Tamoxifen In Postmenopausal Women Research Articles

American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction

PURPOSE To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. METHODS A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER) -positive invasive tumors. Women < or = 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making.

Pharmacogenomic prediction of breast cancer treatment outcome with adjuvant tamoxifen in postmenopausal women with estrogen receptor-positive breast cancer

e11501 Background: The clinical outcome of tamoxifen-treated breast cancer patients may be influenced by the activity of cytochrome P450 enzymes that catalyze the formation of antiestrogenic metabolites endoxifen and 4-hydroxytamoxifen. Methods: The AmpliChip CYP450 Test was used to identify CYP2D6 genotypes which have an impaired ability to metabolize tamoxifen into the active metabolite, endoxifen. Results: Our aim is to determine the share of ultrarapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers in the group of postmenopausal women with estrogen receptor-positive breast cancer. We are presenting first 72 results as the part of long term study on 180 women. It is evident that EM and UM have significantly lower percentage of disease progression (22% respectively 0%) compare to IM (67%). No progression observed at PM needs further monitoring and investigation. Conclusions: The results tentatively support the hypothesis, that the genetic variants associated with activity of CYP2D6 could help to clinicians in determining the therapeutic strategy. [Table: see text] No significant financial relationships to disclose.

Aromatase Inhibitors Prove to Have Edge over Tamoxifen for Postmenopausal Women with Early Breast Cancer

Aromatase Inhibitors Prove to Have Edge over Tamoxifen for Postmenopausal Women with Early Breast Cancer

Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study.

Abstract Abstract #1138 Background. Clinical trials conducted in Western countries have shown that improved disease-free survival (DFS) is associated with the use of aromatase inhibitors instead of tamoxifen in postmenopausal women with early breast cancer. Pharmacogenetic differences in drug metabolizing genes may cause ethnic differences in the response or tolerability to aromatase inhibitors, as well as tamoxifen. In fact, improved DFS by extending the use of letrozole after tamoxifen for 5 years has not been confirmed in women from minority groups (Ann Oncol. 2006 17(11):1637-43). Therefore, assessment of the efficacy of aromatase inhibitors in non-white women is warranted. We report the results of switching adjuvant therapy from tamoxifen to anastrozole in postmenopausal Japanese women with breast cancer enrolled in an open-label, randomized clinical trial (N-SAS BC03 study). Patients and Methods. From November 2002 to December 2005, 706 postmenopausal women with hormone-receptor-positive breast cancer who were receiving adjuvant therapy with tamoxifen for 1 to 4 years were randomly assigned to either continue tamoxifen or to switch to anastrozole; the total duration of treatment was 5 years. Primary endpoints were DFS and adverse events. Secondary endpoints included relapse-free survival (RFS), overall survival (OS) and QOL. Results. After a median follow-up of 42 months (range, 3.2-60), there were 26 events in the anastrozole group as compared with 37 in the tamoxifen group related to DFS, and 15 events in the anastrozole group as compared with 28 in the tamoxifen group related to RFS. The unadjusted hazard ratio was 0.69 (95 percent confidence interval, 0.42 to 1.14; P=0.06 by the log-rank test) for DFS and 0.52 (95 percent confidence interval, 0.28 to 0.98; P=0.02 by the log-rank test) for RFS, both in favor of anastrozole. There was no difference in OS (p=0.49). Conclusion. Switching from tamoxifen to anastrozole was confirmed to be associated with a lower disease recurrence rate than continuing tamoxifen in postmenopausal Japanese women with breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1138.

Tamoxifen and anastrozole as a sequencing strategy in postmenopausal women with hormone-responsive early breast cancer: updated data from the Austrian breast and colorectal cancer study group trial 8.

