BIG 1-98 RESULTS IN PAPER

August 20, 2009 — A large clinical trial has provided data that confirm the value of an approach already widely used in clinical practice — monotherapy with an aromatase inhibitor instead of sequential therapy with an aromatase inhibitor and tamoxifen (or vice versa) — for the adjuvant treatment of postmenopausal women with early breast cancer.

The Breast International Group (BIG) 1-98 trial compared both approaches, using letrozole (Femara, Novartis) as the aromatase inhibitor monotherapy. The results, published in the August 20 issue of the New England Journal of Medicine, show that the 2 approaches were highly similar in terms of disease-free survival, the primary endpoint of the trial.

In another section of the trial, however, which compared letrozole monotherapy and tamoxifen monotherapy, the aromatase inhibitor alone showed a slightly better overall survival. The 5-year overall survival was 91.8% in the letrozole group and 90.9% in the tamoxifen group (hazard ratio, 0.87; 95% confidence interval, 0.75 to 1.02; P = 0.08).

The upshot of both sets of data is to "start with letrozole," according to Henning Mouridsen, MD, PhD, the chair of the BIG 1-98 writing committee and professor of oncology at the Copenhagen University Hospital in Denmark.

This difference in overall survival was not statistically significant (P = .08), but Dr. Mouridsen said: "In my opinion, it's clinically significant. The mortality reduction with letrozole is 13% according to the intention-to-treat analysis and 19% according to the censored analysis," he said, adding that the true survival benefit lies somewhere in between.

"My advice is to treat upfront with letrozole, especially in patients at risk for early recurrence," Dr. Mouridsen said in an interview with Medscape Oncology.

However, he said that other options should be considered for patients at low risk for recurrence, including use of tamoxifen in sequence with letrozole. "In patients at low risk for recurrence, using tamoxifen may make more sense economically in countries where letrozole is much more expensive than tamoxifen. However, in other countries, where the cost difference is small, this may not apply," he said.

First Trial to Answer Question

This is the first trial to provide an answer to a pressing clinical question — whether to use sequential therapy or monotherapy as adjuvant therapy in postmenopausal women with early breast cancer.

The idea of using tamoxifen and an aromatase inhibitor in sequence was born out of the hypothesis that using 2 effective drugs with different mechanisms of action would benefit the patient, explained Dr. Mouridsen. Tamoxifen is a selective estrogen-receptor modulator that prevents estrogen from interacting with its receptor. Aromatase inhibitors inhibit an enzyme involved in the synthesis of estrogen, and hence reduce levels of the hormone.

In the BIG 1-98 trial, 2 years of 1 agent was followed by 3 years of the other. Among 6162 women with hormone-receptor-positive early breast cancer, the sequential therapy groups and the letrozole monotherapy group had highly similar rates of disease-free survival at 5 years into the trial: 87.9% for letrozole alone, 87.6% for letrozole followed by tamoxifen, and 86.2% for tamoxifen followed by letrozole.

"We have not had a randomized controlled trial comparing an upfront monotherapy approach with a sequential strategy. Now we have one," Dr. Mouridsen told Medscape Oncology.

"Neither sequence was superior to letrozole monotherapy, as was originally hypothesized," said Dr. Mouridsen.

The BIG trial also includes a comparison of letrozole and tamoxifen monotherapy among 4922 women with a median follow-up of 76 months, which is where the difference in overall survival was seen.

Earlier data on this monotherapy comparison have been previously reported (J Clin Oncol. 2007;25:486-492); these data are now updated. As was the case earlier, letrozole had a statistically significantly better time to distant recurrence (P =.05).

Support for Superiority of A romatase Inhibitor

The BIG trial results were endorsed, but with caveats, by breast cancer experts approached by Medscape Oncology for comment.

"I support the finding that an aromatase inhibitor is superior to tamoxifen and should be used initially in this setting. However, a comparison with other aromatase inhibitors, such as anastrozole [Arimidex, AstraZeneca], was not a component of the study," said Rowan Chlebowski, MD, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles, explaining that it cannot therefore be said that letrozole is the agent of choice.

But Dr. Mouridsen argues that letrozole should be the standard treatment. The new BIG results indicate that letrozole provides a survival benefit over tamoxifen, albeit slight and not significant. Anastrozole, however, has not shown that benefit. "A large trial has demonstrated no benefit as concerns mortality," he noted, referring to ATAC, a trial comparing tamoxifen and anastrozole monotherapies.

Dr. Mouridsen also said that the slight superiority of letrozole monotherapy over tamoxifen monotherapy in 5-year survival in the BIG trial is probably larger than the intent-to-treat analysis shows, because the trial allowed patients taking tamoxifen to cross over to letrozole after it was learned, about 2 years after randomization, that letrozole was superior to tamoxifen.

He and his colleagues write: "Our belief that this [overall survival] result underestimates the survival benefit that would have accrued if there had been no crossover to letrozole is based on evidence from independent trials that have shown a survival benefit from switching to an aromatase inhibitor after initial treatment with tamoxifen."

Why is this so? "The patients who crossed over from tamoxifen to letrozole had inferior prognostic characteristics compared with those who did not," said Dr. Mouridsen.

However, patients taking tamoxifen who had disease recurrence were not allowed to cross over, which somewhat balances out the fact that many of the crossover patients had inferior prognostic characteristics, Dr. Mouridsen explained. These patients were accounted for in a censored analysis.

Confirmation of Clinical Practice

The community has already voted on this.

Another breast cancer expert believes that the BIG-1 98 trial is important for having investigated the value of sequential therapy. Otherwise, in his opinion, the trial is a confirmation of what is already going on in clinical practice. "The community has already voted on this. The vast majority of these patients are treated initially with aromatase inhibitors," observed Larry Norton, MD, deputy physician-in-chief for Breast Cancer Programs and medical director at the Evelyn H. Lauder Breast Center of Memorial Sloan-Kettering Cancer Center in New York City.

At the same time, Dr. Norton tipped his hat to tamoxifen. "Tamoxifen is a great drug and we understand it really well. However, AIs [aromatase inhibitors] don't have the same level of adverse events, which is a class effect. To say that is not a slight in any way to letrozole, which is a really good drug," he continued.

A question that remains unanswered is the duration of adjuvant therapy in these women. Dr. Norton wondered aloud about how to proceed with patients who have been treated with hormone therapy for 5 years or longer. "Prolonged hormone therapy is provocative," he said.

Also, as Dr. Mouridsen noted, there are no data to indicate the "optimal duration of treatment."

Dr. Norton looks forward to new directions in breast cancer treatment that address the fact that early breast cancer is largely latent cancer.

"Tumor latency is an emerging issue in all cancer care," he said. It is especially interesting in breast cancer because of the role played by the Src gene, which can allow cancer cells to live in bone for years or even decades without causing disease.

"Ninety percent of all estrogen-receptor-positive breast cancers have activation of Src, which means that the cancer cells may live in the bone for a long time," said Dr. Norton.

In a recent paper, Dr. Norton and colleagues discovered a strong association between late-onset bone metastasis and Src activity in a cohort of more than 600 breast cancer patients (Cancer Cell. 2009;16:67-78).

The challenge ahead is to develop ways to prevent these latent cells from dividing and ultimately forming a tumor. "We are starting to rethink how to approach cancer treatment," said Dr. Norton

The study was supported by Novartis. Dr. Mouridsen reports receiving consulting and lecture fees from Novartis. Dr. Chlebowski is a consultant for AstraZeneca, Novartis, and Pfizer, and is on the speakers bureaus of AstraZeneca and Novartis.

N Engl J Med. 2009; 361:766-776.