Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

33rd European Society for Medical Oncology Congress

Stockholm, Sweden / September 12-16, 2008

The estrogen receptor (ER) antagonist tamoxifen long served as a gold standard for adjunctive endocrine therapy in ER-positive (ER+) and progesterone receptor-positive (PR+) postmenopausal breast cancer, but a five-year regimen is no longer recommended in this population. Guidelines issued by the American Society of Clinical Oncology (ASCO) and the St. Gallen International Consensus now recommend either initiating therapy on an aromatase inhibitor (AI) or switching to an AI after an initial two to three years on tamoxifen. Most of the switch studies are based on an improvement in disease-free survival (DFS) but the largest of these demonstrated an improvement in overall survival.

IES a Landmark Investigation

“The IES [Intergroup Exemestane Study] is the only one of the randomized trials conducted in an adjuvant setting to show a survival benefit with the AIs after a switch,” stated Dr. Hope Rugo, Director, Breast Oncology Clinical Trials Program, University of California at San Francisco Comprehensive Cancer Center. “The survival benefit was observed across a variety of subgroups defined by previous therapies, age, and breast cancer characteristics.”

In the IES study published last year (Coombes et al. Lancet 2007;369:559-70), 4724 postmenopausal patients who had been placed on tamoxifen and were disease-free after two to three years of treatment were randomly assigned to switch to exemestane or to continue on tamoxifen. Patients were reassessed approximately 4.5 years after the randomization when outcomes significantly favoured the switch. In those taking the AI, there was a 24% improvement in DFS relative to those who remained on tamoxifen (hazard ratio [HR] 0.76, 95% CI: 0.66-0.88, P=0.0001). In addition, there was a 17% reduction (P=0.05) in all-cause mortality when excluding patients who had ER- disease.

Corroborative Evidence from Other AI Trials

Other switch studies have not demonstrated a survival benefit, but they have demonstrated a DFS advantage over tamoxifen, and there are tolerability advantages for AIs, including a reduced risk of estrogen-mediated side effects such as hot flashes. While tamoxifen provides greater protection against osteoporosis than AIs, AIs are associated with relative protection against deep venous thrombosis, cardiovascular disease and endometrial cancer. It is this favourable benefit-to-risk ratio that provided an impetus for a series of studies comparing an AI to tamoxifen as initial adjuvant therapy. Again, for the primary outcome of DFS, the AIs have been favoured, producing a 13% improvement (HR 0.87, 95% CI: 0.78-0.97, P=0.01) in DFS in the ATAC (Anastrozole, Tamoxifen, Alone or in Combination) trial and a 19% improvement (HR 0.81; 95% CI: 0.70-0.93; P=0.003) in DFS in the BIG (Breast International Group) 1-98 trial.

The ongoing TEAM (Tamoxifen, Exemestane, Adjuvant, Multicenter) trial will be the largest of the upfront AI studies. It randomized 9487 postmenopausal breast cancer patients to five years adjuvant exemestane or two to three years of adjuvant tamoxifen followed by exemestane for a total duration of five years. The study has already provided a preliminary encouraging result from a substudy that evaluated endometrial thickening in the two arms. In data reported one year ago, patients randomized to exemestane were five times less likely to develop endometrial thickening than those on tamoxifen. Final results will be closely evaluated not only for relative DFS but also for relative advantages in quality of life. The TEAM trial is also large enough that it may demonstrate survival differences.

Aromatase Inhibition in Premenopausal and Perimenopausal Women

Due to the relative advantages of AIs in the postmenopausal woman, the optimal adjuvant endocrine therapy in the pre- or perimenopausal woman is being re-evaluated. Although there has been reluctance to use AIs in place of tamoxifen prior to menopause because they increase estrogen-biosynthesis and induce ovulation unless combined with a GnRH analogue, the concern that tamoxifen is less effective than AIs, particularly after the initial three years of therapy, has generated interest in switch studies even in this population.

