Month: July 2010

Can Oral Bisphosphonates Really Reduce the Risk of Breast Cancer in Healthy Women?

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Bisphosphonate therapy has become the pharmacologic treatment of choice for preventing bone loss and fractures in postmenopausal women with osteoporosis.1–3 This is primarily because bisphosphonates have proven efficacy for treating bone loss, relative low cost, ease of use, and low risk of adverse effects versus hormone-replacement therapy, which has been associated with increased risk of breast cancer and cardiovascular disease.4 In addition to the long-standing use of oral bisphosphonates in this setting, intravenous zoledronic acid (5 mg) has been approved as a yearly infusion for treating osteoporosis and as a biennial infusion for women with osteopenic disorder, and ibandronate (3 mg) has been approved as a quarterly injection for treating osteoporosis.5–8 In addition, several recent clinical trials demonstrated the efficacy of bisphosphonates for preventing cancer treatment–induced bone loss (CTIBL) in pre- and postmenopausal women with early-stage breast cancer.9–13 Beyond preventing osteoclast-mediated bone resorption, nitrogen-containing bisphosphonates have also demonstrated anticancer activity in a variety of preclinical and clinical studies.14 There is also evidence for anticancer synergy between cytotoxic chemotherapy agents and zoledronic acid, a finding that was recently confirmed in women receiving neoadjuvant therapy for breast cancer.15 Furthermore, adding adjuvant zoledronic acid in large, randomized clinical trials produced remarkable reductions in disease recurrence in women with breast cancer, and suggests that bisphosphonates have a beneficial effect on the microenvironment in which dormant tumor stem cells survive in early disease.16 Based on these exciting findings, several recent population-based studies examined whether long-term use of oral bisphosphonates in women with postmenopausal osteoporosis may be associated with a reduced risk of breast cancer.

In this issue of Journal of Clinical Oncology (JCO), Chlebowski et al17 report on an analysis of longitudinal data from the Women’s Health Initiative Observational Study (WHI-OS) that included 154,768 women. In summary, their multivariate analysis revealed that women who received bisphosphonates for osteoporosis had a 32% relative reduction in the overall risk of breast cancer compared with those who did not receive bisphosphonates (hazard ratio [HR] = 0.68; 95% CI, 0.52 to 0.88). Interestingly, the risk reduction included both estrogen receptor (ER) –positive and ER-negative breast cancers. Also in this issue, Rennert et al18 report a 28% reduced risk of breast cancer (odds ratio = 0.72; 95% CI, 0.57 to 0.90) among postmenopausal women receiving bisphosphonates for more than 1 year in a similar analysis, this time using the Breast Cancer in Northern Israel Study (BCINIS) database (N = 4,039).

These significant correlations are profound and intriguing, because they suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing breast cancer. If this application of the seed and soil axiom, first introduced by Stephen Paget,19 becomes a reality, the potential implications would be far-reaching. However, the results presented in these two studies must be interpreted with caution. As correctly noted by the authors, several potential confounding factors may have influenced the observed outcomes, including age, ethnicity, tobacco use, alcohol use, physical activity, baseline bone mineral density (BMD), body mass index, prior hormone therapy, calcium and vitamin D supplementation, number of pregnancies, duration of breast feeding, and other unknown factors that may interact with breast cancer risk in these healthy women. Although the authors did their best to control for these confounders, the relative and interrelated risk factors for breast cancer are not yet completely understood, and thus form the major limitation of retrospective analyses. Consequently, in the absence of a prospective randomized study, the analyses should be viewed as hypothesis generating and not practice changing at this time.

Estrogen exposure has been correlated with mammary hyperplasia and ultimately with breast cancers that are stimulated by sex hormone signaling. However, estrogen is also intimately involved in regulating the balanced and coupled processes of bone resorption and formation. Lifetime exposure to estrogen influences not only breast cancer risk but also BMD.20 Therefore, BMD and breast cancer risk may be related. It is well established that women with high BMD are at higher risk of breast cancer compared with women with low BMD,21–23 presumably because high estrogen levels or prolonged exposure to estrogen are more likely to stimulate the growth of ER-positive breast cancer cells. Therefore, by nature, women in whom bisphosphonate therapy would be initiated might represent a lower-risk group for breast cancer than women with normal BMD. However, the breast cancer risk reduction among bisphosphonate-treated versus non–bisphosphonate-treated women was even more pronounced for ER-negative breast cancer, which, according to our current understanding, should not be influenced by estrogen exposure. Moreover, women who developed breast cancer during bisphosphonate therapy had a higher proportion of in situ versus invasive breast cancer.17 This suggests that bisphosphonates may have somehow inhibited breast cancer invasion or at least interfered with the continuous processes of atypia and hyperplasia at the lobuloductal end plate. It remains unclear whether the known immune-mediated anticancer effects of zoledronic acid are also present for oral bisphosphonates or whether these anticancer mechanisms even play a role in this setting. In fact, Rennert et al18 report that women receiving bisphosphonates who developed breast cancer had tumors with better prognostic features, including a lower proportion of human epidermal growth factor receptor 2 (HER2) -positive tumors, compared with women who did not receive bisphosphonates.

