Clinical use of aromatase inhibitors in the treatment of advanced breast cancer

The aim of endocrine therapy is to reduce the estrogenic stimulus for tumour growth. After failure of tamoxifen — the standard “first-line” hormonotherapy for advanced breast cancer (ABC) — the most frequently prescribed endocrine therapies are progestins and aromatase inhibitors (AIs) (“second-line” hormonotherapy). Estrogen deprivation through AIs provides effective treatment of hormone-dependent ABC in postmenopausal (PMP) women. Over the past few years, the goals of our research programme were to develop more potent, more selective and better tolerated AIs than our first AI, aminoglutethimide (AG). Lentaron® (4-hydroxyandrostenedione, formestane), a highly selective steroidal compound was the first of the new AIs to be used in clinical trials. It is a substrate analogue, administered as an i.m. injection every 2 weeks. It is effective in the treatment of ABC with an objective response rate (ORR) similar to tamoxifen and megestrol acetate (MA) and is generally well tolerated; rare instances of injection site reactions have been reported. Afema® (fadrozole HCl), a non-steroidal AI is active orally, and effectively suppresses estrogen levels in PMP women, but it is not completely selective for aromatase when administered at higher than therapeutic doses. At the therapeutic dose of 1 mg twice a day it has an anti-tumour efficacy similar to MA, a good tolerability and no clinically relevant effects on other hormones of the endocrine system. Letrozole is the fourth of our AIs in clinical development. It is a non-steroidal, achiral, orally active, potent and highly selective competitive AI. Clinical endocrine studies have shown that the dose of 0.5 mg a day is the lowest dose achieving maximum estrogen suppression. Over a wide dose range, a lack of clinically relevant effects on other hormones of the endocrine system has confirmed its high selectivity. In four phase Ib/IIa studies in PMP patients with ABC who failed previous therapy, letrozole produced ORRs of 9, 31, 33 and 36%. One phase IIb/III study has been completed and two others are ongoing, comparing two doses of letrozole with MA or AG to confirm the anti-tumour efficacy of letrozole in the treatment of ABC in PMP women after treatment with anti-estrogens. Preliminary results from the completed trial show that letrozole 2.5 mg is superior to 0.5 mg in terms of ORR, time to progression and time to treatment failure, and is superior to the standard dose of MA in terms of ORR and tolerability. Therefore letrozole 2.5 mg can be recommended as a first choice for the treatment of PMP patients with hormone receptor-positive or unknown ABC after anti-estrogen therapy.     

Letrozole versus tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy

Letrozole, a third generation aromatase inhibitor, has been compared with tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. In a first-line trial in advanced disease, 939 post menopausal women were randomised double blind to receive treatment with letrozole 2.5 mg daily or tamoxifen 20 mg daily. Letrozole was significantly superior in terms of median time to progression (9.4 months versus 6.1 months, P = 0.0001), objective response (30% versus 20%, P = 0.0006), and clinical benefit (49% versus 38%, P = 0.0001). Superiority of letrozole was independent of disease site, receptor status, or prior adjuvant anti-oestrogen therapy. In an extended phase of this trial, 200 patients were crossed over to tamoxifen after letrozole, compared with 197 crossed over to letrozole after tamoxifen. Median overall survival was 34 months for letrozole versus 30 months for tamoxifen (not significant).

In a similar randomised double-blind neoadjuvant trial, 337 post menopausal patients with large ER/or PgR positive T2–T4 cancers, either requiring mastectomy or locally advanced, were randomised to preoperative letrozole or tamoxifen for 4 months prior to surgery. Overall response was 55% for letrozole versus 36% for tamoxifen (P < 0.001). Conservative surgery was possible in 45% of patients treated with letrozole versus 35% with tamoxifen (P = 0.022).

In both trials, both treatments were well tolerated with no significant differences in side effects.

These results indicate that letrozole is more active than tamoxifen both as neoadjuvant therapy and as first-line treatment in advanced disease. They support the importance of current adjuvant trials comparing the two treatments.     

Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?

The agents used for endocrine therapy in patients with breast cancer have changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of choice, but could be replaced by the oestrogen receptor down-regulator ICI 182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III) soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase inhibitors of choice, they have been replaced by non-steroidal (anastrozole and letrozole) and steroidal (exemestane) inhibitors of high potency and low side effect profile. Previously, often used treatments such as progestogens (megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely used or confined to fourth or fifth line treatments. The LHRH agonist, goserelin, remains the treatment of choice for pre-menopausal patients with advanced breast cancer although recent randomised trials indicate a response, time to progression and survival advantage for the combination of goserelin and tamoxifen compared with goserelin alone.