“The optimal adjuvant endocrine treatment in the postmenopausal woman is unclear,” reported Dr. Olaf Ortmann, Chair, Department of Obstetrics and Gynaecology, University of Regensburg, Germany. In particular, “if a younger woman is postmenopausal due to chemotherapy-induced ovarian failure or made effectively postmenopausal with a luteinizing hormone-releasing hormone agonist, there is interest in determining whether we can achieve the same types of benefits seen in the large AI trials, such as IES, by replacing tamoxifen.”

Several trials are underway to address this question, including TEXT (Tamoxifen and Exemestane Trial). In this study, 1317 patients were randomized to ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane. Enrolment was completed almost two years ago and the planned follow-up is five years. However, this question is equally relevant to perimenopausal women who enter the postmenopausal state after initiating therapy on tamoxifen. Based on such studies as IES, it is reasonable to presume that such women would achieve added protection against breast cancer recurrence if switched to an AI after an initial two or three years on tamoxifen once they are menopausal.

“The problem in this patient group is that there are many definitions of menopause and there are no dependable clinical signs,” cautioned Dr. Ortmann. In his practice, he advocates measurements of follicle-stimulating hormone and estradiol to obtain objective support that menopause has occurred.

Emerging Role for Anti-angiogenesis Therapy in Breast Cancer

The promise of lower recurrences with effective adjuvant therapies is paralleled by the promise of greater response rates with anti-angiogenesis drugs. As the prototype, bevacizumab has already been incorporated into routine care, but newer agents may have activities that make them better suited for enhancing the effect of traditional chemotherapies. This is important because anti-angiogenesis drugs halt tumour growth but they do not lead directly to tumour cell eradication, making combination strategies with cytotoxic agents important. Unlike the prototype anti-angiogenesis agents, some of the newer targeted drugs have broad effects on multiple growth factors, which may be an advantage because of redundancies in signalling pathways.

“We have become very interested in sunitinib in breast cancer, because it has a very promiscuous pattern of tyrosine kinase (TK) inhibition,” reported Dr. Jonas Bergh, Scientific Director in Oncology, Karolinska Institute, Stockholm, Sweden. He suggested that newer targeted therapies inhibiting a broader array of TKs might provide more profound anti-cancer effects. These newer targeted agents, by offering activity on different TKs, might have advantages over the initial therapies.

Clinical studies support the interest in sunitinib. In one phase Ib study that combined sunitinib with docetaxel, there were 13 partial remissions (59%) in 22 patients, according to Dr. Bergh. Of the remaining nine patients, five achieved stable disease. Importantly, there were no drug-drug interactions with docetaxel, which appeared to be rendered more active by the combination. Although the rate of side effects was substantial, Dr. Bergh speculated that this disadvantage “may actually be a surrogate marker for a good anti-cancer effect.”

The results of this study and a subsequent phase II study also evaluating the combination of sunitinib and docetaxel in solid tumours have been sufficiently compelling that a phase III trial comparing docetaxel alone to docetaxel plus sunitinib is now enrolling patients. Sunitinib is already approved in renal cell carcinoma and in gastrointestinal stromal tumours. Although experimental studies have associated it with significant activity against breast cancers, the real promise is believed to be its ability to enhance the activity of cytotoxic agents. Due to a broad range of molecular targets, sunitinib and other newer targeted drugs promise a different and potentially greater activity profile than targeted agents already in current use.

Summary

In hormone receptor-positive breast cancer, the introduction of AIs appears to build on the benefits previously associated with tamoxifen. Whether used as a switch strategy after two to three years of tamoxifen or as an upfront therapy in place of tamoxifen, outcome has been improved in several trials, including a survival benefit in the multinational trial with exemestane. In targeted therapy, newer anti-angiogenesis drugs such as sunitinib may also build on the benefits associated with the initial targeted drugs. By aiming at a broader array of targets, these may do better in inhibiting redundant signalling pathways. Current studies with both AIs and targeted therapies are poised to redefine optimal care.