Adopting a Biomarker-Driven Approach to Breast Cancer Care

By Patricia Thangaraj

Advancements in genome sciences, molecular biology and systems biology have revealed that breast cancer is one of the most biologically diverse tumour types with different components driving its development and progression.

Some key facts:

• Breast cancer is the most common cancer among Canadian women (excluding non-melanoma skin cancer).
• 28,600 Canadian women will be diagnosed with breast cancer in 2022.
• 5500 Canadian women will die from breast cancer.
• 270 Canadian men will be diagnosed with breast cancer.
• 55 of whom will likely die from it.

Therefore, the need to find treatment options for these Canadians is urgent. Currently, breast cancer can be classified into four main categories. These are Hormone Receptors, HER2 Receptors, Triple-Negative Breast Cancer (TNBC) and BRCA Mutations. Treatment options vary according to these classifications.

Breast Cancer Classifications

Establishing the best management approach for breast cancer would depend heavily on identifying the key receptors or proteins that may be fuelling the growth of the tumour. It is this manifestation of receptors or proteins that in turn defines how the breast cancer is classified.

Hormone Receptors

Since hormones are the major factor in the development of breast tissue, it is not unexcepted that they also play a crucial role in the development of cancerous tissue in the breasts. In fact, the connections between these two things has been well documented for more than 100 years.

The growth and proliferation of female breast tissue occurs during puberty when hormonal factors lead to cellular differentiation. These changes in puberty are induced by two steroid hormones – oestrogen and progesterone, which serve as the “master regulators” of the development of the regular functions of the breasts. These hormones join with cellular receptors and fuel growth. Unfortunately, tumour cells also use oestrogen and progesterone to accelerate their development.

The presence of oestrogen receptors (ER) and/or progesterone receptors (PR) on tumour cells is used as one of the main classification mechanisms for breast cancer. More than 1% of breast cancer cells must have ER or both in order to be classified as hormone receptor (HR)-positive. If these cells contain less than 1% of these receptors (or any receptors at all), they are classified as (HR)-negative and it is unlikely the cause of the tumour growth.

The role of hormones in breast cancer has been well documented and accordingly, some of the first drugs developed to treat breast cancer were hormone therapies. These therapies block the cancer cells from using oestrogen and progesterone.

Oestrogen receptors are more predominant than progesterone receptors in breast cancer. Around 80% of all breast cancers are hormone-dependent and oestrogen receptor-positive (ER+). Incidences of tumours being oestrogen receptor-negative and progesterone receptor-positive (ER-/PR+) are sporadic. Accordingly, treatments are often geared towards conduits involving oestrogen. These are known as endocrine inhibitors.

Available Treatment Options

Aromatase inhibitors (AIs) block oestrogen from being produced by certain tissues, other than the ovaries while other therapies referred to as selective oestrogen receptor modulators (SERMs) compete with oestrogen to connect with receptors, resulting in the effects of oestrogen being thwarted.

Selectively reducing the oestrogen receptor with the use of certain oestrogen receptor degraders (SERDs) is another way of targeting HR+ breast cancer. By reducing the oestrogen receptor, the ER signalling pathway is destroyed and the cancer cells capacity to use oestrogen is likewise, diminished. SERDs are mainly used in metastatic disease. This refers to when the cancer has spread to other organs of the body – and are increasingly used in combinations with other agents to potentially overcome resistance to endocrine therapies.

The number of drugs available to treat HR+ positive breast cancer has continued to evolve over the last few decades and pharmaceutical and biotechnological companies like AstraZeneca are working on developing more drugs to treat women  who have been diagnosed with HR+ breast cancer.

HER2 Receptors

In the early 1980’s, it was discovered that the human epidermal growth factor 2 (HER2) gene, which helps to preserve a healthy cell lifecycle, was also used by cancer cells to develop and proliferate in breast cancer cells when there is an overexpression of the HER2 gene or protein.

High levels of HER2 protein expression is found in around 20% of breast cancers and is linked with an aggressive and fast-growing disease.

Available Treatment Options

Traditionally, HER2 breast cancer is associated with poor prognosis. However, this has changed greatly as monoclonal anti-HER2 antibodies, tyrosine kinase inhibitors and antibody-drug conjugates (ADCs) have been developed to treat the factors which fuel oncogenes.

