Aurelio Castrellon

Chemoprevention of breast cancer

Breast cancer remains the second leading cause of malignancy-related death in women in the USA, regardless of advances in novel therapeutic agents. High priority should be given to research aimed at the study of pharmacological and natural compounds that could potentially prevent the development of breast cancer in susceptible patients. Tamoxifen has been shown to reduce the incidence of estrogen receptor-positive invasive breast cancer in women with a high risk of developing this condition by nearly 50%, and studies in osteoporosis have revealed a similar protective effect of raloxifene in postmenopausal women. The aromatase inhibitors are superior to tamoxifen in reducing the recurrence of breast cancer in postmenopausal women; large clinical trials are currently evaluating the chemopreventive effect of these agents. The list of agents with the potential for chemoprevention in breast cancer is extensive and continues to expand. There is an immense need to develop drugs that will decrease the incidence of estrogen receptor-negative breast cancer in women at high risk of developing the disease. Herein, we review the most important chemopreventive agents in breast cancer and clinical trials that have evaluated their efficacy.

Lapatinib plus capecitabine resolved human epidermal growth factor receptor 2-positive brain metastases.

Brain metastases affect 25%-30% of women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and are associated with a high burden of disease and poor prognosis. A 55-year-old woman presented with HER2-positive, hormone receptor-positive, locally advanced infiltrating ductal carcinoma. She received 4 cycles of neoadjuvant docetaxel (75 mg/m) plus trastuzumab (6 mg/kg) on a 21-day cycle, resulting in complete pathologic response at the time of surgery. Trastuzumab (6 mg/kg every 21 days) plus anastrozole (1 mg/d) was continued for 1 year. Two years later, the patient progressed with pulmonary nodules and a large pleural effusion. Computed tomography and positron emission tomography revealed multiple lesions in the liver and thoracic spine but no evidence of brain metastases. The patient received weekly trastuzumab (2 mg/kg), paclitaxel (80 mg/m), and carboplatin (area under the curve 2) for 6 months; her symptoms resolved and her disease stabilized. Seven months later, she developed diplopia and gait difficulties, and magnetic resonance imaging revealed multiple brain lesions. Whole-brain radiotherapy (30 Gy in 10 fractions) was delivered with excellent clinical results. The patient remained progression free without symptoms for approximately 3 months. When she developed central nervous system symptoms, she was treated with lapatinib (1250 mg/d continuously) plus capecitabine (2000 mg/m given on days 1-14 of a 21-day cycle). Four months later, a brain computed tomography performed shortly before her death from progressive systemic disease revealed near complete resolution of brain metastases. Lapatinib plus capecitabine seems to have clinical activity in HER2-positive brain metastases.

Nasopharyngeal carcinoma: alternative treatment options after disease progression.

Nasopharyngeal carcinoma is a rare malignancy with an incidence well under one per 100,000 person-years, except for some geographic areas, such as Asia. The prognosis of nasopharyngeal carcinoma is related to its potential for locoregional invasion and metastatic spread. Radiotherapy alone remains the standard treatment for early stages. However, for locally advanced disease, chemotherapy may offer some benefit as a radiosensitizer while treating microscopic spread disease. Chemoradiotherapy is now the standard treatment for locally advanced and/or node-positive patients. Platinum-based therapy is the preferred regimen for this therapeutic approach. In this review, we discuss all treatment modalities available for nasopharyngeal carcinoma, including the standard of care and what therapeutic options could be available for those patients who progress after the standard treatment has been delivered.

Second-Line Therapy for Non–Small-Cell Lung Cancer

Carcinogenesis is a complex pathological process induced by abnormalities in the genome, cell-cycle dysregulation, loss of the programmed cell death process, and upregulation of oncogenic pathways associated with proliferation, migration, and survival, among others. Despite recent advances in molecular and tumor biology in non-small-cell lung cancer (NSCLC) and the introduction of several targeted agents, the disease continues to have a dismal survival. Nonetheless, the future looks promising; conventional cytotoxic chemotherapy regimens in combination with targeted agents have shown better response rates and survival than those seen in the past. These targeted agents have the advantage of blocking or inhibiting specific pathways necessary for tumor growth, proliferation, and metastases, without significantly affecting quality of life by having an acceptable toxicity profile. Thus, these novel agents harbor a hope in the treatment of NSCLC and many other malignant diseases when they can be used either in combination with other chemotherapy drugs in several lines of treatment or as a single agent in maintenance therapy until progression of disease, or even more attractively, in combination with other targeted agents themselves. In this review, we discuss second-line treatments for patients who have NSCLC, including targeted agents and their development in this specific setting as part of our armamentarium in lung cancer.

Controversies in the management of stage IIIA non-small-cell lung cancer.

New developments in the management of non-small-cell lung cancer, as well as recent proposals for changing the current lung cancer staging system, are posing a challenge in the therapeutic decision making regarding this disease. For the last two decades, the management of stage IIIA (N2) disease has been controversial and the target for clinical trials has been to determine the best therapeutic approach that may result in better survival outcomes without increasing toxicity. For many years, combined modality treatment (systemic chemotherapy plus radiation therapy) became the standard of care in this setting. However, the poor outcomes seen with combined modality for N2 has obligated us to explore other possibilities. In this sense, recent clinical trials in the neoadjuvant setting using chemotherapy alone or combined modality are providing fruitful results and shifting the paradigm on this stage. A recent, large randomized multicenter trial argues against what has slowly become a current practice in some centers – the use of preoperative modality for N2 disease. Another controversy that we will discuss here is the acceptance of adjuvant therapy for resected stage IB–IIIA non-small-cell lung cancer. It was not long ago that adjuvant radiation therapy was still the standard of care for patients who have pathological nodal disease. We will present the current data on these debatable issues and how to implement this new knowledge into clinical practice.

The role of carboplatin in the neoadjuvant chemotherapy treatment of triple negative breast cancer

Triple negative breast (TNBC) cancer constitutes a heterogeneous group of disease with histologic and molecular differences. Complete pathologic response to neoadjuvant chemotherapy (NACT) in TNBC is associated with improved outcomes. Efforts have been made in identifying drug combinations that will increase the response rate to preoperative chemotherapy. In this review we present recent studies that have incorporated carboplatin (Cb) in the NACT of TNBC. We discuss the homologous recombination deficiency score and the somatic or germline mutation for BRCA as potential biomarkers for future selection of patients that could benefit from the addition of Cb to NACT.

A Review of the Prevention of Invasive Breast Cancer with Raloxifene in Postmenopausal Women

Breast cancer remains the second leading cause of malignancy-related death in women in the United States, regardless of advances in novel therapeutic agents. High priority should be emphasized in research aimed at the study of pharmacological and natural compounds that may potentially prevent the development of breast cancer in susceptible patients. Among the known selective estrogen receptor modulators with proven chemopreventive effects, raloxifene has been studied in a number of clinical trials evaluating this drug for the prevention of osteoporosis and coronary heart disease. The MORE and CORE trials had as a primary end point the efficacy of raloxifene in the treatment of women with osteoporosis. These studies showed that raloxifene reduced the risk of invasive breast cancer in postmenopausal women. However, the STAR trial showed no significant difference between raloxifene and tamoxifen recipients in the incidence of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer. This review focuses on the chemopreventive properties of raloxifene and the clinical trials that have proven its efficacy as a chemopreventive agent in invasive breast cancer.

Pericardial effusion in a patient with acquired factor V inhibitor.

Dear Editor, Acquired inhibitors to the coagulation cascade are uncommon disorders. Acquired factor V (FV) inhibitors are considered to be relatively rare with a worldwide incidence of three cases each year. Factor V is a plasma protein cleaved by thrombin to its active form, factor Va, an essential cofactor on activation of prothrombin from factor Xa [1]. Coagulation factor inhibitors are antibodies that bind to specific coagulation factors and block their participation in normal hemostasis [2]. The first case of a factor V inhibitor was identified and reported in 1955 in a patient with congenital FV deficiency [3]. Since then, around 150 cases of FV inhibitor worldwide were reported, being 16 since 2001. Most patients with FV inhibitors were due to exposure to bovine thrombin, a haemostatic component widely used among surgeries, mainly cardiovascular and neurosurgery. The first case related to bovine-exposure-induced FV inhibitor was in 1990 [4]. However, other reports confirmed the occurrence of FV inhibitors in patients with cancer [5], autoimmune disorders [6], HIV [7], infectious [8] amyloidosis [9], antibiotics [10], non-exposure to bovine thrombin [11], and more recently with valproic acid use [12]. The diagnosis of FV inhibitor is established based on increased partial thromboplastin (PT), activated partial thromboplastin time (aPTT), decreased FV level, and mixing studies or the Bethesda method can confirm the existence of a FV inhibitor. A normal thrombin time strongly supports the diagnosis. The overall prognosis of factor V inhibitors is good, with the best prognosis in patients exposed to bovine thrombin without threatening hemorrhage, and the worst prognosis in ‘idiopathic’ inhibitors [13]. Clinical symptoms range broadly from an asymptomatic laboratory abnormality to clinically severe bleeding. Approximately 72% of reported cases of spontaneous FV inhibitors suffered bleeding complications, with 17% being fatal, usually secondary to gastrointestinal or intracranial bleeding. We report a case in which a patient developed antibodies against FV after being submitted to aortoplasty with bovine pericardium secondary to Streptococcus mitis endocartiditis. Prior to the surgery, screening coagulation tests (aPTT and PT; Fig. 1) were normal, and the patient had no signs of hematuria. About 1 week after the surgery, and the first day on medical floor, macroscopic hematuria was observed. He was not taking aspirin, clopidogrel, coumadin, or heparin; nor had he received any postoperatively. The aPTT and PT were prolonging progressively. Upon transfer, the PT was 80.5 s (reference range, 11.6–13.5 s), the aPTT was 191.8 s (reference range, 22.0–32.0 s), and thrombin time was 17.1 s. Urinalysis revealed 50–70 red blood cells/high power field. Liver function tests and platelets were both normal. His family history was negative for coagulopathies, and social Ann Hematol (2008) 87:339–341 DOI 10.1007/s00277-007-0408-1

Inhibition of the Cyclin-Dependent Kinases (CDK) 4/6 as Therapy for Estrogen Receptor Positive Breast Cancer

Endocrine therapy (ET) is the usual first-line therapy for patients with hormone receptor-positive metastatic breast cancer (HR+MBC). However, resistance to ET frequently occurs during the course of treatment. Cellular pathways involved in cell proliferation are targets for new drugs that interfere with development of resistance to ET. Cyclin-dependent kinases (CDKs) are a subgroup of serine/ threonine kinases that play a key role in regulating cell cycle progression. In this review, we discuss the currently approved and under investigation CDK 4/6 inhibitors, in addition to their preclinical data and clinical trials that demonstrated their benefit in the treatment of HR+ breast cancer.