Article by freelance journalist Dr Ian Mason

The CONFIRM study (COmparisoN of Faslodex In Recurrent or Metastatic breast cancer), a Phase III, randomized, parallel-group trial comparing the currently approved 250mg dose of fulvestrant with fulvestrant at the increased dose of 500mg* in postmenopausal women with oestrogen receptor-positive advanced breast cancer showed the 500mg dose of fulvestrant to be well tolerated and more efficacious than the standard 250mg dose.¹

"We believe that, based on the results of this study, treatment and practice could change," said Dr Angelo Di Leo, Director of the Department of Oncology at the Hospital of Prato, Italy and principal investigator of CONFIRM.

Di Leo and colleagues conducted the CONFIRM study to compare the efficacy, response rate, rate and duration of clinical benefit, overall survival, tolerability and quality of life of fulvestrant at the two doses.

Over a two-year period, the researchers recruited 736 women from 128 centres located in 17 countries. Findings showed that the 500mg dose of fulvestrant was significantly more active but remained just as well tolerated as the 250mg dose.

The results showed a statistically significant 20% reduction in risk of disease progression (TTP) for patients receiving a 500mg dose of fulvestrant (n=362), compared with 250mg (n=374);(HR 0.80; 95% CI 0.68-0.94, p=0.006). As a result, 34% of patients in the fulvestrant 500mg group remained alive and progression-free after 1 year compared with only 25% of those in the 250mg group. "Importantly, the tolerability profile was similar in both groups, with no new safety concerns identified at the 500mg dose," said Dr Di Leo.

He believes that increasing the dose if fulvestrant amplifies down regulation of the oestrogen receptor, which plays a key role in driving proliferation of oestrogen dependent tumours.

Dr Di Leo added that there may be cost implications since the formulation of fulvestrant meant that it would be necessary to purchase two vials of drug (usually injected one vial into each buttock).

 

FACT: Dual drug no better than single agent AI

The FACT study (Fulvestrant and Anastrozole in Combination Trial) was also presented at SABCS 2009.² This investigated the alternative strategy of combining the currently approved 250mg dose of fulvestrant with the aromatase inhibitor anastrozole versus anastrozole alone. The results, presented by Dr Jonas Bergh (Karolinska Institute and University Hospital), showed that no additional advantage was observed by combining therapies. The Kaplan Meier plots of time to progression (TTP, the primary endpoint) for the combined and monotherapy arms were almost identical with medians of 10.8 and 10.2 months respectively.

"Fulvestrant and anastrozole in combination offer no clinical advantage over anastrozole alone and should not be used," said Dr Bergh.

 

TEAM clarifies competing AI strategies

Third generation aromatase inhibitors have shown clear superiority compared to tamoxifen both as initial endocrine therapy (ATAC, BIG 1-98) showing a 23% proportional reduction in recurrence; or introduced as an alternative after 2-3 years of adjuvant tamoxifen (IES, ARNO, ABCSG, ITA) showing a 29% proportional reduction in recurrence. "However if you take patients who have been put on tamoxifen, and who seem to doing well, and after two to three years and you change their treatment to a third generation aromatase inhibitor (AI), you then see a proportionately bigger effect on reduction in risk of recurrence, so there is a dilemma, should you give an AI at the earliest opportunity, because that is a better therapy, or should we be trying to exploit this rather bigger effect by putting patients on tamoxifen first and then trying to exploit the benefit of the AIs?" said Dr Daniel Rea, Senior Lecturer in Medical Oncology, The University of Birmingham, UK and Principal Investigator of the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study - a trial designed to resolve this question.³ "Should we go with a third generation AI upfront or delay initiation for 2-3 years?" said Dr Rea.

TEAM, a Phase III trial compared five years of exemestane as initial therapy compared to five years of tamoxifen followed by exemestane in postmenopausal women with hormone-sensitive early breast cancer. Dr Rea said that TEAM had taken ten years to complete and had recruited 9775 women.

