Walter Alexander, Medical Writer

San Antonio, TX—Based on a positive risk/benefit ratio in long-awaited results of the NCCTG N9831 trial, investigators recommend incorporation of trastuzumab (Herceptin) concurrently with the taxane (paclitaxel) portion of chemotherapy in adjuvant treatment of women with HER2-positive breast cancer. NCCTG N9831 tested chemotherapy alone versus sequential or concurrent addition of 52 weeks of trastuzumab in 3505 women (

). “This is the only trial developed to define the optimal way to incorporate Herceptin in the context of adjuvant chemotherapy,” said lead investigator Edith A. Perez, MD, Mayo Clinic, Jacksonville, Florida.

Herceptin 4 mg/kg loading dose followed by 2 mg/kg

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 A study recommends use of trastuzumab concurrently with the taxane portion of chemotherapy for breast cancer patients.

Concurrent Trastuzumab with Chemotherapy Optimal Regimen

	San Antonio, TX—A better prognostic profile incorporating clinical-pathologic data with biologic markers showed that in the BIG 1-98 trial, high-risk patients did best with 5 years of letrozole (Femara) and low-risk patients did similarly well with any of the trial’s regimens. “Assessing risk by combining multiple factors appears better than any single factor,” said lead investigator Giuseppe Viale, speaking for the BIG 1-98 Collaborative and International Breast Cancer Study Groups (IBCSG) at the CTRC-AACR San Antonio Breast Cancer Symposium 2009 Annual Meeting.

	BIG-I-98 had treatment arms evaluating monotherapies (5 years of tamoxifen or letrozole) and sequential therapy (2 years of letrozole followed by 3 years of tamoxifen and 2 years of tamoxifen followed by 3 of letrozole) as adjuvant endocrine therapy for postmenopausal women with hormone receptor—positive breast cancer. After a median follow-up of 71 months, disease-free survival (DFS) was 87.6% for letrozole→tamoxifen and 86.2% for tamoxifen→letrozole. DFS in the monotherapy arms was 87.9% for letrozole and 84.0% for tamoxifen (data from patients in this group who crossed over selectively to letrozole were censored). Dr Viale noted that the modest differences in DFS between groups does not facilitate a clinician’s choices between treatment regimens. To identify patients who may respond better to a particular treatment regimen, the IBCSG took the same BIG 1-98 database (retrospective tissue collection) and first examined individual tumor markers in 5,177 patients using STEPP (Subpopulation Treatment Effect Pattern Plots). 

	Each of four tumor markers (estrogen receptor [ER], progesterone receptor [PgR], Ki-67 labeling index, and HER2 status) showed a trend favoring letrozole monotherapy at the higher risk end of its spectrum, but none was statistically significant as a predictive factor. Dr Viale and colleagues asked, “Could a composite prognostic risk profile based on St. Gallen risk factors also serve to predict treatment differences?”

	A composite risk profile was calculated using a multivariable Cox model for DFS and using the St. Gallen risk factors (ER, PgR, HER2 Ki-67, number of involved metastatic lymph nodes, tumor grade, tumor size and presence of peritumoral vascular invasion [PVI]). The key contributors to high risk were higher number of positive lymph nodes, lower ER%, higher Ki-67, higher grade, larger tumor size, HER2-positivity, presence of PVI and lower pgR%.

	Dr Viale reported that, as expected, as composite risk increased, 5-year DFS decreased for all treatment regimens. Also, while 5-year DFS is similar for all four treatment regimens at the lowest level of risk, inferior results for tamoxifen alone are seen earlier in the risk spectrum and separation among letrozole-containing treatments is apparent particularly at the highest risk levels. About a third of the BIG 1-98 population fell into each of low-, intermediate- and high-risk strata.

