The Absolute Effect / Evidence / BIG 1-98
BIG 1-98
In postmenopausal women with hormone-receptor-positive early breast cancer, does adjuvant letrozole improve outcomes compared with tamoxifen, and do sequential regimens improve on letrozole alone?
Trial registry: NCT00004205 · One underlying study; follow-up publications consolidated.
Design, population and eligibility
International phase III randomized trial with two-arm and four-arm randomization options.
8,010 patients in the trial; monotherapy comparison included 4,922 women randomized to five years of letrozole or tamoxifen.
Postmenopausal women with steroid hormone receptor-positive early breast cancer after surgery; adjuvant chemotherapy permitted as clinically indicated.
Primary long-term monotherapy analysis at median 8.7 years; later follow-up reported at longer intervals.
Treatment and comparator
Letrozole 2.5 mg orally once daily for five years; sequential arms used two years of one endocrine agent followed by three years of the other.
Tamoxifen 20 mg orally once daily for five years; four-arm randomization also included tamoxifen→letrozole and letrozole→tamoxifen sequences.
Primary endpoint: Disease-free survival (DFS) in the randomized adjuvant endocrine strategy.
Other endpoints: Overall survival, distant recurrence-free interval, breast cancer-free interval and treatment tolerability.
Key efficacy results
At median follow-up 8.7 years, ITT DFS HR for letrozole versus tamoxifen was 0.86 (95% CI 0.78–0.96); OS HR 0.87 (95% CI 0.77–0.999).
Distant recurrence-free interval HR 0.86 (95% CI 0.74–0.998); breast cancer-free interval HR 0.86 (95% CI 0.76–0.98).
In the sequential-treatment analysis, no significant differences were found for the prespecified endpoints comparing either sequence with letrozole monotherapy. Eight-year ITT DFS estimates were 78.6% for letrozole, 77.8% for letrozole→tamoxifen and 77.3% for tamoxifen→letrozole.
Source-reported outcome visualization
Relative effect on invasive disease-free survival · Median follow-up 8.7 years
Relative-effect visualization uses the reported ITT DFS HR; it is not an absolute survival curve.
Absolute effect
The ITT DFS hazard was reduced by 14% with letrozole (HR 0.86). A comparator-specific fixed-time DFS pair is not reproduced here from the primary abstract; therefore no absolute NNT is assigned.
NNT: Not calculated from the HR; fixed-time comparator rates must be taken from the full Kaplan–Meier analysis before assigning NNT.
NNH: Not quantified as a fixed-time grade ≥3 adverse-event endpoint.
Toxicity, harms and treatment burden
Tamoxifen: more thromboembolic events, vaginal bleeding and vasomotor symptoms. Letrozole: more arthralgia/myalgia, vaginal dryness, osteoporosis and fractures; cardiac events require context.
Sequential therapy did not improve efficacy over letrozole monotherapy in the randomized comparison; it may be considered for tolerability and individual risk.
Trial-specific grade 3–5 toxicity and treatment discontinuation rates are not consistently captured in the cited long-term abstract; no rates are fabricated.
Quality of life and patient-reported outcomes
Quality-of-life and symptom trade-offs differ by endocrine agent. The choice may depend on baseline bone health, thromboembolic risk, arthralgia and patient preference; do not imply a global QoL advantage from DFS results alone.
Subgroups, maturity and limitations
Long-term follow-up found continued trends favouring letrozole, with time-dependent contralateral breast cancer effects and potential carryover from tamoxifen.
The monotherapy and sequential-treatment populations arise from different randomization options; do not pool denominators or compare non-randomized treatment sequences as if they were one four-arm trial.
The later long-term follow-up HR for DFS was 0.91 (95% CI 0.81–1.01), emphasizing attenuation and the importance of follow-up and analysis population.
Clinical interpretation
Current-practice context · 1 November 2026 (full guideline freshness review pending): Adjuvant endocrine therapy is individualized by menopausal status, recurrence risk, tolerance and bone/thrombotic comorbidity. The historical five-year comparisons should be integrated with contemporary duration, ovarian suppression and targeted adjuvant strategies.
Primary sources and registry
- Mouridsen et al. / BIG 1-98 8.1-year median follow-up (PubMed)
- BIG 1-98 long-term follow-up
- ClinicalTrials.gov NCT00004205
Source hierarchy: primary randomized report and prespecified follow-up first; registry and current guidance are supplementary. Values not reported in the cited primary sources are explicitly marked unavailable rather than imputed.