The final results showed no difference in efficacy between the two groups, measured as disease-free survival (the primary end point), time to recurrence, or overall survival. "There was no sniff of a survival difference between the two arms" said Dr Rea. There were no outcome differences for node negative or node positive populations at five years. The safety profile was consistent with known side effects of exemestane and tamoxifen.

Upfront exemestane was associated with increased reported incidence of AI associated side-effects such as osteoporosis, fractures, arthralgia, nerve compression, vaginal dryness, hypertension and hyperlipidaemia.

Tamoxifen followed by exemestane was associated with increased reported incidence of tamoxifen associated side effects such as hot flushes, vaginal bleeding and discharge, endometrial pathology, venous thrombosis and muscle cramp.

Dr Rea said that there were 17 endometrial cancers in the patients exposed to tamoxifen and seven in the patients exposed to exemestane alone, a non significant difference.

Dr Rea concluded that TEAM was the first trial prospectively powered to really nail the question of whether five years of AI is superior to a specific sequence starting with tamoxifen then moving to an AI. He noted that "both of these strategies appear to be reasonable approaches to the patient with hormone receptor positive cancer and the choice about which one to use will be based on toxicity profile rather than efficacy."

 

BIG 1-98 update

In another presentation by Dr Meredith Regan a further, unprotocolled, retrospective analysis of the BIG1-98 data to adjust for selective cross-over of patients in this trial concluded that the overall survival benefit of letrozole over tamoxifen was significant in contrast to the original intent-to-treat estimate).⁴

 

IES update

An updated analysis from the Intergroup Exemestane Study (IES) was presented by Dr Judith Bliss on Behalf of the IES Steering Committee.⁵ The results showed that the protective effect of switching to exemestane compared with continuing with tamoxifen on relapse rate is maintained for at least five years post treatment completion.

"In patients treated with tamoxifen for 2-3 years, switching to exemestane as compared with continuing tamoxifen out to five years resulted in a real improvement in breast cancer outcome which appeared to persist for at least nine years," said Dr Bliss. "There was a modest but persistent improvement in overall survival consistent with 50 fewer patients with distant recurrence, consistent with a 2.4% absolute improvement in overall survival."

 

Caution over treatment-emergent symptoms

Musculoskeletal adverse events represent a major obstacle to optimal use of aromatase inhibitors in women with breast cancer. A preliminary analysis of data from study NCIC CTG MA.27 Adjuvant Aromatase Inhibitor Trial, presented by Dr Vered Stearns, showed that in contrast to prior findings, the researchers did not observe a correlation between early emergence of vasomotor or joint symptoms and improved relapse-free survival at three, six and 12 months follow-up.⁶ "Until further data are available, clinicians should not use treatment-emergent symptoms to counsel their patient whether to continue or change their prescribed medication," said Dr Stearns. A related presentation by Dr Jim Ingle reported data from a genome-wide association study in patients experiencing musculoskeletal adverse events on aromatase inhibitors in NCIC CTG Trial MA.27.⁷ The results showed that single nucleotide polymorphisms (SNPs) on chromosome 14 may provide a focus for further research to identify patients at risk for, and means to ameliorate, this adverse event. Women with this SNP may be more sensitive to oestrogen deprivation, the authors believe.

 

Protein kinase inhibitors and AI resistance

Two small studies reported similar findings showing restoration of endocrine sensitivity in selected patients with oestrogen-receptor positive metastatic breast cancer by the addition of a protein kinase inhibitor.^{8, 9} Dr GN Schwartz and colleagues (The University of Colorado Health Science Center), reported preliminary data suggesting a favourable interaction between the tyrosine kinase inhibitor, lapatinib, and both aromatase inhibitors and anti-oestrogens in patients with newly acquired endocrine resistance. In a highly selected group of patients, the addition of lapatinib to the endocrine agent on which the cancer had just progressed maintained the duration of response by an average of six months.