	In individuals with low risk, all treatments including tamoxifen appeared similar; at the intermediate-level all letrozole arms appeared similar and superior to tamoxifen; at the high-risk level, 5-years of letrozole appeared better than either sequence. For high-risk patients, 5-year DFS was ~72% in the letrozole-alone group, ~67% in the tamoxifen→letrozole group, ~65% in the letrozole→tamoxifen group, and ~ 61% in the tamoxifen alone group.

	Dr Viale concluded, “In the BIG 1-98 trial, a composite prognostic profile incorporating clinic-pathological data and biological markers was better able to predict the relative treatment benefit.” SABCS Abstract 76.

In the BIG 1-98 trial, high-risk patients did best with 5 years of letrozole and low-risk patients did similarly well with any of the trial%u2019s regimens. 

Profile Including Clinical Data and Biologic Markers Predicts DFS 

	San Antonio, TX— Findings from the BIG 1- 98 trial have been presented at prior conferences, and at the San Antonio Breast Cancer Symposium, Meredith Regan, ScD, assistant professor, Department of Medicine, Harvard Medical School, spoke on new data that show even after taking into account the effect of patients who decided to crossover, 5 years of treatment with letrozole (Femara) was still associated with significantly better overall survival (OS) than 5 years with tamoxifen (P <.05). Explaining the rationale for conducting the analysis, Dr Regan, who is group statistician for the International Breast Cancer Study Group, which is conducting the trial, said, “We have an obligation to present updated result accounting for women who crossed over to the other arm following report of positive results. In trials with selective crossover, an intent-to-treat analysis is no longer relevant for patient care.”

	BIG 1-98, a randomized phase III double-blind, controlled trial, included 4922 postmenopausal women with hormone receptor—positive early breast cancer. They were randomly assigned to treatment with either the aromatase inhibitor letrozole or tamoxifen. When BIG 1-98 results were first presented in 2005, they demonstrated superior disease-free survival (DFS) and reduced disease recurrence risk for women who received letrozole for an average of 18 months. At that time, the tamoxifen-only treatment arm was unblinded, and 25% of women in that group selectively crossed-over to the letrozole arm.

	After a median follow-up of 76 months, an intention-to-treat (ITT) analysis revealed significant benefits in DFS (HR, 0.88; P = .03) and time to distance recurrence (TDR; HR, 0.85; P = .05) for letrozole, but the OS benefit did not achieve statistical significance (HR, 0.87; P = .08).

	While selective crossover is in the best interest of patients, it does complicate further trial analyses, Dr Regan said. “The trial becomes a hybrid of a randomized trial and an observational study,” she commented, adding that accurate assessment of outcomes requiring longer follow-up, such as OS, becomes difficult. With the ITT analysis, the effects of letrozole were attenuated by the crossovers, which moved the randomized trial more toward an observational study. As a result, Dr Regan said, statistical methods needed to be modified.

	The solution lies in alternative modeling strategies, Dr Regan explained. In the case of BIG 1-98, using inverse probability of censoring weighted analysis (IPCW), an established modeling method for addressing bias due to treatment selection, 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 cross over. The weighting adjusts for factors associated with OS and selective crossover, including baseline factors like age, nodal status, tumor grade, and time-varying performance status. It estimates outcomes, she said, that would have been observed had there been no selective crossover.

	With IPCW and censoring follow-up at selective crossover, the OS HR for letrozole was 0.83 (P <.05), a statistically significant benefit. “The ITT analysis on updated data from BIG 1-98 is inaccurate and no longer relevant for patient care.” Dr Regan concluded, “Our best estimate is that 5 years of letrozole is significantly better than tamoxifen for DFS, OS and TDR.”

	In an interview, Dr Regan emphasized, “We owe it to clinicians and to patients to learn as much as we can from trials. This method deals with selective crossover, and gives an estimate of the important longer-term outcome of overall survival. It gives clinicians good information for making decisions for patients.” SABCS Abstract 16.

Letrozole treatment over 5 years was still associated with significantly better overall survival than 5 years with tamoxifen.

Walter Alexander, Medical Writer

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