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.

Author's Conclusions

  • 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.

Clinical/Scientific Implications

This abstract reports data from a large, well designed randomized phase III double blind trial comparing letrozole to tamoxifen.  The major criticism of this abstract is that the median follow-up time for these patients was short.  Twenty-six months is considered a short follow-up time in breast cancer given the known natural history of this disease.  However, if this trial is compared to another similarly designed trial of aromatase inhibitors versus tamoxifen ( the ATAC trial  anastrazole for 5 years vs. tamoxifen for 5 years), one notices very similar survival curves.  The magnitude of the improvement in disease free survival calculated in this trial of 2.6% is remarkably similar to the benefit seen in the ATAC trial, and the ATAC trial had 5 years of median follow-up.  It seems reasonable to predict that this trial will demonstrate similar results at 5 years.  Although the rate of adverse events in this trial was low, physicians who use this medication must counsel their patients about the specific risks of letrozole compared to tamoxifen, including risks of cardiac events and hypercholesterolemia.  Finally, society as a whole needs to consider the magnitude of the benefit of this medication compared to tamoxifen while remembering its significantly higher price tag.

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