Tamoxifen In Terms Research Articles

An Update on Tamoxifen and the Chemo-Preventive Potential of Vitamin E in Breast Cancer Management.

Breast cancer (BC) is the most common female cancer in terms of incidence and mortality worldwide. Tamoxifen (Nolvadex) is a widely prescribed, oral anti-estrogen drug for the hormonal treatment of estrogen-receptor-positive BC, which represents 70% of all BC subtypes. This review assesses the current knowledge on the molecular pharmacology of tamoxifen in terms of its anticancer and chemo-preventive actions. Due to the importance of vitamin E compounds, which are widely taken as a supplementary dietary component, the review focuses only on the potential importance of vitamin E in BC chemo-prevention. The chemo-preventive and onco-protective effects of tamoxifen combined with the potential effects of vitamin E can alter the anticancer actions of tamoxifen. Therefore, methods involving an individually designed, nutritional intervention for patients with BC warrant further consideration. These data are of great importance for tamoxifen chemo-prevention strategies in future epidemiological studies.

Significance of the Estrogen Hormoneand Single Nucleotide Polymorphisms in the Progression of Breast Cancer among Female.

Breast cancer is one of the most frequent types of malignancies among women and is internationally recognized as the main reason for cancer-caused mortality. Most breast tumors are heterogeneousand genetically complicated due to the involvement of several genes. Therefore, it is clinically important to study genetic variants that increase the risk of breast cancer. It is identified that the presence of polymorphisms in genes encoding regulatory hormones is linked to a higher risk of breast cancer. Additionally, circulating estrogen levels are connected to aromatase (CYP19A1) genes, which isa recognized risk factor for breast cancer progression. In this paper, the authors present a review study on the effect of estrogen and its Single Nucleotide Polymorphisms (SNPs) in the occurrence of breast cancer. This review mainly aimed to find out the connection between CYP19A1 gene variations and the risk of breast cancer, as well as its clinical characteristics and prognosis. Due to the highly special activityof the CYP19A1 enzyme in steroid production, suppression of the targeted CYP19A1 is a focused medication for breast cancer patients,which has only minor adverse effects. Numerous clinical trials over the last decade have shown that Aromatase inhibitors (AIs) not only outperform tamoxifen in terms of effectiveness but also have a lower adverse effect profile.The AI is now widely accepted as a routine therapy option for postmenopausal femaleswith Estrogen receptor-positive (ER+) breast cancer. Furthermore, not only dysregulation of gene expression in different genes related to distinguished pathways, such as estrogen metabolism, is essential in the progression of breast cancer but also particular SNPs can play an essential role in particular genes, such as CYP19A1. Different studies have demonstrated that these SNPs can be located in different sites of these genes, which are collected in this review. In a nutshell, more specific clinical trials are required to demonstrate the precise meditative role of anti-estrogen drugs in the treatment of ER+ breast cancer patients. Furthermore, more genotype analyses are needed to confirm the role of SNPs in the progression of breast cancer.

The Optimized Formulation of Tamoxifen-Loaded Niosomes Efficiently Induced Apoptosis and Cell Cycle Arrest in Breast Cancer Cells.

The aim, as proof of concept, was to optimize niosomal formulations of tamoxifen in terms of size, morphology, encapsulation efficiency, and release kinetics for further treatment of the breast cancer (BC). Different assays were carried out to evaluate the pro-apoptotic and cytotoxicity impact of tamoxifen-loaded niosomes in two BC cells, MDA-MB-231 and SKBR3. In this study, tamoxifen was loaded in niosomes after optimization in the formulation. The formulation of niosomes supported maximized drug entrapment and minimized their size. The novel formulation showed improvement in storage stability, and after 60 days only, small changes in size, polydispersity index, and drug entrapment were observed. Besides, a pH-dependent release pattern of formulated niosomes displayed slow release at physiological pH (7.4) and a considerable increase of release at acidic pH (5.4), making them a promising candidate for drug delivery in the BC treatment. The cytotoxicity study exhibited high biocompatibility with MCF10A healthy cells, while remarkable inhibitory effects were observed after treatment of cancerous lines, MDA-MB-231, and SKBR3 cells. The IC50 values for the tamoxifen-loaded niosomes were significantly less than other groups. Moreover, treatment with drug-loaded niosomes significantly changed the gene expression pattern of BC cells. Statistically significant down-regulation of cyclin D, cyclin E, VEGFR-1, MMP-2, and MMP-9 genes and up-regulation of caspase-3 and caspase-9 were observed. These results were in correlation with cell cycle arrest, lessoned migration capacity, and increased caspase activity and apoptosis induction in cancerous cells. Optimization in the formulation of tamoxifen-loaded niosomes can make them a novel candidate for drug delivery in BC treatment.

Letrozole versus tamoxifen for ovulation induction in non-polycystic ovarian syndrome anovulatory infertile females

Background: Anovulation is the most common cause for infertility, different oral agents are used for induction of ovulation, tamoxifen may be effective as letrozole in this era.Objective: The aim of this study was to compare the effectiveness of tamoxifen and letrozole in terms of ovulation induction outcomes in non PCOS anovulatory patients.Patients and Methods: This randomized single blinded clinical trial was conducted among a total of 120 patients with anovulatory infertility that were randomized to one of two treatment arms: Letrozole group and Tamoxifen group. The treatment was continued for three consecutive cycles. Main outcome measures were number of follicles ≥ 18mm, endometrial thickness and ovulation rate. Secondary outcomes measures were cumulative pregnancy rate and spontaneous abortion rates.Results: Mean number of mature of follicles ≥ 18 mm was statistically significantly higher in Tamoxifen group (1.9 ± 1.1) when compared to Letrozole group (1.5 ± 0.9) with p-value=0.03. Also, endometrial thickness was significantly different between both groups; as it was higher in Tamoxifen group (8.2 ± 1.6 mm versus 7.08 ± 2.4 mm) in Letrozole group (p-value=0.02). No significant difference was reported between both groups as regarding ovulation rate, pregnancy rate and spontaneous abortion rate, ovulation rate was 73.3% with Letrozole and 63.3% with Tamoxifen (P =0.3), cumulative pregnancy rate was 30% with Letrozole group and 23.3% with Tamoxifen group (p=0.5) and spontaneous abortion rate was 3.3% in Letrozole group and 5% in Tamoxifen group (p=0.9).Conclusion: Tamoxifen drug has comparable ovulation induction outcomes to letrozole with very low costs and side effects. Tamoxifen could be considered suitable for ovulation induction in developing countries

Abstract P6-13-06: Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm

Abstract OBJECTIVE: To compare, in the setting of breast cancer (BrCa) prevention, the impact of estrogen-based hormone replacement therapy (E-HRT) vs. tamoxifen (TAM) on breast cancer mortality (BrCa-M) and breast cancer case fatality ratio (BrCa-CFR), by analyzing data from the Women's Health Initiative Trial 2 (WHI HRT Trial 2, E-HRT vs. placebo [P])1 and the International Breast Cancer Intervention Study 1 (IBIS-1), TAM vs. P.2 METHODS: Hazard ratios (HR) and confidence intervals (CI) for BrCa incidence and mortality were extracted from the original WHI HRT Trial 2 and IBIS-1 trials.1,2 BrCa-CFRs were estimated by dividing the mortality HR by the incidence HR. Subsequently, to compare E-HRT vs. TAM outcomes, the ratios of HRs (HR1/HR2) between the two trials were estimated separately for BrCa-M and BrCa-CFR. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Mortality and Case Fatality Outcomes: Impact of E-HRT versus TAM, expressed as ratio of HRs E-HRT vs. Placebo, HR1TAM vs. Placebo, HR2HR1/HR2pMortality0.55 (0.33-0.92)1.19 (0.68-2.10)0.46 (0.22-0.99)0.046Case Fatality0.70 (0.40-1.20)1.68 (0.93-3.01)0.42 (0.18-0.94)0.040 CONCLUSIONS: While acknowledging between-trial comparisons including eligibility differences, E-HRT yields significant reductions in BrCa mortality and case fatality as compared with TAM (54% and 58% respectively). These unexpected breast cancer mortality reductions represent major public health gains, additional to the already known superiority of E-HRT over TAM in terms of skeletal fracture rates and Alzheimer's dementia mortality reduction, and, in women entering menopause, also of cardiac and all-cause mortality reductions. REFERENCES: 1. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. 2. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology 2015;16:67-75. Citation Format: Ragaz J, Shakeraneh S, Qian H, Wilson KS, Wong H, Spinelli JJ. Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-06.

Longitudinal Effects of Adjuvant Endocrine Therapy on the Quality of Life of Post-menopausal Women with Non-metastatic ER+ Breast Cancer: A Systematic Review.

BackgroundAnti-estrogen (ER) endocrine therapy is an effective treatment strategy in reducing breast cancer mortality. This therapy has a better therapeutic index than chemotherapy but can still affect patients’ quality of life (QOL) over time.ObjectiveThe objectives of this systematic review were to (1) describe QOL instruments used in ER-positive (ER+) non-metastatic breast cancer trials and (2) document the longitudinal effects of adjuvant endocrine therapy on the QOL of post-menopausal women with ER+ non-metastatic breast cancer.MethodsWe searched three electronic bibliographic databases for articles published from inception to October 2017 that described (1) a randomized controlled trial (RCT) of non-metastatic breast cancer containing an adjuvant endocrine regimen in at least one arm; (2) the use of a patient self-report measure assessing general or breast cancer-specific QOL; and (3) QOL outcomes at multiple time points during follow-up of at least 5 years. All included trials were independently evaluated by two reviewers, and data were extracted using standardized forms.ResultsIn total, 13 studies met our inclusion criteria and were assessed in this review. The quality of the trials was reasonably good. The top three most commonly used QOL instruments in the trials were the Functional Assessment of Cancer Therapy/Functional Assessment of Chronic Illness Therapy, the Short Form-36 and the Menopause-Specific Quality of Life. Most studies found no differences between tamoxifen and aromatase inhibitor groups in terms of global QOL. QOL data affected treatment regimen recommendations in a few cases. A meta-analysis was not feasible because the RCTs included in our review varied in terms of sample size, comparators, QOL instrument used, and timing of QOL measurement. Additionally, as no search strategy has perfect sensitivity, specificity and accuracy, there is always a chance that potentially relevant articles were missed.ConclusionThis systematic review suggests that the QOL of post-menopausal women is unlikely to be adversely affected by long-term use of adjuvant endocrine therapy. Efforts are needed to improve the quality of QOL reporting in clinical trials.Electronic supplementary materialThe online version of this article (10.1007/s41669-018-0070-7) contains supplementary material, which is available to authorized users.

Which women decide to take tamoxifen?

To identify factors which predict, among estrogen receptor (ER)-positive breast cancer patients, who chooses to take adjuvant tamoxifen. We studied 1347 women with ER-positive breast cancer who were treated at Women's College Hospital between 1987 and 2000. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, ER status, treatments received and dates of local recurrence and of death. We compared women who did and who did not take tamoxifen for a range of factors. We used the Kaplan-Meier method to estimate 15-year local recurrence-free and breast cancer-specific survival rates for women who did and who did not take tamoxifen. Overall, 50.4% of women who had a mastectomy took tamoxifen and 61.0% of women who had a lumpectomy took tamoxifen (p=0.002). Tamoxifen use did not correlate with any of the factors that were predictive of a high risk of death from breast cancer, such as young age, large tumour size and positive lymph node status. Young women (<40years) experienced much higher mortality (41.1%) than older (>60years) women (14.1%, p<0.01), but were much less likely to have taken tamoxifen (35.0 vs. 74.6%, p<0.01). Approximately one-half of women with ER-positive breast cancer who are candidates for tamoxifen did not take tamoxifen. Women with lumpectomy were more likely to take tamoxifen than women with mastectomy. Paradoxically, women at high risk of death from breast cancer (less than 40 at diagnosis and/or lymph node positive) and who are expected to receive the greatest benefit from tamoxifen in terms of mortality reduction were less likely to take it than were low-risk women (older women, lymph node negative). These findings suggest that women consider the reduction in risk from local recurrence to be more important than the reduction in risk of death from breast cancer when they consider taking tamoxifen.

Aromatase inhibitors in premenopause: Great expectations fulfilled?

Tamoxifen and GnRH analogues (GnRHa) represent the mainstay of endocrine manipulations in premenopausal women. The estrogen blockade obtained by aromatase inhibitors (AIs) plus GnRHa suppresses circulating estrogens more deeply than tamoxifen plus GnRHa. Retrospective and prospective evidence confirm a substantial activity for AIs and GnRHa in locally advanced and metastatic breast cancer. In early breast cancer inconsistent evidence emerged from 2 large randomized studies with anastrozole performing as tamoxifen in terms of DFS, but significantly worse as of OS while exemestane outperformed tamoxifen as of DFS particularly in very young and high-risk women. These findings support the use of AIs plus GnRHa in advanced breast cancer while long term efficacy and safety data are expected to define the appropriate indication of AIs in early breast cancer. In addition the clinical significance of persistent circulating estrogens and long term effects of estrogen deprivation in young women need further clarification.

Abstract P1-12-11: Prospective study of aromatase inhibitor-induced bone loss and lipid levels in early hormone sensitive breast cancer treated with AI during 8 years

Abstract Introduction: AI’s are the preferred adjuvant hormonal treatment for postmenopausal(PM) estrogen receptor positive (ER+) disease because of the improved efficacy over tamoxifen in terms of disease free survival and reduction in distant recurrence. AI’s have been associated with increased bone loss by blocking peripheral tissue estrogen synthesis, arthralgia and a negative effect on lipid metabolism. In this prospective study we wanted to assess the amount of bone loss and the changes in lipid levels in early breast cancer(EBC) patients (pts) treated with 3yrs of extended letrozole as part of the SOLE study after 5 yrs of adjuvant AI. Objectives: the primary objective of the study is to calculate the mean percentage change in bone mineral density(BMD)(g/cm2) after 8 yrs of letrozole and to compare between the continuous(C) and intermittent(I) intake of letrozole. The secondary objectives are to correlate the mean change in BMD with the initial value, BMI and to describe the evolution of the lipid levels in both groups. Patients and methods: BMD was measured at the lumbar spine (L2-4) and hip by dual energy X-ray absorptiometry (DEXA) in PM pts. with ER+ EBC. We also measured the fasting lipid levels baseline and after 8 yrs of an AI. Differences between the two groups were assessed by the independent samples T-test and the correlation by the linear regression analysis. Results: Fifty four pts were included in the study with a mean age of 62.5 yrs(+/-8.6 yrs). Seventeen pts are too early to be evaluable, 8 pts stopped letrozole due to adverse events and 2 pts had no baseline DEXA values. Two pts received tamoxifen 2 to 5 yrs before inclusion in the SOLE study. The remaining 25 pts showed a mean change in BMD for the lumbar spine of -1.1 (10.6SD) and for the hip -4.4 (7.04SD). Currently 13 pts in the C arm demonstrated a mean decrease in BMD for the (LS) of -2.7(10.2SD), and for the hip of -2.7(5.5SD). Twelve pts included in the I arm experienced a mean increase in BMD for the LS of 0.65(SD11.2) and a mean decrease in BMD for the hip of -4.9(9.1SD). The difference between the two treatment groups was not significant for the LS measurements after 8yrs (p=0.4) nor for the hip (p=0.23) neither was it at baseline (p=0.9; 0.1). Only three pts had fractures due to trauma. The overall fracture rate was only 0.05%.There was no correlation with the BMI, but there was a significant correlation with baseline BMD.(p=0.002)The mean fasting cholesterol levels at 8yrs in the C arm was 214mg/dl(41.3SD) and in the I arm was 218mg/dl(35.6SD)and was not significantly different(p=0.8), nor was it at baseline(p=0.5). Conclusion: This first prospective long term BMD and lipid follow-up study in PM EBC pts taking adjuvant letrozole beyond 5 yrs shows a decline in BMD. Until now no significant differences were observed between continuous and intermittent letrozole. An updated and detailed follow-up on more patients will be presented. Citation Format: Christel Fontaine, Lore Decoster, Denis Schallier, Leen Vanacker, Jacques De Grève, Marian Vanhoeij, Guy Verfaillie, Jan Lamote. Prospective study of aromatase inhibitor-induced bone loss and lipid levels in early hormone sensitive breast cancer treated with AI during 8 years [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-11.

C–X–C ligand 10 and C–X–C receptor 3 status can predict tamoxifen treatment response in breast cancer patients

To investigate the expression levels of CXCL10 and CXCR3 in tumors from breast cancer patients randomized to adjuvant tamoxifen treatment or no endocrine treatment, in order to further study the connection to prognosis and prediction of tamoxifen treatment outcome. Immunohistochemistry on tissue microarrays from 912 breast cancer patients randomized to tamoxifen or no endocrine treatment. CXCR3 status was found to be a prognostic tool in predicting distant recurrence, as well as reduced breast cancer-specific survival. In patients with estrogen receptor (ER)-positive tumors, tumors with strong CXCL10 levels had improved effect of tamoxifen treatment in terms of local recurrence-free survival [risk ratio (RR) 0.46 (95 % CI 0.25–0.85, P = 0.01)] compared with patients with tumors expressing weak CXCL10 expression. Further, patients with ER-positive tumors with strong CXCR3 expression had an improved effect of tamoxifen in terms of breast cancer-specific survival [RR 0.34 (95 % CI 0.19–0.62, P < 0.001)] compared with the group with weak CXCR3 levels [RR 1.33 (95 % CI 0.38–4.79, P = 0.65)]. We show here for the first time that CXCL10 and CXCR3 expression are both predictors of favorable outcome in patients treated with tamoxifen.

Fertility preservation in young breast cancer patients: addressing individual patient needs

SUMMARY In female patients, infertility may be regarded as an essential loss of femininity and infertility after cancer, and is known to be associated with psychosocial distress. Fertility preservation is thus an important issue for young women diagnosed with breast cancer. Nevertheless, breast cancer patients have traditionally not been offered the most well-established methods for fertility preservation, such as embryo and oocyte freezing, as a rise in estradiol during standard stimulation protocols has been regarded as potentially deleterious in these patients. Alternative protocols for stimulation, such as those using tamoxifen and aromatase inhibitors, have therefore been developed. Protocols including aromatase inhibitors have been demonstrated to be more effective than those using tamoxifen in terms of the number of oocytes and embryos obtained, while maintaining estradiol levels within the normal range of a menstrual cycle. Cryopreservation of immature oocytes and ovarian cortical tissue are methods that are still under development. Reports of children born after application of these experimental methods are currently increasing and these methods are thus gaining a place within the options for fertility preservation in breast cancer patients.

