Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab.

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA.

Analysis of pro- and anti-inflammatory cytokine gene variants and serum cytokine levels as prognostic markers in breast cancer.

The aim of current study was to evaluate the genetic variation in all the genes encoding pro- and anti-inflammatory cytokines in association with breast cancer development in patients from Malwa region of Punjab. The importance of the levels of interleukin (IL)-17, tumor necrosis factor, interferon γ, IL-10, IL-6, IL-4, and IL-2 with respect to clinicopathological data, prognosis, and disease-free survival was also determined in these patients. Two hundred and fifty female breast cancer patients and 250 age-matched controls were screened for variations in cytokine-encoding genes using global screening array microchip. The level of cytokines was estimated in 150 patients and 60 age-matched controls using BD™ Cytometric Bead Array (CBA) Human Th1/Th2/Th17 cytokine kit by BD Accuri flow cytometer. The difference in cytokine levels was evaluated by Mann-Whitney test. No significant variation in the genes encoding various cytokines was found between patients and controls. Out of the seven cytokines evaluated, the levels of IL-6 and IL-17a were found to be significantly high in patients in comparison with controls ( p = 0.001 and 0.02, respectively). The elevated levels of these cytokines are also associated significantly with poor outcome. We did not find any specific variation in the genes encoding various cytokines between patients and controls. However, there was a significant difference in the serum levels of IL-6 and IL-17a between patients and controls, and the elevated levels of these two cytokines associated significantly with poor outcome in breast cancer patients and, therefore, can be used as prognostic markers.

HER2 Tyrosine Kinase Inhibitors in the Sensitization to Cancers Resistant to HER2 Antibodies.

Human epidermal growth factor receptor (HER2) is a well-established histopathological marker. It is aberrantly expressed in various cancers, predominantly in breast cancer. HER2 protein overexpression and/or HER2 gene amplification induces HER2 dimerization, tyrosine kinase (TK) phosphorylation, activation of different signaling pathways including the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and hence, carcinogenesis. HER2 antibodies like trastuzumab and pertuzumab act on the extracellular domain (ECD) of the HER2 receptor. These were developed to treat HER2-overexpressing or amplified cancers. These effectively inhibit HER2 dimerization and, hence, further signaling. However, antibody resistance and, thereby, disease relapse have emerged as serious concerns. HER2 splicing, cross-signaling, and intracellular alterations are the most common factors causing HER2-antibody resistance. To overcome the therapeutic resistance associated with trastuzumab, TK inhibitors (TKIs) were developed. These bind to the intracellular TK domain and inhibit TK phosphorylation and, therefore, signaling. Though less selective, TKIs have been reported to show activity against HER2 spliced variants and inhibit breast cancers resistant to HER2 antibodies. However, these have not really been established as monotherapeutic agents and have remained as alternative therapeutics only on the account of resistance, toxicity, and poor pharmacokinetic profile. These issues can be resolved by employing combination treatment regimens including HER2-antibody and HER2 TKI. The HER2 TKI in conjunction with HER2 antibody sensitize the refractory HER2-positive cancers towards HER2-anti-body therapy. In addition, these act synergistically with the HER2-antibody resulting in an additive clinical response in patients. This chapter will explore various HER2 TKIs- lapatinib, neratinib, afatinib, sapitinib, CP-724,714, dacomitinib, tucatinib, pyrotinib, and poziotinib as promising clinical tools in sensitizing resistant cancers to HER2 antibodies.

Subclinical Hypothyroidism and Associated Cardiovascular Risk Factor in Perimenopausal Females.

BACKGROUND: Perimenopause refers to the period around menopause (40-55 years). This includes the period before menopause and the first year after menopause. Perimenopausal age is an important stage in a women's life. Many women are diagnosed with hypothyroidism at midlife. Hypothyroidism - both overt and subclinical are associated with increased risk of CVS diseases. Subclinical hypothyroidism is more important as this stage is usually ignored from treatment point of view and if early intervention is done in SCH worsening of metabolic derangement may be avoided. OBJECTIVES: The present study was aimed to know the prevalence of subclinical hypothyroidism and associated dyslipidemia in perimenopausal females. MATERIAL AND METHODS: In our retrospective study we took 100 perimenopausal females (40-55years) who were investigated for thyroid and lipid profile. Atherogenic indices like TC/HDL-c, LDL-c/HDL-c, TG/HDL-c ratios were calculated from the individual lipid profile parameters. The reference guidelines for lipid profile was according to NCEP ATP III. RESULT: Subclinical hypothyroidism was found to be present in 18% of perimenopausal females The mean TSH levels were found to be higher in SCH as compared to euthyroid females with a mean value of 7.56±3.54(µIU/ ml). Dyslipidemia was seen in patients with SCH. TSH levels were found to be positively correlated with total cholesterol. CONCLUSION: We conclude that subclinical hypothyroidism is present in 18% females of perimenopausal age group. Increased TSH levels are associated with hypertension, hypertriglyceridemia, and elevated TC/HDL-C ratio and non cholesterol HDL. In perimenopausal women the condition is usually underdiagnosed and ignored but subclinical hypothyroidism in these females should be screened and treated timely to decrease the risk of accelerated atherosclerosis and premature coronary artery disease in them.

Recent Updates on the Therapeutic Potential of HER2 Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer.

HER2 positive breast cancer is characterized by the low survival rate in the metastatic patients. Development of resistance and disease-relapse are the major problems associated with the currently available therapies for HER2 positive breast cancer. There are two major targeted therapies for HER2 positive breast cancer viz. monoclonal antibodies and tyrosine-kinase inhibitors, and both of these therapies have their advantages and limitations. To address the limitations associated with the existing therapies, use of antibodies and TKIs as combination therapy proved to be more effective. Various chemical modifications can be performed on tyrosine-kinase inhibitors to develop novel ligands with increased selectivity for HER2 kinase. A number of tyrosine-kinase inhibitors are in various phases of clinical trials for the treatment of HER2 positive breast cancer. In the current review article, recent developments on various HER2 tyrosine-kinase inhibitors have been reported. Various structurally different scaffolds bind to the HER2 receptor and exhibit potent anti-cancer activities. The structural and pharmacophoric requirements of the scaffolds are discussed in detail so as to discover effective drug candidates for the treatment of HER2 positive breast cancer.

Role of Genomic Alterations in HER2 Positive Breast Carcinoma: Focus on Susceptibility and Trastuzumab-therapy.

BACKGROUND: Breast cancer is the most frequently diagnosed life-threatening malignancy among women, across the globe. HER2 positive is a distinct breast cancer subtype, on account of its unique biology and physiological behavior. RESULTS: Amplification of HER2 oncogene/polysomy 17 leads to HER2 overexpression that is a significant causal implication in HER2 positive breast cancer. HER2 gene variants, as well as other genes/gene variants, are involved in its overexpression, disease prognosis and in predicting the susceptibility towards HER2 positive breast cancer. Trastuzumab (Herceptin) is the most commonly used therapy for treating patients with HER2 positive status. Genomic alterations are incriminated in the development of trastuzumab-resistance, which influences the response towards trastuzumab-therapy. CONCLUSION: In the current review article, we have summarized the genomic alterations that are responsible for overexpression of HER2 and therefore, increased risk of breast cancer. In addition, the gene variants affecting response towards trastuzumab-therapy have also been discussed.

Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies.

HER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance-development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled.