Hamdy A. Azim

Safety of pregnancy following breast cancer diagnosis: A meta-analysis of 14 studies

BACKGROUND Due to the rising trend of delaying pregnancy to later in life, more women are diagnosed with breast cancer before completing their families. Therefore, enquiry into the feasibility and safety of pregnancy following breast cancer diagnosis is on the rise. Available evidence suggests that women with a history of breast cancer are frequently advised against future conception for fear that pregnancy could adversely affect their breast cancer outcome. Hence, we conducted a meta-analysis to understand the effect of pregnancy on overall survival of women with a history of breast cancer. METHODS Two of the authors independently performed a literature search up to September 2009 with no language restrictions. Eligible studies were published retrospective control-matched, population-based and hospital-based studies that have addressed the impact of pregnancy on the overall survival of women with history of breast cancer. Pooling of data was done using the random effect model. Unpublished statistics from three studies were obtained to perform further subgroup and sensitivity analyses. This included examining the effect of pregnancy according to age at diagnosis, healthy mother effect, type of study, nodal status and other parameters. RESULTS Fourteen studies were included in this meta-analysis (1244 cases and 18,145 controls). Women who got pregnant following breast cancer diagnosis had a 41% reduced risk of death compared to women who did not get pregnant [PRR: 0.59 (90% confidence interval (CI): 0.50-0.70)]. This difference was seen irrespective of the type of the study and particularly in women with history of node-negative disease. In a subgroup analysis, we compared the outcome of women with history of breast cancer who became pregnant to breast cancer patients who did not get pregnant and were known to be free of relapse. In this analysis, we did not find significant differences in survival between either group [PRR: 0.85; 95% CI: 0.53-1.35]. CONCLUSIONS This study confirms that pregnancy in women with history of breast cancer is safe and does not compromise their overall survival. Hence, breast cancer survivors should not be denied the opportunity of future conception.

Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge

The diagnosis of cancer during the course of pregnancy is a relatively rare clinical situation. Cancer complicates approximately one out of 1000 pregnancies, with an estimated 6000 new cases diagno...

Trastuzumab versus lapatinib: The cardiac side of the story

HER2 gene plays a pivotal role in the pathogenesis of 20% of breast cancer patients. At the same time, it is one of the main cardiac survival pathways when subjected to bio-mechanical stress including exposure to anthracyclines. With the emergence of the anti-HER2 targeting agents, concerns raised regarding the potential cardiac toxicities of these drugs. In the early clinical trials with trastuzumab, it was evident that it has a significant cardiac toxicity. The incidence of symptomatic heart failure ranged from 4% to 7% with trastuzumab alone, and 27% when administered concurrently with doxorubicin. On the other hand, available data suggest that lapatinib is much less cardiotoxic. The incidence of symptomatic heart failure has been constantly reported to be less than 0.5%. In this review, we discuss the possible theories behind the differences in the cardiac profile of both agents. We emphasize on the role of cardiac bioenergetics and the effects of trastuzumab and lapatinib on ATP production through the different effects they exert on the cardiac mitochondria.

Targeting Her-2/neu in Breast Cancer: As Easy as This!

Her-2/neu-positive tumors account for approximately 20% of all breast cancer and these tumors carry poor prognosis. Trastuzumab and lapatinib are 2 agents that have gained FDA approval for treating Her-2/neu-positive breast cancer. Trastuzumab has been shown to improve all endpoints when added to chemotherapy compared to chemotherapy alone, both in the adjuvant and metastatic phases. The addition of lapatinib to capecitabine has recently been shown to improve time to progression in trastuzumab-refractory patients with unique activity against brain metastasis. In spite of their impressive results, a significant fraction of patients still develop either primary or secondary resistance, a fact that entails the discussion of possible mechanisms of resistance. Biomarkers including PTEN, p95HER2, IGF1R and others have been linked to response to Her-2/neu-targeting agents. In this article, we overview the Her-2/neu signaling pathways and how a better understanding of the different molecular aspects of this oncogene could serve in optimizing the use of Her-2/neu-targeting agents. We also discuss the preclinical and clinical data of these biomarkers that may guide clinicians in choosing the right drug whenever possible.

Targeting RANKL in breast cancer: bone metastasis and beyond

In breast cancer, RANK ligand (RANKL) appears to play an important role in the process of chemotaxis between circulating tumor cells and the bone microenvironment, which enables RANK-expressing breast cancer cells to migrate into the bone. Mounting clinical evidence has further demonstrated that the anti-RANKL monoclonal antibody; denosumab is the most effective approach in the prevention of skeletal-related events. On the other hand, inhibiting RANKL in preclinical models, not only reduced breast cancer formation but also decreased the development of lung metastases, suggesting RANKL as a novel target for breast cancer chemoprevention. In addition, recent data have pointed to a potential role of RANKL in the biology of breast cancer arising at a young age. Hence, RANKL emerges as a key molecule, not only in the field of breast cancer bone metastasis but also in the biology of breast cancer as a whole.