The newer treatments have led to questions concerning the optimum sequence of agents to use in advanced breast cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two trials of anastrozole compared with tamoxifen and one trial of letrozole compared with tamoxifen indicate that the new triazole aromatase inhibitors have a significant advantage over the anti-oestrogen with respect to time to progression and survival. Similarly, triazole aromatase inhibitors give faster and more complete responses compared with tamoxifen when used in post-menopausal women before surgery.

Major research questions remain with respect to the aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone or in combination with tamoxifen compared with tamoxifen in the ‘so-called’ ATAC trial. Over 9000 patients have been randomised to this important study: the results will be available late-2001. A similar study comparing letrozole and tamoxifen started recently under the auspices of the Breast International Group. Importantly, this trial is also comparing the sequence of tamoxifen followed by letrozole (or vice versa). A similar trial of exemestane given after 2–3 years of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study comparing letrozole (or placebo) for 5 years after 5 years of adjuvant tamoxifen. These studies may show that aromatase inhibitors are superior to tamoxifen or that a sequence is preferable.

ICI 182780 causes complete oestrogen receptor down-regulation leading to a the lack of agonist activity of the drug. Two trials of ICI 182780 compared with anastrozole for advanced disease will report later this year and a comparison with tamoxifen next year. Arzoxifene (SERM III) is being tested against tamoxifen. These studies are likely to result in new anti-oestrogens being introduced into the clinic.

Most of our endocrine treatments deprived the tumour cell of oestradiol. In vitro experiments with MCF-7 cells indicate that tumour cells can adapt and then grow in response to low oestrogen concentrations in the tissue—culture medium. Importantly, the cells were shown to apoptose in response to high oestrogen concentrations. A recent clinical trial has demonstrated a high response rate to stilboestrol given after a median of four previous oestrogen depriving endocrine therapies. These data and the newer treatments available indicate a need to re-think our general approach to endocrine therapy and endocrine prevention.     

Are aromatase inhibitors superior to antiestrogens?

Aromatase inhibitors (AIs) have been in use to treat metastatic breast cancer for over 25 years. Recently potent and specific AIs have been introduced, which, because of their low toxicity profile, are being used in the adjuvant and neoadjuvant situation and also for the prevention of breast cancer. The two non-steroidal AIs, anastrozole and letrozole, and the steroidal AI, exemestane, have all shown superiority to tamoxifen as first-line treatment for advanced breast cancer. Interestingly, the oestrogen receptor downregulator, fulvestrant, was shown to be equivalent to anastrozole when compared as second-line therapy after the failure of tamoxifen. The first adjuvant AI trial began in 1996 and recruited over 9000 patients (ATAC trial). Anastrozole was compared with tamoxifen and a combination of the two drugs. There were no significant differences between tamoxifen and the combination. However, anastrozole showed about a 20% improvement in disease-free survival in ER+ disease compared with the other treatments. An overall survival analysis will be reported later this year. Two trials have compared 5 years of tamoxifen with 2–3 years of tamoxifen, followed by 2–3 years of AI (one trial (ITA) used anastrozole and another (intergroup) exemestane). Both trials show a disease-free advantage for the switch to AI. In another study (MA17) 5 years of tamoxifen was followed by a randomisation to letrozole or placebo and showed a significant disease-free advantage to the AI. Both letrozole and anastrozole show superiority to tamoxifen when used as a neoadjuvant therapy. Anastrozole significantly reduced contralateral breast cancer compared with tamoxifen, and this has led to two prevention trials: one in women at risk comparing anastrozole with placebo and the other after excision of DCIS comparing anastrozole with tamoxifen (IBIS II). The NCI Canada has also just initiated a trial of exemestane for prevention. Nearly all data available indicate that AIs are superior to tamoxifen. The important question is whether survival is improved when they are used as adjuvant therapy?     

