Source: DGNews  |  Posted 2 years ago

By Walter Alexander

ORLANDO, Fla -- June 1, 2009 -- Women taking letrozole during the last 3 of 5 years of treatment for breast cancer had better cognitive function than those taking tamoxifen, according to trial data presented here at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO).

This finding arose out of a substudy for the Breast International Group (BIG) 1-98 trial evaluating the impact of endocrine treatments on cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen for breast cancer. The substudy data were presented here on May 30 by Karin Ribi, PhD, International Breast Cancer Study Group, Bern, Switzerland.

Dr. Ribi noted that, while cognitive dysfunction has been recognised as a potential long-term side effect of adjuvant chemotherapy for breast cancer, when BIG 1-98 was initiated, studies on the effect of tamoxifen or aromatase inhibitors on cognition were few and conflicting. “It was expected that because of the oestrogen deprivation associated with aromatase inhibitors, patients who received letrozole would have worse cognitive function compared to those who received tamoxifen,” Dr. Ribi said.

In BIG I-98, postmenopausal women with hormone receptor-positive, early-stage breast cancer were randomised to receive adjuvant endocrine treatment of either tamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years followed by letrozole for 3 years, or letrozole for 2 years followed by tamoxifen for 3 years. During the fifth year of trial treatment, components of objective cognitive function (speed of psychomotor function, visual attention, working and verbal memory, learning) were evaluated by computerised tests.

Among 120 eligible patients with a mean age of 64.5 years, each of 7 cognitive measures (expressed through differences in Z-score means) exhibited trends favouring letrozole. The only individual component achieving a statistically significant benefit favouring letrozole, however, was the cognitive domain of visual attention (P = .05). The primary endpoint -- composite score -- did favour letrozole significantly (P = .04) as well. In a test of clinical significance, impairment (defined as Z scores more than 1.96 standard deviations below the norm) was found with both drugs for all cognitive tasks. The greatest difference appeared for memory, impaired by 6.2% for those receiving letrozole and 25.5% for those receiving tamoxifen (P = .003).

“These substudy findings do refute our initial hypothesis,” Dr. Ribi said, “and show better cognitive function for patients taking letrozole.” Dr. Ribi pointed out that some preclinical studies have revealed adverse effects of tamoxifen and cognition enhancement with letrozole.

Dr. Ribi acknowledged study limitations, though, including the lack of a true baseline assessment prior to endocrine therapy, the lack of longitudinal design allowing evaluation of changes during treatment and low accrual. Vered Stearns, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, an ASCO committee member, pointed out further study limitations, such as the mixed population (varying types of surgery, various treatment types and sequences, and differing concomitant medications) and the exclusion of women from analysis who withdrew from the study.

Dr. Stearns did say, however, that these findings are consistent with other datasets, such as that from the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) study, which showed worsened verbal memory and executive functioning compared with healthy controls with 1 year of tamoxifen and no significant differences in any cognitive domain for the aromatase inhibitor exemestane, as compared with healthy controls.

“Prospective studies are needed to determine the magnitude of effect, if any, [on] the specific domains affected by individual agents, and predictive factors,” Dr. Stearns pointed out.

[Presentation Title: Cognitive Function in Postmenopausal Women Receiving Adjuvant Letrozole or Tamoxifen in the Breast International Group (BIG) 1-98 Trial. Abstract 510]