 3), hyperglycemia (

= 2), mucositis (

= 2), and elevated lipase (

= 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (

= 5), hypokalemia (

= 3), and hypomagnesemia (

= 2).