Phase II trial with letrozole to maximum response as primary systemic therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

Letrozole is superior to tamoxifen in terms of response and breast preservation rates as primary systemic therapy (PST) in postmenopausal women with ER-positive early breast cancer. However, the optimum duration of endocrine PST remains uncertain. A phase 2 multicentre, open-label trial was conducted to evaluate the efficacy of letrozole over a preoperative period of 4 months to 1 year. Seventy postmenopausal patients (over 65 years) were recruited in four centers. The primary endpoint was to establish the optimal duration of treatment defined as the time required to attain the maximum response by clinical palpation. The median age of the group was 79 years (66-91) and the median tumour size 35 mm (range 25-100 mm). No severe adverse events were reported. Fifty-six patients were evaluable for the primary objective. A total of 43 patients (76.8%) achieved an objective response; 29 (51.8%) being partial and 14 (25.0%) complete. The median time to objective response was 3.9 months (95% CI, 3.3-4.5) and the median time to maximum response was 4.2 months (95% CI, 4.0-4.5), although 20 (37.1%) patients achieved the maximal response within 6-12 months. Letrozole shows a high activity and excellent tolerability as neoadjuvant therapy in elderly patients with endocrine-dependent breast cancer. Four to six months of letrozole as PST is an optimum duration with modest benefits thereafter.

An Overview of Letrozole in Postmenopausal Women with Hormone-Responsive Breast Cancer

Third-generation aromatase inhibitors (AIs) have proven to be superior to tamoxifen in terms of time to disease progression in patients with hormone receptor (HR) positive (HR+) status and, nowadays, are used in the adjuvant and neoadjuvant settings, and first-line therapy for advanced breast cancer. Letrozole is a third generation AI, as are anastrozole and exemestane. In the past, clinical studies had demonstrated that letrozole was effective as a second-line treatment of metastatic breast cancer. In this paper, pharmacokinetic and pharmacodynamic properties of letrozole are reviewed along with its activity in preclinical and clinical settings. Additionally, the results of important clinical trials such as Breast International Group (BIG) 1-98, which tested the optimal initial adjuvant endocrine treatment and the sequential therapy with letrozole and tamoxifen, MA-17 that evaluates the benefits of extended adjuvant therapy, and other important studies in advanced and neoadjuvant disease, are reviewed. Safety comparisons of treatments are also addressed. Interestingly, about 50% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers are HR+. However, HER2 positivity is a marker of antiestrogen treatment resistance. Because of this, a dual treatment is a logical approach when both receptors are overexpressed. The combination of lapatinib and letrozole leads to a significant improvement in the overall disease outcome. Also, the combination of everolimus plus letrozole has been tested in this setting. In fact, the coadministration of both agents seems to increase the efficacy of letrozole in newly-diagnosed HR+ patients. Once resistance to sequential trastuzumab and AI as monotherapy has been found, trastuzumab and letrozole combined in HR+ and HER2+ patients with advanced breast cancer can overcome resistance to both drugs administered as single agents, according to recently reported results.

Aromatase inhibitors: what is the true cost?