Abstract Abstract #14 Background: Historically, standard endocrine treatment for postmenopausal women with hormone-sensitive early breast cancer (EBC) was 5 years' tamoxifen. However, the inclusion of an aromatase inhibitor (AI) is now considered standard practice. There is increasing evidence that whether as initial adjuvant treatment or as a switch treatment following 2-3 years of tamoxifen therapy, Ais improve patients' outcomes compared with 5 years' tamoxifen monotherapy.&amp;#x2028; To date, there is limited evidence comparing a prospective sequencing strategy of 2 years of tamoxifen followed by 3 years of an AI compared with 5 years' tamoxifen. Previously presented data from ABCSG Trial 8 (SABCS 2005), at a median follow-up of 55 months, revealed a 24% reduction in the risk of recurrence in favor of a sequencing strategy compared with 5 years' tamoxifen (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.56-1.02), although the difference was not statistically significant (p=0.07). Here we present updated data from ABCSG Trial 8.&amp;#x2028; Methods: Postmenopausal women with histologically verified G1 or G2, locally radically treated invasive or minimally invasive hormone receptor-positive breast cancer were eligible for inclusion. Newly diagnosed patients were randomized to receive 5 years' tamoxifen therapy or 2 years' tamoxifen followed by anastrozole for 3 years. The primary endpoint was event-free survival, including locoregional and distant metastatic recurrences and new contralateral breast cancers.&amp;#x2028; Results: This final analysis will report the data cut-off point, the number of eligible patients, and the median follow-up period of the trial, which will exceed 5 years. The incidence of first events, local recurrences, distant metastases, and contralateral breast cancers for the two treatment arms of the study will be presented. The effect of treatment on the trial endpoint will be analyzed using a Cox proportional hazards model and data will be presented as estimated HRs with two-sided 95% CIs and p-values.&amp;#x2028; Conclusions: The updated analyses of ABCSG Trial 8 will provide evidence regarding 2 years' treatment with tamoxifen followed by 3 years' anastrozole in comparison to 5 years' tamoxifen for postmenopausal women with newly diagnosed hormone-sensitive EBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 14.

NCIC CTG MA.17: hormone receptor expression of in-breast recurrences and contralateral primary breast cancers arising on aromatase inhibitors.

Abstract Abstract #1134 Background: The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of ER+ (but not ER-) invasive breast cancers in healthy women at high risk for developing breast cancer. Aromatase inhibitors (AIs) given as adjuvant therapy to treatment-naïve or post-tamoxifen patients significantly reduce the risk of in-breast recurrences (IBRs) and contralateral breast cancers (CBCs) and are currently in clinical trials for breast cancer prevention (NCIC CTG MAP.3 and IBIS-II). It is hypothesized that SERMS inhibit promotion of ER+ breast cancer whereas AIs may reduce both ER+ and ER- breast cancer by inhibiting both tumor initiation and promotion. Little is known about the characteristics of IBRs and CBCs that arise on AI therapy. We present the ER/PR expression and clinicopathologic features of IBRs and CBCs that occurred on MA.17.&amp;#x2028; Methods: We examined ER/PR status of IBRs and CBCs that arose on letrozole vs. placebo among women enrolled in MA.17, a placebo-controlled (PLAC) trial of letrozole (LET) following 5 years of tamoxifen in postmenopausal women with early stage breast cancer.&amp;#x2028; Results: Seventy-one patients (pts) developed an IBR and 87 developed a CBC on trial. Consistent with results previously reported, fewer IBRs (LET 20 vs PLAC 51) and CBCs (LET 35 vs PLAC 52) were observed in the LET group. ER and PR status is currently available on 35 women with an IBR and 39 with a CBC. The majority of IBRs were ER+ in both the LET and PLAC groups (10/11 [91%] vs 18/24 [75%], respectively; p=NS) but numbers of both ER+ and – IBRs were less in LET group, suggesting that letrozole may decrease both ER+ and ER- IBRs. CBCs that arose on PLAC were more likely to be ER+ than on LET (16/22 [73%] vs 6/19 pts [32%], respectively; p=0.01), suggesting that letrozole predominantly prevents ER+ CBCs. Discordance in ER expression between primary breast cancer and IBRs among women randomized to LET vs. PLAC was observed in 1/11 [9%] and 6/24 [26%] women respectively (p=NS) and between primary breast cancer and CBCs in 12/18 pts [67%] vs. 6/21 [29%] women respectively (p=0.01). Other clinicopathologic characteristics such as grade, tumor size, PR, HER-2/neu, and nodal status of IBRs and CBCs will be presented at the meeting.&amp;#x2028; Conclusion: Extended adjuvant endocrine therapy with letrozole results in fewer IBRs and CBCs compared with placebo as previously reported. Our data suggests that letrozole may decrease both ER+ and ER- IBRs. Letrozole appears to prevent ER+ CBCs but has little or no apparent effect on the development of ER- CBCs. These results need confirmation in the primary prevention trials of AIs.&amp;#x2028; &amp;#x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1134.

