Expanding horizons in breast cancer treatment

Cancer of the breast is a malignant tumour arising from breast tissue that grows uncontrollably, invades its surroundings, penetrates blood or lymphatic vessels, circulates in the body and spreads to distant organs.

When tumour cells proliferate at the new organ or distant site, it is called metastasis.

First described in 1600 BC in Egypt, breast cancer has now become a major health problem throughout the world, with more than one million women diagnosed annually.

At present, one in nine women face the risk of developing breast cancer in their lifetime. In Malaysia, breast cancer is the most common cancer type overall.

Although the worldwide incidence of breast cancer continues to rise, mortality from breast cancer has shown a declining trend, concomitant with a substantial improvement in its overall prognosis. This is certainly a result of heightened patient awareness leading to earlier diagnosis, an improved access to cancer care, better pathology services and molecular classification of breast cancer, and a genuine positive treatment effect.

Seeking treatment early

Early breast cancers which are confined to just the affected breast and axillary lymph nodes can be cured. More than 60 per cent of Malaysian women present in the early stages at diagnosis, according to a 2007 national cancer registry report. Once metastases to organs such as bones, liver or lung occur, the cancer becomes advanced and incurable.

Nevertheless, unlike the older days where therapeutic nihilism was dominant, metastatic breast cancer can still be controlled with newer treatments and technologies, allowing patients to live a good number of years with reasonable quality.

Breast cancer treatment involves a multidisciplinary team consisting of breast surgeon, oncologist, radiation therapist and other health personnel. The treatment choice depends largely on cancer stage, tumour biology and the patient's fitness for therapy.

Besides localised treatment with surgery and radiotherapy, the standard systemic treatment is with chemotherapy, while hormone therapy is used in oestrogen receptor (ER) positive type of cancer.

There has been incredible growth in the understanding of cancer biology and the concept of cancer as a "genetic disease" in the last 40 years due to intensive research on "molecular" lesions responsible for cancer formation.

Comprehensive lists of genes associated with important cellular processes involved in tumour formation, growth and progression such as uncontrolled proliferation, sustained formation of new blood vessels (angiogenesis) and ability for metastases has been found and better identified by active researchers.

Zooming on a target

Targeted therapy encompasses usage of drugs that block the growth of cancer by interfering with specific molecules involved in its growth and progression, a novel mechanism distinct from that of chemotherapy or hormones.

The principle of cell killing by chemotherapy is based on its actions on fast growing cancer cells. Although effective, cytotoxic chemotherapy drugs cannot differentiate between fast-growing cancer cells and normal fast-growing cells.

Meanwhile, hormone treatment acts by eliminating the effect of oestrogen on the growth of breast cancer cells.

Targeted therapies focus on specific molecular processes characteristic of cancer cells, thereby inhibiting its growth. Therefore, it is less harmful to normal cells and may potentially avoid toxicity associated with conventional treatment.

Discovery of the breast cancer-specific therapeutic target, Human Epidermal Growth Receptor 2 (HER2) in1984 has led to the successful development of therapies that are effective only in patients whose tumour harbour the target.

HER2 is a pro-growth protein molecule in breast cells that is present in excessive numbers in HER2 positive tumours, leading to uncontrollable growth and cancer formation. Approximately one out of four women with breast cancer have HER2-positive disease.

HER2 positive cancers exhibit more aggressive behaviour, recur earlier, and have an overall poorer prognosis.

Amongst the earliest prototype drug in this genre are the monoclonal antibodies, which are proteins that target a specific antigen on the surface of cells. The intravenous drug trastuzumab is a type of monoclonal antibody targeting the HER2 receptor protein.

Once attached to the receptor, they recruit other parts of the immune system to destroy the tumour cells that over-express the HER2 receptor.

Trastuzumab arrests cancer growth and stimulates the immune system to more effectively destroy the cancer cells. In early breast cancer, one year of treatment with trastuzumab halves the risk of dying from breast cancer, and this is considered the standard of care.

Trastuzumab is also approved in combination with chemotherapy or hormone therapy in metastatic HER2 positive breast cancer.

Exciting developments

Following its success, a new chapter of exciting and rapid evolution of new approaches in breast cancer therapy began. More anti-HER2 agents were introduced, either as single therapy or in combination with trastuzumab or other treatments in both early and advanced breast cancer.

One such agent is lapatinib, a targeted therapy in oral form that blocks HER2 receptor and another growth-activating protein called Epidermal Growth Factor Receptor (EGFR).

It has been approved for use in combination with chemotherapy or with hormones in postmenopausal patients with ER positive breast cancer and HER2-positive cancers who are found to be resistant to trastuzumab.

Another drug called pertuzumab is a new class of targeted anti-HER2 monoclonal antibody that blocks the HER2 protein at a different site at the cellular level, but with effects similar to that of trastuzumab.

Of considerable interest is the novel agent trastuzumab emtansine 1 (TDM-1), which combines the HER2-targeting properties of trastuzumab with targeted delivery of a highly potent chemotherapy agent called DM1 into the cells.

After binding to HER2, T-DM1 enters the cell to release the cytotoxic agent only within the target cells, thus avoiding toxic effects in normal tissues not harbouring the HER2 target.

Pertuzumab and TDM-1 have proven to be efficacious in metastatic breast cancer and have just been approved by global health authorities to be used in this setting.

In HER2 negative metastatic breast cancer, bevacizumab, a monoclonal antibody against the protein involved in tumourigenic angiogenesis process, may be an option when given together with select chemotherapy.

Angiogenesis is the process that involves new blood vessel formation in tissues. Growth of the vascular network is important for survival and metastatic spread of cancer tissue as they need to be supplied nutrients, oxygen and immune cells, besides removal of waste.

In addition, treatment with everolimus, an oral targeted agent against an intracellular growth pathway called mammalian target of Rapamycin (mTOR), in combination with the steroidal hormone exemestane is another viable option in patients with HER2 negative, ER positive breast cancer.

This combination has been shown to improve survival in comparison with just hormonal therapy alone as a first line treatment of advanced or metastatic cancer.

Finally, the addition of denosumab, a monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL), a target for bone resorption in bone metastases from breast cancer, has been shown to prevent multiple complications that may arise from having metastases in the bones, and thus improves patients' quality of life and possibly survival.

This drug has been tested in various types of cancer known to spread to the bones, showing benefit and a much lesser toxicity. It is now approved for prevention of skeletal related events from cancer in breast cancer and other solid tumours.

Targeted therapies are indeed an essential component of breast cancer treatment today. Although 100 per cent cure is still beyond our reach, and barriers continue to exist, the availability of these various targeted agents to treat breast cancer provide us with hope of having a much larger proportion of patients being cured from cancer.