Pharmacogenetic study of Fc gamma receptor and HER2 genes in breast cancer

PhD ThesisBreast cancer is a complex set of diseases with different biological and clinical characteristics. An important contribution to this diversity is provided by germ-line genetic variations. The HER2-positive breast cancers have been extensively studied with particular regard to their biology and targeted treatments. However, the influence of pharmacogenetic (PG) factors on these aspects remains largely unexplored. This research focused on the possible effects of common single nucleotide polymorphisms (SNPs) on specific aspects of HER2-positive disease. Initially we analysed two coding SNPs in the HER2 gene (Ile655Val and Ala1170Pro) in breast cancer patients and evaluated their potential association with HER2 expression in tumour samples. The proline variant of the Ala1170Pro SNP was associated (odds ratio = 1.7, p = 0.01) with HER2 over-expression/amplification in over 360 breast cancer patients. In contrast, Ile655Val was not associated with HER2 over-expression/amplification. Bioinformatics tools predict that Ala1170Pro might affect the structure or function of the HER2 protein. The same variants were explored in the context of DNA extracted from the patients’ primary tumours in 241 patients. We hypothesized that the proline allele of Ala1170Pro could undergo allele-specific amplification during the development of HER2-positive tumours. This hypothesis, however, was not confirmed. Although the association of the proline allele of Ala1170Pro with HER2 positivity is intriguing, the role of the two SNPs in HER2 over-expression/amplification remains to be elucidated. Trastuzumab has radically changed the treatment of HER2-positive breast cancer. However, resistance to treatment and toxicity can limit its effectiveness. The second objective of this project was the analysis of PG, biomarker and pharmacokinetic (PK) parameters in trastuzumab-treated patients. Fc Gamma Receptors (FcRs) are key proteins in the trastuzumab-induced Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and two coding SNPs in these genes (FCGR2A His131Arg and FCGR3A Phe158Val) were analysed. The measurement of trastuzumab in plasma was made possible by the development of a novel cell-based ELISA. Only 28 patients with advanced disease treated with trastuzumab were recruited. However, we observed a possible association of the valine allele of the FCGR3A Phe158Val SNP with a longer time to progression (p = 0.03). Cardiac toxicity was assessed in a group of 139 patients treated with adjuvant trastuzumab. Although a role of germ-line genetic variants could not be demonstrated, the analysis highlighted the challenges and limitations encountered in the conduct of an observational pharmacogenetic study. This project leaves a legacy archive composed of germ-line DNA samples, tumour DNA samples, plasma samples and tumour FFPE blocks from over 360 breast cancer patients. These samples and data are available for the exploration of further potential factors which might influence the biology of the disease and/or its response to treatment

Effect of exercise before and/or during taxane-containing chemotherapy treatment on chemotherapy-induced peripheral neuropathy symptoms in women with breast cancer: systematic review and meta-analysis

Purpose To systematically review and meta-analyse the efficacy of exercise interventions delivered before and/or during taxane-containing chemotherapy regimens on chemotherapy-induced peripheral neuropathy (CIPN), fatigue, and health-related quality of life (HR-QoL), in women with breast cancer.Methods Seven electronic databases were systematically searched for randomised controlled trials (RCTs) reporting on the effects of exercise interventions in women with breast cancer receiving taxane-containing chemotherapeutic treatment. Meta-analyses evaluated the effects of exercise on CIPN symptoms, fatigue, and HR-QoL.Results Ten trials involving exercise interventions ranging between 2 and 12 months were included. The combined results of four RCTs consisting of 171 participants showed a reduction in CIPN symptoms following exercise compared with usual care (standardised mean difference − 0.71, 95% CI − 1.24 to − 0.17, p = 0.012; moderate-quality evidence, I2 = 76.9%). Pooled results from six RCTs with 609 participants showed that exercise interventions before and/or during taxane-containing chemotherapy regimens improved HR-QoL (SMD 0.42, 95% CI 0.07 to 0.76, p = 0.03; moderate-quality evidence, I2 = 49.6%). There was no evidence of an effect of exercise on fatigue (− 0.39, 95% CI − 0.95 to 0.18, p = 0.15; very low-quality evidence, I2 = 90.1%).Conclusions This systematic review found reduced levels of CIPN symptoms and an improvement in HR-QoL in women with breast cancer who exercised before and/or during taxane-based chemotherapy versus usual care controls.Implications for Cancer Survivors This evidence supports the role of exercise as an adjunctive treatment for attenuating the adverse effects of taxane-containing chemotherapy on CIPN symptoms and HR-QoL

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT)

Introduction: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin’s lymphoma (NHL) receiving anthracycline-based chemotherapy. Methods and analysis: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. Ethics and dissemination: A favourable opinion was given following research ethics committee review by West Midlands—Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom

Background: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. Methods: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. Results: 132 pts were included. Median age was 56 years (28–91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5–6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. Conclusion: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience

The content of selected minerals and vitamin C for potatoes (Solanum tuberosum L.) from the high Tiber Valley area, southeast Tuscany

Potatoes (Solanum tuberosum L.) from the high Tiber valley area (TVA; Tuscany, Italy), have been sampled and analyzed for selected mineral content (Na, Mg, K, Ca, and Mn, Fe, Cu and Zn) and vitamin C, the year 2012; some samples from 2011 and 2013 crops were also collected and analyzed. The varieties were Daytona (DAY), Kennebec (MEN), Sifra (SIF) and Volare (VOL). Control samples consisted of mixed commercial varieties from the local market, namely C1, C2 and C3. The low content of sodium, especially for KEN (46 +/- 3 mg/kg FD (freeze dry), year 2012) and SIF (47 +/- 3) (VOL (55 +/- 3) and DAY (61 +/- 3) have a little higher values) is worth of note and in agreement with the scarce concentration of Na in the soil (291 +/- 12 mg/kg DM). Magnesium was abundant in KEN (1434 +/- 75 mg/kg FD, year 2012) and VOL (1334 +/- 70). The content of K for DAY and KEN (13,147 +/- 900 and 13,185 +/- 900 mg/kg FD) was higher than for VOL and SIF; whereas Ca was in the range 340 +/- 16-490 +/- 28 mg/kg FD. The contents of Cu and Zn were higher in KEN (8.1 +/- 0.3 and 25 +/- 1 mg/kg FD) when compared to the other varieties and controls. The content of vitamin C is high for KEN and SIF and decreased significantly upon cooking (50% for KEN)