Duration of bisphosphonate use also somewhat correlated with reduction in breast cancer risk, but this finding was inconsistent between the two studies. In Chlebowski et al,17 the greatest reduction in breast cancer risk was in women who had received bisphosphonates for less than 2 years. This may suggest that oral bisphosphonates might be able to delay breast cancer, but they cannot prevent it. In contrast, Rennert et al18 showed that the greatest risk reduction was in women who had received bisphosphonates for more than 1 year, but that the risk reduction persisted in patients with more than 5 years of exposure, reflecting a longer course of prevention. However, differences in patient demographics or criteria for bisphosphonate use between these United States–based and Israel-based studies could be responsible for the inconsistencies.

In support of these two articles, a recent population-based, case-controlled study in Wisconsin (N = 5,911) from Newcomb et al24 found that current bisphosphonate use was associated with a comparable 33% reduction in the risk of breast cancer (odds ratio = 0.67; 95% CI, 0.51 to 0.89). Important confounders such as body mass index and hormone-replacement therapy were considered. Although it was a smaller study, this represents an additional, independent report of the correlation between bisphosphonate use and decreased breast cancer risk. It is interesting to note that the relative breast cancer risk reduction is approximately 30% across all three studies.

Potential anticancer effects of bisphosphonates have also been reported in pre- and postmenopausal women with early-stage breast cancer. For example, early clinical evidence for the anticancer effects of bisphosphonates was obtained from two separate clinical trials in women with breast cancer (total N = 1,371) in which 2 years of oral clodronate delayed the appearance of bone metastases and prolonged disease-free and overall survival.25,26 However, another trial (N = 299) found no significant clinical benefit with oral clodronate.27,28 Similarly, a trial of oral pamidronate (N = 953) failed to show a reduction in breast cancer recurrence in bone or prolongation of survival.29) More recently, in the ZO-FAST (Zometa-Femara Adjuvant Synergy Trial) study (N = 1,065), postmenopausal women receiving zoledronic acid plus adjuvant letrozole for endocrine-responsive breast cancer had a 41% reduced risk of disease-free survival events compared with those who received letrozole therapy alone (HR = 0.59; 95% CI, 0.36 to 0.96; P = .0314).10 Similarly, premenopausal women in the Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12; N = 1,803) receiving endocrine therapy (ovarian suppression plus anastrozole or tamoxifen) plus zoledronic acid experienced a 36% relative reduction in the risk of disease progression compared with endocrine therapy alone (HR = 0.64; 95% CI, 0.46 to 0.91; P = .01).30 In both of these trials, adding zoledronic acid reduced disease recurrence in bone and nonbone sites (including contralateral breast cancer). The reduction in disease recurrence with adjuvant bisphosphonate therapy may result, in part, from modification of the bone marrow microenvironment, making this niche less receptive to tumor stem cells. As recently demonstrated by Aft and others,31–34 disseminated tumor cells in the bone marrow, which are thought to seed future distant metastases, can be reduced or eliminated by indirect bisphosphonate-mediated modification of the bone marrow niche.

Bisphosphonates have also demonstrated direct and indirect anticancer effects on cancer cells—including inducing cancer cell apoptosis; inhibiting cancer cell adhesion and extravasation, anticancer synergy with endocrine therapy and cytotoxic chemotherapy; deterring angiogenesis; and activating immune cells with anticancer activity ({gamma}{delta} T cells); among others.14 Indeed, these anticancer effects of bisphosphonates likely account for the reduction in residual invasive tumor size and improved pathologic complete response with zoledronic acid versus no zoledronic acid reported in a recently published exploratory analysis of the subset of women who received neoadjuvant therapy in the AZURE (Adjuvant Zoledronic Acid Reduce Recurrence) trial (n = 205), a randomized study evaluating the effects of adding zoledronic acid to early breast cancer treatment regimens.15 In this study, patients receiving neoadjuvant chemotherapy plus zoledronic acid had a 43% relative reduction in mean residual invasive tumor size compared with patients receiving chemotherapy alone (15.5 v 27.4 mm, respectively; P = 0.006). Furthermore, adding zoledronic acid improved pathologic complete response by nearly two-fold compared with chemotherapy alone (6.9% v 11.7%, respectively; P = .146) and reduced the number of mastectomies.