Targeting mTOR in cancer: renal cell is just a beginning

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation. The mTOR pathway integrates signals from nutrients, energy status and extracellular growth factors to regulate many processes, including cell cycle progression, angiogenesis, ribosome biogenesis, and metabolism. Growth factors such as insulin-like growth factor, epidermal growth factor and vascular endothelial growth factor bind to and activate their corresponding tyrosine kinase receptors (TKR) located on the cell surface, to induce signal transduction to the nucleus. TKR induces intracellular signaling cascades via the phosphorylation of the phosphatidylinositol 3-kinase, which in turn phosphorylates Akt. Of particular interest among the Akt targets is the downstream effect on mTOR, which is responsible for protein synthesis of molecules necessary for nutrient uptake, angiogenesis, ribosome biogenesis, cell growth, and proliferation. Growing evidence suggests that mTOR deregulation is associated with many types of human cancer. The importance of mTOR signaling in tumor biology is now widely accepted. Consequently, a number of agents that selectively target mTOR are being developed for cancer treatment and currently temsirolimus and everolimus are approved for the treatment of advanced renal cell cancer. However, the therapeutic benefit of mTOR inhibitors in the clinic may vary depending on the activation state of the different components of the mTOR pathway in a given case. Therefore it seems clear that predicting sensitivity to rapamycins in different cancers will likely require assessing multiple molecular markers related to mTOR signaling pathway, such as phosphatase and tensin homolog (PTEN), phospho-Akt, cytoplasmic p27, and phospho-S6 kinase.

Bone metastasis in breast cancer: the story of RANK-ligand.

The primary cellular mechanism responsible for osteolytic bone metastases is osteoclastic activation. Preclinical models have shown that breast cancer cells can produce parathyroid hormone-related protein (PTHrP), and other osteolytic molecules, which stimulate excessive osteoclastic bone resorption and establishment of osteolytic lesions. It has been shown that PTHrP by itself cannot directly induce osteoclastic activation, but it mediates its effect through the transactivation of RANK-ligand (RANKL) gene on stromal and osteoblastic cells. Accordingly RANKL up-regulation has been considered as a prerequisite in virtually all conditions of cancer induced bone destruction. Hence, therapeutic targeting of RANKL seems to be a rational approach to treat or even to prevent the process of bone metastases. In this review, we will focus on the unique patho-physiological aspects related to the evolution of bone metastases in breast cancer, emphasizing the pivotal role of RANKL and some other key molecules in osteoclastic bone resorption. We will discuss the therapeutic interventions using bisphosphonates and RANKL inhibitors in patients with bone metastases and the outcome of this novel approach.

A randomized, phase 2 study comparing pemetrexed plus best supportive care versus best supportive care as maintenance therapy after first-line treatment with pemetrexed and cisplatin for advanced, non-squamous, non-small cell lung cancer

BackgroundMaintenance therapy for non-small cell lung cancer (NSCLC) aims to extend disease control after first-line chemotherapy with active and well-tolerated agents. The utility of continuation maintenance therapy requires further research.MethodsThis multicenter, randomized, phase 2 study compared continuation maintenance therapy with pemetrexed (500 mg/m2 every 21 days) and best supportive care (BSC) versus BSC alone in patients with advanced, non-squamous NSCLC who had not progressed after 4 cycles of induction chemotherapy with pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). The primary endpoint was progression-free survival (PFS) from randomization, was analyzed using a Cox model, stratified for the tumor response at the end of induction therapy, at a one-sided alpha of 0.2. Secondary endpoints: response and disease control rates, overall survival (OS), one year survival rates, and treatment-emergent adverse events (TEAEs).ResultsA total of 106 patients commenced induction therapy, of whom 55 patients were randomized to maintenance pemetrexed/BSC (n = 28) or BSC (n = 27). Although the median PFS time for maintenance phase for both arms was 3.2 months, the one-sided p-value for the PFS HR comparison was less than the prespecified limit of 0.2 (HR = 0.76, two-sided 95% confidence interval [CI]: 0.42 to 1.37; one-sided p-value = 0.1815), indicating that PFS was sufficiently long in the pemetrexed/BSC arm to warrant further investigation. Similar PFS results were observed for the overall study period (induction plus maintenance) and when the PFS analysis was adjusted for sex, baseline disease stage, and the ECOG PS prior to randomization. The median OS for the maintenance phase was 12.2 months (95%CI: 5.6 to 20.6) for the pemetrexed/BSC arm and 11.8 months (95% CI: 6.3 to 25.6) for BSC arm. The one-year survival probabilities were similar for both arms for the maintenance phase and the overall study period. Both the induction and continuation maintenance therapies were generally well-tolerated, and similar proportion of patients in each arm experienced at least 1 grade 3/4 TEAE (pemetrexed/BSC, 17.9%; BSC, 18.5%).ConclusionsContinuation pemetrexed maintenance therapy resulted in promising PFS with an acceptable safety profile in a Middle Eastern population with advanced non-squamous NSCLC and is worthy of further investigation.Trial registrationNCT00606021

