Ramon Andrade de Mello

HER2 therapies and gastric cancer: A step forward

Gastric cancer usually is diagnosed in advanced stages and thus current medical practice affords limited therapeutic options. However, recent studies established the role of human epidermal growth factor receptor 2 (HER2) in clinical management. Trastuzumab, an anti-HER2 monoclonal antibody, acquired a main role in advanced gastric cancer harboring HER2 overexpression and/or amplification improving survival to 17.1 mo according to trastuzumab for gastric cancer phase III trial results. Also, new promising drugs, such as c-Met inhibitors, are in development and assessment for this setting. Certainly, novel drugs will emerge in the next feel years for help oncologists improve clinical management of advanced gastric cancer providing higher survival and quality of life. In this mini-review we will discuss some issues in this regard and provide an actual overview of this setting.

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Lung cancer is currently the leading cause of cancer death in Western nations. Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers, and adenocarcinoma is the predominant histological type. Despite the intensive research carried out on this field and therapeutic advances, the overall prognosis of these patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Nowadays, pharmacogenetics and pharmacogenomics represent the key to successful treatment. Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma: one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor (EGFR). The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR (erlotinib and gefitinib) and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs. This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR, K-Ras and EGFR targeted therapies in NSCLC tumor behavior.

Insights into Angiogenesis in Non-Small Cell Lung Cancer: Molecular Mechanisms, Polymorphic Genes, and Targeted Therapies

Lung cancer is a highly prevalent disease worldwide. Currently, there are more than 150 million patients with lung cancer in the world, with more than 1 million new cases diagnosed per year. Tumoral angiogenesis is an important hallmark of this disease, but despite being extensively studied, the complete angiogenic mechanisms are not fully elucidated. Recent studies have reported a correlation between pharmacological inhibition of these angiogenic mechanisms and improvement of overall survival in lung cancer patients, mainly for those in advanced stages. The family of vascular endothelial growth factor (VEGF) proteins has critical roles in tumoral angiogenesis. An interaction between VEGF-A and VEGF receptor 2 (VEGFR-2) is the main pathway of activation and maintenance of angiogenesis. In tumors, this process is intimately correlative with progression and metastasis. Some studies suggested that serum levels of VEGF are higher in patients with lung cancer, especially in some types of non-small cell lung cancer (NSCLC). Other studies revealed that genetic polymorphisms of VEGF correlate with susceptibility, prognosis, and therapeutic response of some patients with NSCLC. This paper aims to review the impact of angiogenesis, especially on VEGF pathways, in NSCLC, and highlights the relevance of known and new patents disclosed of anti-angiogenic therapies in these patients.

EGFR and KRAS mutations, and ALK fusions: current developments and personalized therapies for patients with advanced non-small-cell lung cancer

Personalized therapy has significantly developed in lung cancer treatment over recent years. VEGF and EGF play a major role in non-small-cell lung cancer (NSCLC) tumor angiogenesis and aggressiveness. EGFR mutation as well as KRAS and ALK rearrangements are important biomarkers in the field owing to potential targeted therapies involved in clinical practice: erlotinib, geftinib, cetuximab and crizotinib. More recently, regulation of tumor immunity through CTLA4 and PD1/L1 has emerged as a promising field in NSCLC management. This review will focus on the current and future biomarkers in the advanced NSCLC field and also address potential related targeted therapies for these patients.

Anti-angiogenic therapies for metastatic colorectal cancer: Current and future perspectives

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of cancer death in both men and women in the United States, with about 142820 new cases and 50830 deaths expected in 2013. Metastatic disease (mCRC) remains a challenge for oncologists worldwide due to its potential comorbidities. Recently, chemotherapy regimens containing 5-fluorouracil, leucovorin, oxaliplatin and irinotecan combinations are a standard of care in the metastatic disease. Currently, biological therapies involving vascular endothelial growth factor and epidermal growth factor receptor pathways, such as bevacizumab and cetuximab, have emerged as good option for improving mCRC patient survival. Now, aflibercept plus standard chemotherapy has also been approved in second line regimen for mCRC patients. Our review will discuss novel biological drugs and their indications for mCRC patients and will bring future perspectives in this regard.

Immunotherapy and lung cancer: current developments and novel targeted therapies

Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinicians therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC.