Cost-effectiveness of anastrozole versus tamoxifen as adjuvant therapy in early breast cancer (EBC) – a German health economic analysis.

Abstract Abstract #6109 Background: The non-steroidal aromatase inhibitor (AI) anastrozole is superior to tamoxifen in terms of efficacy and safety in the adjuvant treatment of postmenopausal patients with hormone receptor-positive (HR+) early breast cancer (EBC). The aim of the current study was to evaluate the cost-effectiveness of anastrozole versus tamoxifen from the German health care perspective.&amp;#x2028; Methods: A probabilistic Markov model was developed using data from the published literature and expert opinion to project trial outcomes to 25 years based on a cohort of 1000 postmenopausal women with HR+ EBC. Resource use data and costs were obtained from standard sources and expert opinion. Utility scores for the different heath states were obtained from a patient-based utility study using the standard gamble technique. Results were expressed as incremental cost-effectiveness ratios (ICERs) per quality adjusted life-years (QALYs) gained. Costs and benefits were discounted at 5% annually.&amp;#x2028; Results: Total costs over the 25 year period for anastrozole and tamoxifen were €12,422 and €6,757, respectively. The cost per life year (LY) for anastrozole compared to tamoxifen was €24,822/LY gained. The ICER of anastrozole compared to tamoxifen was €21,050/QALY gained (95% CI €9,841 - €62,344). The result remained robust to all parameters tested in the sensitivity analysis. Cost-effectiveness probability curves indicated a &amp;gt;90% probability that the cost per QALY gained with anastrozole would be &amp;lt;€42,000.&amp;#x2028; Conclusions: In this model, five years of adjuvant anastrozole is a cost-effective treatment alternative to tamoxifen in postmenopausal women with HR+ EBC from the German health care perspective. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6109.

Extended follow-up of breast cancer patients in clinic wastes time for both patients and doctors: the case against.

Extended follow-up of breast cancer patients in clinic wastes time for both patients and doctors: the case against.

Extended follow-up of breast cancer patients in clinic wastes time for both patients and doctors: the case for

Extended follow-up of breast cancer patients in clinic wastes time for both patients and doctors: the case for

Response: Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis

Adjuvant endocrine treatment with aromatase inhibitors improves disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor-positive breast cancer. This difference could be due to differences in tamoxifen metabolism because levels of endoxifen, the active tamoxifen metabolite, vary with the number of mutant alleles, including the *4 allele, of the gene encoding cytochrome P450 2D6 (CYP2D6).We created a Markov model to determine whether tamoxifen or aromatase inhibitor monotherapy maximized 5-year disease-free survival for patients with the wild-type CYP2D6 genotype (wt/wt). Annual risks of recurrence with aromatase inhibitors and tamoxifen in breast cancer patients who were not selected by CYP2D6 genotype were derived from the Breast International Group 1-98 trial. Genotype frequencies and the hazard ratio for cancer recurrence on tamoxifen among patients with the *4/*4 genotype relative to the wt/wt or wt/*4 genotypes (HR(*4/*4) = 1.86) were based on data from an analysis of the North Central Cancer Treatment Group trial of adjuvant tamoxifen. We explored the impact of CYP2D6(*4) heterozygosity on disease-free survival for wt/wt patients by studying a range of effect (ie, recurrence on tamoxifen) estimates, from no effect of the single mutation (Eff(wt/*4) = 0, recurrence rate in wt/*4 patients same as that in wt/wt patients) to complete effect (Eff(wt/*4) = 1 recurrence rate in wt/*4 patients same as that in *4/*4 patients).With HR(*4/*4) = 1.86 and Eff(wt/*4) = 0.5, the 5-year disease-free survival of tamoxifen-treated patients with no mutations (wt/wt) was 83.9%, that is, essentially the same as that (84.0%) for genotypically unselected patients who were treated with aromatase inhibitors. With greater HR(*4/*4) estimates, disease-free survival with tamoxifen exceed that with aromatase inhibitors in wt/wt patients, even at lower assumed Eff(wt/*4) ratios.Modeling suggests that among patients who are wild type for CYP2D6, 5-year disease-free survival outcomes are similar to or perhaps even superior with tamoxifen than with aromatase inhibitors. Endocrine therapy tailored to CYP2D6 genotype could be considered for women who are newly diagnosed with breast cancer, particularly those who have with concerns about either the relative toxicity or the increased cost of aromatase inhibitors.

Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis

Adjuvant endocrine therapy reduces the risk of recurrence and improves survival among women with hormone receptor–positive breast cancer (1). Because most breast cancers, especially those among postmenopausal women, are hormone receptor positive, hundreds of thousands of women worldwide initiate adjuvant endocrine treatment each year. Historically, the standard recommendation for such patients has been 5 years of therapy with the selective estrogen receptor modulator tamoxifen (1). Two large randomized clinical trials—the Breast International Group Trial 1–98 (BIG 1–98) (2) and the Arimidex, Tamoxifen Alone or in Combination trial (3)—have shown that initial adjuvant endocrine treatment with aromatase inhibitors yields improved disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor–positive breast cancer. These findings have led many oncologists to adopt aromatase inhibitors as their preferred initial adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer (4). However, interpretation of these trial results is complicated by new pharmacogenomic data that suggest that the clinical benefit of tamoxifen may vary according to the cytochrome P450 (CYP) 2D6 genotype of the patient (5–7). CYP2D6 is the cytochrome P450 isoform that is mainly responsible for catalyzing the conversion of tamoxifen to endoxifen (8), the tamoxifen metabolite that is thought to be the primary mediator of estrogen-dependent suppression of cell proliferation (9). The CYP2D6 gene has multiple allelic variants, some of which, including the *4 allele, result in the loss of CYP2D6 enzyme function. Population genetic studies (10–12) have revealed that variations in the CYP2D6 gene sequence correspond to pharmacogenomic variations in endoxifen levels among women taking tamoxifen. For example, in a study of 80 newly diagnosed breast cancer patients who were beginning tamoxifen treatment, Jin et al. (10) found that those who carried either the homozygous (*4/*4) or the heterozygous (wt/*4) variant genotype of CYP2D6 had statistically significantly lower mean plasma endoxifen levels (20.0 and 43.1 nM, respectively) than those who carried the homozygous wild-type (wt/wt) genotype (78.0 nM). Additional studies have also supported the finding of a CYP2D6 gene dose effect on plasma concentrations of endoxifen (11,12). These data prompted a Food and Drug Administration advisory panel to recommend in October 2006 that a warning label be added to tamoxifen; the panel cited the new pharmacogenomic studies (5,12) indicating that the drug is less effective in women who carry a mutation in one of the enzymes used to metabolize tamoxifen than in those who do not. Both of the landmark clinical studies (2,3) that revealed improved disease-free survival outcomes for up-front adjuvant treatment with aromatase inhibitors vs tamoxifen accrued patients irrespective of their CYP2D6 gene mutation status. Given the link between CYP2D6 mutation status and compromised clinical outcomes among mutation carriers on tamoxifen, it is likely that aromatase inhibitors would be the preferred treatment for a woman with deficiencies in tamoxifen metabolism, such as those heterozygous (wt/*4) or homozygous (*4/*4) for the *4 mutation of CYP2D6. However, for women who do not carry a CYP2D6 gene mutation that affects tamoxifen metabolism, the decision about which type of adjuvant endocrine therapy to undergo is not as clear. To date, no genotype analysis of patients who participated in the randomized trials comparing adjuvant tamoxifen with aromatase inhibitors has been performed. However, it is reasonable to infer that if these trials had been restricted to women with wild-type tamoxifen metabolism, the women in the tamoxifen arms would have had better outcomes than those that were reported. To study the magnitude of difference between reported outcomes on tamoxifen and the estimated efficacy of tamoxifen in patients with-out CYP2D6 gene mutations, we constructed a decision-analytic model using data from CYP2D6 pharmacogenomic studies and used the model to evaluate whether an aromatase inhibitor or tamoxifen is the optimal initial treatment choice for the large majority of postmenopausal women who do not carry a mutation that affects the function of the CYP2D6 enzyme.

Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?

Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?

Aromatase Inhibitors: A New Reality for the Adjuvant Endocrine Treatment of Early-Stage Breast Cancer in Postmenopausal Women

Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for many decades as the "gold standard" adjuvant treatment for patients with hormone-receptor-positive early breast cancer. This drug, when administered for 5 years, reduces the risk for recurrence, contralateral breast cancer (BC) and death. The optimal duration of tamoxifen in the adjuvant setting has not been established yet, but it has been demonstrated that 5 years are better than shorter treatment while it is still unclear if a prolongation of the treatment for more than 5 years is worthwhile. In the last few years, third generation aromatase inhibitors (AIs), either steroidal (exemestane) or non-steroidal (anastrozole, letrozole), have shown to be an effective alternative to tamoxifen in postmenopausal patients with BC regardless of its stage. These agents act by blocking the aromatase enzyme which converts androgens into estrogens. The goal of this article was to review the results of recent randomized trials comparing AIs to tamoxifen in postmenopausal women in the adjuvant setting. Two strategies have been utilized: a direct upfront comparison in which both tamoxifen and AIs were given for 5 years or an early switch in which AIs were administered after 2-3 years of tamoxifen for 3-2 years or vice versa. Both strategies have shown a superiority of AIs over tamoxifen and a different safety profile but, the optimal treatment modality has yet to be defined. Moreover, in an attempt to further reduce patients' risk of recurrence after the administration of tamoxifen for 5 years, three trials have evaluated the role of prolonging the adjuvant treatment with AIs for 5 more years in comparison to placebo (late switch). A significant improvement of disease-free survival and of overall survival in the subgroup of node-positive patients, at least in one trial, has been observed with AIs. Despite these important results several unanswered questions remain and the results of ongoing trials will hopefully clarify some of them.

The Effects of Neoadjuvant Anastrozole and Tamoxifen on Circulating Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor 1 in Breast Cancer

Vascular endothelial growth factor (VEGF) is a key angiogenic factor mediating neovascularization. Soluble VEGF receptor 1 (sVEGFR-1) is an intrinsic negative counterpart of VEGF signaling and the ratio of sVEGFR-1 to VEGF has been shown to be a prognostic factor. Estrogen-bound estrogen receptor enhances VEGF expression, providing a common link between these signaling pathways that may be targeted by endocrine therapy. We investigated the effects of anastrozole and tamoxifen over time on serum VEGF and sVEGFR-1. The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial compared the preoperative use of anastrozole with tamoxifen in postmenopausal women with estrogen receptor-positive primary operable breast cancer over 12 weeks. Circulating VEGF and sVEGFR-1 were measured by ELISA in 106 patients treated with anastrozole or tamoxifen alone at baseline and after 2 and 12 weeks of treatment. The increase in serum VEGF from baseline to 12 weeks was significantly different between anastrozole and tamoxifen (anastrozole versus tamoxifen, 6% versus 38%; P = 0.047). There was a significant increase in sVEGFR-1 levels after 12 weeks of anastrozole (P = 0.037). The sVEGFR-1/VEGF ratio significantly decreased in the tamoxifen arm (P = 0.013) and the change in sVEGFR-1/VEGF ratio from baseline to 12 weeks was significantly different between anastrozole and tamoxifen (anastrozole versus tamoxifen, 24% increase versus 34% decrease; P = 0.013). Treatment with anastrozole and tamoxifen resulted in differential effects on serum angiogenic markers. This may be related to the relative effectiveness of the treatments. These data provide further support for cross talk between estrogen receptor and VEGF.

Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis

Adjuvant endocrine treatment with aromatase inhibitors improves disease-free survival compared with tamoxifen in postmenopausal women with estrogen receptor-positive breast cancer. This difference could be due to differences in tamoxifen metabolism because levels of endoxifen, the active tamoxifen metabolite, vary with the number of mutant alleles, including the *4 allele, of the gene encoding cytochrome P450 2D6 (CYP2D6). We created a Markov model to determine whether tamoxifen or aromatase inhibitor monotherapy maximized 5-year disease-free survival for patients with the wild-type CYP2D6 genotype (wt/wt). Annual risks of recurrence with aromatase inhibitors and tamoxifen in breast cancer patients who were not selected by CYP2D6 genotype were derived from the Breast International Group 1-98 trial. Genotype frequencies and the hazard ratio for cancer recurrence on tamoxifen among patients with the *4/*4 genotype relative to the wt/wt or wt/*4 genotypes (HR(*4/*4) = 1.86) were based on data from an analysis of the North Central Cancer Treatment Group trial of adjuvant tamoxifen. We explored the impact of CYP2D6(*4) heterozygosity on disease-free survival for wt/wt patients by studying a range of effect (ie, recurrence on tamoxifen) estimates, from no effect of the single mutation (Eff(wt/*4) = 0, recurrence rate in wt/*4 patients same as that in wt/wt patients) to complete effect (Eff(wt/*4) = 1 recurrence rate in wt/*4 patients same as that in *4/*4 patients). With HR(*4/*4) = 1.86 and Eff(wt/*4) = 0.5, the 5-year disease-free survival of tamoxifen-treated patients with no mutations (wt/wt) was 83.9%, that is, essentially the same as that (84.0%) for genotypically unselected patients who were treated with aromatase inhibitors. With greater HR(*4/*4) estimates, disease-free survival with tamoxifen exceed that with aromatase inhibitors in wt/wt patients, even at lower assumed Eff(wt/*4) ratios. Modeling suggests that among patients who are wild type for CYP2D6, 5-year disease-free survival outcomes are similar to or perhaps even superior with tamoxifen than with aromatase inhibitors. Endocrine therapy tailored to CYP2D6 genotype could be considered for women who are newly diagnosed with breast cancer, particularly those who have with concerns about either the relative toxicity or the increased cost of aromatase inhibitors.

