Dr. von Minckwitz urged caution in using pCR as an end point, however, particularly among patients with HER2-positive and estrogen receptor (ER)-positive disease. His own meta-analysis presented at ASCO of seven German neoadjuvant breast trials using anthracycline/taxane regimens with or without trastuzumab, showed that pCR strongly correlates with disease-free survival in higher risk groups such as ductal, HER2-positive, and ER-negative disease, but not in luminal A-like and ER-positive/HER2-positive tumors (Abstract 1028).
Lapatinib vs. Trastuzumab Sans Chemo
The third study used neoadjuvant lapatinib 1,000 mg daily plus trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg weekly, without chemotherapy, in women with large HER2-positive tumors (median 6 cm; range 1.5-30 cm). In an effort to overcome estrogen receptor crosstalk, ER-positive patients also received letrozole (Femara), plus goserelin, if premenopausal.
A pCR, defined as no invasive cancer in the breast only, was achieved by 28% of the 64 evaluable patients – 21% of ER-positive and 40% of ER-negative patients, Dr. Jenny C. Chang reported on behalf of the Translational Breast Cancer Research Consortium (TBCRC) 006 investigators. No patient progressed during the 12 weeks of targeted therapy alone.
The secondary end point of residual disease of less than 1 cm (near pCR) was seen in 56% of ER-positive and 48% of ER-negative patients, suggesting that these patients may benefit from longer therapy, she said. In all, 62% of patients were ER positive, 62% had a tumor size greater than 5 cm, and 54% were premenopausal.
The regimen in the phase II TBCRC 006 study was very well tolerated, with only five patients discontinuing therapy and 3 reports of grade 3/4 abnormal liver function tests that completely resolved.
Further study is needed before suggesting that select patients with HER2-positive tumors may not need neoadjuvant chemotherapy, said Dr. Chang, director of the Methodist Cancer Center in Houston.
The data compare favorably with those reported at the 2010 San Antonio Breast Cancer Symposium from the phase II NEOSPHERE trial, in which 17% of patients overall, 6% of ER-positive and 29% of ER-negative patients experienced a pCR after 12 weeks of neoadjuvant trastuzumab plus the monoclonal antibody, pertuzumab, Dr. von Minckwitz observed.
New insights are expected from three upcoming neoadjuvant chemotherapy trials in HER2-positive breast cancer: Cancer and Leukemia Group B 40601, European Organization for Research and Treatment of Cancer 10054 and a National Surgical Adjuvant Breast and Bowel Project B-41.
Molecular Profiles Begin to Emerge
Dr. Holmes and her colleagues conducted a variety of molecular analyses in tumor samples from 49 patients before and after anti-HER2 therapy. She reported that their findings indicate the following:
• Baseline phosphorylated EGFR tyrosine1068 is a marker of nonresponse to lapatinib.
• Baseline activation of autophagy correlates with no pCR to all therapies.
• Baseline ratios of phosphorylated Forkhead box O to PTEN and PI3K correlate with response.
• Phosphorylated STAT5 after trastuzumab correlates with pCR.
The molecular profiles suggest that pCR tumors rely on a truncated, rudimentary social network, while resistant tumors use a far more extensive network of autophagy and stem cell–regulated pathways to evade therapy and are thus harder to kill, Dr. Holmes said.
"Despite the limitations, this exploratory analysis shows that the pathway to accelerating the cure of breast cancer is available in every oncologist’s office if she or he can network to tissue-based research trials," she said.
The CHER-LOB investigators tested tumor samples for p95HER2, which is expressed in approximately 30% of HER2-positive breast cancer patients and thought to confer resistance to trastuzumab. No significant differences were observed in all treatment arms in pCR rates based on p95HER2 expression, Dr. Guarneri said.
The p95HER2 results contradict earlier research, observed Dr. von Minckwitz. "We really have to design these biomarker studies very cautiously and the first [issue] we have to address is that we have to have sufficient numbers to study," he added.
CHER-LOB was supported by GlaxoSmithKline. Dr. Guarneri reports no conflicts. Dr. Holmes reports a consultant-advisory role with Phillips Home Monitoring and honoraria from Genentech and Novartis. Dr. Chang reports no relevant conflicts. Dr. Von Minckwitz reports honoraria from Amgen, Roche, and Sanofi-Aventis and research funding from Abraxis BioScience, Amgen, Bayer, GSK, Novartis, Pfizer, Roche, Sanofi-Aventis, and bioMérieux.