The major tenets of systemic anti-cancer therapy should be to improve either or both overall survival and quality of life with acceptable cost–benefit. In this issue of the Journal, Vitry et al. discuss the rising costs associated with the use of aromatase inhibitors (AIs) in the treatment of breast cancer.1 As they point out, this class of drugs is now the preferred choice in Australia despite the lack of evidence of improvement in overall survival and the cost being six times that of the alternative drug, tamoxifen. Tamoxifen, a selective oestrogen receptor modulator, has a proven survival benefit in the adjuvant setting, along with a well-understood side-effect profile that includes hot flushes (common) as well as deep vein thrombosis and uterine cancer at a combined rate of 0.2% per decade among women on treatment for 5 years.2 An overview of randomized trials of tamoxifen has shown an absolute improvement in survival of 9.2% at 15 years after diagnosis compared with no tamoxifen.2 For individual women the magnitude of benefit will vary with the risk of recurrence. The AIs prevent the synthesis of oestrogen from adrenal produced androgen by blocking the aromatase enzyme. They are suitable only for postmenopausal women. Their side effects include hot flushes and arthralgia; the latter can affect 15–25% of women.3 AIs can cause a fall in bone mineral density (BMD) and a subsequent increased risk of fracture during treatment. This increased risk resolves after stopping treatment.3 Patients on an AI should have their BMD measured at baseline and every 2 years while on treatment. A fall in BMD or a low baseline can be treated with an oral or i.v. bisphosphonate, with their inherent toxicities and costs. Adjuvant AI therapy has consistently been shown to be superior to tamoxifen in terms of disease-free survival (delaying recurrence) but has not been shown to improve overall survival.4 Ten-year survival data for 5 years of tamoxifen compared with 5 years of the AI anastrozole, the most mature AI trial to date, have recently been published. The absolute reduction in recurrence with anastrozole compared with tamoxifen was 4.3% at 10 years. There was no improvement in overall survival. The number of deaths after breast cancer recurrence in the anastrozole arm of the trial was reduced. However, the increase in the number of deaths from other cancers and other causes in those without breast cancer recurrence resulted in similar overall survival to tamoxifen.5 Letrozole, another AI compared with tamoxifen in the adjuvant setting, now has 6-year data.6 An earlier interim analysis had shown an improvement in disease-free survival and subsequent unblinding allowed cross-over to the AI arm. Intention-to-treat analysis has not shown a significant improvement in survival. Subgroup analyses excluding patients who were allowed to cross-over are underpowered and post-hoc but do show a small advantage in this group.6 It may be that a true survival advantage exists but is likely now never to be proven. This will be an ongoing problem in oncology as primary outcomes other than overall survival are now frequent and these early results often prompt cross-over in trials. Vitry et al. discuss the cost to the Pharmaceutical Benefits Scheme of the increase in prescribing of AIs. The true total cost of this treatment must include the cost of measuring, preventing and treating the effects on BMD, including the costs borne by patients of calcium and vitamin D supplementation and analgesia for arthralgia. This would seem likely to be more than the cost of managing the side effects of tamoxifen. We know from the chemotherapy published work that breast cancer patients will accept side effects for even very small advantages in survival, but it is less clear whether they accept this for delayed recurrence alone. Certainly, the compliance with any adjuvant hormone therapy is known to be poor. Aromatase inhibitors are not cheap. They offer a choice to women and their oncologists with regard to side-effect profile and have a role in delaying recurrence. They are just one example of new cancer treatments, often expensive, which provide improvements in disease-free survival in the adjuvant setting or progression-free survival in the metastatic setting but have no clear overall survival benefit. As a society, are we prepared to continue to bear the cost of these medications, or should we adopt a more hardline stance and only accept expensive new drugs if there is an improvement in quality of life and/or a clear and meaningful overall survival advantage?

One size does not fit all: quality of life during adjuvant aromatase inhibitor therapy

Adjuvant endocrine therapy for breast cancer is associated with significant improvements in disease-related outcomes. Five years of tamoxifen therapy is associated with 41 and 34% reductions in annual breast cancer recurrence and death rate, respectively [1]. Adjuvant aromatase inhibitor (AI) use instead of or in sequence with tamoxifen is slightly superior to single agent tamoxifen in terms of improvement in disease-free survival, but with comparable overall survival benefit [2, 3]. Despite these beneficial outcomes, up to 50% of women discontinue these potentially life-saving medications prior to completion of the recommended 5 years of therapy [4–7]. One of the main reasons for treatment discontinuation is medication-associated side effects that may negatively impact quality of life. Few studies reported to date have compared outcomes and emergence of symptoms in women with early stage breast cancer treated with different AIs. In this issue, Dixon and colleagues report results from a prospective study investigating the effects of two nonsteroidal AIs on patient-reported outcomes using a crossover trial design, in an attempt to elucidate differences in tolerability of AIs by individual patients. The authors randomized 181 postmenopausal women with early stage breast cancer to letrozole for 12 weeks followed immediately by anastrozole for 12 weeks, or the reverse sequence. The primary endpoint, difference in quality of life measures between the two drugs, was evaluated using the validated Functional Assessment of Cancer TherapyBreast (FACT-B)-endocrine subscale (ES) questionnaire. Secondary endpoints included differences between patientreported side effects and medication preference. Consistent with prior reports, the most common adverse events reported by Dixon and colleagues were arthralgias and hot flashes. Importantly, no differences were observed between regimens for adverse events, quality of life, or treatment discontinuation rates. Overall, 11.6% (21/181) of participants discontinued either AI, with 9 withdrawals during the first 12 weeks of therapy (2 on anastrozole and 7 on letrozole), and an additional 10 withdrawals following the transition to the second medication (5 on each AI). Despite the lack of differences in adverse event reporting between letrozole and anastrozole for all study endpoints, about two-thirds of individuals reported a preference for one AI versus the other. Given the substantial improvements in breast cancerrelated outcomes associated with endocrine therapy, minimizing drug-related toxicity and insuring high quality of life for an individual who is receiving the therapy is critical. The study by Dixon et al. confirms reports from prior prospective studies demonstrating that the most common AI-associated toxicity is musculoskeletal, affecting about half of treated patients, and results in early treatment discontinuation in 10–15% of women [8–10]. Although most AI-associated toxicities are believed to be due to a class effect, this study demonstrated that the majority of women have a clear preference for one AI compared to another based on side effects and quality of life. This finding of an individual preference for a specific AI is consistent with a previously published crossover study of anastrozole This is an invited commentary to article doi: 10.1007/s10549-010-1091-9.