The bisphosphonates used varied among patients in the three published database studies. Therefore, it is possible that the reported correlations represent a class effect. However, it is unclear whether this is a class effect of bisphosphonates or of antiresorptive therapies in general. It is unknown whether a new antiresorptive agent, the antireceptor activator of nuclear factor {kappa} B (RANKL) antibody, denosumab, will have similar anticancer activity in women with osteoporosis. Although denosumab was reported to prevent cancer treatment–induced bone loss (CTIBL) in women receiving adjuvant aromatase-inhibitor therapy35 and was superior to zoledronic acid for reducing skeletal-related events in women with bone metastases from breast cancer,36 to date there has been no reported evidence of reduced breast cancer recurrence in the CTIBL trial or of breast cancer prevention in the large postmenopausal osteoporosis trial.

Taken together, the results of the two studies in this issue of JCO are important additional steps toward understanding several unresolved issues, including how best to target the early precursors of malignancy and the role of the microenvironment in tumor development.17,18 Ongoing translational and clinical research studies are scheduled to report their findings in the near future and may help to further elucidate the potential role of bisphosphonates in preventing breast and other cancers. Results from these studies and others will need to identify the precise anticancer mechanisms contributing to the different settings, but the hypothetical benefits of bisphosphonates as anticancer therapies may now extend well into the early stages of the continuum of breast cancer development and progression.

At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women. However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy, in addition to its bone-protecting effects, when evaluating treatment options in women with postmenopausal osteoporosis, especially considering that bisphosphonates are generally well tolerated in this population.

In summary, there are strong signals that bisphosphonate therapy for postmenopausal osteoporosis might significantly reduce the risk of breast cancer. This supports the idea that the seed and soil theory is equally relevant in preventing breast cancer in healthy postmenopausal women as it is in preventing breast cancer recurrence in women with early-stage breast cancer. The growing body of evidence suggests that targeting the microenvironment in addition to the cancer cells themselves may be an important aspect of future anticancer strategies. The two reports presented in this issue of JCO now add further support to this exciting possibility.

Chlordecone Exposure and Risk of Prostate Cancer

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Purpose Determining whether environmental estrogens are associated with the risk of prostate cancer may have important implications for our general understanding of this disease. The estrogenic insecticide chlordecone was used extensively in the French West Indies, contaminating the population for more than 30 years. We analyzed the relationship between exposure to chlordecone and the risk of prostate cancer.

Patients and Methods We investigated 623 men with prostate cancer and 671 controls. Exposure was analyzed according to case-control status, using either current plasma concentration or a cumulative exposure index based on years of exposure. We genotyped two single-nucleotide polymorphisms (rs3829125 and rs17134592) in the gene encoding chlordecone reductase.

Results We found a significant increase in the risk of prostate cancer with increasing plasma chlordecone concentration (odds ratio [OR], 1.77; 95% CI, 1.21 to 2.58 for the highest tertile of values above the limit of detection [LD]; P trend = .002) and for cumulative exposure index (OR, 1.73; 95% CI, 1.04 to 2.88 for the highest quartile; P trend = .004). Stronger associations were observed among those with a positive family history of prostate cancer and among those who had lived in a Western country. The rs3829125 and rs17134592 allele variants were in complete linkage disequilibrium and were found at low frequency (0.04). Among subjects with plasma chlordecone concentrations above the LD, carriers of the allele variants had a higher risk of prostate cancer (OR, 5.23; 95% CI, 0.82 to 33.32).

Conclusion These findings support the hypothesis that exposure to environmental estrogens increases the risk of prostate cancer.

source:JCO

Longer-Term Assessment of Trastuzumab-Related Cardiac Adverse Events in the Herceptin Adjuvant (HERA) Trial

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Purpose We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant (HERA) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy.

Patients and Methods The HERA trial is a three-group, randomized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 (HER2) –positive early breast cancer. Eligible patients had normal left ventricular ejection fraction (LVEF; ≥ 55%) after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Cardiac function was monitored throughout the trial. This analysis considers patients randomly assigned to 1 year of trastuzumab treatment or observation.

Results There were 1,698 patients randomly assigned to observation and 1,703 randomly assigned to 1 year of trastuzumab treatment; 94.1% of patients had been treated with anthracyclines. The incidence of discontinuation of trastuzumab because of cardiac disorders was low (5.1%). At a median follow-up of 3.6 years, the incidence of cardiac end points remained low, though it was higher in the trastuzumab group than in the observation group (severe CHF, 0.8% v 0.0%; confirmed significant LVEF decreases, 3.6% v 0.6%) In the trastuzumab group, 59 of 73 patients with a cardiac end point reached acute recovery; of these 59 patients, 52 were considered by the cardiac advisory board (CAB) to have a favorable outcome from the cardiac end point.

Conclusion The incidence of cardiac end points remains low even after longer-term follow-up. The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year, but it remains relatively constant thereafter.

source:JCO

Trastuzumab-Related Cardiotoxicity Following Anthracycline-Based Adjuvant Chemotherapy: How Worried Should We Be?

