Herceptin/Taxotere Ups DFS in Early HER2+ Breast Ca

Oncology NEWS InternationalOncology NEWS International Vol 15 No 1
Volume 15
Issue 1

The first interim results from the BCIRG 006 phase III trial showed that trastuzumab (Herceptin) combined with docetaxel (Taxotere)-based regimens significantly improved disease-free survival (DFS) in early HER2-positive breast cancer. Genetic studies further delineated a subgroup of patients for whom truly targeted therapy may be applied in the future.

SAN ANTONIO—The first interim results from the BCIRG 006 phase III trial showed that trastuzumab (Herceptin) combined with docetaxel (Taxotere)-based regimens significantly improved disease-free survival (DFS) in early HER2-positive breast cancer. Genetic studies further delineated a subgroup of patients for whom truly targeted therapy may be applied in the future. Dennis Slamon, PhD, MD, co-chair of the Breast Cancer International Research Group (BCIRG) 006 adjuvant study and director of clinical and translational research at UCLA's Jonsson Comprehensive Cancer Center, presented the 23-month follow-up data at the 28th Annual San Antonio Breast Cancer Symposium (abstract 1).

"Both the experimental arms containing trastuzumab significantly exceeded the control arm in terms of efficacy," Dr. Slamon said. Importantly, he added, since cardiotoxicity is a concern with trastuzumab, the non-anthracycline-containing regimen reduced the risk of recurrence without increasing cardiotoxicity.

Dr. Slamon also presented exciting new findings regarding "coamplification" of the HER2 gene and the topoisomerase II-α gene (TOPO II-α), which is the target of anthracyclines. Patients who had amplification of both these genes had the best outcomes with trastuzumab plus anthracycline. "We just got these data on Thursday night. It's hot off the press," Dr. Slamon said. "I think that others will want to repeat these data, but we are pretty confident that this is correct."

The BCIRG 006 study was designed to evaluate how to potentially maximize efficacy of trastuzumab-based therapy in the adjuvant treatment of HER2-positive breast cancer, while minimizing toxicity. In particular, investigators aimed to determine if the increased toxicity seen with the combination of trastuzumab and doxorubicin could be avoided using a novel non-anthracycline-containing regimen that has demonstrated activity preclinically. Docetaxel was used in the regimen, rather than paclitaxel, based on preclinical evidence indicating an interaction with trastuzumab, he said.

The adjuvant study included 3,222 women with FISH-positive HER2-overexpressing tumors who were node-positive or otherwise at high risk for recurrence. Approximately half had received hormonal therapy and over half received mastectomy and radiotherapy. Patient groups were well balanced among arms.

Patients were randomized to receive one of the following regimens:

  • Standard treatment with four cycles of doxorubicin and cyclophosphamide (60/600 mg/m2), followed by docetaxel 100 mg/m2 for four cycles (AC→T) (n = 1,073).

  • Experimental treatment with the above regimen together with 1 year of trastuzumab started concomitantly with docetaxel (AC→TH) (n = 1,074).

  • Experimental treatment of six cycles of docetaxel 75 mg/m2 and carboplatin to AUC 6 with 1 year of trastuzumab, the latter started at the same time as the chemotherapy (TCH) (n = 1,074).

The first interim analysis was conducted at a median follow-up of 23 months after the occurrence of 322 events, including 84 deaths.

At 4 years, disease-free survival was 84% for AC→TH, 80% for TCH, and 73% for AC→T. The analysis showed a relative reduction in the risk of relapse of 51% for AC→TH (P < .0000005) and 39% for TCH (P < .00015) vs the control arm of AC→T. There have been 147 events in the control AC→T arm, 98 in the TCH arm, and 77 in the AC→TH arm. At this time, the 21 events separating the two experimental arms are not statistically significant (P = .16).

Deaths occurred in 36 patients in the control arm, 20 receiving AC→TH, and 28 receiving TCH (only 3 breast cancer deaths separated the two experimental arms). The data are insufficient for evaluating overall survival differences.

