Abstract: ABSTRACT: The concept of 'targeted' therapies implies that such drugs only act on cells that specifically express the particular target, therefore giving rise to a low incidence of side effects. However, targeted therapies currently approved for the treatment of breast cancer have demonstrated a relatively high incidence of cardiovascular events. The anti-HER2 agents trastuzumab and lapatinib may cause left ventricular dysfunction or even congestive heart failure. Bevacizumab, an antiangiogenic drug, has been shown to increase the risk of hypertension, cardiovascular dysfunction and thromboembolic events. In addition, several anti-human epidermal growth factor receptor 2 (HER2) and antiangiogenic agents plus their combinations are currently being developed and evaluated for the treatment of breast cancer. In this review, we aim to assess the incidence of cardiac adverse events associated with targeted therapies designed to block HER2 and angiogenic pathways.
Abstract: BackgroundHuman epidermal growth factor receptor 2 (HER2) overexpression is detected in approximately 15% to 20% of all breast cancers (BCs). A revolutionary change in the prognosis of this subgroup of patients has occurred since trastuzumab therapy was introduced into daily clinical practice. However, because trastuzumab resistance is common, new molecules with complementary and/or synergistic mechanisms of action have been developed. Pertuzumab is a new anti-HER2 humanized monoclonal antibody that prevents the formation of HER2 dimers.Material and methodsA computer-based literature search was carried out using PubMed (keywords: breast neoplasm, dimerization, HER-2, pertuzumab); data reported at international meetings are included.ResultsThis paper describes pertuzumab's mechanism of action, safety, and role in HER2-positive BCs. It also explores the role of pertuzumab as a single agent or combined with trastuzumab by reviewing data from preclinical research to ongoing clinical trials. Recently published trials, particularly the CLEOPATRA study, highlight the efficacy, tolerability, and increase in disease-free survival associated with this novel agent when combined with trastuzumab.ConclusionThe pertuzumab and trastuzumab anti-HER2 dual blockade is likely to represent a substantial advance for patients with HER2-positive BCs and a new milestone on the way to personalized medicine.
Abstract: BackgroundThe prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC.MethodsGene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS).ResultsA total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HR(GG3 vs GG1) 5.6 (2.1-15.3); PÂ <Â 0.001] and OS [HR(GG3 vs GG1) 7.2, 95% CI (1.6-32.2); PÂ =Â 0.01].ConclusionsGG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status.
Abstract: Background. Randomized studies have shown different magnitude of bevacizumab benefit in the treatment of advanced breast cancer. Regulatory agencies have modified bevacizumab treatment indications across different regions. In this study, we perform a meta-analysis of phase III studies aiming to interrogate the magnitude of bevacizumab benefit for the treatment of first-line HER2-negative metastatic breast cancer (MBC). Methods. Data from studies E2100, AVADO and RIBBON-1 were used to calculate the benefit of bevacizumab in terms of tumor overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Combined statistical estimates of hazard ratios (HR) and odds ratios were calculated using fixed-effects or random-effects models. Results. A total of 2,695 patients were evaluated. Combining bevacizumab with different chemotherapy backbones resulted in a 30% risk reduction of PFS events (HR = 0.70; 95% confidence interval [CI], 0.57-0.86) and increased ORR (odds ratio 1.81; 95% CI, 1.53-2.14). No OS benefit could be demonstrated (HR = 0.95; 95% CI, 0.85-1.06). Bevacizumab significantly increased the incidence of adverse events such as proteinuria, hypertension and cardiovascular events. Conclusions. Bevacizumab combined with chemotherapy in the first-line treatment of MBC significantly improved ORR and PFS, but also increased grade 3-4 toxicities. No significant OS advantage was observed.
Abstract: An evaluation of the benefit-versus-risk of bevacizumab in the treatment of advanced breast cancer is timely and relevant. Recently, the US FDA has withdrawn the approval of bevacizumab as a therapeutic option for the treatment of advanced breast cancer, generating controversy in the scientific community. Although the pivotal study (Eastern Cooperative Oncology Group 2100 trial [E2100]) had shown doubling of the progression-free survival when bevacizumab was added to chemotherapy, this magnitude of benefit could not be replicated in subsequent studies. Furthermore, individual studies and meta-analyses failed to demonstrate an overall survival benefit with the addition of bevacizumab to different chemotherapy regimens. In addition, this agent is associated with an increased incidence of serious adverse events such as hypertension, congestive heart failure and thromboembolism, and its cost is likely to be a consideration in its use for many patients worldwide. Retrospective biomarker-based studies aiming to identify the subpopulation of patients most likely to benefit from the addition of bevacizumab to standard chemotherapy in breast cancer should be a research priority.