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Trastuzumab has improved the clinical course of HER2-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings.1–6 The joint analysis of the National Surgical Adjuvant Breast and Bowel (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials demonstrated that the addition of 1 year of trastuzumab to sequential anthracycline-taxane chemotherapy reduced the risk of recurrence by approximately half (hazard ratio [HR], 0.48; P < .0001) and the risk of death by one third (HR, 0.67; P = .015).5 A similar benefit was seen in the Herceptin Adjuvant (HERA) trial, for patients randomly assigned to 1 year of trastuzumab (or not) given only after the completion of adjuvant chemotherapy.4 In all three of these initial reports, and as predicted by experience in the earlier metastatic disease trials, trastuzumab’s benefits are associated with the potential for increased cardiotoxicity.1 With broad adoption of adjuvant trastuzumab, it is appropriate to ask several related questions on this issue. How frequent and how severe is the toxicity and what modulates the risk?

Because of the cardiac safety signal in the earlier metastatic disease trials,7 the risk of serious and life-threatening cardiotoxicity with the combination of anthracyclines and trastuzumab was a recognized concern when these phase III adjuvant studies of trastuzumab commenced. To mitigate this risk, strict cardiac criteria that excluded patients predicted to have greater likelihood of cardiac toxicity were used. In addition, rigorous, if arbitrary, cardiac monitoring was incorporated to allow early detection of any signals of increased cardiac risk. Not knowing the magnitude of the benefit for trastuzumab, early stopping rules allowed an increase in congestive heart failure (CHF) and cardiac deaths of up to 4% in some studies, a limit that was nearly breached.8,9

Collectively, the available studies demonstrated that the risk of serious cardiotoxicity with adjuvant trastuzumab was lower than the preset threshold for early stopping and that trastuzumab-related cardiotoxicity, in contrast to anthracycline-induced cardiotoxicity, may occur as an early and reversible event. Perhaps because of increased awareness and scrutiny, the most frequent events were asymptomatic declines in left ventricular ejection fraction (LVEF) for which the long-term clinical significance is largely unknown.

In this issue of the Journal of Clinical Oncology, updated cardiac safety data are presented from patients treated with anthracyclines and trastuzumab in three of the previously reported adjuvant trastuzumab trials. First, Russell et al10 retrospectively reviewed patients with CHF in the NSABP B-31 and NCCTG N9831 studies. Patients with possible cardiac events were identified from the trial database and reviewed by a committee of six oncologists and cardiologists. These reviewers were independent of the original study and were blinded to trastuzumab treatment and the investigators’ original cardiac diagnosis. CHF was rigorously defined by symptoms, physical signs, and objective findings and included an LVEF drop of 10% or a drop to an absolute LVEF of < 50% by locally obtained multigated radionuclide angiography or echocardiogram. This independent review confirmed earlier risk estimates by showing that the addition of trastuzumab to anthracycline-based chemotherapy increased the incidence of CHF nearly four-fold, from 0.45% to 2.0%, at a median follow-up of 1.9 and 2.0 years, respectively. Among those assigned to trastuzumab, 133 (7.4%) patients with possible cardiac events were reviewed, yielding 36 that were deemed to have definitely suffered a cardiac event. Again, consistent with earlier reports,11 Russell et al note that a majority of these patients recovered completely (20 [55.5%]) or partially (11 [30.6%]). In addition, the independent review highlighted three cardiac deaths (< 0.2%) among 1,799 patients randomly assigned to trastuzumab. Two of these occurred before the initiation of trastuzumab. In an attempt to develop a risk stratification model for these adverse events, Russell et al identified age older than 50 years (2.84-fold increase v age < 50 years) and low LVEF post anthracycline treatment (P = .0106) as possible risk factors for cardiac events. Patients with baseline hypertension had a 1.89-fold increased risk of a cardiac event, although this result was not statistically significant.

In another article in this issue of JCO, Procter et al12 report a similar analysis from the HERA study. As expected, the most common cardiac event noted was a “significant” LVEF drop, defined as an absolute decline of at least 10 percentage points from baseline to below 50%. This occurred in 164 (9.8%) trastuzumab-treated patients compared with 49 (2.9%) controls. The clinical significance of these LVEF declines is unclear because they may have been spurious, or at least quickly reversible, since fewer than half these patients overall (73 or 4.3% overall) had a confirmed cardiac event (CHF or second confirmed LVEF decline). Indeed, these observed changes in LVEF rarely translated into symptomatic CHF, which occurred in 32 (1.9%) trastuzumab-treated patients versus two (0.1%) controls (difference, 1.8%; 95% CI, 1.1% to 2.5%).

