Activity and resistance of trastuzumab according to different clinical settings

Activity and resistance of trastuzumab according to different clinical settings: Publication year: 2012


Trastuzumab, a humanized monoclonal antibody directed against HER2, has shown efficacy in breast cancers; however many patients do not respond to this reagent. Here, we discuss the potential mechanisms of trastuzumab efficacy and resistance in different clinical settings as a step toward optimizing the appropriate application of this antibody. The three major antitumor mechanisms of trastuzumab, i.e., inhibition of proliferation, antibody-dependent cell cytotoxicity (ADCC) and inhibition of DNA repair, appear to be differentially operative in different clinical settings. ADCC appears to be the prevalent mechanism in trastuzumab neoadjuvant monotherapy, whereas in neoadjuvant, adjuvant or metastatic settings in which trastuzumab is combined with chemotherapy, the relative role of ADCC is probably small, considering the compromising effects of chemotherapy on the immune cells that mediate this mechanism. In neoadjuvant and adjuvant settings involving concomitant use of trastuzumab and chemotherapy, the primary mechanism at play is presumably inhibition of DNA repair by the antibody, while in sequential protocols, the antibody acts mostly by exerting cytostatic activity through inhibition of HER2-mediated tumor cell proliferation. According to the ability of the antibody to induce cytotoxic or cytostatic antitumor effects depending on the clinical setting, different criteria, i.e., RECIST for cytotoxic effect, OS, and DFS for cytostatic, must be considered in accurately estimating antibody efficacy. Moreover, since trastuzumab resistance likely depends directly on the mechanisms responsible for its antitumor activity, resistance mechanisms must also be considered with respect to the different clinical settings.

abstract: Trastuzumab and pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies.

NCI Cancer Bulletin: (U.S.) FDA Approves Test to Identify Candidates for Breast Cancer Drug - Trastuzumab (Herceptin) - HER2 gene

FDA Approves Test to Identify Candidates for Breast Cancer Drug

The Food and Drug Administration (FDA) has approved a genetic test that doctors can use to help identify women with breast cancer who have extra copies of the HER2 gene and therefore may benefit from the drug trastuzumab (Herceptin).
Trastuzumab targets the protein made by the HER2 gene, which is located on chromosome 17. Approximately 25 percent of breast cancers have extra copies of the HER2 gene and produce higher levels of the HER2 protein. These tumors tend to grow faster and are more likely to recur than tumors that don’t overexpress HER2........cont'd

Trastuzumab (Herceptin) Beyond Progression in Retrospective Analyses: An Issue of Equal Opportunities -- The Oncologist

Note: Trastuzumab is also known as Herceptin "Based on these considerations, it would be interesting if Extra and colleagues could reanalyze their data by distinguishing patients stopping trastuzumab according to whether or not they had "equal opportunities" to patients continuing trastuzumab beyond progression." (The Oncologist) Editor's note: Dr. Extra was invited to reply but declined comment.

no abstract: Bilateral macular ischemia and severe visual loss following trastuzumab (Herceptin) therapy

Abstract/full free access: The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors

In research/technical:

Conclusions

Cetuximab (Erbitux) and trastuzumab (Herceptin) distribute slowly, but at higher doses achieve a relatively uniform distribution after about 24 hours, most likely due to their long half-lives in the circulation. There remains poor distribution within hypoxic (hypoxia - a deficiency of oxygen reaching the tissues of the body) regions of tumors.