Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in
Sara A Hurvitz1, Jennifer L Caswell-Jin2,3, Katherine L McNamara2,3,4
1David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. SHurvitz@mednet.ucla.edu.
Abstract:
In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.
Insights
Trastuzumab and trastuzumab plus lapatinib showed similar pathologic complete response rates in early-stage HER2-positive breast cancer. Lapatinib alone resulted in a lower response rate and treatment completion.
Area of Science:
- Oncology
- Pharmacology
Background:
- Early-stage HER2-positive breast cancer treatment often involves neoadjuvant anti-HER2 therapy.
- Assessing treatment response and tumor biology early is crucial for optimizing outcomes.
Purpose of the Study:
- To compare the efficacy of trastuzumab, lapatinib, and their combination as neoadjuvant HER2-targeted therapy in early-stage HER2-positive breast cancer.
- To investigate gene expression changes and their correlation with treatment response.
Main Methods:
- A multicenter, randomized phase II neoadjuvant trial (TRIO-US B07) involving 128 participants.
- Randomization to trastuzumab (T), lapatinib (L), or both (TL) for one cycle, followed by six cycles of combination chemotherapy with the same anti-HER2 agent.
- Primary endpoint: pathologic complete response (pCR) rate. Secondary: gene expression analysis.
Main Results:
- Similar pCR rates were observed for T (47%) and TL (52%), while L showed a lower rate (25%).
- Treatment completion rates were highest in the T arm (100%), followed by TL (74%) and L (69%).
- Higher HER2 amplification and hormone receptor-negative status correlated with higher pCR. Significant gene expression shifts, including immune signatures, occurred after one cycle of therapy.
Conclusions:
- Trastuzumab and the combination of trastuzumab plus lapatinib demonstrate comparable efficacy in achieving pCR in this neoadjuvant setting.
- Lapatinib monotherapy showed reduced efficacy and treatment completion. Early gene expression changes, particularly immune responses, may predict treatment sensitivity.
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