In both of these articles, the increased rate of clinical CHF (1.9% and 2%) at a median follow-up of 3.6 and 2 years should be seen in the context of the absolute improvements in disease-free survival at 3 years (6.3% and 11.7%, respectively) attributable to the addition of adjuvant trastuzumab to anthracycline-based chemotherapy.5,13 Both articles suggest that these events are usually reversible. For example, in the article by Procter et al, 57 (78%) of 73 were deemed to have a favorable outcome. Reversibility is also suggested by the finding that they attributed no cardiac deaths to trastuzumab.13

Each of these two independent reviews of large prospective clinical trials offer evidence that long-term cardiotoxicity with trastuzumab following anthracycline-based chemotherapy for HER2-positive early breast cancer is relatively infrequent and generally associated with a favorable outcome. If this is reassuring, there remain several cautions and considerations. In these two analyses, cases were selected for review on the basis of previously documented cardiotoxicity, and the independent committees did not review original data from all enrolled patients. Although unlikely, it remains possible that other cardiac events may not have been reported. In addition, the independent review committees assessed reversibility on the basis of the weight of available evidence, but a prospective assessment of reversibility would have been preferable, as would incorporation of a standardized management approach for suspected CHF and possibly a quality-of-life measure to determine the true clinical significance of these events. Although the relatively constant rate of cardiac events in NSABP B-31 in years 1 to 3 suggests that longer-term follow-up is unlikely to change the results of any of these studies,14 relatively small numbers of patients have reached 4-year follow-up (> 500 in HERA). Since anthracycline-mediated cardiotoxicity may occur many years after treatment, we could still see unanticipated long-term effects in the future.

The articles by Russell et al10 and Procter et al12 add to the evidence that patients with HER2-positive early breast cancer and normal baseline LVEF can be safely treated with sequential anthracycline-taxane–based chemotherapy incorporating trastuzumab. The question many will ask is whether we should avoid the entire issue by substituting an evidence-based alternative such as docetaxel, carboplatin, and trastuzumab (TCH) from Breast Cancer International Research Group (BCIRG) 006, or even an as yet untested approach like docetaxel plus cyclophosphamide with trastuzumab (or other drugs). The former can be discussed with available phase III data; the latter has not yet been reported. To date, the significant evidence as reviewed above supports the routine use of sequential anthracyclines and trastuzumab with an overall low risk of cardiotoxicity demonstrated in more than 4,500 patients and confirmed on independent cardiac reviews of almost 3,500 of these (Table 1) . TCH is an alternative therapy, albeit one that has been tested only in a single trial where it did not appear to have inferior efficacy to a relatively standard anthracycline/taxane/trastuzumab regimen. For TCH, there are not yet long-term cardiac safety data for the approximately 1,000 treated patients.

An alternative way of framing the issue is to ask whether there is adequate evidence or reason to abandon anthracyclines followed by trastuzumab for HER2-positive breast cancer. Some in our community have already made this decision, but it is worth noting that the advantages of continuing to treat this way are that it offers a more consistently demonstrated overall survival advantage. The cardiac event rate for sequential anthracyclines and trastuzumab is higher than the same treatment without trastuzumab, but still low, and the events are largely reversible. The sequential use of generic anthracyclines and taxanes can possibly be less expensive than agents such as docetaxel; if the dose-dense approach is used, it can be safer and faster.16 In this regard, we note that in contrast to some preconceived expectations, patients with normal baseline LVEF can safely be treated with dose-dense anthracycline-based chemotherapy and trastuzumab with no evidence of an increased risk of short- or long-term cardiotoxicity to date.16,17 Additionally, experience at the M. D. Anderson Cancer Center has demonstrated that trastuzumab can be combined with both anthracyclines and taxanes in the preoperative setting with no increase in cardiac toxicity.18,19 This finding was confirmed in the randomized phase III Neoadjuvant Herceptin (NOAH) study, in which the addition of trastuzumab to preoperative chemotherapy doubled the complete response rate and, despite concurrent anthracycline-trastuzumab therapy, was associated with a similar low risk of cardiotoxicity.20

Yet another way to approach the issue is to ask whether there are patients without overt cardiac dysfunction whom we should select for an available non-anthracycline containing adjuvant regimen with trastuzumab. The current reports add to the growing evidence that older patients with borderline LVEF function and baseline hypertension may be at increased risk of cardiotoxicity, but no study has prospectively compared treatment regimens in this subset, and the alternative (TCH) might or might not be as toxic or more toxic in other ways for this population.15 The risk-benefit calculations for these patients are challenging, and predictive biomarkers to improve risk stratification and to predict for trastuzumab-induced cardiotoxicity are needed. Unfortunately, putative cardiac biomarkers such as troponin I and C-reactive protein have been disappointing, with no validated serum marker for cardiotoxicity emerging to date.21

