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HER2-Targeted Immunotherapy and Combined Protocols Showed Promising Antiproliferative Effects in Feline Mammary Carcinoma Cell-Based Models.

ABSTRACT: Feline mammary carcinoma (FMC) is a highly prevalent tumor, showing aggressive clinicopathological features, with HER2-positive being the most frequent subtype. While, in human breast cancer, the use of anti-HER2 monoclonal antibodies (mAbs) is common, acting by blocking the extracellular domain (ECD) of the HER2 protein and by inducing cell apoptosis, scarce information is available on use these immunoagents in FMC. Thus, the antiproliferative effects of two mAbs (trastuzumab and pertuzumab), of an antibody-drug conjugate compound (T-DM1) and of combined treatments with a tyrosine kinase inhibitor (lapatinib) were evaluated on three FMC cell lines (CAT-MT, FMCm and FMCp). In parallel, the DNA sequence of the her2 ECD (subdomains II and IV) was analyzed in 40 clinical samples of FMC, in order to identify mutations, which can lead to antibody resistance or be used as prognostic biomarkers. Results obtained revealed a strong antiproliferative effect in all feline cell lines, and a synergistic response was observed when combined therapies were performed. Additionally, the mutations found were not described as inducing resistance to therapy in breast cancer patients. Altogether, our results suggested that anti-HER2 mAbs could become useful in the treatment of FMC, particularly, if combined with lapatinib, since drug-resistance seems to be rare.

SUBMITTER: Gameiro A

PROVIDER: S-EPMC8122524 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTaxane, carboplatin and trastuzumab (TCH) is an effective neoadjuvant regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer with high pathologic complete response (pCR) rate. The KATHERINE trial changes the outlook for high-risk HER2-positive breast cancer, which suggests that escalation treatment for patients with residual disease after neoadjuvant anti-HER2 therapy may improve survival. The major objective of this study was to investigate the fewest cycles of neoadjuvant TCH therapy needed to screen out non-pCR patients.MethodsThis retrospective study included patients with HER2-positive breast cancer who received either four or six cycles of TCH preoperatively at Fudan University Shanghai Cancer Center between 2008 and 2019. The pCR status was evaluated, and relevant factors associated with pCR were identified using univariate and multivariable analyses. The pathological results of core needle biopsy (CNB) in the breast tumor after two cycles of neoadjuvant chemotherapy were also collected. Kaplan-Meier curve was used to estimate the event-free survival (EFS).ResultsOf 758 eligible patients, 303 were included and analyzed in the four-cycle group and 455 in the six-cycle group. There was no significant difference between the two groups in terms of the pCR rate (46.5% [95% CI 40.9% - 52.2%] in the four-cycle group and 49.9% [95% CI 45.3% - 54.5%] in the six-cycle group, p = 0.365) or the four-year EFS (90.8% in four-cycle group and 93.8% in six-cycle group; p = 0.264). Multivariable analysis indicated that a negative hormone receptor status and the weekly paclitaxel were independent factors for predicting pCR. After adjusting for factors in the multivariable analysis, there was still no significant difference between four and six cycles of neoadjuvant TCH (OR = 1.252, 95% CI 0.904 - 1.733, p = 0.176). Furthermore, 17.9% patients with invasive carcinoma on CNB after two cycles of TCH ultimately achieved pCR in the breast after the completion of neoadjuvant treatment.ConclusionFour cycles of taxane/carboplatin-based neoadjuvant anti-HER2 therapy may be applied as an optimal treatment duration for screening high-risk HER2-positive breast cancer patients for escalation treatment. Further prospective study is warranted.

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HER2-Targeted Immunotherapy and Combined Protocols Showed Promising Antiproliferative Effects in Feline Mammary Carcinoma Cell-Based Models.

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