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31st Congress of the European Society for Medical Oncology

Istanbul, Turkey / September 29 - October 3, 2006

In presenting more than four years data of the Breast International Group (BIG) 1-98, Dr. Alan S. Coates, School of Public Health, University of Sydney, Australia, explained that the trial randomized more than 8000 postmenopausal women with hormone receptor-positive (HR+) breast cancer to one of four regimens: five years of tamoxifen or the aromatase inhibitor (AI) letrozole; tamoxifen for two years followed by letrozole for three years; or letrozole for two years and then tamoxifen for three years.

Data at 51 Months

The 51-month analysis was based on the nearly 5000 women in the first two arms. The sequential arms were excluded for the 51-month analysis because they might have unduly weighed down the results with early events and distorted long-term findings.

According to Dr. Coates, “This updated analysis of the monotherapy arms of the BIG 1-98 study with twice the median follow-up time of the first 26-month evaluation confirms the earlier published findings [N Engl J Med 2005; 353:2747-57] showing letrozole to be superior to tamoxifen in the defined primary end point of disease-free survival (DFS), and a number of secondary end points, importantly, including time to distant recurrence over the long term.”

Dr. Coates reported that very few individuals withdrew from follow-up, and the intent-to-treat analysis included almost all patients. “This leaves us with an end point number for DFS of 352 events in the letrozole arm and 418 in the tamoxifen arm, which is rather similar to all four arms in the original NEJM article. Similar numbers of systemic DFS events (331 and 374) were also similar to the original publication, but rather more deaths were available (194 and 211) than in the earlier follow-up (166 and 192),” he stated.

After the median long-term follow-up of more than four years, postmenopausal women with hormone-sensitive early breast cancer given the AI still achieved a significant 18% reduction in overall disease recurrence. The risk of distant metastasis, a well-recognized predictor of breast cancer death, was reduced by 19% at 51 months. Importantly, the increased risk of recurrence among women diagnosed with node-positive disease and those who had received chemotherapy was significantly reduced by 23% (P=0.004) and 26% (P=0.03), respectively.

Safety Profile Update

“Investigators have sometimes worried about the possibility that the superiority of the AI over tamoxifen might differ according to patient subgroups. What is clear from this analysis is that no subgroup—whether by age, primary tumour size, node-negative or -positive, progesterone receptor-positive or -negative [all patients were estrogen receptor-positive], or by the type of surgery or radiotherapy, or presence or absence of adjuvant chemotherapy—none of those groups show any evidence that the effectiveness of letrozole over tamoxifen is any different from the group as a whole,” Dr. Coates remarked. “It would be dangerous to conclude from these data that there is any group in which letrozole is not superior to tamoxifen to the same extent as is true for the overall group,” he added.

The safety profile of the study agents at 51 months was essentially the same as that published following the 26-month review, Dr. Coates observed. Patients treated with tamoxifen experienced significantly more frequent and higher-grade thrombo-embolic events in addition to endometrial pathology, hot flushes, night sweats and vaginal bleeding. Patients treated with the AI experienced more bone fractures, arthralgia and low-grade hypercholesterolemia, which turned out to be an artifact of the cholesterol-lowering effect of tamoxifen.

After a thorough review, Dr. Coates’ BIG 1-98 group reported that there was no significant difference in the distribution of cardiac toxicity grades or total cardiac events between the AI and tamoxifen treatment arms (Figure 1). “That is true of the rather smaller number of events of ischemic heart disease of various grades and is true of an even smaller number of cardiac failure events of various grades,” he explained.

Figure 1. Any Cardiac Event: Grade

“The safety profile is essentially similar to what has already been published for the primary core analysis, confirming the efficacy and safety of letrozole,” Dr. Coates concluded. “With more follow-up, we may see even more superiority that might be of long-term value to patients. The 51-month safety profile essentially mirrors what has already been published for these agents.”

Hypercholesterolemia and Cardiovascular Data

The total cardiovascular (CV) event difference was not significant between letrozole and tamoxifen in BIG 1-98. The relative neutral effect of AIs on cholesterolemia and CV events was further demonstrated in a study presented at this meeting. Led by Dr. Alain Monnier, Department of Medical Oncology, Centre Hospitalier de Belfort-Montbéliard, Montbéliard, France, the relative risk of CV events in patients randomized to AIs was compared to that of placebo rather than tamoxifen.

Investigators noted that in such trials as MA.17, no difference in lipid changes or in CV events was observed between letrozole and placebo. They reported that these data demonstrate that the AI is not associated with hypercholesterolemia or increased CV risk. Rather, the investigators speculated that the 1% higher rate of grade 3 to 5 cardiac events (2.1% vs. 1.1%) among those randomized to letrozole vs. tamoxifen in BIG 1-98 is most likely due to the lipid-lowering effects of tamoxifen.

The frequency of fatal CV events in the adjuvant AI trials is comparable to an age-matched population of postmenopausal women without breast cancer. This likely suggests that AIs do not increase the incidence of fatal CV complications but lack the cardioprotective effects of tamoxifen, authors concluded.

Putting Updated Findings into Clinical Perspective

Dr. Gabriel Hortobagyi, University of Texas M.D. Anderson Cancer Center, Houston, remarked that adopting a strategy suggesting anything other than early institution of an AI would lead to some patients experiencing relapses that would not have occurred had an AI been introduced. An AI alone or after initial treatment with tamoxifen is the optimal intervention for postmenopausal women and improved survival is emerging in several ongoing trials.

The questions yet to be answered about AIs include optimal treatment duration, crossover vs. up-front strategies, the optimal sequence and if there is a role for selective estrogen receptor modulators and selective estrogen receptor down-regulator after AI. “Probably more important is to determine if there are subsets of HR+ tumours that require different strategies. It is quite possible that some patients with HR+ tumours will benefit more from an AI upfront, and others will benefit equally or even more from a sequencing strategy,” Dr. Hortobagyi concluded.