Pertuzumab its development and potential for use in the treatment of breast cancer

By

TABLE OF CONTENTS

LITERATURE REVIEW1

Introduction1

Usage of Pertuzumab in Breast Cancer1

Effects of Pertuzumab2

The anti-tumour effect3

The CLEOPATRA Study4

Conclusion5

REFERENCES7

LITERATURE REVIEW

Introduction

Women with HER2 positive metastatic breast cancer who have received the new monoclonal antibody pertuzumab in addition to standard chemotherapy, based on docetaxel are shrinking by 38% the risk of worsening disease and death. The data come from a trial whose data had been anticipated last July and is now in final form were presented at the British Breast Cancer Symposium, and, simultaneously, have been published in the British Journal of Ontology (Zhang, 2008).

The erbB2 heterodimerization inhibitor pertuzumab has also been shown to be effective at inhibiting tumor growth rates in our 231-H2N model system both in vitro and in vivo and has been reported to act synergistically in combination with trastuzumab (Zhang, 2008). An improved anti-tumor efficacy of combining erbB2-directed antibodies recognizing multiple epitopes on the extracellular domain of erbB2 was also shown by (Peterson, 2003,) when compared to the same antibodies used individually.

Usage of Pertuzumab in Breast Cancer

Using pertuzumab for breast cancer may be a potential second-line therapy as it inhibits the dimerization of erbB2 with EGFR and erbB3, both of which are potent heterodimers involved in the expression of VEGF. This efficacy in erbB2 negative cancers is important as clonal selection of cells expressing lower levels of erbB2 may be involved in some circumstances of trastuzumab resistance in those studies presented here and potentially in the clinic.

For women bearing breast cancer resistant to trastuzumab and metronomic CTX, monitoring of tumor growth illustrated that bevacizumab was the most effective therapy at delaying tumor growth for a period of time after initiation of second-line treatment (Tobin, 2004, 44). In contrast, the addition of pertuzumab provided no benefit compared to those women maintained only on trastuzumab and metronomic CTX. Cetuximab appeared to delay the tumor growth rate for a few weeks prior to the onset of rapid tumor progression. The A12 antibody indicated an impressive delay in tumor growth to bevacizumab, but women had indications of extensive metastases throughout the peritoneal cavity. Mice from all treatment groups were sacrificed at treatment day 144 due to poor general health, which could be associated with the long-term administration of CTX, systemic response to the multiple antibody-based therapies used, or a consequence of bearing tumors for greater than 180 days. The health status of women in the trastuzumab related experiment did not decline, but these women were younger, had tumors for much shorter periods of time, and was not given CTX (Peterson, 2003).

Mechanistic studies suggest that an increase in p27kiP1 degradation as a result of IGF-1 R signaling prevents the upregulation of p27kiP1 normally induced by trastuzumab through down regulation of erbB2 signaling, thereby antagonizing the ability of trastuzumab to induce cell cycle arrest (Greenberg, 2005).

Effects of Pertuzumab

The effects of these second-line therapies were assessed in two experiments, where tumors had become resistant to trastuzumab therapy alone and trastuzumab in combination with low-dose CTX (Dickersin, ...