1. JOURNAL OF CLINICAL ONCOLOGY 25:486-492
Five Years of Letrozole Compared With Tamoxifen As Initial adjuvant Therapy For Postmenopausal Women With Endocrine-Responsive Early Breast Cancer: Update of Study BIG Alan S. Coates, Aparna Keshaviah, Beat Thu¨rlimann, Henning Mouridsen, Louis Mauriac, John F. Forbes, Robert Paridaens, Monica Castiglione-Gertsch
JOURNAL OF CLINICAL ONCOLOGY 25:

2. BACKGROUND

3. Value of third generation aromatase inhibitors
adjuvant systemic therapy
postmenopausal women
endocrine-responsive early breast cancer
→ recommended as part of the standard care
Breast International Group (BIG) 1-98 study :
5 years of monotherapy with tamoxifen or letrozole
Sequences of 2 years of one, followed by 3 years of the other
→ gives considerable weight to early events
& difficult to compare with other studies
Analysis of data derived only from continuous tamoxifen or
letrozole on monotherapy → protocol-defined updated results

4. METHODS

5. BIG 1-98 : randomized, phase III, double-blind trial comparing the following four options
monotherapy with letrozole for 5 years
monotherapy with tamoxifen for 5 years
sequential therapy of tamoxifen for 2 years followed by letrozole for 3 years
letrozole for 2 years followed by tamoxifen for 3 years
Patients in postmenopausal women with estrogen receptor– and/or progesterone receptor – positive operable invasive breast cancer

6. letrozole (2.5mg daily)
tamoxifen (20mg daily)

7. Primary end point : disease-free survival (DFS)
Earliest time of invasive recurrence in local, regional or distant sites
new invasive breast cancer in the contralateral breast
any second (nonbreast) malignancy
Earliest time of death from any cause
secondary end points
overall survival : time to death from any cause
systemic DFS : time to systemic recurrence

8. RESULTS
1. Efficacy
2. Safety

9. Patient characteristics
: well-balanced & similar to primary core analysis
Discontinuation of treatment
d/t adverse event
12.3% in letrozole vs 11.1% in tamoxifen
d/t disease progression
7.9% in letrozole vs 11.5% in tamoxifen
Median follow-up time of the monotherapy
: 51 months
→ longer than the primary core analysis (25.8 months)

10. Hazard ratio : 0.82 (p=.007)

12. 81.1 %
84.0%
90.1 %
90.8%

13. Endometrial ca ( 4 vs 16) Colon ca (10 vs 13) Lung ca (5 vs 8)
Oviarian ca (2 vs 6)
Renal ca (3 vs 8)
Others (39 vs 31)
Fig 4. Cumulative incidence of (A) breast relapse, (B) second (nonbreast) malignancy, and (C) death without prior cancer event
comparing letrozole with tamoxifen.
CVA (8 vs 3)
Thromboembolic (3 vs 3)
Cardiac (12 vs 7)
Sudden death (7 vs 11)
Others (30 vs 24)

14. At least one adverse event of any grade : More in letrozole (2,292 vs 2,165)
At least one life-threatening or fatal adverse event : 113 [4.6%] vs 92 [3.8%]
Similar to the primary core results
patients on tamoxifen experienced significantly more
thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding.
Patients on letrozole experienced significantly more
bone fractures, arthralgia, low-grade cholesterol elevation, and cardiovascular events other than ischemic heart disease and cardiac failure.
The relatively higher recording of low-grade cholesterol elevation on letrozole  may be a cholesterollowering effect of tamoxifen.
Although the overall incidence of cardiac adverse events did not differ significantly between the two treatments,
a trend for higher grade cardiac events on letrozole compared with tamoxifen was seen (Table 2)

15. DISCUSSION

16. Modern aromatase inhibitors
: reduce the risk of relapse of early breast cancer among postmenopausal women with endocrine-responsive early breast cancer
Optimal time to aromatase inhibitor therapy
Initially or combination
after approximately 2 years of tamoxifen
after completion of 5 years of tamoxifen
Meta-analysis of aromatase inhibitor trials
To present data more directly comparable with other studies
early benefits of aromatase inhibitors - maintained with prolonged follow-up?

17. In the present analysis of BIG 1-98
Most relevant comparison : hormone receptor–positive cohort in the first update of the ATAC trial : comparison of 5 years of tamoxifen with anastrozole
median follow-up time : 47 months
635 DFS events and a hazard ratio of 0.82 (95% CI, 0.65 to 0.93) favoring anastrozole
In the present analysis of BIG 1-98
Median follow-up time : 51 months
after ignoring second (nonbreast) primary events
671 DFS events : hazard ratio of 0.83 (95% CI, 0.71 to 0.96) favoring letrozole
a role for the inclusion of an aromatase inhibitor in the adjuvant therapy of postmenopausal women with receptorpositive early breast cancer

18. Conclusions Present analysis
(limited to pts on monotherapy arms in BIG 1-98)
essentially confirmatory of the primary core analysis
but more directly comparable