Aromatase inhibitors for therapy of advanced breast cancer

In postmenopausal women with advanced breast cancer, numerous phase III trials have been performed comparing the third-generation non-steroidal aromatase inhibitors (NS-AIs) anastrozole and letrozole and the steroidal AI (S-AI) exemestane in the “first-line” setting against tamoxifen and in the “second-line” setting against megestrol acetate. In both settings, the AIs were at least as efficacious or superior in some endpoints with a preferable toxicity profile including a lower incidence of thrombotic events. Relatively small differences in potency between the three AIs have been identified and it has not been demonstrated that these differences have clinical implications. The recent establishment of the value of AIs in the adjuvant setting for postmenopausal women will impact on their utilization in advanced disease. In premenopausal women the third-generation AIs have not been studied as monotherapy and there is a paucity of data in combination with ovarian function suppression in the advanced disease setting. The main area of future investigations for the AIs in premenopausal women will be in the adjuvant therapy setting in combination with suppression of ovarian function.     

PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer

The phosphatidylinositol 3′ kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = −0.43, p = 0.008) compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R = −0.11, p = 0.37) but with relative change in phosphorlyated S6 (S240) (R = −0.46, p = 0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.     

Surgical issues surrounding use of aromatase inhibitors

There are important surgical issues related to the use of the third generation aromatase inhibitors in both the neoadjuvant and adjuvant settings. Neoadjuvant hormone therapy is effective at downstaging tumours, particularly large tumours initially thought to be inoperable or requiring mastectomy. Randomised trials have shown that the newer aromatase inhibitors letrozole and anastrozole increase the numbers of women who are suitable for breast-conservation compared with tamoxifen, and that letrozole is superior to tamoxifen in terms of clinical response.

Aromatase inhibitors are most effective in ER-rich tumours and are clinically and biologically effective in both HER2 positive and negative tumours, whereas HER2 positive tumours show a level of resistance to tamoxifen.

In neoadjuvant studies comparing aromatase inhibitors with tamoxifen, the duration of use has been 3–4 months, by which time any response is usually evident but longer treatment periods produce continued shrinkage and response. The re-excision rate following breast conservation surgery after neoadjuvant hormone therapy is favourable compared with the rates following immediate wide local excision. Local recurrence rates are acceptable in patients undergoing neoadjuvant therapy and breast-conserving surgery providing post-operative radiotherapy is given.

Adjuvant aromatase inhibitors, as well as having an effect on metastatic disease and survival, reduce local and regional recurrence.     

Adjuvant endocrine therapy in postmenopausal hormone-sensitive breast cancer: to start, to switch or to extend?

From the big randomized clinical trials there are evidences that adjuvant endocrine therapy for hormone-sensitive early breast cancer in postmenopausal women should include an aromatase inhibitor (AI). Anastrozole or letrozole should be used upfront for 5 years (ATAC and BIG 1-98), the sequential approach of tamoxifen for 2-3 years, followed by anastrozole or exemestane for 2-3 years is a reasonable alternative (ABCSG8, ARNO 95, IES, ITA), and mostly in patients with node-positive disease completing 5 years of tamoxifen should be offered letrozole up to 4-5 years (MA-17). In each of these trials incorporation of an AI resulted in significant improvement in study endpoints. Further results will be needed to establish the optimal beneficial effect, use, duration and safety of adjuvant AI therapies.     

Presurgical (neoadjuvant) endocrine therapy is a useful model to predict response and outcome to endocrine treatment in breast cancer patients

Endocrine therapy of breast cancer has been improved continuously during the last decades. Currently, aromatase inhibitors are dominating treatment algorithms for postmenopausal women with hormone-receptor positive breast cancer while tamoxifen still is the most widely used drug for premenopausal women. Several research tools and study designs have been used to challenge established drugs and develop the field of antihormonal therapy. One pivotal study option has been the observation of clinical responses during presurgical/neoadjuvant endocrine therapy (PSET/NET). This strategy has several major advantages. First, the breast tumor, still present in the patient's breast during therapy, can be followed by clinical observations and radiological measurements and any treatment effect will be immediately registered. Second, tumor biopsies may be obtained before initiation and following therapy allowing intra-patient comparisons. These tumor-biopsies may be used for the evaluation of intra-tumor changes associated with drug treatment. As examples, presurgical breast cancer trials have been used to evaluate intra-tumor estrogen levels during therapy with aromatase inhibitors and also to study mechanisms involved in the adaptation processes to estrogen suppression. Biomarker studies have provided information that may be used for patient selection in the future. Finally, recently published results from presurgical trials testing combinations of classical endocrine drugs and novel targeted therapies have produced promising results.     

