BIG 1-98: What the Breast Cancer Trial Found

The comparison BIG 1-98 was built to make

For years, tamoxifen was the standard hormone treatment after surgery for breast cancer that responds to estrogen. BIG 1-98 asked whether letrozole, a newer kind of hormone drug, did the job better in postmenopausal women.

It was a randomized, double-blind phase 3 trial, registered as NCT00004205 and run by the Breast International Group. The results were published in the New England Journal of Medicine in December 2005.

Two ways to take estrogen out of the picture

Both drugs work on estrogen, but from opposite ends.

Tamoxifen is a selective estrogen receptor modulator. It sits in the estrogen receptor on breast cancer cells so estrogen cannot. The hormone is still in the body; the cancer just cannot hear it.

Letrozole is an aromatase inhibitor. After menopause, most estrogen is made by an enzyme called aromatase, which converts other hormones into estrogen in fat and other tissues. Letrozole blocks that enzyme, so less estrogen is made at all. This only works after menopause, when the ovaries are no longer the main source.

Our page on hormone therapy for breast cancer covers both classes in more detail.

The design, and one thing worth noticing about it

The full trial had four arms: five years of letrozole; five years of tamoxifen; letrozole then tamoxifen; and tamoxifen then letrozole.

The 2005 analysis compared the two groups that started on letrozole against the two that started on tamoxifen. Events and follow-up from the sequential arms counted only up to the point where the drugs were switched. A total of 8,010 women with assessable data were enrolled: 4,003 in the letrozole group and 4,007 in the tamoxifen group.

The main measure was disease-free survival: time without recurrence, without a new cancer and without death.

What the numbers showed

After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group against 428 in the tamoxifen group.

Estimated five-year disease-free survival was 84.0 percent with letrozole and 81.4 percent with tamoxifen, a difference of about 2.6 percentage points. The hazard ratio was 0.81, with a 95 percent confidence interval of 0.70 to 0.93 and a p-value of 0.003. In plain terms, letrozole lowered the risk of an event by roughly 19 percent at any given moment.

The effect was strongest for cancer spreading to distant organs: hazard ratio 0.73, confidence interval 0.60 to 0.88, p-value 0.001. That subgroup matters, because distant spread is what drives deaths from breast cancer.

The harms did not simply favor one drug

This is the part most summaries flatten, and it deserves its own space.

Tamoxifen caused more blood clots, more cancer of the lining of the uterus, and more vaginal bleeding. Letrozole caused more bone and skeletal problems, including fractures, more cardiac events, and more high cholesterol.

The two drugs trade one set of harms for another. Which trade fits a particular person depends on her bones, her heart, her clotting history and her own priorities. That is a real conversation, not a formality. Our page on side effects sets out how side effects are graded and tracked.

What changed afterward

This trial, together with others in the same era, moved aromatase inhibitors from a second option to a standard first choice for hormone treatment after surgery in postmenopausal women.

The registry record shows BIG 1-98 as completed, with 8,028 participants enrolled. Longer follow-up analyses were published in later years, and it is those, rather than this first report, that carry the mature picture.

Where breast cancer sits statistically

The American Cancer Society projects 321,910 new female breast cancers in the United States in 2026 and 42,140 deaths. In NCI's own SEER data, about 64 percent are found while confined to the breast and 27 percent after spread to nearby lymph nodes.

Five-year relative survival across all stages was 91.9 percent for women diagnosed from 2016 through 2022, and death rates are falling. Those are group statistics about women diagnosed years ago, well after this trial began, and they describe no individual.

What this study cannot tell you

• Median follow-up at this report was only 25.8 months. The five-year figures are statistical projections, not observed five-year outcomes.
• No overall survival advantage was reported at this analysis. The endpoint was disease-free survival, which is a different question.
• The side effect profiles differ rather than one drug simply being safer.
• It applies to postmenopausal women with hormone receptor-positive early breast cancer. Aromatase inhibitors do not work the same way before menopause.
• Trial participants are chosen by entry criteria, so results may not carry over to everyone with this diagnosis.

Our guides to clinical trial phases and what standard of care means in a trial explain why a first report and a mature one are read so differently.

Sources

• https://pubmed.ncbi.nlm.nih.gov/16382061/
• https://clinicaltrials.gov/api/v2/studies/NCT00004205
• https://www.cancer.gov/types/breast
• https://seer.cancer.gov/statfacts/html/breast.html

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

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