Although the overwhelming body of evidence from rigorously conducted randomized control studies supports anthracyclines as the mainstay of current adjuvant trastuzumab-based chemotherapy regimens, the potential omission of anthracyclines for appropriately selected patients has become a major research focus. Subgroup tissue analyses from prospective trials attempting to more precisely define the role of anthracyclines have had conflicting results; some studies suggest that only HER2-positive tumors benefit from anthracyclines,22,23 and other data show that HER2-positive tumors do not benefit from the addition of anthracyclines.24 Attempts to omit anthracyclines from trastuzumab-based chemotherapy have focused on possible biomarkers such as the topoisomerase II alpha (TOPO-II) gene, the putative target of the anthracyclines, which is closely related to the HER2 gene on chromosome 17.25 Preliminary data from a subgroup analysis from BCIRG 006 suggested that anthracyclines may not be needed for trastuzumab-treated patients with coamplification of HER2 and TOPO-II. In contrast, recent data from the National Cancer Institute of Canada Clinical Trials Group Mammary.5 (MA5) trial, which randomly assigned patients to CMF or anthracycline-based chemotherapy, suggested that the anthracycline benefit was confined to patients with tumors with TOPO-II gene deletions as well as amplifications.26 Most strikingly, in a multivariate analysis, when adjusted for TOPO-II status, HER2-positive tumors continued to derive a survival benefit from anthracyclines (HR, 0.44; P = .02).26 The reasons for the extensive inconsistencies surrounding the putative predictive effect of TOPO-II are largely unclear. A possible explanation is that many studies have depended on fluorescent in situ hydridization (FISH) to determine TOPO-II status, and the width of commercial FISH probes may limit specificity. High-resolution techniques, such as comparative genomic hybridization or representational oligonucleotide microarray analysis (ROMA), which allow a more precise definition of these genes, have demonstrated that so-called amplification of HER2 and TOPO-II may be far more complex than previously thought.27 In part, the expression of other genes in the same area on chromosome 17 may play an important role in the interaction of HER2 and TOPO-II as detected by FISH.28 Finally, it is important to recall that TOPO-II is only one of several targets of anthracyclines in cancer. Given these uncertainties, TOPO-II status cannot be used to tailor therapy and, as recently noted in JCO, there are currently insufficient data to recommend replacing anthracyclines in general in adjuvant chemotherapy regimens.29 The current studies extend this caution to the HER2-positive setting in which trastuzumab is used.

One more related issue is the definition of the optimum duration of trastuzumab therapy and the potential interaction of duration on cardiac events. In the smaller Finland Herceptin (FinHer) study, the magnitude of benefit for 9 weeks of trastuzumab was similar to that seen in larger studies incorporating 1 year of therapy (Table 1).3 In the combined N9831–B-31 study, 29.5% of patients discontinued trastuzumab before the planned 1-year duration for reasons other than recurrence, compared with only 10.2% in the HERA trial.5,12 Despite this, there is neither a suggestion that the shorter delivered dose of trastuzumab was associated with an inferior outcome nor a change in cardiac risk. Relevant studies are ongoing, such as the French Protocol of Herceptin Adjuvant With Reduced Exposure (PHARE) study, in which patients are randomly assigned to either 6 months or 1 year of adjuvant trastuzumab, and the Synergism Or Long Duration (SOLD) study, in which patients are randomly assigned to 9 weeks or 1 year of trastuzumab in combination with sequential taxane-anthracycline chemotherapy.30,31

The incorporation of trastuzumab into adjuvant chemotherapy regimens for HER2-positive early breast cancer has been a major clinical advance. Long-term data from HERA and N9831–B-31 suggest that the benefits are durable and that cardiotoxicity is uncommon and generally reversible. Confirmation of equivalent efficacy for a non-anthracycline–containing regimen will be important as will the development of biomarkers and predictive models for toxicity.

Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study

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Objective To examine the presence and extent of small study effects in clinical osteoarthritis research.

Design Meta-epidemiological study.

Data sources 13 meta-analyses including 153 randomised trials (41 605 patients) that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patients’ reported pain as an outcome.

Methods We compared estimated benefits of treatment between large trials (at least 100 patients per arm) and small trials, explored funnel plots supplemented with lines of predicted effects and contours of significance, and used three approaches to estimate treatment effects: meta-analyses including all trials irrespective of sample size, meta-analyses restricted to large trials, and treatment effects predicted for large trials.

Results On average, treatment effects were more beneficial in small than in large trials (difference in effect sizes –0.21, 95% confidence interval –0.34 to –0.08, P=0.001). Depending on criteria used, six to eight funnel plots indicated small study effects. In six of 13 meta-analyses, the overall pooled estimate suggested a clinically relevant, significant benefit of treatment, whereas analyses restricted to large trials and predicted effects in large trials yielded smaller non-significant estimates.

Conclusions Small study effects can often distort results of meta-analyses. The influence of small trials on estimated treatment effects should be routinely assessed.

source:BMJ

Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis

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Objective To evaluate whether including a test for faecal calprotectin, a sensitive marker of intestinal inflammation, in the investigation of suspected inflammatory bowel disease reduces the number of unnecessary endoscopic procedures.