An optimal Bayesian predictive probability design for phase II clinical trials with simple and complicated endpoints

Most existing phase II clinical trial designs focus on conventional chemotherapy with binary tumor response as the endpoint. The advent of novel therapies, such as molecularly targeted agents and immunotherapy, has made the endpoint of phase II trials more complicated, often involving ordinal, nested, and coprimary endpoints. We propose a simple and flexible Bayesian optimal phase II predictive probability (OPP) design that handles binary and complex endpoints in a unified way. The Dirichlet-multinomial model is employed to accommodate different types of endpoints. At each interim, given the observed interim data, we calculate the Bayesian predictive probability of success, should the trial continue to the maximum planned sample size, and use it to make the go/no-go decision. The OPP design controls the type I error rate, maximizes power or minimizes the expected sample size, and is easy to implement, because the go/no-go decision boundaries can be enumerated and included in the protocol before the onset of the trial. Simulation studies show that the OPP design has satisfactory operating characteristics.     

Clinical Efficacy of Including Capecitabine in Neoadjuvant Chemotherapy for Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background

Capecitabine has proven effective as a chemotherapy for metastatic breast cancer. Though several Phase II/III studies of capecitabine as neoadjuvant chemotherapy have been conducted, the results still remain inconsistent. Therefore, we performed a meta-analysis to obtain more precise understanding of the role of capecitabine in neoadjuvant chemotherapy for breast cancer patients.

Methods

The electronic database PubMed and online abstracts from ASCO and SABCS were searched to identify randomized clinical trials comparing neoadjuvant chemotherapy with or without capecitabine in early/operable breast cancer patients without distant metastasis. Risk ratios were used to estimate the association between capecitabine in neoadjuvant chemotherapy and various efficacy outcomes. Fixed- or random-effect models were adopted to pool data in RevMan 5.1.

Results

Five studies were included in the meta-analysis. Neoadjuvant use of capecitabine with anthracycline and/or taxane based therapy was not associated with significant improvement in clinical outcomes including: pathologic complete response in breast (pCR; RR = 1.10, 95% CI 0.87–1.40, p = 0.43), pCR in breast tumor and nodes (tnpCR RR = 0.99, 95% CI 0.83–1.18, p = 0.90), overall response rate (ORR; RR = 1.00, 95% CI 0.94–1.07, p = 0.93), or breast-conserving surgery (BCS; RR = 0.98, 95% CI 0.93–1.04, p = 0.49).

Conclusions

Neoadjuvant treatment of breast cancer involving capecitabine did not significantly improve pCR, tnpCR, BCS or ORR. Thus adding capecitabine to neoadjuvant chemotherapy regimes is unlikely to improve outcomes in breast cancer patients without distant metastasis. Further research is required to establish the condition that capecitabine may be useful in breast cancer neoadjuvant chemotherapy.     

The pharmacology of letrozole

Recent clinical trials indicate that the third-generation aromatase inhibitors may be more effective than tamoxifen as first line endocrine therapy in ER+ metastatic breast cancer in postmenopausal women. This review will focus exclusively on the pharmacology of the non-steroidal inhibitor letrozole. Aromatase derived from a variety of sources is inhibited at low nM concentrations of the drug. In non-cellular systems, letrozole is 2-5 times more potent than anastrozole and exemestane in its inhibition of aromatase, whilst in cellular systems it is 10-20 times more potent. Anti-tumour effects of letrozole have been demonstrated in several animal models. In postmenopausal women, letrozole commonly suppresses circulating concentrations of estrone and estradiol to below the sensitivity limit of the assays used to measure them. In a recent randomized cross-over study, letrozole (2.5mg daily) achieved a significantly greater suppression of the plasma concentrations of both estrone and estrone sulphate than anastrozole (1mg daily) and a greater inhibition of in vivo aromatization. Letrozole appears to have a small effect on adrenal steroidogenesis such that a small number of patients exhibit an abnormal response to synthetic ACTH during letrozole therapy. This is unlikely to have any clinical significance. In short-term studies letrozole has been shown to increase markers of bone resorption indicating the need to monitor bone integrity when the drug is used for extended periods of time. A consistent effect of letrozole on serum lipids has not been demonstrated.     

