Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer.

Purpose: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations.

Experimental Design: Sixty-two patients with MBC were included.

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation.

Background: The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation.

Methods: The primary endpoint was objective response rate (ORR).

Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor.

The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells.

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors.

Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient-derived xenografts (PDX) largely generated from residual tumors following neoadjuvant chemotherapy.

Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.

Preclinical data suggest multiple roles for the IGF1 receptor (IGF1R) in neuroendocrine tumors (NETs), including mediating resistance to mammalian target of rapamycin (mTOR) inhibitors. Everolimus, an oral mTOR inhibitor, and octreotide long-acting repeatable (LAR) are approved for subgroups of well-differentiated NET. The primary objective of the present study was to establish the safety and recommended phase II dose (RP2D) of cixutumumab, a monoclonal antibody (MAB) against IGF1R, with everolimus and octreotide LAR.

SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer.

Background: There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer.

Methods: Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg.

Influence of biospecimen variables on proteomic biomarkers in breast cancer.

Background: PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer. We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers.

Methods: Intraoperative image-guided core-needle biopsies (CNB), and central and peripheral surgical tumor specimens were prospectively collected in 53 patients with invasive breast cancer.

Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.

Purpose: We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity.

Experimental Design: MK-2206 effects on cell signaling were assessed in vitro and in vivo. Its antitumor efficacy was assessed in vitro in a panel of cancer cell lines with differing PIK3CA and PTEN status.

Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples.

Molecular targeted therapy represents a promising new strategy for treating cancers because many small-molecule inhibitors targeting protein kinases have recently become available. Reverse-phase protein microarrays (RPPAs) are a useful platform for identifying dysregulated signaling pathways in tumors and can provide insight into patient-specific differences. In the present study, RPPAs were used to examine 60 protein end points (predominantly phosphoproteins) in matched tumor and nonmalignant biopsy specimens from 23 patients with head and neck squamous cell carcinoma to characterize the cancer phosphoproteome.

Performance of chromogenic in situ hybridization on testing HER2 Status in breast carcinomas with chromosome 17 polysomy and equivocal (2+) herceptest results: a study of two institutions using the conventional and new ASCO/CAP scoring criteria.

This study specifically addressed the performance of chromogenic in situ hybridization (CISH) on HER2 testing in 66 breast carcinomas with chromosome 17 polysomy and 49 carcinomas with an equivocal HercepTest (DakoCytomation, Carpinteria, CA) score by comparing CISH with corresponding FISH results at 2 test sites and evaluating intersite agreement of CISH results. For tumors with chromosome 17 polysomy, when using the manufacturers' criteria, the concordance values between CISH and FISH at site A, site B, and intersite CISH agreement were 95.8%, 95.

Implementation of American Society of Clinical Oncology/College of American Pathologists HER2 Guideline Recommendations in a tertiary care facility increases HER2 immunohistochemistry and fluorescence in situ hybridization concordance and decreases the number of inconclusive cases.

Context: The American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guideline recommendations from January 2007 identified many sources of immunohistochemistry (IHC) testing variation.

Objective: In this current study, we implemented the guidelines and addressed our institution's preanalytic, analytic, and postanalytic variables relating to HER2 testing to improve clinical outcomes.

Design: We evaluated core biopsies performed on breast lesions from 2006 through 2007.

Chromogenic in situ hybridization is a reliable method for detecting HER2 gene status in breast cancer: a multicenter study using conventional scoring criteria and the new ASCO/CAP recommendations.

Chromogenic in situ hybridization (CISH) has shown the potential to replace fluorescence in situ hybridization (FISH) to determine HER2 gene status. To validate the reliability of CISH, we used 226 consecutive breast carcinomas from 2 institutions and tested CISH and FISH on the same tumor set simultaneously at different test sites. Besides manufacturers' scoring criteria, the new American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines were used to interpret HER2 status.

HER Receptor Family: Novel Candidate for Targeted Therapy for Gallbladder and Extrahepatic Bile Duct Cancer.

Purpose: Biliary tract cancers (BTC) are uncommon in the United States, but are endemic in parts of South America and Asia. BTCs are aggressive tumors associated with poor survival. Activation of HER-2/neu (erbB2) and/or epidermal growth factor receptor (EGFR) are important in breast, colon, and lung cancers.

A human papillomavirus testing system in women with abnormal Pap results: a comparison study with follow-up biopsies.

Objective: To evaluate the efficacy of INFORM HPV using the SurePath collection method in women whose Pap tests indicated abnormal results.

Study Design: Ninety-two women from the gynecology clinics at The University of Texas M.D.

Detection of numerical aberrations of chromosomes 7 and 9 in cytologic specimens of pleural malignant mesothelioma.

Background: Accurate diagnosis of malignant mesothelioma (MM) in effusion fluid specimens can be challenging. Previous cytogenetic studies demonstrated that chromosomal aneusomy is commonly associated with MM. The authors attempted to determine whether the detection of numerical chromosomal aberrations in the effusion fluid specimens could be a useful diagnostic adjunct in morphologically inconclusive cases for MM.