Cardiac Safety

Grade 3 and 4 hematologic and nonhematologic toxicities were very similar among the arms. Neurotoxicity and renal toxicities of any grade were not significantly increased by any of the regimens, he said. "Trastuzumab is generally a very well tolerated drug, but its one problem is cardiac toxicity," he said, noting that differences between the experimental arms did emerge with regard to this side effect. "The differences we saw were not due to disproportionate cardiovascular risk factors, which were very well balanced among the arms."

There were no cardiac deaths. Clinically significant cardiac events per the Independent Review Panel occurred at the following rates: 0.95% (10 events) with AC→T, 2.34% (25 events) with AC→TH, and 1.33% (14 events) for TCH, with a significant P value (P = .016) between AC→TH and AC→T. Clinical heart failure occurred in 3 patients, 17 patients, and 4 patients, respectively.

BCIRG 006 also included categories for arrhythmias and ischemia or infarction, cardiotoxicity categories not included in other trials of trastuzumab, Dr. Slamon said. Grade 3-4 arrhythmias were seen in 7 patients on AC→T, 4 patients on AC→TH, and 9 on TCH (5 of these 20 are not yet adjudicated). Grade 3-4 ischemia or infarction occurred in 0, 4, and 1 patient, respectively.

"The interaction between trastuzumab and anthracycline seems to come to the fore here," Dr. Slamon observed. "By our definition of cardiac toxicity—grade 3 and 4 congestive heart failure, arrhythmias and infarctions—the difference is about twofold for AC→TH."

Regarding left ventricular dysfunction—another common observation among trastuzumab recipients in general—a total of 353 patients experienced a greater than 10% relative asymptomatic decrease in left ventricular ejection fraction (LVEF). This occurred in 9% of patients in the AC→T arm, 17.3% in the AC→TH arm, and 8% in the TCH arm, highly statistically significant for AC→TH vs AC→T (P = .002) or TCH (P < .0001).

"We have all heard that this is not a problem because patients get better when they go off drug. Certainly their congestive heart failure gets better when they are treated for it, but what about subclinical loss?" he said. In this study, most patients receiving a doxorubicin-containing regimen experienced a sustained loss in LVEF over time (greater than 550 days at the time of analysis). "This phenomenon is real and it is not short-term," he said. In contrast, the vast majority of LVEF declines seen in the TCH arm recovered fully. In summary, he said, the incidence of asymptomatic and persistent LVEF declines is significantly higher in AC→TH than in AC→T and TCH.

Molecular Analysis

There can be as many as 40 genes in the HER2 amplicon, the critical one being the HER2 gene in the core region. The TOPO II-α gene also occurs in this amplicon in approximately 35% of HER2-positive patients and was prospectively evaluated as a biomarker in the BCIRG 006 trial. The analysis showed that the 744 "coamplified" patients (out of 2,120 analyzed) had a significantly improved disease-free survival, compared with the 1,376 "non-coamplified" patients (who had normal TOPO II-α or a deletion). Events occurred in 57 of 744 coamplified patients vs 191 of 1,376 non-coamplified patients (P < .001).

When the coamplified patients were compared according to treatment arm, AC→TH proved to be "far superior" to either of the other two arms. "Here, we are hitting two targets: both HER2 with trastuzumab and TOPO II-α with the anthracycline," he explained. In the non-coamplified patients, there was no difference in disease-free survival between the AC→TH and TCH arms.

Dr. Slamon hypothesized that coamplification of the TOPO II-α gene may confer a therapeutic advantage to anthracycline-based/trastuzumab combination regimens. "HER2-positive patients who are not coamplified for TOPO II-α (approximately 65%) do not appear to have this same benefit and may be ideal candidates for efficacious, non-anthracycline-based regimens, thus avoiding potential cardiac toxicity," he said. He noted that efforts are underway to make a commercial test for coamplification.ONI

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