Abstract: Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.
Abstract: In 1997, the anti-CD20 monoclonal antibody (MAb) rituximab became the first MAb approved for clinical use in oncology, and ushered in a new era of rationally designed targeted agents in cancer therapeutics. It is currently approved for use in non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and rheumatoid arthritis (RA). Rituximab is non-mutagenic, associated with low treatment-related toxicity, and few, if any, long term adverse events, making it an attractive agent to be tried in off-label settings like Hodgkin lymphoma (HL). HL consists of two distinct subtypes - classic HL (cHL) and lymphocyte predominant HL (LPHL). CD20 is present in virtually all patients with LPHL, and in a significant minority of patients with cHL. In this CD20 positive sub-population, the use of rituximab is a rational intervention strategy. Rituximab has been used in patients with cHL as well as LPHL with good efficacy. In this article, we provide a clinically-oriented overview of the use of rituximab in the different sub-types of HL, and report updated results of our series of 8 LPHL patients treated with rituximab. A systematic review of the literature is also presented.
Abstract: SUMMARY: HER2-positive tumors comprise 15% to 20% of all breast cancers (BC) and are associated with worse clinical outcomes [Slamon et al., Science 1987;235:177-82]. Trastuzumab is a humanized monoclonal antibody designed to target the extracellular domain of the HER2 receptor, and is the foundation of care of women with early and advanced HER2-positive BC. However, a significant proportion of patients with this type of BC display either primary or secondary resistance to trastuzumab. Therefore, in an effort to overcome such resistance and further improve the outcome of patients with HER2-positive disease, several new anti-HER2 agents are currently being developed. These include small molecules that inhibit the HER2 tyrosine kinase activity (lapatinib, neratinib), monoclonal antibodies directed at other epitopes of the HER2 extracellular domain (pertuzumab), antibody-drug conjugates (trastuzumab-DMl), and heat shock protein 90 inhibitors (tanespimycin). A great deal of interest has been generated by recent data from the randomized neo-adjuvant studies NeoALTTO and NeoSphere, which have shown that dual blockade of the HER2 receptor with anti-HER2 agents is significantly superior to using one agent alone. If these results are validated in larger ongoing and planned phase III studies in early BC, they could lead to a paradigm shift in treatment strategy. Therefore, to avoid unnecessary toxicities and costs, it is critical to intensify the research for biomarkers that can identify those patients most likely to benefit from specific targeted therapies.
Abstract: Breast cancer is a molecularly, biologically and clinically heterogeneous group of disorders. Understanding this diversity is essential to improving diagnosis and optimizing treatment. Both genetic and acquired epigenetic abnormalities participate in cancer, but the involvement of the epigenome in breast cancer and its contribution to the complexity of the disease are still poorly understood. By means of DNA methylation profiling of 248 breast tissues, we have highlighted the existence of previously unrecognized breast cancer groups that go beyond the currently known 'expression subtypes'. Interestingly, we showed that DNA methylation profiling can reflect the cell type composition of the tumour microenvironment, and in particular a T lymphocyte infiltration of the tumours. Further, we highlighted a set of immune genes having high prognostic value in specific tumour categories. The immune component uncovered here by DNA methylation profiles provides a new perspective for the importance of the microenvironment in breast cancer, holding implications for better management of breast cancer patients.
Abstract: Targeted therapies have evolved dramatically over the last few years. The heterogeneity of breast cancer is now understood on a molecular level, and different targeted therapeutic strategies have been approved in an attempt to tailor treatment strategies. Although the incidence of side effects is expected to be low due to target specificity, this is not always the case. Adverse events such as congestive heart failure and life threatening diarrhoea are sometimes observed because of off-target drug effects. In this article, we discuss the incidence, prevention and management of serious adverse events associated with trastuzumab, lapatinib, and bevacizumab. We critically analyse the available evidence and provide some insights on how to manage these toxicities in the clinical setting.
