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INTRODUCTION


Cancer deaths rose to 8.2 million worldwide in 2012, an increase of 8% from 2008, with a sharp rise in breast cancer deaths, up 14%, in the same period. There is therefore a ready market for a novel treatment that is able to improve survival in patients diagnosed with cancer who might progress to metastatic disease. For example, the current leading metastatic breast cancer agent Avastin is also indicated for glioblastoma and cancers of the colon, lung, renal system, cervix and ovaries, and had global sales of US$6.75bn in 2013.



BREAST CANCER


Approximately 20 per cent. of breast cancer sufferers are diagnosed with “triple-negative tumour”, an often aggressive form of the disease that invariably leads to metastasis. A triple negative tumour is one that when tested following biopsy or surgical removal does not have receptors for the hormones oestrogen or progesterone, or for the HER2 protein. A further approximately 20% of the patient population have HER2-positive disease which also predisposes patients to metastasis. Certain demographic groups are seen to have triple negative breast cancer at a higher frequency, such as those women who develop breast cancer under the age of 40.


TARGETED THERAPEUTICS


The classification of cancers has historically been characterised by their location in the human body: e.g. breast, colon, liver etc.

Recent understanding of cancers at a cellular level has shown that they are characterised by

  1. specific DNA mutations in cancer-related genes

  2. misregulation of oncogenes – epigenetic changes


  1. This market today is dominated by the taxanes and VEGF(R) inhibitors, with new market leads arising from alternative analogues of these agents or their combination with improved drug-delivery methods.

  2. Emerging novel therapeutics, identified through rational targeting of metastatic mechanisms and originating from research of the biology of metastatic disease, are predicted to occupy more than 25 per cent. of this market by 2019.

  3. The main drivers of this emerging market are the unmet clinical needs for increased efficacy over and above that provided by existing agents and increasing the life-span for terminally ill patients.

 
There has been a trend in recent years within the cancer therapeutics field away from cytotoxic chemotherapy (non-specific targeting of DNA and cell division) towards more targeted therapies based on advancing knowledge of molecular targets that are over-expressed or (selectively) expressed in tumour progression. However, alongside the established anti-hormonal agents (breast and prostate cancer), the cancer drug development field is still dominated by anti-proliferative / anti-angiogenic agents, such as tyrosine kinase inhibitors against targets such as the EGFR, HER2 and cyclin-dependent kinases (CDK's). A focus on targets such as kinase inhibitors continues to dominate the field despite their lack of clinical efficacy in a number of recent cases (gefitinib / EGFR; Avastin / VEGF), and despite the fact that the majority of cancer deaths are caused by the poorly targeted process of cancer metastasis.

CURRENT STANDARD OF CARE


Women who have breast cancer with hormone receptors present may be prescribed hormonal treatments, such as tamoxifen or anastrozole.  Women with breast cancers that have high levels of HER2 receptors may be given the drug trastuzumab (Herceptin®). However, women with triple negative breast cancer do not benefit from these treatment regimens and are commonly treated with chemotherapy.

The anti-angiogenic drug bevacizumab (Avastin®, used in combination with a chemotherapeutic paclitaxel such as Taxol) is currently the leading agent in triple negative breast cancer, but the US FDA’s Oncologic Drugs Advisory Committee (ODAC) has advised its removal from breast cancer treatment due to poor efficacy in clinical trials.

Abraxane (nanoparticle paclitaxel) is considered the most efficacious drug for the disease currently, but it is likely that combined ramacurimab (antibody against VEGFR2, acting on the same pathway as Avastin) plus Taxotere (docetaxel, a paclitaxel variant) will supersede this by 2016.

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KEY POINTS


  1. Metastasis, the spread of tumours around the body, accounts for more than 90% of all cancer related deaths

  2. Cancer deaths rose to 8.2 million worldwide in 2012, an increase of 8% from 2008, with a particularly sharp rise in breast cancer deaths (up 14%) in the same period

  3. There were approximately 522,000 worldwide deaths attributable to breast cancer in 2012.

  4. The breast cancer drug market is predicted to be US$10.4bn in 2019, of which 25% is expected to comprise targeted therapeutics

 

Cancer Science

The spread of tumours around the body, termed metastasis, accounts for more than 90% of all cancer-related deaths. For a cancer cell to metastasise, it must break away from the primary tumour and invade nearby normal tissue. It then needs to invade either the lymphatic or circulatory system, which carries the cell to a new location in the new body, allowing it to establish itself in a new site. Cancer metastasis usually indicates a later stage of the disease, with poorer outcomes for the patient.