ADCs contain two cancer-fighting drugs in one. These are a cytotoxic agent, also referred to as chemotherapy or the “payload,” and a monoclonal antibody, which attaches to a specific target expressed on cancer cells that have been joined together by a linker. This results in the highly targeted delivery of a cytotoxic agent, which is known for having poor specificity towards cancer cells, directly into the cancer cells, leading to normal cells being spared

Triple-Negative Breast Cancer (TNBC)

Triple-Negative Breast Cancer (TNBC) do not express oestrogen receptors, progesterone receptors and do not have high levels of HER2 overexpression. Therefore, they are cogitated ‘negative’ for all three. TNBC accounts for 10-15% of all breast cancers and is more common in women under the age of 40. This type of breast cancer is known to be intensely aggressive and fast growing, has a high risk of metastasis and is more likely to recur after treatment compared to other breast cancers.  

Available Treatment Options

Unfortunately, the options available to treat TNBC is limited compared to other forms of breast cancer because of the absence of identifiable actionable biomarker targets. However, just like other breast cancers, if the disease has not yet metastasised, surgery can be used with chemotherapy to either decrease the tumour before surgery or reduce the chances of the cancer recuring after surgery. In certain cases, women with TNBC may also be suitable candidates for immunotherapy. This is when the body’s own immune system is used to fight the disease.

BRCA Mutations

Genomic developments have identified further biomarkers which can be used to target breast cancer. These are the two breast cancer susceptibility BRCA genes known as BRCA1 and BRCA2.

These two BRCA genes are considered ‘tumour suppressors’ because they help to repair the damage caused to our DNA in a course of action referred to as the DNA Damage Response (DDR), particularly in homologous recombination repair (HRR), which is only one of the pathways to do so. It is also important to recognize that another component of the DDR is a family of enzymes referred to as PARPs (Poly(ADP-Ribose)Polymerases) which helps to repair the damage via another pathway.

However, when the BRCA genes are mutated, they are unable to perform as they should, thereby increasing the risks of being diagnosed with breast cancer. A woman with a BRCA1 or BRCA2 gene mutation has approximately a 7 in 10 chance of developing breast cancer by age 80.

Available Treatment Options

At a cellular level, mutated BRCA genes result in dysfunctional HRR pathways and in order to survive, the cell must depend on other pathways. This is what clinicians can use to treat the cancer. PARP inhibitors block the PARP enzyme and prevent single-stranded DNA breaks from being repaired. This results in an increase of double-stranded DNA breaks, which cannot be repaired by the dysfunctional HRR pathway. The cell must then depend on an alternative pathway which is not as precise and susceptible to error. It is at this point that the level of DNA damage moves past the manageable limit, which results in the destruction of  cancer cells.

Transforming the Classification and Treatment of Breast Cancer in the Future

Going forward, clinician research would play a crucial role in redefining the breast cancer treatment paradigm aimed at improving the outcomes for breast cancer patient populations, especially those with poor clinical prognosis.

A key component of this would be developing pioneering drugs including targeting monotherapies and precision/personalized combinations, all of which have been proven to result in positive results for women with breast cancer.

Enhancing diagnostic tests, improving on medical and surgical procedures and developing medical and surgical devices to better meet the needs of breast cancer patients, survivors and previvors would also play a critical role in identifying the actionable targets of each individual’s breast cancer and bring the advantages of a biomarker-driven approach to even more patients.

This would call for multi-stakeholder partnerships between clinicians; hospitals; health care non-profits; patient and family advisory councils; caregivers; federal, provincial and territorial governments; pharmaceutical and biotechnological companies, health care research companies and services and other health care providers, health care administrators, policy makers and patient advocates working together to increase their understanding of biologically diverse breast cancer tumours at every stage of the disease continuum and across the various lines of treatment.

They can then develop different mechanisms of action based on the underlying breast cancer biology that would address improved treatment pathways aimed at enhancing the lives of breast cancer patients, survivors and previvors.

References

AstraZeneca: https://www.astrazeneca.com/our-therapy-areas/oncology/breast-cancer.html

Canadian Cancer Society: https://cancer.ca/en/cancer-information/cancer-types/breast/statistics