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Postmenopausal Patients: Letrozole Benefit Varies by Histology and ER-Subtype

Carlson, Robert H.

doi: 10.1097/01.COT.0000427364.87531.7a

SAN ANTONIO—A report from the Breast International Group (BIG) may help medical oncologists fine-tune hormonal therapy for postmenopausal women with breast cancer.

In an unplanned analysis of the international BIG 1-98 trial, researchers found that letrozole was more effective than tamoxifen for both progression-free and overall survival in postmenopausal women who have either classic lobular or ductal carcinoma that is estrogen receptor-positive and HER2-negative breast cancer.

But the effect of letrozole was greater in women with classic lobular carcinoma than for women with ductal carcinoma, and greater for women with luminal B vs luminal A disease.

The study was presented at the CTRC-AACR San Antonio Breast Cancer Symposium by Otto Metzger-Filho, MD, a research fellow in medicine at Dana-Farber Cancer Institute, on behalf of the Collaborative Group, International Breast Cancer Study Group.

The data came from a 12-year update on the monotherapy arms of the randomized Phase III BIG 1-98 study, which compared five years of tamoxifen monotherapy or letrozole monotherapy, or their sequences in postmenopausal women with ER-positive early breast cancer. This new analysis included data on 2,599 patients with invasive ductal carcinoma, 55.3 percent of whom had luminal-A and 44.7 percent of whom had luminal-B tumors; and 324 patients with invasive lobular carcinoma, 73.1 percent with luminal-A and 26.9 percent with luminal-B tumors.

Disease-free and overall survival were estimated using “inverse probability of censoring weighted” (IPCW) analysis, which Metzger-Filho said provides a better estimate of treatment benefit than the intent-to-treat analysis in the BIG 1-98 due to the high selective crossover rate of 25 percent from tamoxifen to letrozole after the initial study results were presented in 2005.

“IPCW analysis weights the follow-up for the women who stay on tamoxifen so that they account not only for themselves but also for the censored follow-up of matched patients who crossed over,” he said.

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Five-Year Disease-Free Survival and Overall Survival

Significant interactions were observed between treatment and histology, and between treatment and subgroups. At eight years of follow-up, the disease-free survival rate was 82 percent for ductal carcinoma treated with letrozole vs 75 percent for ductal carcinoma treated with tamoxifen, for a statistically significant hazard ratio of 0.80.

Also at eight years, the disease-free survival rate was 82 percent for patients with lobular carcinoma treated with letrozole vs 66 percent for patients with lobular carcinoma treated with tamoxifen, for a statistically significant hazard ratio of 0.48.

Patients with ductal carcinoma had a 20 percent reduction in the hazard of a disease-free survival event, while patients with lobular carcinoma had a 52 percent reduction, he reported. Overall survival at eight years follow-up was 88 percent for ductal carcinoma treated with letrozole vs 84 percent for ductal carcinoma treated with tamoxifen, for a hazard ratio of 0.73.

And overall survival at eight years was 82 percent for lobular carcinoma treated with letrozole vs 66 percent for lobular carcinoma treated with tamoxifen, for a hazard ratio of 0.48.

Metzger-Filho said further validation is needed since the results were based on an unplanned analysis. He said that since letrozole is an approved regimen for postmenopausal women with hormone-receptor positive breast cancer, clinicians might consider letrozole over tamoxifen for the upfront treatment of patients diagnosed with lobular carcinoma, regardless of proliferation status.

The next step he said, will be an investigation into the relative effectiveness of letrozole compared with tamoxifen in the sequential arms of BIG 1-98.

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Take-Home Points from Kathy Albain

Kathy S. Albain, MD, Professor of Medicine in the Division of Hematology/Oncology at Loyola University Medical Center, the moderator of the session where the results were presented, was asked to comment on the study afterwards for this article.

She said the first take-home point was that there was an interaction between histology subtype and degree of benefit to letrozole over tamoxifen, so that the women with lobular carcinomas tended to have a greater degree of benefit to letrozole versus tamoxifen than did the women with invasive ductal carcinomas.

Further, she said, using Ki-67 as a surrogate for intrinsic subtyping of tumors into luminal A or luminal B, the BIG 1-98 investigators found that the luminal A invasive ductal carcinomas had no benefit to letrozole versus tamoxifen.

“There are many women who either cannot tolerate the aromatase inhibitors due to the bone side effects, or are fearful of those, and do not want to consider it. For those postmenopausal women with luminal-A invasive ductal cancers we can now feel relatively confident, at least at this stage of the work, that we could offer them tamoxifen, and that the aromatase inhibitor or letrozole wouldn't give them an additional benefit. But for the invasive lobular tumors, you might tend less toward offering frontline tamoxifen.”

Albain said she didn't consider the report to be practice changing yet, though, since the researchers still have to validate the findings about histology and intrinsic subtype interaction with treatment choice.

“I would say more ‘practice impacting’ in our decision-making. But it's going to help me as I speak with patients. If I see a very typical luminal-A type invasive ductal patient who does not have a massive risk of recurrence, [it will help me] to feel very comfortable recommending tamoxifen, where in the past I might have tended, based on the superiority of an AI over tamoxifen in general, to recommend an AI,” she said.

“And it's also going to steer me toward letrozole over tamoxifen in high-risk, invasive lobulars.”

© 2013 Lippincott Williams & Wilkins, Inc.
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