BIG 1-98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for post-menopausal women with receptor-positive breast cancer.
Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: May 15, 2005
Presenter: B.J. Thurlimann
Presenter's Affiliation: BIG 1-98 Collaborative, Bern, Switzerland
Type of Session: Scientific
- Letrozole is a drug in a class of medications known as aromatase inhibitors, which almost completely inhibit the synthesis of estrogen.
- Tamoxifen is an estrogen receptor blocker.
- Women with breast cancers that express estrogen receptors have been shown to derive significant benefit from adjuvant tamoxifen given for 5 years following local therapy.
- Letrozole has recently proven beneficial both in metastatic breast cancer patients and in patients who remained disease free after five years of tamoxifen.
- This study was designed to compare the two medications.
Materials and Methods
- An international breast cancer study group (BIG 1-98) randomized 8028 patients on a phase III, double blind study of adjuvant therapy for breast cancer.
- Four arms were established: 5 years of tamoxifen, 5 years of letrozole, 2 years of tamoxifen followed by 3 years of letrozole, and 2 years of letrozole followed by 3 years of tamoxifen.
- 8010 patients were evaluable using an intent-to-treat analysis.
- The median follow-up was 25.8 months.
- Patients were required to have hormonally responsive tumors, and the vast majority (>99%) had ER+ tumors.
- The arms were well balanced in terms of disease and demographic variables including: age, tumor size, nodal status, history of chemotherapy, and hormonal receptor positivity.
- Primary endpoint was disease free survival.
- Disease free survival was defined as: no evidence of recurrent disease, contralateral breast cancer, second malignancy or death from other causes.
- For this analysis, only the arms with 5 years of tamoxifen and 5 years of letrozole were compared
- The letrozole arm had significantly improved disease free survival compared to the tamoxifen arm (hazard ratio 0.81, p=0.003)
- This translates to an overall benefit in disease free survival of 2.6% in the letrozole arm.
- The cumulative incidence of any breast cancer event at 5 years was 10.2% for the letrozole arm and 13.6% for the tamoxifen arm.
- Letrozole was noted to improve distant control compared to tamoxifen at 5 years (distant failure 4.4% letrozole arm vs. 5.8% tamoxifen arm, p=0.005)
- There was no significant difference seen in overall survival between the two arms.
- The adverse event rates were generally similar between both arms.
- There were more thromboembolic events, endometrial cancers and endometrial biopsies seen with tamoxifen.
- There were more cardiac events, joint problems and diagnoses of hypercholesterolemia in the letrozole arm.
- Five years of letrozole improves disease free survival compared to five years of tamoxifen when given as adjuvant therapy in hormonally responsive breast cancers.
- In particular, letrozole seems to improve rates of distant metastasis compared with tamoxifen.
- The two medications have similar low rates of adverse events, although the types of events differ.
- Further follow-up is needed to solidify the superiority of letrozole over tamoxifen, and future analyses will examine the crossover patients.