Benefit with aromatase inhibitors in the adjuvant setting for postmenopausal women with breast cancer

The third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, have been shown to be effective both as alternatives to tamoxifen in first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women and following failure of first-line tamoxifen for endocrine therapy. These 3 agents are now being investigated as adjuvant therapy of early breast cancer, as alternative or complementary treatments to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy), sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy), or following 5 years of tamoxifen (extended adjuvant therapy). In the first adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC]), anastrozole was significantly superior to tamoxifen in reducing risk of disease recurrence, and recently, the Breast International Group (BIG) trial BIG 1-98 demonstrated the significant superiority of letrozole over tamoxifen in improving disease-free survival. A large trial (International Collaborative Cancer Group [ICCG] trial 96) investigated sequencing of 2 to 3 years of exemestane after 2 to 3 years of tamoxifen and found that switching to exemestane was significantly superior in disease-free survival compared with continuing on tamoxifen. The Arimidex or Nolvadex (ARNO) and the small ITA (Italian Tamoxifen Arimidex) trials similarly sequenced anastrozole after tamoxifen and also found that sequencing reduced the hazard of recurrence compared with remaining on tamoxifen. Trial MA.17 evaluated extended adjuvant therapy with letrozole vs placebo following 5 years of tamoxifen. Disease-free survival was significantly improved with letrozole vs placebo, irrespective of whether patients had lymph node-positive or node-negative tumors. All 3 aromatase inhibitors were generally well tolerated. Results of these trials indicate that aromatase inhibitors provide important benefits relative to tamoxifen in each of these adjuvant treatment settings, but the optimal approach still needs to be defined. Other trials continue to investigate some of these adjuvant treatment strategies.     

The intratumoral aromatase model: studies with aromatase inhibitors and antiestrogens

Aromatase inhibitors have now been approved as first-line treatment options for hormone-dependent advanced breast cancer. When compared to tamoxifen, these aromatase inhibitors provide significant survival and tolerability advantages. However, the optimal use of an aromatase inhibitor and tamoxifen remains to be established. To date, the intratumoral aromatase xenograft model has proved accurate in predicting the outcome of clinical trials. Utilizing this model, we performed long-term studies with tamoxifen and letrozole to determine time to disease progression with each of the treatment regimens. Aromatase-transfected MCF-7Ca human breast cancer cells were grown as tumor xenografts in female ovariectomized athymic nude mice in which androstenedione was converted to estrogen and stimulated tumor growth. When tumor volumes were approximately 300 mm³, the animals were grouped for continued supplementation with androstenedione only (control) or for treatment with letrozole 10 μg per day (long-term), tamoxifen 100 μg per day (long-term), letrozole alternating to tamoxifen (4-week rotation), tamoxifen alternating to letrozole (4-week rotation), or a combination of the two drugs. Tumors of control mice had doubled in volume in 3–4 weeks. In mice treated with tamoxifen and the combination, tumor doubling time was significantly shorter (16 and 18 weeks, respectively) than with letrozole (34 weeks). Furthermore, alternating letrozole and tamoxifen treatment every 4 weeks was less effective than letrozole alone. Tumors doubled in 17–18 weeks when the starting treatment was tamoxifen and in 22 weeks when the starting treatment was letrozole. Tumors progressing on tamoxifen remained sensitive to second-line therapy with letrozole (10 μg per day). However, when mice with letrozole-resistant tumors were switched to antiestrogen treatment, tumors did not respond to tamoxifen (100 μg per day) or faslodex (1 mg per day). This suggests that advanced breast cancers treated with letrozole may be insensitive to subsequent second-line hormonal agents. Thus, although letrozole was determined to be an effective second-line treatment option for tumors progressing on tamoxifen, antiestrogen therapy does not appear to be effective for tumors progressing on letrozole. However, response to second-line treatment was observed in a model where tumors that had progressed on letrozole were transplanted to new mice. These tumors had been allowed to grow in the presence of supplemented androstenedione but absence of letrozole. This suggests that resistance to letrozole may be reversible, allowing tumors to respond to subsequent antiestrogens and letrozole.     