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AbstractReferrals from BootsThe majority of people requesting Boots' erectile dysfunction or weight management programmes are referred to their GP(Pharm J 2008;280:297).The programmes are run under patient group directions and exclude people with elevated blood pressure, blood glucose or cholesterol. Over 80 per cent of customers screened for the erectile dysfunction programme in Manchester and two‐thirds of those screened for the national obesity programme were referred.Vildagliptin: new DPP‐4 inhibitor for diabetesNovartis has introduced the DPP‐4 inhibitor vildagliptin for the treatment of type 2 diabetes. Two formulations are available: Galvus (vildagliptin 50mg) is licensed for use with metformin, a sulphonylurea or a thiazolidinedione when these agents do not achieve glycaemic control alone, and Eucreas (vildagliptin 50mg plus metformin 850 or 1000mg) is licensed for patients requiring combined therapy with vildagliptin and metformin.Inhibition of DPP‐4 blocks the breakdown of the incretin hormones GIP and GLP‐1, reducing fasting plasma glucose and postprandial hyperglycaemia.Vildagliptin is the second DPP‐4 inhibitor to be introduced; the first was sitagliptin (Januvia), which has similar licensed indications. The third available drug acting on the incretin system is the incretinmimetic exenatide (Byetta); administered by injection, this is licensed for use with metformin and/or a sulphonylurea and is the only agent in this class to be approved for triple therapy.No comparative trials of these agents have been published.A month's treatment with twice‐daily vildagliptin 50mg or either strength of vildagliptin plus metformin costs £31.76. Sitagliptin 100mg once daily costs £33.26.Sinusitis symptoms don't guide treatmentThe severity and duration of symptoms do not help to identify which patients with sinusitis will be helped by antibiotics, a new meta‐analysis suggests (Lancet 2008;371: 908‐14).The analysis of patient‐level data from nine trials involving a total of 2547 adults showed that the number needed to treat (NNT) to cure one patient with rhinosinusitis was 15. Cure took longer to achieve in older patients and in those reporting symptoms for longer or with more severe symptoms.The authors comment that treatment is not justified given the risk of resistance and adverse effects and cost of antibiotics.Draft guidance from the National Institute for Health and Clinical Excellence (NICE) on the management of respiratory infections states that no antibiotic therapy or a delayed antibiotic prescribing strategy should be negotiated for patients with acute sinusitis.Taking cod liver oil leads to fewer NSAIDsCod liver oil could help some patients with rheumatoid arthritis to reduce their NSAID consumption, according to a study from Dundee (Rheumatology online: 24 March 2008; doi: 10.1093/rheumatology/ ken024).A total of 97 patients were randomised to nine months' treatment with cod liver oil 10g per day or placebo. After 12 weeks, patients attempted to reduce or stop their use of NSAIDs.Significantly more of those taking cod liver oil achieved at least a 30 per cent reduction in NSAID use compared with placebo (39 vs 10 per cent). There were no differences in adverse effects or disease activity.Welsh prescriptions upThe reduction in the prescription charge in Wales in 2004 was followed by an increase in prescribing of nonsedating antihistamines in wealthier areas, a study suggests (Health Policy online: 5 March 2008; doi:10.1016/j. healthpol.2008.01.006).In the two years preceding the cut, prescriptions for nonsedating antihistamines increased by about 7 per cent; in the two years after the cut, the increase was nearly 14 per cent. By contrast, there was no change in the rate of increase in the south‐east of England (4–5 per cent in both periods). The increased growth in prescribing was statistically significant in the five least deprived but not in the five most deprived health boards in Wales.Aspirin linked with reduced asthma riskLow‐dose aspirin is associated with a reduced risk of developing asthma, a new analysis of the Women's Health Study has shown (Thorax online: 13 March 2008; doi:10.1136/ thx.2007.091447).The analysis included 37 270 women with no asthma at baseline who were randomised to take placebo or aspirin 100mg every other day. After 10 years, 872 cases of asthma occurred in women taking aspirin and 963 with placebo, a 10 per cent reduction in risk. However, risk was not reduced in obese women.The mechanism by which aspirin may affect the risk of asthma is unknown. The latest evidence is consistent with findings published by the same investigators after analysis of two other large observational studies, the Physicians' Health Study and the Nurses Health Study.Anastrozole bone lossLong‐term follow‐up of the ATAC (Anastrozole, Tamoxifen, Alone or in Combination) trial has confirmed that adjuvant therapy with anastrozole (Arimidex) is associated with greater loss of bone mineral density (BMD) than tamoxifen in postmenopausal women with invasive primary breast cancer (J Clin Oncol 2008;26: 1051–7).After five years, median BMD was reduced by 6 and 7 per cent in the lumbar spine and hip with anastrozole compared with approximately 3 and 1 per cent respectively for tamoxifen, though no patients developed osteoporosis. Copyright © 2008 Wiley Interface Ltd

The effects on lipid serum levels of a 2-year adjuvant treatment with exemestane after tamoxifen in postmenopausal women with early breast cancer

BackgroundThe third-generation aromatase inhibitor exemestane represents a new development in the treatment of estrogen-positive breast cancer. The aim of this study was to evaluate the effects on lipid profile and body composition of the shift from tamoxifen to exemestane. MethodsAfter 2–3years of tamoxifen adjuvant treatment, 68 postmenopausal women were randomly assigned to either continue tamoxifen 20 mg/day (n = 35) or to switch to exemestane 25 mg/day (n = 33). ResultsNo significant changes in lipid profile were found in patients continuing on tamoxifen. In the exemestane group, serum HDL-cholesterol (HDL-C) and triglycerides (TG) decreased significantly (p < 0.01) and serum LDL-cholesterol (LDL-C) increased significantly (p < 0.05) with respect to baseline. The difference between the two groups was significant. Moreover, in the exemestane group, fat mass (FM) and fat-free mass (FFM) showed an opposite trend, which determined a progressive and significant increase in the FFM/FM ratio. ConclusionThis study shows that the choice of first-line treatment or adjuvant therapy for breast cancer should also take the individual lipid and body composition profile into account.

