Standard Tamoxifen Research Articles

Cancer Therapy Disparity: Unequal Access to Breast Cancer Therapeutics and Drug Funding in Canada

Adjuvant therapy has made a significant contribution in reducing breast cancer-specific mortality. Standard chemotherapeutics and tamoxifen have been the mainstay treatment for years, but recent clinical evidence supports the use of novel small-molecule therapy and aromatase inhibitor therapy in selected settings, challenging not only the traditional paradigm of breast cancer treatment, but also provincial funding of oncologic care across Canada. The disparity in access to aromatase inhibitor therapy for postmenopausal women with early-stage hormone-sensitive breast cancer across Canada is highlighted as an example.

The discovery and mechanism of action of letrozole

Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara®) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.

Hormonal therapies for early breast cancer: systematic review and economic evaluation

Hormonal therapies for early breast cancer: systematic review and economic evaluation

Disease-free survival (DFS) as surrogate end point for overall survival (OS) in adjuvant aromatase inhibitors (AIs) trials for breast cancer (BC): Meta-analysis of 10 randomized clinical trials (RCTs) exploring the magnitude of the benefit

539 Background. The issue regarding the eventual correlation of DFS with OS has not actually been explored in trials addressing the role of AIs. For this purpose, we meta-analyzed all RCTs in which patients were randomized to receive standard tamoxifen or AIs, whatever applied strategies. Methods. A literature-based meta-analysis was accomplished, and event-based relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed- (FEM) and a random-effect (REM) model and heterogeneity test were applied as well. Absolute benefits (AB) and the Number of patients Needed to Treat (NNT) were calculated. A linear regression model considering both each single outcome pair (5-years DFS and OS) has been adopted to explore for correlation, estimated according to Pearson, R2 (parametric) and Spearman (non-parametric) coefficients. Results. Ten RCTs were gathered (27,653 patients); two RCTs did not report the OS result, so they were not evaluable. DFS was significantly improved with AIs, with a AB of 2.3–3.5%, which translate into 29–43 NNT. OS was significantly improved in both overall and early switch strategy, with an AB of 0.8–1.61%, which translate into 120 and 62 NNT, respectively. A strong correlation was found between DFS and OS in the overall (r=0.78, R2=0.60, p=0.001; Rho=0.77, p=0.001) and in the early switch strategy (r=0.83, R2=0.68, p=0.003; Rho=0.84, p=0.002). Although a stronger correlation was found in the upfront strategy, the low number of RCTs did not allow to reaching statistical significance. Conclusions. The strong correlation between DFS and OS in AIs adjuvant endocrine treatment for early BC underlines the choice of DFS as a surrogate end-point for OS. The predictive value of earlier DFS (3-years) estimation for overall survival deserves a further analysis. [Table: see text] No significant financial relationships to disclose.

Update on the MA.17 extended adjuvant trial

For women with early breast cancer, a substantial risk of relapse remains after surgical resection of the primary tumor, despite adjuvant therapy. Adjuvant endocrine therapy with tamoxifen has been used for many years in the treatment of hormone-receptor-positive (HR+) disease, but exposure to the agent is limited to 5 years due to an unfavorable risk:benefit profile in later years. Despite the beneficial carry-over effects of tamoxifen, the majority of breast cancer recurrences and deaths occur after completion of adjuvant tamoxifen, that is, more than 5 years after initial diagnosis. Hence, additional endocrine therapy could greatly improve outcomes for women with HR+ early breast cancer, but until recently, no agent had been shown to provide a significant benefit over no further treatment. The first interim analysis of the NCIC CTG MA.17 trial showed that the third-generation aromatase inhibitor, letrozole, significantly reduced the risk of relapse, including distant metastases, compared with placebo in women who remained disease-free for up to 3 months after completion of standard adjuvant tamoxifen. On the basis of these results, the trial was stopped and unblinded. Final analysis confirmed these findings and also showed that letrozole significantly improved overall survival in patients with node-positive disease at diagnosis. Retrospective analysis of MA.17 data has shown that the benefit achieved with letrozole increases with the duration of therapy, at least up to 48 months, raising important questions regarding the optimal duration of extended adjuvant letrozole. Additional retrospective analyses investigating the impact of estrogen- and progesterone-receptor status on response to therapy, and whether letrozole is effective following a prolonged treatment-free interval after stopping tamoxifen, are ongoing, and will help to optimize the use of letrozole in women who have completed tamoxifen.

Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse

To assess the clinical significance of tumor-infiltrating FOXP3-positive regulatory T cells (TR) in breast cancer patients with long-term follow-up. FOXP3-positive TR were detected by immunohistochemistry with our new, extensively characterized FOXP3 monoclonal antibody, 236A/E7. Numbers of FOXP3-positive lymphocytes in tissue microarray cores from pure ductal carcinoma in situ (DCIS; n = 62), invasive breast cancer (n = 237) or from comparable areas of normal terminal duct lobular breast tissue (n = 10) were determined. A median cutoff of > or = 15 defined patients with high numbers of TR. TR numbers were significantly higher in in situ and invasive breast carcinomas than in normal breast; invasive tumors have significantly higher numbers than DCIS (P = .001). High numbers of FOXP3-positive TR identified patients with DCIS at increased risk of relapse (P = .04) and patients with invasive tumors with both shorter relapse-free (P = .004) and overall survival (P = .007). High TR numbers were present in high-grade tumors (P < or = .001), in patients with lymph node involvement (P = .01), and in estrogen receptor (ER) -negative tumors (P = .001). Importantly, high numbers of TR within ER-positive tumors identified high-risk patients (P = .005). Unlike conventional clinicopathologic factors, high numbers of FOXP3-positive TR can identify patients at risk of relapse after 5 years. These findings indicate that quantification of FOXP3-positive TR in breast tumors is valuable for assessing disease prognosis and progression, and that TR are an important therapeutic target for breast cancer. FOXP3-positive TR represent a novel marker for identifying late-relapse patients who may benefit from aromatase therapy after standard tamoxifen treatment.

The Emerging Role of Aromatase Inhibitors in the Adjuvant Management of Breast Cancer

Adjuvant hormonal therapy for patients with endocrine sensitive breast cancer has been dominated for several decades by the gold standard tamoxifen. Promising data on third generation aromatase inhibitors (AI), anastrozole, letrozole and exemestane, in metastatic setting led to the development of these agents in early breast cancer. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting remain discussed. Various approaches have been evaluated ranging from: 1. Front line 5 year use of AI instead of tamoxifen for newly diagnosed patients, to 2. Switching to AI after 2 or 3 years of tamoxifen for patients presently on tamoxifen (total of 5 years), or 3. Continuing with an AI after completion of 5 years of adjuvant tamoxifen. However, it is unclear today whether one of these AI strategies is superior to the other ones. The overall therapeutic index of AIs appears superior to that of tamoxifen with proven improved efficacy and better toxicity profile. AIs are all less toxic than tamoxifen in terms of thromboembolic disease and gynaecological complications while musculoskeletal disorders and joint pains are more frequent seen with AIs. This review will explore the results from the available adjuvant AIs trials and will define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.

NCIC CTG MA.17: Tolerability of letrozole among ethnic minority women

6018 Background: Disease free survival was significantly improved in women receiving letrozole after standard adjuvant tamoxifen in the MA.17 trial. Based on the results of MA.17 and of other trials of aromatase inhibitors in early stage breast cancer, chronic aromatase inhibitor therapy, in postmenopausal women free of breast cancer recurrence, is now being widely employed. We analyzed the toxicity of letrozole according to ethnic status among women enrolled in MA.17. Methods: The chi-square test was used for comparison of rates of side effects between the two groups, Caucasian vs. ethnic minority (defined as all non-Caucasians). In a subset of women, quality of life (QOL) was assessed by the SF-36 Health Survey. Mean change scores in QOL from baseline were compared between groups for summary measures and domains using the Wilcoxon test. Results: 352 minority women and 4,708 Caucasians were enrolled in MA.17, of which 183 minority women and 2,339 Caucasians were randomized to receive letrozole. Caucasians were older than minority women and had a slightly longer duration of treatment with prior tamoxifen. Tumor size and nodal status were not significantly different between the two groups. In women who received letrozole, minority women had significantly lower incidence of hot flashes (49% vs. 58%; p = 0.02), fatigue (29% vs. 39%; p = 0.005), and arthritis (2% vs. 7%; p = 0.006) compared with Caucasians. Mean QOL change scores of SF-36 domains for women who received letrozole were not different but minority women had better mental health at 6 month assessment (p = 0.02) and worse bodily pain at 12 month assessment (p = 0.046). Conclusions: Minority women tolerated letrozole considerably better than Caucasians in the MA.17 trial. These preliminary findings suggest that minority women respond differently to letrozole in terms of toxicity. Recent demonstration of genotypic variations in the aromatase gene in different ethnic groups plus likely pharmacogenomic differences suggests that further research is needed to clarify the clinical outcomes of aromatase inhibition in women of diverse ethnicities. Future research strategies should focus on examining in vivo genotype-phenotype correlations to determine the effects of genetic variation on response to anticancer therapy and on toxicities and end-organ effects. [Table: see text]

Early switch with aromatase inhibitors as adjuvant hormonal therapy for postmenopausal breast cancer: Pooled-analysis of 8,794 patients

635 Background: The magnitude of the survival benefit of aromatase inhibitors (AIs) after 2–3 years of tamoxifen as adjuvant hormonal therapy for early breast cancer is still unclear. We performed a pooled-analysis of phase III trials, to look how much advantages adjuvant the “early switch” strategy add over standard tamoxifen for 5 years. Methods: All phase III trials were considered eligible. A pooled analysis was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. Significant differences in primary outcome (EFS and RFS, event- and relapse-free survival), and secondary outcomes (OS, overall survival, deaths in absence of progression, other cancers and toxicities), were explored. Magnitude outcome measures were: absolute benefits (AB) and number of patients needed to treat (NNT). Heterogeneity test was applied as well. Results: Four trials designed to look if AIs after 2–3 yrs of TAM improve EFS (8794 patients) were gathered. Conclusions: Considered all the available phase III trials, the early switch strategy improves survival over standard tamoxifen for 5 years, with a different toxicity profile. The lack of significant heterogeneity in the analysis underscores the homogenous effect across all trials. [Table: see text] No significant financial relationships to disclose.

Preventing Relapse Beyond 5 Years: The MA.17 Extended Adjuvant Trial

For patients with hormone-receptor-positive breast cancer, the risk of relapse remains significant even after successfully completing 5 years of adjuvant tamoxifen. The use of tamoxifen beyond 5 years is not recommended, but the need to protect against relapse following tamoxifen is clear. The third-generation aromatase inhibitors offer a new approach to treating postmenopausal women with receptor-positive early stage breast cancer through the potent and specific systemic inhibition of estrogen synthesis. MA.17, a large, randomized, double-blind, placebo-controlled phase III study, investigated whether extended adjuvant therapy with letrozole following completion of around 5 years of standard tamoxifen therapy could prolong disease-free survival in postmenopausal women with hormone-receptor-positive or receptor-unknown early stage breast cancer. The updated analyses of the trial results (median follow-up, 2.5 years) confirm that letrozole significantly reduced the risk of recurrent breast cancer (42%) regardless of the patient's nodal status or receipt of prior chemotherapy, and significantly reduced the risk of distant metastasis (40%). Importantly, letrozole as extended adjuvant therapy achieved a significant improvement in overall survival in women with node-positive disease. Mortality was reduced by 39% among the approximately 2,500 women with node-positive disease randomized in the study. Letrozole showed minimal side effects compared with placebo; adverse effects on bone metabolism of uncertain clinical significance were the most noteworthy side effect. Thus, the updated results from the MA.17 trial support the previous findings and show extended adjuvant therapy with letrozole to be a well-tolerated protection against the continuing risk of breast cancer recurrence for thousands of women currently receiving standard adjuvant tamoxifen. The re-randomization of MA.17 patients to an additional 5 years of letrozole or to no treatment will provide further insights into the benefits and side effects of long-term treatment.

Sequential Adjuvant Hormone Therapy in Postmenopausal Breast Cancer: Rationale and Clinical Results

For the past 15 years tamoxifen has been the standard adjuvant hormone therapy for women with early-stage breast cancer and estrogen receptor (ER)-positive tumors, irrespective of nodal status and other clinicopathological parameters. Recent studies provided evidence that the optimal duration of tamoxifen treatment is 5 years. Based on the positive clinical results obtained with the administration of aromatase inhibitors (AIs) in the metastatic setting, several controlled clinical trials have evaluated the efficacy and side effects of AIs versus standard tamoxifen also as adjuvant therapy in postmenopausal breast cancer patients. The results of the above studies, suggest a therapeutic advantage of AIs over tamoxifen with regard to relapse-free survival and the risk of metachronous contralateral breast cancer. We review the rationale and the available clinical data on initial or sequential hormone treatment with AIs and we propose a novel scenario for possible therapeutic strategies based on the clinicopathological characteristics of the patients and on the biology of each single tumor.

Sequential adjuvant hormone therapy in postmenopausal breast cancer: rationale and clinical results

For the past 15 years tamoxifen has been the standard adjuvant hormone therapy for women with early-stage breast cancer and estrogen receptor (ER)-positive tumors, irrespective of nodal status and other clinicopathological parameters. Recent studies provided evidence that the optimal duration of tamoxifen treatment is 5 years. Based on the positive clinical results obtained with the administration of aromatase inhibitors (AIs) in the metastatic setting, several controlled clinical trials have evaluated the efficacy and side effects of AIs versus standard tamoxifen also as adjuvant therapy in postmenopausal breast cancer patients. The results of the above studies, suggest a therapeutic advantage of AIs over tamoxifen with regard to relapse-free survival and the risk of metachronous contralateral breast cancer. We review the rationale and the available clinical data on initial or sequential hormone treatment with AIs and we propose a novel scenario for possible therapeutic strategies based on the clinicopathological characteristics of the patients and on the biology of each single tumor.

Long-term risk of breast cancer recurrence: the need for extended adjuvant therapy

All women with early breast cancer, even those with small tumors and negative nodes, remain at appreciable risk of recurrence after surgery over the subsequent 10-15 years. In women with tumors expressing estrogen receptors and/or progesterone receptors, standard systemic adjuvant therapy is 5 years of tamoxifen, which substantially reduces the risk of recurrence and breast cancer-related death. Tamoxifen efficacy benefits are limited to 5 years of treatment, presumably a consequence of acquired tamoxifen resistance. The third-generation aromatase inhibitors, which are highly selective and potent in suppressing whole-body estrogen synthesis in postmenopausal women, are being investigated as alternative or complementary treatments to tamoxifen. For treatment beyond adjuvant tamoxifen for 5 years, letrozole is the only aromatase inhibitor for which clinical trial data were reported. That trial, MA.17, evaluated letrozole as extended adjuvant treatment following standard adjuvant tamoxifen in postmenopausal women with predominantly estrogen receptor--and/or progesterone receptor--positive early breast cancer. Compared with placebo, letrozole markedly reduced the residual risk of recurrence, by 42%, and the improvement in disease-free survival was irrespective of patient nodal status. A significant improvement in overall survival has already been seen in the patients at highest risk, those with positive nodes. On the basis of these results, extended adjuvant letrozole is recommended for all patients completing 5 years of adjuvant tamoxifen, including women generally considered at minimal risk.

The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L)

The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.

Changing clinical practice: Extending the benefits of adjuvant endocrine therapy in breast cancer

Five years of tamoxifen is standard adjuvant therapy for hormone-sensitive early breast cancer, but women remain at appreciable risk of recurrence for many years following that therapy, and further tamoxifen does not appear to be beneficial. Trial MA.17 was designed to determine whether, following 5 years of tamoxifen, switching disease-free postmenopausal women to the aromatase inhibitor letrozole for 5 years improved disease-free survival compared with switching to placebo. The rationale was that as residual cancer cells become tamoxifen resistant, their growth may be stimulated by the minor agonist effect of tamoxifen as well as by very low estrogen concentrations. Those cells might be particularly sensitive to tamoxifen withdrawal coupled with treatment with a potent suppressor of estrogen synthesis. At the first planned interim analysis of MA.17, "extended adjuvant" letrozole significantly improved estimated 4-year disease-free survival overall (93% for letrozole v 87% for placebo; P < .001), irrespective of nodal status. Recurrences were reduced to a comparable extent for all included events, locoregional and distant recurrences (53% and 38%, respectively) and new primary cancers in the contralateral breast (46%). Breast cancer deaths were reduced by 47% with letrozole versus placebo. Letrozole treatment was well tolerated, with most adverse events mild and expected as symptoms of estrogen deprivation. This is the first demonstration that extended adjuvant therapy after standard tamoxifen in postmenopausal women with early breast cancer has a clinically significant impact on outcome.