Bayesian adaptive trial design for a newly validated surrogate endpoint

The evaluation of surrogate endpoints for primary use in future clinical trials is an increasingly important research area, due to demands for more efficient trials coupled with recent regulatory acceptance of some surrogates as 'valid.' However, little consideration has been given to how a trial that utilizes a newly validated surrogate endpoint as its primary endpoint might be appropriately designed. We propose a novel Bayesian adaptive trial design that allows the new surrogate endpoint to play a dominant role in assessing the effect of an intervention, while remaining realistically cautious about its use. By incorporating multitrial historical information on the validated relationship between the surrogate and clinical endpoints, then subsequently evaluating accumulating data against this relationship as the new trial progresses, we adaptively guard against an erroneous assessment of treatment based upon a truly invalid surrogate. When the joint outcomes in the new trial seem plausible given similar historical trials, we proceed with the surrogate endpoint as the primary endpoint, and do so adaptively-perhaps stopping the trial for early success or inferiority of the experimental treatment, or for futility. Otherwise, we discard the surrogate and switch adaptive determinations to the original primary endpoint. We use simulation to test the operating characteristics of this new design compared to a standard O'Brien-Fleming approach, as well as the ability of our design to discriminate trustworthy from untrustworthy surrogates in hypothetical future trials. Furthermore, we investigate possible benefits using patient-level data from 18 adjuvant therapy trials in colon cancer, where disease-free survival is considered a newly validated surrogate endpoint for overall survival.     

Aromatase inhibitors versus tamoxifen for management of postmenopausal breast cancer in the advanced disease and neoadjuvant settings

The third-generation aromatase inhibitors anastrozole, exemestane and letrozole have become firmly established as the agents of choice in patients with tamoxifen-resistant tumors. Large, well-conducted, double-blind clinical trials directly comparing the non-steroidal aromatase inhibitors anastrozole and letrozole with tamoxifen in the advanced disease setting have matured. Based on these trials, there is sufficient evidence to choose one of these agents over tamoxifen because of a superior time to disease progression and acceptable toxicity which includes a lower incidence of thromboembolic complications. Information for the steroidal aromatase inhibitor exemestane will be forthcoming from a phase III trial which has completed accrual. Consistent with the findings in the advanced disease setting, a double-blind trial comparing letrozole with tamoxifen in the neoadjuvant setting revealed superiority for letrozole in terms of clinical response rate. This provides a strong impetus for further study of the aromatase inhibitors in the preoperative setting.     

Endocrine approaches for the treatment of early and advanced breast cancer in postmenopausal women

Preventing clinical progression is the major treatment goal for both early and advanced breast cancer. For hormone-responsive cases (about 70% of the total), this can necessitate the use of sequential hormone therapies at various points during the patient's life. Newer hormonal therapies, such as the third-generation aromatase inhibitor anastrozole, are now competing with tamoxifen as first choice endocrine therapy in breast cancer. In addition, a further non-steroidal aromatase inhibitor letrozole has been shown to be beneficial when given at completion of 5 years adjuvant tamoxifen. In light of these new data, current treatment paradigms need to be reviewed. Already well established as second-line treatments for advanced breast cancer, the improved risk:benefit profiles of anastrozole and letrozole compared with tamoxifen mean that these agents are now also recognised alternative treatments in the first-line relapse setting. More recent studies demonstrate that anastrozole may also have an improved risk:benefit profile compared with tamoxifen when used as initial adjuvant therapy in early breast cancer. Anastrozole is also being evaluated as a preventative treatment in women at high risk of developing breast cancer. A new addition to the endocrine treatment armamentarium is the oestrogen receptor antagonist fulvestrant, which, unlike tamoxifen, has no agonist effects. Fulvestrant is at least as effective as anastrozole in the second-line treatment of advanced breast cancer, and provides similar benefits to tamoxifen when used as first-line therapy in patients with advanced, hormone receptor-positive tumours.     

The evaluation of multiple surrogate endpoints

Surrogate endpoints are desirable because they typically result in smaller, faster efficacy studies compared with the ones using the clinical endpoints. Research on surrogate endpoints has received substantial attention lately, but most investigations have focused on the validity of using a single biomarker as a surrogate. Our paper studies whether the use of multiple markers can improve inferences about a treatment's effects on a clinical endpoint. We propose a joint model for a time to clinical event and for repeated measures over time on multiple biomarkers that are potential surrogates. This model extends the formulation of Xu and Zeger (2001, in press) and Fawcett and Thomas (1996, Statistics in Medicine 15, 1663-1685). We propose two complementary measures of the relative benefit of multiple surrogates as opposed to a single one. Markov chain Monte Carlo is implemented to estimate model parameters. The methodology is illustrated with an analysis of data from a schizophrenia clinical trial.