Abstract: BACKGROUND: The optimal management of patients with breast cancer (BC) requires the expertise of specialists from different disciplines. This has led to the evolution of multidisciplinary teams (MDTs), allowing all key professionals to jointly discuss individual patients and to contribute independently to clinical decisions. Data regarding BC MDTs in different regions and countries are scarce. METHODS: The investigators of a large global phase III adjuvant BC trial being conducted by the Breast International Group were invited to respond to a questionnaire about the extent, structure, and function of BC MDTs. RESULTS: One hundred and fifty-two responses from 39 countries were received, and remarkable differences were noted in different geographic regions. Sixty-five percent of the respondents from eastern Europe, 63% from western Europe, 35% from Asia, and 25% from South America declared that MDT was a mandatory part of BC care in their country. Ninety percent of the respondents from Europe stated their MDTs met weekly, compared with only half of the respondents from Asia. CONCLUSION: This survey is perhaps the first large-scale effort to collect information regarding BC MDTs from different parts of the world and provides objective information of frequency, composition, function, and working mechanism of BC MDTs.
Abstract: Tamoxifen was the first targeted anticancer agent for breast cancer patients and its effects on reduction of breast cancer events and improvement in overall survival are undisputed. Hence, it has long been considered an essential part of patient care. Recent results of several large adjuvant hormonal trials evaluating the use of aromatase inhibitors in comparison with the previous standard of five years of tamoxifen has led to a paradigm shift, ensuring the inclusion of an aromatase inhibitor as part of standard endocrine therapy for most postmenopausal women diagnosed today with estrogen receptor-positive breast cancer. However, one could argue that despite statistically significant improvements in breast cancer events, an overall survival advantage has not been clear. In this review, we discuss recent genomic and molecular data pertaining to estrogen receptor-positive breast cancer and how this knowledge may aid clinicians to prescribe adjuvant hormonal treatment in the future. A combination of gene expression and genetic aberration markers may be most useful in discerning a population that is still appropriate for adjuvant tamoxifen treatment.
Abstract: Pruritus is a defining feature of polycythemia vera (PV) and is seen in approximately 40% of patients. In most cases, the pruritus is characteristically triggered by contact with water (aquagenic) at any temperature.
Abstract: Primary kidney sarcomas are rare neoplasms. Pre-operative signs and symptoms are non-specific, thus making early diagnosis of this condition difficult. The presenting features are similar to other common renal tumors.
Abstract: Plasma cell leukemia (PCL) is a rare entity. There are two presentations of PCL, primary or secondary. The primary or de novo form of PCL presents with an acute and rapidly progressive leukemic phase. This form occurs when the patient has no pre-existing multiple myeloma (MM). The secondary form is the most advanced form of MM. The PCL is a rare disorder representing 1-2% of the diagnosed cases of MM. Median age at presentation is usually above 50 years. The monoclonal protein in patients with PCL may be IgG (50%), IgA (15%), or in rare cases IgD or IgE (6%). We report a case of IgA primary PCL that is very rare. Patient was started on combination therapy with vincristine, adriamycin, and dexamethasone. There was poor response and patient died three months after diagnosis.
Abstract: Non-pulmonary metastases in osteosarcoma are increasingly recognized because of improved longevity in patients receiving modern treatment. One rare site of metastasis is the orbit, with only three cases reported so far. This report describes a 16-year-old male patient, who underwent above-knee amputation for right tibial osteosarcoma and later presented with a painful protrusion of the right eyeball and near-normal vision. The uncommon features in the present case are the site of metastasis and near-normal vision.
Abstract: Magnetic resonance spectroscopy (MRS) is a new, noninvasive method of diagnosing a lesion in cases where magnetic resonance (MR) imaging cannot reliably differentiate between two or more possible aetiologies. This case report describes a 20-year-old pregnant woman who developed sudden onset of left-sided hemiparesis. MR imaging of the brain revealed an infarct of the right middle cerebral artery and a suprasellar mass. The endocrine workup was normal. As she was 20 weeks pregnant, the option of a transsphenoidal biopsy of the pituitary lesion was rejected in favour of MRS . It demonstrated features characteristic of a tuberculoma. She showed marked clinical improvement after she was started on anti-tuberculous drugs. MRS is a rapidly-developing diagnostic modality, and may be a useful and safe option for investigating intracranial lesions in patients who cannot undergo invasive procedures.
