INTRODUCTION

In recent years, breast cancer awareness has grown considerably but the disease itself remains deadly and is the second leading cause of cancer related deaths among women in the US. Approximately 30% of breast cancer diagnoses, particularly the more aggressive cases, are characterized by overexpression of human epidermal growth factor receptor 2 (HER2). HER2 is one of a family of four HER cell surface tyrosine kinase receptors, which is also know as Neu, erbB-2, CD40, and p-185. Unlike the other HER family members, HER2 does not bind any known ligands but rather remains constitutively in a conformation that favors dimerization with other HER receptors.

HER dimers that include HER2 are more potent activators of their downstream signaling cascades, which favor cell proliferation and differentiation. In breast cancers, overexpression of HER2 correlates with a poor prognosis and shorter disease free survival. For these reasons, the search for breast cancer treatments has focused largely on identifying inhibitors of HER2 activity.

MECHANISM OF HER2 INHIBITION

The first drug to be developed for inhibition of HER2 was Herceptin (transtuzumab), which was a monoclonal antibody that binds the extracellular domain of HER2 to inhibit dimerization. Herceptin remains the first line treatment for HER2 positive breast cancers.

Afatinib and Lapatinib are the second generation HER2 inhibitors that are commonly used to treat cases that have progressed after initial treatment with herceptin. Both afatinib and lapatinib are tyrosine kinase inhibitors that block the downstream signaling of HER2.

A new second generation drug, Neratinib, is currently in clinical trials where it is demonstrating better results than either of its predecessors.

NERATINIB

In 2009, the first results of an ongoing Phase I/II trail studying the efficacy of Neratinib in breast cancer were reported. This study showed that neratinib in combination with a pre-existing therapeutic had an overall response rate of 69%.

A second report from a Phase II clinical trial was published in the Journal of Clinical Oncology in 2010. The study enrolled 136 patients with stage III or IV, HER2 positive, breast cancer. Approximately half of the patients enrolled had received previous herceptin treatment. In this study, neratinib was used as a stand alone therapeutic. The results showed that 16-week progression-free survival was 59% among women who had previously been treated with herceptin and 78% among women with no prior treatment. Furthermore, 24% of women who had previously been treated with herceptin responded to the therapy as did 56% of women who had had no previous treatment. The conclusions of this study stated that neratinib is an active and reasonably well tolerated therapeutic for advanced, HER2 positive breast cancer. Because of these favorable outcomes, neratinb proceeded to Phase III trials.

I-SPY2 STUDY

In March, 2010 a study called Investigation of Serial Studies to Predict your Therapeutic Response with Imaging and Molecular Analysis, or I-SPY2, launched as a collaboration between three pharmaceutical companies, the FDA, the National Institute of Health (NIH), and non-profit groups. The goal of I-SPY2 is to use DNA to match one of five drugs to each individual patient for the best outcome. The study is expected to last five years and cost $26 million.

Neratinib is one of the drugs being studied in I-SPY2, along with veliparib (a PARP inhibitor), conatumumab, AMG386, and figitumumab (a IGFR inhibitor). Patients at 20 cancer centers will have DNA testing done on their biopsy specimens and will be treated with one of the drugs pre-surgery to determine if the drug used can prevent progression of the tumor.

SUMMARY

The I-SPY2 study is the first of its kind in that the FDA has granted approval for up to 12 different drugs to be tested without having to halt the trial and write a new protocol. The hope is that level of deregulation will make the trial more efficient and allow it to have faster and greater impacts on a number of diseases. It is the first study to combine the study of biomarkers and therapeutics in order ot forge a path to personalized medicine.

REFERENCES

1. Burstein HJ, Sun Y, Dirix LY et al. Neratinib, an irreversible ErbB Receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. Journal of Clinical Oncology. 2010; 28: 1301-1307.
2. Rabindran SK, Discafani CM, Rosfjord EC, et al. (June 2004). Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 64 (11): 395865.
3. Minami Y, Shimamura T, Shah K, et al. (July 2007). The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Oncogene 26 (34): 50237.
4. Mnard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000;182:150-162.
5. Seshadri R, Firgaira FA, Horsfall DJ, et al. Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group. J Clin Oncol. 1993;11:1936-1942.
6. Baselga J. A new anti-ErbB2 strategy in the treatment of cancer: prevention of ligand-dependent ErbB2 receptor heterodimerization. Cancer Cell. 2002;2:93-94.
7. Tsou HR, Overbeek-Klumpers EG, Hallett WA, et al. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem. 2005 Feb 24;48(4):1107-31.

RELATED POSTS

Second generation HER inhibitors effectively treat relapsed breast and ovarian cancers

EGFR(HER) inhibitors greatly improve prognosis for lung and pancreatic cancer
Related to Neratinib, a novel HER2 inhibitor, shows promise in new breast cancer biomarker study

Second generation HER inhibitors effectively treat relapsed breast and ovarian cancers

INTRODUCTION Breast cancer is the leading cause of cancer related deaths in women. Ovarian cancer is the second most common cancer in women, affecting approximately …
PARP inhibitors show promise in treatment of hereditary breast and ovarian cancer

INTRODUCTION For some time we have understood that there was a genetic component to breast and ovarian cancers because some families appear to have higher …
Development of OSI-906, a IGF-1R inhibitor, for reversal of acquired erlotinib resistance

INTRODUCTION Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane tyrosine kinase receptor for IGF-1 and IGF-2. The normal physiological function of IGF and IGFR is …