Effect of p95HER2/611CTF on the response to trastuzumab and chemotherapy
Josep Lluís Parra-Palau1, Beatriz Morancho1, Vicente Peg2
1*Authors contributed equally to this work.
Abstract:
Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906 mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259 mm(3), 95% confidence interval = 387 to 131 mm(3); P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.
Insights
Human epidermal growth factor receptor 2 (HER2)-positive breast cancers with p95HER2 fragments respond to chemotherapy. Chemotherapy sensitizes these tumors to trastuzumab, offering a new treatment strategy for HER2-positive breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are treated with trastuzumab.
- A subset of these tumors express p95HER2, a truncated form of HER2, which can confer resistance to trastuzumab.
- The specific fragment p95HER2/611CTF's role in treatment response remains unclear.
Purpose of the Study:
- To investigate the differential response of HER2-positive breast cancer cells and xenografts expressing p95HER2/611CTF to chemotherapy.
- To determine if chemotherapy can sensitize p95HER2/611CTF-positive tumors to trastuzumab.
Main Methods:
- Cell lines transfected with p95HER2/611CTF were analyzed.
- Patient-derived xenografts (n=7 mice/group) with varying p95HER2 levels were treated with chemotherapy agents and/or trastuzumab.
- Tumor response was assessed by measuring tumor volume.
Main Results:
- p95HER2/611CTF-negative and -positive tumors exhibited distinct responses to chemotherapeutic agents.
- Chemotherapy demonstrated particular efficacy against p95HER2/611CTF-positive cells.
- Chemotherapy significantly sensitized p95HER2/611CTF-positive xenograft tumors to trastuzumab (mean tumor volume reduced from 906 mm³ to 259 mm³).
Conclusions:
- The presence of p95HER2/611CTF influences the response to chemotherapy in HER2-positive breast cancer.
- Chemotherapy can overcome trastuzumab resistance in p95HER2/611CTF-positive tumors by sensitizing them to trastuzumab.
- This sensitization may involve chemotherapy-induced stabilization of HER2 in p95HER2/611CTF-positive cells.
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