Dr Claudine Isaacs and colleagues Georgetown University, Washington, DC, reported a Phase II study in which the multi (Raf)-kinase inhibitor sorafenib (400mg twice daily) was combined with anastrozole to overcome AI-resistance in patients with (ER/PR ) metastatic breast cancer. The combination demonstrated a clinical benefit rate of 20%. "Given the negligible activity of single-agent sorafenib in metastatic breast cancer, we believe that the benefit may be attributable to the restoration of sensitivity to AIs through inhibition of the Ras-Raf-MAPK pathway," they reported. The most common adverse events (all Grade 3/4) were fatigue (66%; 14%), diarrhoea (54%; 6%), nausea/vomiting (60%; 9%), and skin rash of any kind (66%; 43%) including hand-foot syndrome (57%; 34%). G3/4 hypertension occurred in 11%.

References
1. Di Leo A, Jerusalem G, Petruzelka L et al. CONFIRM: Phase III, randomized, parallel-group trial comparing fulvestrant 250 mg vs fulvestrant 500 mg in postmenopausal women with oestrogen receptor-positive advanced breast cancer. San Antonio Breast Cancer Symposium 2009. Oral session 2 on Thursday 10th December 2009 at 16.00 PST. Abstract 25.
2. Bergh J, Jönsson PE, Lidbrink E et al. First results from FACT - An open-label, randomized phase III study investigating loading dose of fulvestrant combined with anastrozole versus anastrozole at first relapse in hormone receptor positive breast cancer. San Antonio Breast Cancer Symposium 2009. Oral session 2 on Thursday 10th December 2009 at 15.30 PST. Abstract 23.
3. Rea D, Hasenburg A, Seynaeve C et al. Five years of exemestane as initial therapy compared to 5 years of tamoxifen followed by exemestane: the TEAM trial, a prospective, randomized, phase III trial in postmenopausal women with hormone-sensitive early breast cancer. San Antonio Breast Cancer Symposium 2009. San Antonio Breast Cancer Symposium 2009. General Session 1 on Thursday 10th December 2009 at 9.15 PST. Abstract 11.
4. Regan MM, Colleoni M, Giobbie-Hurder A et al. Adjusting for selective crossover in analyses of letrozole (let) versus tamoxifen (tam) in the BIG 1-98 trial. San Antonio Breast Cancer Symposium 2009. General session 1 on Thursday 10th December 2009 at 10.30 PST. Abstract 16.
5. Bliss JM, Kilburn LS, Coleman RE et al. Disease related outcome with long term follow-up: an updated analysis of the intergroup exemestane study (IES). San Antonio Breast Cancer Symposium 2009. General session 1 on Thursday 10th December 2009 at 9.30 PST. Abstract 12.
6. Stearns V, Chapman J-A, Ma C et al. treatment-emergent symptoms and the risk of breast cancer recurrence in the NCIC CTG MA.27 adjuvant aromatase inhibitor trial. San Antonio Breast Cancer Symposium 2009. General session 1 on Thursday 10th December 2009 at 10.00 PST. Abstract 14.
7. Ingle J, Schaid D, Goss P et al. A genome-wide association study in patients experiencing musculoskeletal adverse events on aromatase inhibitors as adjuvant therapy in early breast cancer entered on NCIC CTG Trial MA.27. A pharmacogenetics research network-RIKEN collaboration. San Antonio Breast Cancer Symposium 2009. General session 1 on Thursday 10th December 2009 at 10.15 PST. Abstract 15.
8. Schwartz GN, Borges VF, Weiselberg LR et al. Lapatinib restores endocrine sensitivity in selected patients with estrogen receptor (ER) positive metastatic breast cancer. San Antonio Breast Cancer Symposium 2009. Poster session 3 on Friday 11th December 2009 at 10.00 PST. Poster 3089.
9. Isaacs C, Wilkinson M, Liu MC et al. Phase II study of sorafenib with anastrozole to overcome resistance to aromatase inhibitors (AIs) in patients with hormone receptor positive (ER/PR ) AI resistant metastatic breast cancer (MBC). San Antonio Breast Cancer Symposium 2009. Poster session 3 on Friday 11th December 2009 at 10.00 PST. Poster 3090.