Anastrozole (Arimidex™) in clinical practice versus the old ‘gold standard’, tamoxifen

For the past 25 years, the estrogen antagonist tamoxifen has been considered the ‘gold standard’ for the treatment of breast cancer, despite certain tolerability issues and the risk of developing resistance. The aromatase inhibitors work by blocking the conversion of androgens to estrogen and were developed for use in patients where ovarian function had ceased (naturally, surgically or pharmacologically). Anastrozole, a third-generation nonsteroidal aromatase inhibitor that is a highly potent and selective inhibitor of the aromatase enzyme, has been shown to be superior to the gold standard tamoxifen for the first-line treatment of postmenopausal women with advanced breast cancer . As second-line therapy, anastrozole has shown superior survival compared with megestrol acetate and is also efficacious as neoadjuvant treatment in postmenopausal women and in combination with goserelin for the treatment of premenopausal women with advanced breast cancer. More recently, the results of the ATAC (anastrozole, tamoxifen, alone or in combination) trial, a large study in 9366 patients, demonstrated that anastrozole was significantly superior to tamoxifen for the treatment of postmenopausal women with early breast cancer, with regards to disease-free survival (p = 0.013) and incidence of contralateral breast cancer (p = 0.007). In addition, anastrozole was shown to be significantly better tolerated than tamoxifen with respect to endometrial cancer (p = 0.02), vaginal bleeding/discharge (p < 0.0001 for both), ischaemic cerebrovascular events (p = 0.0006), thromboembolic events (p = 0.0006) and hot flushes (p < 0.0001), while tamoxifen was associated with significantly less musculoskeletal disorders and fractures than anastrozole (p < 0.0001 for both). This review focuses on both the clinical pharmacology and the clinical data of anastrozole with emphasis on its future applications.

Determination of amiodarone and desethylamiodarone in human plasma by high-performance liquid chromatography–electrospray ionization tandem mass spectrometry with an ion trap detector

A sensitive and specific high-performance liquid chromatography–electrospray ionization-tandem mass spectrometry (HPLC–ESI-MS–MS) method has been developed for the simultaneous determination of amiodarone and desethylamiodarone in human plasma. After the addition of the internal standard tamoxifen, plasma samples were extracted using Oasis ® MCX solid-phase extraction cartridges. The compounds were separated on a 5 μm Symmetry C 18 (Waters) column (150×3.0 mm, internal diameter) with a mobile phase of acetonitrile–0.1% formic acid (46:54, v/v) at a flow-rate of 0.5 ml/min. The overall extraction efficiency was more than 89% for both compounds. The assay was sensitive down to 1 μg/l for amiodarone and down to 0.5 μg/l for desethylamiodarone. Within-run accuracies for quality-control samples were between 95 and 108% of the target concentration, with coefficients of variation <8%. The proposed method enables the unambiguous identification and quantitation of amiodarone and desethylamiodarone in both clinical and forensic specimens.

Determination of 2-methyl derivatives of tamoxifen in cell culture medium using high-performance liquid chromatography and electrochemical detection.

The 2-methyl derivatives of tamoxifen (2-methyltamoxifen and 2-methyl-4-hydroxytamoxifen) were extracted from a cell culture medium at pH 5.4 (Earle's Minimum Essential Medium) with an internal standard (tamoxifen) on a phenyl sorbent cartridge. The compounds were then separated by high-performance liquid chromatography on a nitrile column eluted with acetonitrile-methanol-0.05 M sodium dihydrogenphosphate (19:4:11.6:69,v/v) containing 0.11 mmol/l disodium EDTA and determined by electrochemical detection at +1.1 V vs. Ag/AgCl/3 M NaCl. The absolute detection limits were 50 pg for 2-methyl-4-hydroxytamoxifen and 100 pg for tamoxifen and 2-methyltamoxifen at a sensitivity of 1 nA/V.