Design Meta-analysis of diagnostic accuracy studies.

Data sources Studies published in Medline and Embase up to October 2009.

Interventions reviewed Measurement of faecal calprotectin level (index test) compared with endoscopy and histopathology of segmental biopsy samples (reference standard).

Inclusion criteria Studies that had collected data prospectively in patients with suspected inflammatory bowel disease and allowed for construction of a two by two table. For each study, sensitivity and specificity of faecal calprotectin were analysed as bivariate data to account for a possible negative correlation within studies.

Results 13 studies were included: six in adults (n=670), seven in children and teenagers (n=371). Inflammatory bowel disease was confirmed by endoscopy in 32% (n=215) of the adults and 61% (n=226) of the children and teenagers. In the studies of adults, the pooled sensitivity and pooled specificity of calprotectin was 0.93 (95% confidence interval 0.85 to 0.97) and 0.96 (0.79 to 0.99) and in the studies of children and teenagers was 0.92 (0.84 to 0.96) and 0.76 (0.62 to 0.86). The lower specificity in the studies of children and teenagers was significantly different from that in the studies of adults (P=0.048). Screening by measuring faecal calprotectin levels would result in a 67% reduction in the number of adults requiring endoscopy. Three of 33 adults who undergo endoscopy will not have inflammatory bowel disease but may have a different condition for which endoscopy is inevitable. The downside of this screening strategy is delayed diagnosis in 6% of adults because of a false negative test result. In the population of children and teenagers, 65 instead of 100 would undergo endoscopy. Nine of them will not have inflammatory bowel disease, and diagnosis will be delayed in 8% of the affected children.

Conclusion Testing for faecal calprotectin is a useful screening tool for identifying patients who are most likely to need endoscopy for suspected inflammatory bowel disease. The discriminative power to safely exclude inflammatory bowel disease was significantly better in studies of adults than in studies of children.

source:BMJ

Vitamin D and Risk of Cognitive Decline in Elderly Persons

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Background To our knowledge, no prospective study has examined the association between vitamin D and cognitive decline or dementia.

Methods We determined whether low levels of serum 25-hydroxyvitamin D (25[OH]D) were associated with an increased risk of substantial cognitive decline in the InCHIANTI population–based study conducted in Italy between 1998 and 2006 with follow-up assessments every 3 years. A total of 858 adults 65 years or older completed interviews, cognitive assessments, and medical examinations and provided blood samples. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE), and substantial decline was defined as 3 or more points. The Trail-Making Tests A and B were also used, and substantial decline was defined as the worst 10% of the distribution of decline or as discontinued testing.

Results The multivariate adjusted relative risk (95% confidence interval [CI]) of substantial cognitive decline on the MMSE in participants who were severely serum 25(OH)D deficient (levels <25 nmol/L) in comparison with those with sufficient levels of 25(OH)D (≥75 nmol/L) was 1.60 (95% CI, 1.19-2.00). Multivariate adjusted random-effects models demonstrated that the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D. The relative risk for substantial decline on Trail-Making Test B was 1.31 (95% CI, 1.03-1.51) among those who were severely 25(OH)D deficient compared with those with sufficient levels of 25(OH)D. No significant association was observed for Trail-Making Test A.

Conclusion Low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied over a 6-year period, which raises important new possibilities for treatment and prevention.

Cardiovascular disorders: MicroRNA modulation of cholesterol

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BRANDX

Two independent papers published in Science have shown that microRNA-33 (miR-33) helps to regulate the homeostasis of high density lipoprotein (HDL; ‘good’) cholesterol, suggesting that it might be a possible target for cardiovascular and metabolic disorders.

MicroRNAs are small non-coding double-stranded RNAs that bind to complementary sequences of target mRNA transcripts, resulting in gene silencing through translational repression and/or mRNA destabilization. MiR-33 is encoded by a sequence embedded within introns of the sterol response element-binding factors (SREBFs), which are transcription factors that regulate the expression of genes involved in the biosynthesis and cellular uptake of cholesterol.

In the studies, miR-33 was identified by two different routes. Rayner and colleagues used a genome-wide screen of microRNAs that were differentially modulated by cellular cholesterol depletion and enrichment, whereas Najafi-Shoushtari and colleagues undertook studies of gene regulation by SREBFs.

Both groups reported similar or complementary findings. Expression of miR-33 was found in various cells and tissues, including macrophages, hepatic cells, endothelial cells, brain, liver, colon, small intestine and skeletal muscle. The predominant target identified for miR-33 was the gene encoding the ATP binding cassette transporter ABCA1, which is involved in cellular cholesterol mobilization. Moreover, overexpression of miR-33 reduced ABCA1 protein levels. In mice, hepatic miR-33 levels correlated inversely with cholesterol levels and Abca1 expression, and positively correlated with Srebf2 mRNA levels, suggesting that miR-33 and SREBF2 expression are co-transcribed and that miR-33 is regulated by dietary cholesterol.

