Femara Effective Even After Years of No Therapy

April 1, 2006

Two analyses from the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.17 letrozole (Femara) trial strongly support the ability of this aromatase inhibitor to significantly reduce disease recurrence among postmenopausal women previously treated with tamoxifen.

SAN ANTONIO—Two analyses from the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.17 letrozole (Femara) trial strongly support the ability of this aromatase inhibitor to significantly reduce disease recurrence among postmenopausal women previously treated with tamoxifen. This holds true even among women who are switched to the drug after a prolonged interval without treatment, according to trial results presented at the 28th Annual San Antonio Breast Cancer Symposium.

In the first presentation (abstract 16), Paul Goss, MD, PhD, principal investigator of MA.17, briefly reviewed the study findings prior to unblinding of this double-blind trial. The 5,137 women in the study had received tamoxifen for up to 5 years and had then been randomized to letrozole or placebo. The final analysis of disease-free survival before the unblinding (median follow-up, 30 months) showed a hazard ratio (HR) of 0.58 in favor of letrozole. The magnitude of the benefit led to unblinding of MA.17 at which time women on placebo were given the opportunity to be treated with letrozole for 5 years. Given this option, 1,655 of the placebo-treated women elected to switch, and 613 women chose no further treatment. "Older women tended not to switch to letrozole," reported Dr. Goss, director, Breast Cancer Research, Massachusetts General Hospital, and professor of medicine, Harvard Medical School. "Interestingly, more women with a worse ECOG performance status elected to switch."

In general, women who opted to take letrozole were younger, had more advanced disease, had a worse performance status, and were more likely to have had adjuvant chemotherapy. Dr. Goss noted that women who did not opt for letrozole treatment may have had a better prognosis or more comorbid disease.

In their analysis, the researchers compared outcomes in women who had switched from placebo to letrozole against outcomes in women who had received placebo and then opted for no further treatment. Results were adjusted for variables such as tumor size, nodal status, and prior adjuvant chemotherapy. Women who switched to letrozole did better on all outcome measurements.

"A substantially lower percentage of women experienced a new primary recurrent breast cancer, locoregional recurrence, distant recurrence, or contralateral new primary breast cancer," Dr. Goss said. The HRs were 0.31 for disease-free survival, 0.28 for distant disease-free survival, 0.53 for overall survival, and 0.23 for contralateral breast cancer.

Letrozole toxicity was primarily a numerical but not statistically significant increase in bone fractures in women switching to letrozole, and an increase in self-reported new diagnoses of osteoporosis in this group. No differences in cardiovascular events were seen.

While Dr. Goss noted that the two groups compared post-unblinding had very different baseline characteristics, he emphasized that, "if anything, women who chose to switch to letrozole had a higher risk of disease recurrence, as reflected by their higher lymph node status." The significant improvement seen in these women after a prolonged delay following completion of tamoxifen suggests that other women with a similar treatment history should be considered for letrozole treatment, he added.

Similar to other recent aromatase inhibitor adjuvant trials, MA.17 was not designed to address optimal duration of treatment, Dr. Goss said. In a second MA.17 presentation (abstract 17), coinvestigator James N. Ingle, MD, did provide some insight from the blinded portion of the trial into event rates with letrozole over time. Dr. Ingle is professor of oncology and head of the Breast Cancer Research Program, Mayo Clinic College of Medicine, Rochester, Minnesota.

Dr. Ingle reported the analysis of the effects of treatment duration among women in the original, blinded period. The overall finding was that, at least through the 48 months of the analysis, the longer the women stayed on letrozole, the better off they were.

For the primary endpoint of the trial (disease-free survival), the HR for letrozole over placebo was 0.52 at 12 months, 0.45 at 24 months, 0.35 at 36 months, and 0.19 at 48 months. "The decreasing trend of hazard ratios over time was significant, indicating a greater letrozole benefit over the time period examined," Dr. Ingle said. "Distant disease-free survival showed a similar pattern of increasing superiority for letrozole over time, which was significant. For overall survival, the HR was always less than 1, but the trend was not significant."

Among node-positive patients, the HRs for all three endpoints decreased significantly over time. In the node-negative patients, the decreasing HRs for disease-free survival were significant, but the trends were not significant for the other two endpoints. "At least out to about 48 months, longer duration of letrozole is associated with greater benefit," Dr. Ingle concluded. "The only subset in which HRs were not superior with letrozole was overall survival in node-negative patients," who showed an increase in non-cancer-, non-treatment-related deaths.

To further define the optimal adjuvant therapy in postmenopausal women with node-positive early breast cancer, Novartis has initiated the FACE trial (Femara vs Anastrozole Clinical Evaluation), comparing letrozole vs anastrozole (Arimidex) as initial adjuvant therapy after breast cancer surgery.