THE BIG 1-98
CLINICAL TRIAL

What Is The BIG 1-98 Clinical Trial?

If you’re a post-menopausal woman with early breast cancer, you may have been treated with an aromatase inhibitor.

This was proven to be the most effective treatment for endocrine responsive early breast cancer through the BIG 1-98 clinical trial.

Clinical trials are designed to find out if new treatments or prevention strategies are more effective than those currently accepted as the best available standard treatment.

Chair of the Breast Cancer Trials Scientific Advisory Committee, Associate Professor Prue Francis said the BIG 1-98 clinical trial helped to stop breast cancer returning and improved survival rates for some women.

“BIG 1-98 was a pivotal trial.”

“It was studying post-menopausal women with early breast cancer that was hormone receptor positive, so estrogen receptor positive.”

“The standard hormonal therapy at the time, for these women, was to take tamoxifen for five years” said Associate Professor Francis.

“The BIG 1-98 trial was comparing an aromatase inhibitor called Letrozole for five years to tamoxifen for five years, with the hypothesis that Letrozole might be more effective.”

“It was also comparing two other strategies which was to give in the first couple of years, Letrozole and the remaining three years with tamoxifen or vice versa, and the first couple of years with tamoxifen and then switching to the Letrozole.”

“So, it had four different ways of delivering the oral hormones.”

The early results of the clinical trial indicated that Letrozole was the more effective treatment compared with Tamoxifen for women with post-menopausal estrogen receptor positive breast cancer.

“But that’s not to say that every post-menopausal women with breast cancer needs an aromatase inhibitor because there are some women that have relatively good prognosis in their post-menopausal breast cancer who would probably do equally well in terms of their long-term cure rate regardless of whether they got tamoxifen or an aromatase inhibitor like Letrozole” said Associate Professor Francis.

“But for women who have a higher risk situation, the difference between a more effective therapy like Letrozole than tamoxifen could be really quite important.”

How BIG 1-98 Changed Practice

Combined with another clinical trial, the ATTACK trial which studied anastrozole, the BIG 1-98 clinical trial was pivotal in shifting the standard of care for post-menopausal women with early hormone receptor breast cancer. It is now more common for women with this type of breast cancer to be treated with an aromatase inhibitor hormone therapy than tamoxifen.

It has been a decade since the Big 1-98 clinical trial, with ten year follow up results being published this year.

However, these results are complicated as there was a cross-over that occurred in the trial, after the early results were released which showed the aromatase inhibitor appeared to be more effective.

“When those early results became available, those running the trial then recommended that the women who were randomised in the trial to receive the five years of standard therapy with tamoxifen should have the option to cross over to Letrozole, which was being shown to be a more effective option” said Associate Professor Francis.

“So, the long-term results of the trial became more complicated because there wasn’t a direct comparison of five years of Letrozole to five years of tamoxifen.”

“When we conduct clinical trials, there is monitoring of the trial by independent committees as well as the trial committee to try and look at whether the ongoing treatments of the trial are still appropriate to continue studying.”

“Along the way it was deemed that there was enough information to notify the doctors and women participating in the trial that it should be an option for the people in the control group to no longer remain on their control treatment tamoxifen, should they wish to switch.”

The HERA Clinical Trial

This cross-over has occurred before in the Breast Cancer Trials HERA clinical trial.

“The HERA trial that the group participated in which was one of the pivotal trials that showed that adjuvant Trastuzumab, sometimes referred to as Herceptin, could improve survival and reduce relapse rates in HER2 positive early breast cancer.”

“There were women in the HERA trial who were in the control group and in that trial, the control group was your standard chemotherapy and hormone therapy with no Trastuzumab, no Herceptin, and those women were subsequentially offered a cross over and if they wished to receive Herceptin.”

“But it does make the long term follow up results of trials complex if there’s been a cross over because potentially it can dilute the improvement that might have been seen otherwise.”

“But one of the things with Breast Cancer Trials is they often have a very long natural history, so we will typically be following women usually for at least ten years and sometimes longer. So sometimes there is newer information that might become available either from the trial itself or from other trials that sometimes requires a change in what is considered appropriate for the control group.”