The studies next investigated whether miR-33 could modulate cholesterol efflux from macrophages — which is an important anti-atherosclerotic mechanism in plaques. Under conditions of cholesterol depletion, expression of miR-33 and the SREBF2 host gene were increased, together with a concomitant decrease in the levels of ABCA1 protein and cholesterol efflux. Conversely, antagonism of endogenous miR-33 (using miR-33 antisense oligonucleotides) increased ABCA1 protein levels and cholesterol efflux, showing that manipulation of cellular miR-33 levels alters cholesterol efflux from macrophages.

Last, the authors investigated the effects of reducing miR-33 levels in mice. Rayner et al. used lentiviral delivery of anti-miR-33, and showed that this increased plasma HDL levels. Similar results were seen by Najafi-Shoushtari et al., who used locked nucleic acid miR-33-specific antisense RNA and also demonstrated that antisense RNA-treated animals had no changes in the levels of low-density lipoprotein cholesterol, triglyceride or glucose.

Together, these studies show a new role for miR-33 in the epigenetic regulation of cholesterol homeostasis. Although further work is needed — including optimization of the knockdown strategy and proof of concept in animal models of disease — miR-33 might represent a novel target in cardiovascular disorders.

source: nature

Inflammation: Hope for sepsis treatment

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The incidence of sepsis (and death from septic shock) is increasing, and treatments are still inadequate. Now a study in Science offers promise for a new treatment option involving blockade of sphingosine kinase 1 (SPHK1), which protected mice from lethal and uncontrolled systemic inflammation induced by bacterial products or polymicrobial sepsis.

Consistent with previous studies describing a link between SPHK1 and the inflammatory response, SPHK1 expression was found to be highly upregulated in neutrophils and macrophages stimulated with various bacteria or bacterial components, including lipopolysaccharide (LPS). Moreover, silencing of SPHK1 expression, using small interfering RNA (siRNA) or the specific inhibitor 5c, led to failed activation of nuclear factor-κB (NF-κB) and reduced production of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1β (IL-1β) and IL-6 by LPS-stimulated macrophages, but it had no effect on interferon responses. Innate immune cells isolated from the peritoneal cavity of patients with septic shock showed a similar abrogation of inflammatory responses following treatment with 5c.

Next, the authors tested the effects of SPHK1 blockade on two mouse models of sepsis — the first involving intraperitoneal injection of a lethal dose of LPS and the second involving caecal ligation and puncture (CLP) to trigger polymicrobial sepsis. 100% of mice survived the lethal LPS injection if they were pretreated with SPHK1-targeted siRNA. These mice showed lower levels of inflammatory cytokines in the blood and reduced immune cell infiltration of the liver and lungs. SPHK1-specific siRNA and 5c also protected mice against CLP-induced systemic inflammation and mortality. Blockade of SPHK1 with 5c was most effective (100%) if given 2 hours after CLP, and it had much reduced efficacy (10%) if given 12 hours after CLP. However, combined treatment with 5c and the broad-spectrum antibiotic co-amoxiclav (which is currently used to treat patients with sepsis) had synergistic effects, extending the time window for treatment and resulting in better outcomes than either drug alone.

It is therefore hoped that administration of SPHK1 inhibitors — alone or in combination with antibiotics — might prove to be a useful treatment for septic shock in humans.

source:NATURE

Feasibility and safety of outpatient radiofrequency catheter ablation procedures for atrial fibrillation

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Introduction Percutaneous catheter ablation for atrial fibrillation (AF) is a procedure performed typically in an inpatient setting. The feasibility and safety of catheter ablation in patients with paroxysmal and persistent AF were evaluated on an outpatient basis.

Methods 230 AF ablation procedures were performed in 206 patients (74% male; mean age 56±9 years). Patients were admitted to the hospital outpatient facility in the morning for the AF ablation procedure on the same day. The ablation strategy consisted of wide area circumferential lines around both ipsilateral pulmonary veins. After monitoring in the outpatient service, patients were discharged on the same day, if they were clinically stable.

Results Mean procedure time was 201±31 min. Major complications occurred in seven patients (3%). One patient (0.4%) suffered a minor stroke and six patients had pericardial tamponade requiring percutaneous drainage. Patients could be discharged on the same day following 205 (89%) procedures. Among the 148 patients whose clinical outcome was assessed at 6 months, 127 (86%) had a reduction of the total symptomatic AF episodes, compared to pre-ablation, with a complete lack of symptoms in 101 patients (68%).

Conclusion Catheter ablation of AF on the day of admission is feasible and safe with a low risk of complications. The vast majority of the patients can be discharged on the same day.