Breast cancer in Egypt, China and Chinese: statistics and beyond

According to the latest report of The International Agency for Research on Cancer (GLOBOCAN 2012), breast cancer (BC) is by far the world’s most common cancer among women, and the most likely cause that a woman will die from cancer worldwide (1). The disease is reported as the most frequent cancer among women in 140 of 184 countries worldwide including China the world’s most populous country (1,2). Notably, the incidence rates of BC varies dramatically across the globe, being always highest in more developed regions, namely North America, Western Europe (more than 90 new cases/105 women annually), compared with less than 30/105 women annually in regions like Eastern Asia (1). In the current issue of JTD, Zeng et al. (3), have published the first national dataset on the incidence and mortality of female BC in China, for the year 2010, highlighting also some trends in incidence, and mortality, in different geographical regions within China. The authors should be commended for being the first to provide the literature with a wealth of data regarding BC statistics in China, which harbors around one fifth of all women around the world. According to the authors’ estimations, the age standardized incidence rate (ASIR) of BC is 24.2/105 and age standardized mortality rate (ASMR) is 6.36/105. As such, these figures would confirm the known fact, that the mainland Chinese women have one of lowest BC incidence and mortality rates, when compared to the rest of the world. Two important questions should be raised with this kind of findings: how far the authors could accurately quantify BC burden (occurrence and outcome) in China? and if their figures are true, then why the mainland Chinese women are so much protected against BC versus Chinese women in other Asian or western counties? To start with, we need to emphasize that Zeng et al. analysis included only 12.96% of the female population of China. This means that the vast majority of Chinese women are not truly represented in their analysis, especially in the western region (less than 10% of their sample size), where the incidence is ~30% less than that reported in other areas. Obviously, “a cautious interpretation” is warranted with this kind of national epidemiological studies, when so many regions in a given country have low or no accurate registry data. Nonetheless, this is a common situation in many countries with emerging population-based registries (4). For instance, in Egypt; with its much smaller scale in geographical and population size, a network of five regional population-based registries, spreading over the whole country, was developed during the last two decades. For the sake of national cancer statistics, Egypt was divided into three regions namely upper, middle and lower Egypt. One or more defined states (governorates), with a regional population-based registry, were selected to represent each region (4). The data evolved on cancer incidence from each cancer registry were extrapolated in a similar methodology like that adopted by Chinese group. BC is estimated to be the most common female cancer in both China and Egypt, despite a marked difference in incidence rates, being much higher among Egyptian women compared to Chinese (ASIR are 48.8/105 and 24.2/105 respectively) (3,4). In the two countries BC incidence differs considerably among rural and urban populations, with the higher urban incidence being consistent across all women above the age of 45 years (3,5). A similar observation was also found in many developing countries like India, where BC incidence in rural registry of Barshi was 7.2/105 compared to 31.3/105 in adjoining city of Mumbai (6). In fact, the urban population in developing countries, might suffer from a higher exposure to xenoestrogens, which have been linked to evolution of hormone receptor positive BC in industrialized countries (7).

Systemic treatment of brain metastases in HER2-positive breast cancer: current status and future directions

In recent years, brain metastases have emerged as a main challenge affecting the morbidity and mortality of patients with HER2-positive metastatic breast cancer. In the era following trastuzumab, approximately 30% of these patients develop brain metastases. Trastuzumab does not cross the blood-brain barrier, hence its role is limited to controlling extra-CNS metastases. Lapatinib emerged as a potential candidate; however, its use as a single agent was associated with modest responses. Combination with capecitabine was associated with good results, particularly in patients with newly diagnosed brain metastases. In this article, we discuss the role of trastuzumab and lapatinib in patients with HER2-positive breast cancer with brain metastases. We also highlight the complex structure of the blood-brain barrier and elucidate different potential strategies that could be useful in improving drug delivery.