The Impact of Polymorphic Variations in the 5p15, 6p12, 6p21 and 15q25 Loci on the Risk and Prognosis of Portuguese Patients with Non-Small Cell Lung Cancer

Introduction Polymorphic variants in the 5p15, 6p12, 6p21, and 15q25 loci were demonstrated to potentially contribute to lung cancer carcinogenesis. Therefore, this study was performed to assess the role of those variants in non-small cell lung cancer (NSCLC) risk and prognosis in a Portuguese population. Materials and Methods Blood from patients with NSCLC was prospectively collected. To perform an association study, DNA from these patients and healthy controls were genotyped for a panel of 19 SNPs using a Sequenom® MassARRAY platform. Kaplan-Meier curves were used to assess the overall survival (OS) and progression-free survival (PFS). Results One hundred and forty-four patients with NSCLC were successfully consecutively genotyped for the 19 SNPs. One SNP was associated with NSCLC risk: rs9295740 G/A. Two SNPs were associated with non-squamous histology: rs3024994 (VEGF intron 2) T/C and rs401681 C/T. Three SNPs were associated with response rate: rs3025035 (VEGF intron 7) C/T, rs833061 (VEGF –460) C/T and rs9295740 G/A. One SNP demonstrated an influence on PFS: rs401681 C/T at 5p15, p = 0.021. Four SNPs demonstrated an influence on OS: rs2010963 (VEGF +405 G/C), p = 0.042; rs3025010 (VEGF intron 5 C/T), p = 0.047; rs401681 C/T at 5p15, p = 0.046; and rs31489 C/A at 5p15, p = 0.029. Conclusions Our study suggests that SNPs in the 6p12, 6p21, and 5p15 loci may serve as risk, predictive and prognostic NSCLC biomarkers. In the future, SNPs identified in the genomes of patients may improve NSCLC screening strategies and therapeutic management as well.

Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a retrospective study in a single comprehensive European cancer institution.

Background The use of cetuximab in combination with platinum (P) plus 5-fluorouracil (F) has previously been demonstrated to be effective in the treatment of metastatic squamous cell cancer of head and neck (SCCHN). We investigated the efficacy and outcome of this protocol as a first-line treatment for patients with recurrent or metastatic disease. We evaluated overall-survival (OS), progression-free-survival (PFS), overall response rate (ORR) and the treatment toxicity profile in a retrospective cohort. Patients and Methods This study enrolled 121 patients with untreated recurrent or metastatic SCCHN. The patients received PF+ cetuximab every 3 weeks for a maximum of 6 cycles. Patients with stable disease who received PF+ cetuximab continued to receive cetuximab until disease progressed or unacceptable toxic effects were experienced, whichever occurred first. Results The median patient age was 53 (37–78) years. The patient cohort was 86.8% male. The addition of cetuximab to PF in the recurrent or metastatic setting provided an OS of 11 months (Confidential Interval, CI, 95%, 8.684–13.316) and PFS of 8 months (CI 95%, 6.051–9.949). The disease control rate was 48.9%, and the ORR was 23.91%. The most common grade 3 or 4 adverse events in the PF+ cetuximab regimen were febrile neutropenia (5.7%), skin rash (3.8%) and mucosistis (3.8%). Conclusions The results of this study suggest that cetuximab plus platinum–fluorouracil chemotherapy is a good option for systemic treatment in advanced SSCHN patients. This regimen has a well-tolerated toxicity profile.

Personalizing therapies for gastric cancer: Molecular mechanisms and novel targeted therapies

Globally, gastric cancer is the 4(th) most frequently diagnosed cancer and the 2(nd) leading cause of death from cancer, with an estimated 990000 new cases and 738000 deaths registered in 2008. In the advanced setting, standard chemotherapies protocols acquired an important role since last decades in prolong survival. Moreover, recent advances in molecular therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER2) therapies. Trastuzumab, an anti-HER2 monoclonal antibody, was the first target drug in the metastatic setting that showed benefit in overall survival when in association with platinum-5-fluorouracil based chemotherapy. Further, HER2 overexpression analysis acquired a main role in predict response for trastuzumab in this field. Thus, we conducted a review that will discuss the main points concerning trastuzumab and HER2 in gastric cancer, providing a comprehensive overview of molecular mechanisms and novel trials involved.

Targeting HER family in HER2-positive metastatic breast cancer: potential biomarkers and novel targeted therapies

HER2-targeted therapies have radically changed the prognosis of HER2-positive breast cancer over the last few years. However, resistance to these therapies has been a constant, leading to treatment-failure and new tumor progression. Recently, the kinase-impaired HER3 emerged as a pivotal player in oncogenic signaling, with an important role in both non-treated progression and treatment response. HER2/HER3 dimerization is required for full signaling potential and constitutes the key oncogenic unit. Also, when inhibiting PI3K/AKT pathway (as with anti-HER2 drugs) feedback mechanisms lead to a rebound in HER3 activity, which is one of the main roads to resistance. As current strategies to treat HER2-positive breast cancer are unable to inhibit this feedback response, two great promises emerged: the combination of targeted-therapies and drugs targeting HER3. In this article HER2 and HER3-targeted drugs and possible combinations between them, as well as the biomarkers to predict and monitor these drugs effect, are reviewed.