Abstract C49: Combination treatment with metronomic cyclophosphamide and the EGFR monoclonal antibody nimotuzumab is efficacious and non-toxic in a preclinical model of advanced triple negative breast cancer
Bibliographic record
Abstract
Abstract Low dose, metronomic chemotherapy with cyclophosphamide has shown activity in the treatment of advanced breast cancer, and has been paired with targeted agents such as trastuzumab and bevacizumab for long term therapy, with encouraging results. The epidermal growth factor receptor (EGFR) pathway may be a relevant target for the treatment of triple-negative breast cancer, a tumor type with an aggressive behavior and limited therapeutic options. Nimotuzumab is a humanized monoclonal antibody targeting EGFR with an affinity that is lower than currently approved agents, such as cetuximab and panitumumab. This leads to preferential targeting of EGFR-overexpressing tumors, minimizing toxicity, making it well suited for long term dosing, including possible combination therapy with minimally toxic chemotherapeutic regimens, when treating tumors with high EGFR expression. The objective of this study was to evaluate nimotuzumab in combination with metronomic cyclophosphamide in a preclinical model of advanced, triple negative breast cancer. Increasingly aggressive metastatic variants of the MDA-MB-231 human breast cancer cell line were selected through passage in vivo, resulting in a line termed 164/8-1B, characterized as highly metastatic to many organs, including lymph nodes, lung, and brain. This variant also had increased EGFR expression compared to the parental cell line. Combination therapy with nimotuzimab twice weekly and continous low-dose cyclophosphamide resulted in significant primary tumor growth delay in the metastatic variant, compared to the parental cell line. In addition, the combination resulted in a significant survival advantage over cyclophosphamide alone in the advanced metastatic model. Nimotuzumab displayed single agent activity in primary tumor xenografts but not in the treatment of advanced metastatic disease. Primary tumor regrowth in the mammary fat pad occurred with similar frequency across treatment groups, however the resulting tumor size was decreased in mice receiving combination treatment. Lymph node metastasis was observed in 40–60% of mice in each treatment group, with the exception of those that received combination therapy, where no gross evidence of lymphadenomegaly was observed. Finally, cell lines established from lung metastases from 3 mice receiving combination therapy showed EGFR expression, suggesting that resistance to treatment was not associated with loss of target expression. In conclusion, combination therapy with low dose, continuous cyclophosphamide and the EGFR monoclonal antibody nimotuzumab was an efficacious regimen in this advanced, metastatic, triple negative, EGFR overexpressing breast cancer model, and would be expected to be minimally toxic to patients. This combination approach should be considered for this patient population in future clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C49.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".