Predictive relevance of HOXB13 protein expression for tamoxifen benefit in breast cancer

IntroductionThe HOXB13:IL17BR index has been identified to predict clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer. Further studies have shown that HOXB13 in particular can indicate benefit of prolonged tamoxifen treatment. Patients with high-expressing tumors did not benefit from prolonged treatment, suggesting that HOXB13 might be involved in tamoxifen resistance. No studies have been made regarding the HOXB13 protein levels in breast cancer. The aim of our study was to investigate whether tamoxifen benefit can be correlated to different levels of HOXB13 protein expression.MethodsWe used immunohistochemistry to analyze protein levels of HOXB13 in tumor samples from 912 postmenopausal node-negative breast cancer patients randomized to adjuvant tamoxifen therapy or no endocrine treatment.ResultsTamoxifen-treated patients with estrogen receptor-positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (DRFS) (hazard ratio = 0.38, 95% confidence interval = 0.23 to 0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared with the untreated patients (hazard ratio = 0.88, 95% confidence interval = 0.47 to 1.65, P = 0.69). Interaction between HOXB13 expression and benefit from tamoxifen was statistically significant for DRFS (P = 0.035). No prognostic value could be ascribed to HOXB13 among systemically untreated patients.ConclusionsA high HOXB13 expression was associated with decreased benefit from tamoxifen, which indicates that HOXB13 protein level may be used as a predictive marker for tamoxifen treatment.

Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer

To undertake a systematic review of three first-line treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC) in post-menopausal women. We searched six databases from inception up to January 2009 for relevant trials regardless of language or publication status. Randomised controlled clinical trials assessing the safety and efficacy of first-line AIs for post-menopausal women with hormone receptor-positive (HR+, i.e. ER+ and/or PgR+) with or without ErbB2 (HER2)-positive MBC, who have not received prior therapy for advanced or metastatic disease were included. Where meta-analysis using direct or indirect comparisons was considered unsuitable for some or all of the data, we employed a narrative synthesis method. Four studies (25 papers) met the inclusion criteria. From the available evidence, it was possible to directly compare the three AIs with tamoxifen. In addition, by using a network meta-analysis it was possible to compare the three AIs with each other. Based on direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-to-progression (TTP) (HR = 0.70 (95% CI: 0.60, 0.82)), objective response rate (RR = 0.65 (95% CI: 0.52, 0.82)) and quality-adjusted time without symptoms or toxicity (Q-Twist difference = 1.5; P < 0.001). Exemestane seemed significantly superior to tamoxifen in terms of objective response rate (RR = 0.68 (95% CI: 0.53, 0.89)). Anastrozole seemed significantly superior to tamoxifen in terms of TTP in one trial (HR = 1.42 (95% CI: 1.15, NR)), but not in the other (HR = 1.01 (95% CI: 0.87, NR)). In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane (OR = 0.61 (95% CI: 0.38, 0.97)); while exemestane was associated with significantly more arthralgia in comparison with tamoxifen (OR = 2.33 (95% CI: 1.07, 5.11)). Anastrozole was associated with significantly more total adverse events (OR = 1.04 (95% CI: 1.00, 1.09)) and hot flushes (OR = 1.39 (95% CI: 1.03, 1.89)) in comparison with tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs with each other in women with post-menopausal, hormone sensitive advanced or MBC showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes overall survival (OS) and progression-free survival (PFS) showed no significant differences between AIs. OS and PFS showed no significant differences between AIs and hence based on these results a class effect for all AIs is possible. However, these results are based on indirect comparisons and a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with appropriate caution. Head-to-head comparisons between letrozole, anastrozole and exemestane in the first-line MBC setting are warranted.

Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer

Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators, are therapeutically equivalent treatments for metastatic breast cancer. We hypothesized that toremifene as compared with tamoxifen given as adjuvant therapy for early stage breast cancer would result in equivalent survival with an improved side effect profile, therefore, providing superior therapeutic efficacy. The North American Fareston versus Tamoxifen Adjuvant trial assigned 1813 perimenopausal or postmenopausal women with hormone receptor (HR)-positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS) and overall survival (OS). Median follow-up was 59 months. The baseline characteristics of the 2 treatment groups were well-balanced. On the basis of intent-to-treat, 5-year actuarial DFS was not significantly different between tamoxifen and toremifene (91.2% [standard error of the mean [SE] 1.2%] vs 91.2% [SE 1.1%], respectively). Similarly, 5-year actuarial OS was not significantly different between tamoxifen and toremifene (92.7% [SE 1.1%] vs 93.7% [SE 1.0%], respectively). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene versus tamoxifen in terms of OS (OR = 0.951; 95% confidence interval [CI], 0.623-1.451, P = .951) or DFS (OR = 1.037; 95% CI, 0.721-1.491, P = .846). Adverse events were similar in the 2 groups. Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of HR-positive patients with either tamoxifen or toremifene is appropriate.

Biological profile of oestrogen receptor alpha positive (ERalpha+) primary breast cancers in the elderly and their response to primary endocrine therapy

e20622 Background: Aromatase inhibitors (AIs) have been shown to be superior to tamoxifen in several settings. However, it is unclear whether this superiority extends to its use as primary endocrine therapy in elderly patients with early operable primary breast cancer. Biological characteristics of the tumours may aid in selecting the most suitable agent. Methods: Primary endocrine therapy with one of the AIs (anastrozole) in 64 women &gt;70 years with ERα+ breast cancer was compared to that in 84 treated with tamoxifen during the same period. Their selection was entirely based on contraindications e.g. thromboembolic risks. Needle core biopsies were assessed, by immunohistochemistry, for expression of biomarkers as described below. Results: There was no significant difference between the two groups (anastrozole vs tamoxifen) in terms of response at 6 months (clinical benefit (objective response + stable disease) rates = 97 vs 100%, p=0.099) or progression free survival (median = 16.5 vs 22.5 months, p=0.376). There were no withdrawals due to side effects from anastrozole, compared to four with tamoxifen. For all patients progesterone receptor (PgR), ERβ2, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and Ki-67 were over-expressed in 48%, 99%, 8%, 4% and 64% respectively. HER2 (18 vs 21 months, p=0.003) and Ki-67 (17.5 vs 23 months, p=0.042) over-expression were significantly associated with shorter progression free survival. Conclusions: These results thus far show that primary endocrine therapy with anastrozole in elderly patients with early operable ERα+ breast cancer is similar to tamoxifen in terms of efficacy, but may be better tolerated. In this population, ERα+ breast cancer also appears to have a less aggressive biological profile favouring better hormone sensitivity. [Table: see text]

Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer.

Abstract Abstract #1130 Purpose: Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators (SERMs), are therapeutically equivalent in treating metastatic breast cancer. We hypothesized that toremifene may have superior therapeutic efficacy as adjuvant therapy for early breast cancer.&amp;#x2028; Patients and Methods: The North American Fareston versus Tamoxifen Adjuvant (NAFTA) trial, a multicenter investigator-initiated randomized controlled trial, assigned 1813 female peri- or post-menopausal patients with hormone receptor positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS), defined as the time from registration to local and/or systemic recurrence, and overall survival (OS), defined as the time from registration until death from any cause. Both an intention-to-treat and a per-protocol analysis were performed.&amp;#x2028; Results: Median follow-up was 59 months. The baseline characteristics of the two treatment groups were generally well balanced, although the tamoxifen group tended to be older (median age: 68 vs. 67 years, p=0.096), with larger tumors (median tumor size: 1.3 cm vs. 1.2 cm, p=0.086), of higher grade (proportion Grade 3: 18.3% vs. 15.7%, p=0.081). Based on intention-to-treat, mean OS was not significantly different between tamoxifen and toremifene ((98.1 mo. vs. 98.6 mo., respectively, p=0.628). Similarly, mean DFS was not significantly different between tamoxifen and toremifene (96.4 mo. vs. 96.7 mo., respectively, p=0.790). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene vs. tamoxifen in terms of OS (OR = 0.951; 95% CI: 0.623-1.451, p=0.951) or DFS (OR = 1.037; 95% CI: 0.721-1.491, p=0.846). Of the 1813 patients in the study, 104 (5.7%) had a protocol violation after randomization and did not start a study drug. The proportion of such patients was evenly distributed between the tamoxifen and toremifene groups (5.2% vs. 6.3%, respectively, p=0.394). Excluding these patients, survival times were similar between the tamoxifen and toremifene groups (mean OS: 96.401 vs. 96.776, p=0.766; DFS: 98.170 vs. 98.646, p=0.607). Cox proportional hazards models for OS (p=0.951) and DFS (p=0.843) failed to demonstrate a significant difference between the two treatment arms in the per-protocol analysis.&amp;#x2028; Conclusions: Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of hormone receptor positive patients with either of these SERMs is appropriate. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1130.