Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer.

Purpose: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC.

Patients And Methods: Analysis of a prospectively collected clinical database was performed.

Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer.

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX).

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.

Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion.

Background: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples.

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).

Cooperative Effect of Oncogenic and in an HGF-Dominant Environment in Breast Cancer.

There is compelling evidence that oncogenic and signaling pathways contribute to breast cancer. However, the activity of pharmacologic targeting of either pathway is modest. Mechanisms of resistance to these monotherapies have not been clarified.

Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer.

Background: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo.

Methods: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro.

Effects of CDK4/6 Inhibition in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Cells with Acquired Resistance to Paclitaxel.

Among patients with hormone receptor (HR)-positive breast cancer, those with residual disease after neoadjuvant chemotherapy have a higher risk of relapse and poorer survival than those with a complete response. Previous studies have revealed a correlation between activation of cell cycle-regulating pathways in HR-positive breast cancer, particularly cyclin-dependent kinase (CDK) 4 and 6/cyclin D1 signaling, and resistance to standard therapies. Although CDK4/6 inhibition by palbociclib in combination with endocrine therapy has shown potent antiproliferative effects in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, the potential role of palbociclib in re-sensitizing chemotherapy-resistant HR-positive breast cancer is not well defined.

The Association between EGFR and cMET Expression and Phosphorylation and Its Prognostic Implication in Patients with Breast Cancer.

EGFR and cMET cross-talk is involved in breast cancer (BC) progression and resistance to different targeted therapies, however little is known about the co-expression patterns of EGFR and cMET or its prognostic significance in BC. Protein levels of EGFR, cMET and their phosphorylated proteins were measured in 825 BC samples using reverse phase protein array (RPPA). Given unimodal distribution of proteins, the median was selected as a cut-off after sensitivity analyses.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline.

Purpose: To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer.

Methods: A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival.

Multigene clinical mutational profiling of breast carcinoma using next-generation sequencing.

Objectives: The advent of next-generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics provides multigene mutational profiling through massively parallel sequencing.

Methods: We analyzed 415 breast carcinoma samples from 354 patients using NGS in known hotspots of 46 commonly known cancer-causing genes.

Results: A total of 281 somatic nonsynonymous mutations were detected in 62.

Antiepileptic drug use improves overall survival in breast cancer patients with brain metastases in the setting of whole brain radiotherapy.

Background And Purpose: There is mounting evidence that histone deacetylase (HDAC) inhibitors, e.g. valproic acid (VPA), synergize with radiation to improve outcomes in several cancers.

Recurrence and survival among breast cancer patients achieving a pathological complete response to neoadjuvant chemotherapy.

Patients who achieve a pathological complete response (pCR) after neoadjuvant therapy, including chemotherapy with or without trastuzumab (NAT) have better outcomes than patients with residual disease. Despite the excellent prognosis associated with achieving a pCR, tumors still recur. The objective of this study was to evaluate factors associated with tumor recurrence and survival among patients achieving pCR after NAT.

Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy.

Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1(+)TIE2(Hi)CXCR4(Hi)) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release.

Effect of 21-Gene RT-PCR Assay on Adjuvant Therapy and Outcomes in Patients With Stage I Breast Cancer.

Background: Recurrence score (RS) derived from a 21-gene reverse transcriptase-polymerase chain reaction assay is used to stratify patients with early-stage estrogen receptor-positive, HER2-normal breast cancer into 3 groups on the basis of 10-year distant metastasis risk: low, intermediate, and high. Published data are limited regarding the effect of RS on choice of adjuvant therapy for T1 breast cancer. We investigated the relationship between RS and choice of adjuvant therapy, prognosis, and benefit of chemotherapy (CT) in stage I breast cancer.

Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline.

Purpose: To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer.

Methods: A literature search and prospectively defined study selection identified systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective-retrospective studies, and prospective comparative observational studies published from 2006 through September 2014.

Results: The literature search revealed 17 articles that met criteria for further review: 11 studies reporting discordances between primary tumors and metastases in expression of hormone receptors or human epidermal growth factor receptor 2 (HER2), one RCT that addressed the use of a biomarker to decide whether to change or continue a treatment regimen, and five prospective-retrospective studies that evaluated the clinical utility of biomarkers.

Validation and Development of a Modified Breast Graded Prognostic Assessment As a Tool for Survival in Patients With Breast Cancer and Brain Metastases.

Purpose: Several indices have been developed to predict overall survival (OS) in patients with breast cancer with brain metastases, including the breast graded prognostic assessment (breast-GPA), comprising age, tumor subtype, and Karnofsky performance score. However, number of brain metastases-a highly relevant clinical variable-is less often incorporated into the final model. We sought to validate the existing breast-GPA in an independent larger cohort and refine it integrating number of brain metastases.

Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype?

Significant research has been conducted to better understand the extensive, heterogeneous molecular features of triple-negative breast cancer (TNBC). We reviewed published TNBC molecular classifications to identify major groupings that have potential for clinical trial development. With the ultimate aim to streamline translational medicine, we linked these categories of TNBC according to their gene-expression signatures, biological function, and clinical outcome.

Phase II Randomized Study of Ixabepilone Versus Observation in Patients With Significant Residual Disease After Neoadjuvant Systemic Therapy for HER2-Negative Breast Cancer.

Background: Residual disease (RD) after neoadjuvant chemotherapy carries an increased risk for recurrence. Ixabepilone has activity in anthracycline/taxanes-resistant breast cancer. We explored adjuvant ixabepilone in patients with significant RD HER2-negative breast cancer.

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.

Functional consequence of the MET-T1010I polymorphism in breast cancer.

Major breast cancer predisposition genes, only account for approximately 30% of high-risk breast cancer families and only explain 15% of breast cancer familial relative risk. The HGF growth factor receptor MET is potentially functionally altered due to an uncommon germline single nucleotide polymorphism (SNP), MET-T1010I, in many cancer lineages including breast cancer where the MET-T1010I SNP is present in 2% of patients with metastatic breast cancer. Expression of MET-T1010I in the context of mammary epithelium increases colony formation, cell migration and invasion in-vitro and tumor growth and invasion in-vivo.

Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for germline pharmacogenetic studies.

Background: Controversy exists regarding the impact of CYP2D6 genotype on tamoxifen responsiveness. We examined loss of heterozygosity (LOH) at the CYP2D6 locus and determined its impact on genotyping error when tumor tissue is used as a DNA source.

Methods: Genomic tumor data from the adjuvant and metastatic settings (The Cancer Genome Atlas [TCGA] and Foundation Medicine [FM]) were analyzed to characterize the impact of CYP2D6 copy number alterations (CNAs) and LOH on Hardy Weinberg equilibrium (HWE).