Phospho-Ser-VCP Is Required for DNA Damage Response and Is Associated with Poor Prognosis of Chemotherapy-Treated Breast Cancer.

Spatiotemporal protein reorganization at DNA damage sites induced by genotoxic chemotherapies is crucial for DNA damage response (DDR), which influences treatment response by directing cancer cell fate. This process is orchestrated by valosin-containing protein (VCP), an AAA+ ATPase that extracts polyubiquinated chromatin proteins and facilitates their turnover. However, because of the essential and pleiotropic effects of VCP in global proteostasis, it remains challenging practically to understand and target its DDR-specific functions.

Diagnostic Accuracy in Fit-for-Purpose PD-L1 Testing.

PD-L1 testing by immunohistochemistry (IHC) has presented significant challenges not only for clinical laboratories, but also for external quality assurance (EQA) entities that provide proficiency testing (PT) for clinical laboratories. Canadian Immunohistochemistry Quality Control (CIQC) has used educational runs to explore approaches to sample design and analysis of results that would enhance patient safety. As PT for predictive biomarkers requires modeling at every level (design of the run, assessment of the run, and reporting of "pass" or "fail") based on "fit-for-purpose" principles, CIQC has applied those principles to PD-L1 PT runs.

Basal biomarkers nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: Samples from the phase III SBG0102 clinical trial.

In a formal prospective-retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine-docetaxel or to single agent docetaxel, patients with basal-like tumors by PAM50 gene expression had significantly better overall survival in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but more specific biomarkers have since become available defining basal-like by nestin positivity or loss of inositol-polyphosphate-4-phosphate (INPP4B). Here, we evaluate their capacity to identify which patients benefit from gemcitabine in the metastatic setting.

Nestin expression in breast cancer: association with prognosis and subtype on 3641 cases with long-term follow-up.

Background: Basal-like breast cancers, originally recognized by gene expression profiling, can be clinically identified using immunohistochemical (IHC) definitions that require estrogen receptor (ER) negativity. However, some basal cases are ER positive and are mistakenly considered to be luminal by standard IHC approaches, leading to suboptimal treatment choices. Nestin, an intermediate filament expressed in many stem cells, is a recently identified positive marker of basal-like phenotype independent of ER status.

Cell Cycle-Dependent Tumor Engraftment and Migration Are Enabled by Aurora-A.

Cell-cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell-cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multiparameter imaging of wound closure assays was used to track cell-cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell-cycle indicator.

Basal biomarkers nestin and INPP4b identify intrinsic subtypes accurately in breast cancers that are weakly positive for oestrogen receptor.

Aims: Recent evidence indicates that weakly positive immunohistochemical staining of oestrogen receptor (ER) is not associated reliably with a luminal subtype, with the majority reclassified as basal-like by gene expression profile. In this study we assessed the capacity of recently identified immunohistochemical markers of basal-like subtype not dependent upon ER status - positive expression of nestin or loss of inositol polyphosphate-4-phosphatase (INPP4b) - to discriminate intrinsic subtypes, focusing on clinically problematic cases with weak ER positivity.

Methods And Results: Formalin-fixed paraffin-embedded blocks, enriched for large proportions of ER-negative and ER weakly positive breast cancers, were selected from two previous studies conducted in the period 2008-13 and used for (i) RNA extraction for 50-gene subtype predictor (PAM50) intrinsic subtyping and (ii) tissue microarray construction for immunohistochemical assessment of nestin and INPP4b.

Molecular subtype profiling of invasive breast cancers weakly positive for estrogen receptor.

The estrogen receptor (ER) is a key predictive biomarker in the treatment of breast cancer. There is uncertainty regarding the use of hormonal therapy in the setting of weakly positive ER by immunohistochemistry (IHC). We report intrinsic subtype classification on a cohort of ER weakly positive early-stage breast cancers.

Quantitative Detection and Resolution of BRAF V600 Status in Colorectal Cancer Using Droplet Digital PCR and a Novel Wild-Type Negative Assay.

A need exists for robust and cost-effective assays to detect a single or small set of actionable point mutations, or a complete set of clinically informative mutant alleles. Knowledge of these mutations can be used to alert the clinician to a rare mutation that might necessitate more aggressive clinical monitoring or a personalized course of treatment. An example is BRAF, a (proto)oncogene susceptible to either common or rare mutations in codon V600 and adjacent codons.

Developing ALK Immunohistochemistry and In Situ Hybridization Proficiency Testing for Non-Small Cell Lung Cancer in Canada: Canadian Immunohistochemistry Quality Control Challenges and Successes.

Intrachromosomal rearrangements involving the ALK gene are found in 3% to 5% of non-small cell lung cancers. Crizotinib is a tyrosine kinase inhibitor that has been shown to prolong progression-free survival in patients with advanced non-small cell lung cancer harboring ALK gene rearrangements. In Canada, ALK immunohistochemistry (IHC) is used as a screening test before confirmation by fluorescence in situ hybridization (FISH).

A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard.

Gene expression profiling of breast cancer delineates a particularly aggressive subtype referred to as 'basal-like', which comprises ∼15% of all breast cancers, afflicts younger women and is refractory to endocrine and anti-HER2 therapies. Immunohistochemical surrogate definitions for basal-like breast cancer, such as the clinical ER/PR/HER2 triple-negative phenotype and models incorporating positive expression for CK5 (CK5/6) and/or EGFR are heavily cited. However, many additional biomarkers for basal-like breast cancer have been described in the literature.