Meta-analysis of pre-operative aromatase inhibitor versus tamoxifen in postmenopausal woman with hormone receptor-positive breast cancer

Clinical trials have reported conflicting results as to whether pre-operative aromatase inhibitors (AIs) improve outcome over pre-operative tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. We performed a meta-analysis comparing primary and secondary end points of pre-operative AI and pre-operative tamoxifen. The event-based risk ratio (RR) with 95% confidence intervals (95% Cis) were derived, and a test of heterogeneity was applied. Four studies (1,160 patients) met the inclusion criteria for the analysis. Meta-analysis showed that pre-operative AI was more effective than pre-operative tamoxifen. Pooled results of clinical efficacy were as follows: clinical objective response rate (RR, 1.29; 95% CI, 1.14-1.47; P < 0.001), ultrasound objective response rate (RR, 1.29; 95% CI, 1.10-1.51; P = 0.002), and breast conserving surgery (BCS) rate (RR, 1.36; 95% CI, 1.16-1.59; P < 0.001). Hot flashes, nausea, and fatigue were not different between the pre-operative AI and pre-operative tamoxifen groups. Although headache was more frequent in the pre-operative AI group (P = 0.011), it was a manageable toxicity and was not clinically relevant. Pre-operative AI has better BCS rate than tamoxifen and in terms of toxicities, is not inferior to tamoxifen; therefore, we could suggest pre-operative AI instead of tamoxifen for those postmenopausal patients with hormone receptor positive breast cancer, not eligible for chemotherapy.

Carbonic anhydrase IX and response to postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of the DBCG82 b and c trials.

IntroductionA significant survival improvement after postmastectomy radiotherapy was identified in the Danish Breast Cancer Cooperative Group (DBCG82) b and c studies and in the British Columbia Randomized Radiation Trial. Recently, potential predictive value regarding response to postmastectomy radiotherapy was reported for carbonic anhydrase (CA) IX in a study (reported in abstract form) that included 160 patients. The purpose of the present study was to examine the importance of CA IX to response to postmastectomy radiotherapy in the larger scaled DBCG82 b and c studies.MethodsThe DBCG82 b and c studies included 3,083 high-risk Danish breast cancer patients. The women were randomly assigned to postmastectomy radiotherapy plus systemic therapy (cyclophosfamide, methotrexate and fluorouracil in premenopausal women; and tamoxifen in postmenopausal women) or to systemic therapy alone. Cores from invasive tumour-containing paraffin blocks from 1,000 patients (more than seven nodes surgically removed) were transferred to tissue microarrays. Tissue microarray sections were stained immunohistochemically for CA IX (M75). The median follow up for patients remaining alive was 17 years. Clinical end-points were loco-regional recurrence, distant metastases, disease-specific survival and overall survival. Statistical analyses included κ statistics, χ2 or exact tests, Kaplan-Meier probability plots, Log-rank test and Cox regression analyses.ResultsCA IX was assessable in 945 cores. The percentage of tumours positive for CA IX was 16% (≥ 10% invasive tumour staining). CA IX was not an independent prognostic marker for survival, distant metastases, or locoregional recurrence in the subgroup of 945 patients or within either of the two randomization arms. In subgroup analyses, however, CA IX was an independent prognostic marker for overall survival among postmenopausal women (P = 0.001), women with one to three positive nodes (P = 0.02) and hormone receptor positive women (P = 0.001). Fifteen-year probabilities of overall survival were improved by 9% and 7% after postmastectomy radiotherapy for the subgroups of CA IX negative and CA IX positive patients, respectively.ConclusionWithin this series of 945 high-risk premenopausal and postmenopausal women, positivity for CA IX was not overall an independent prognostic marker for survival; only in subgroup analyses was it found to have prognostic value. The improvement in 15-year survival after postmastectomy radiotherapy was of similar magnitude in the two subgroups of CA IX positive and CA IX negative patients.

Intergroup Exemestane Study mature analysis: overall survival data

The findings of the Intergroup Exemestane Study (IES) challenge the standard adjuvant endocrine therapy consisting of 5 years of tamoxifen therapy in women with oestrogen receptor-positive breast cancer. The IES study confirmed that switching to an aromatase inhibitor (AI) such as exemestane after 2-3 years of tamoxifen therapy resulted in improved survival relative to women remaining on 5 years of tamoxifen therapy. Data from IES concur with the findings of other studies with AIs that support the rationale of switching from tamoxifen to an AI after 2-3 years of tamoxifen in postmenopausal women who remain disease-free.