Introduction
Breast cancer is a type of cancer that starts in the breasts when cells divide and grow in an uncontrollable way that leads to the formation of tumours. A breast is made up of fat, lobes made of milk-producing tissue, and milk ducts that extend to the nipples; breast cancer usually starts among the cells that cover the milk ducts. Breast cancer can affect both people assigned female at birth and those assigned male at birth, with the risk of developing it being 13% and 1% respectively.
It is important to treat breast cancer because if it is left untreated, cancerous cells will spread from the breasts to other organs, and when these vital organs are affected, the patient will eventually die. The main ways of treating breast cancer include:
- Surgery
- Radiotherapy
- Chemotherapy
- Targeted therapy (immunotherapy drugs, hormonal therapy)
This article will mainly focus on targeted therapy. Most patients with breast cancer require surgery. Targeted therapy can work on its own or along with chemotherapy. It works by targeting key cells or proteins that allow the growth of cancerous cells.
Targeted drugs are most commonly given before or after surgery. Before the surgery, drugs are given to reduce the size of the cancer and, therefore, have a smaller operation. After the surgery, drugs are taken to reduce the risk of the cancer from coming back.
Targeted therapy is relatively more modern compared to more traditional cancer treatments like chemotherapy and radiotherapy. One advantage of targeted therapy is that it does not kill normal cells that are usually killed by chemo and radiotherapy. As a benefit of this, if only received on its own, targeted therapy reduces the chance of getting side effects like hair loss that is usually present in traditional methods.
Types of breast cancer and biomarkers
There are different types of breast cancer, and the two most common types are Invasive ductal carcinoma and invasive lobular carcinoma; the names suggest that cancer spreads from the cells lining the duct and lobule (structures that branch from lobes) to surrounding tissues, respectively. Different types of breast cancer are diagnosed using a set of methods:
- Examination of the breast
- Breast X-Ray (Mammogram)
- Breast Ultrasound
- Taking a piece of breast tissue (biopsy)
Invasive breast cancer is also called “No Special Type” (NST), which means that there are no features spotted during the last step when doctors observe a biopsy under a microscope. Observing a biopsy also allows doctors to identify certain biomarkers. Biomarkers are key molecules or proteins that reveal important information about the specific type of cancer, they help doctors determine what type of treatment the patient should undertake.
Here are some common NST breast cancer:
Receptor-positive breast cancer
Receptors are protein structures usually located on the outermost layer of cells, and they can be stimulated when certain molecules or hormones bind to them; upon stimulation, a series of actions will be triggered inside the cells, and in the case of cancer, activation of certain receptors will encourage the growth of tumour cells.
Hormone receptor-positive (HR+) breast cancer
HR+ breast cancer refers to the type of breast cancer that has receptors for either of the hormones estrogen or progesterone on the cells in the tumour; both hormones promote cell growth and thus the growth of the tumour.
HER2-positive breast cancer
HER2+ breast cancer refers to the type of breast cancer that has receptors for the hormone human epidermal growth factor receptor 2. When tumour cells have this receptor, a large amount of protein called human epidermal growth factor, which is associated with some aggressive types of cancer.
Triple-negative breast cancer (TNBC)
TNBC breast cancer refers to the type of breast cancer that does not have the receptor for estrogen, progesterone or human epidermal growth factor. Patients with TNBC are more likely to carry non-functional BRCA1/2 genes, which, when functional, inhibit out-of-control cell growth.
PIK3CA mutation
PIK3CA is a gene that has a similar function to BRCA1/2 genes, it regulates the process of cell division and growth; therefore, when mutated, it will also cause cells to divide uncontrollably.
PIK3CA mutation more frequently occurs in HR+ and HER2- patients.
Gene mutations like BRCA1/2 and PIK3CA mutations are detected during genetic testing, which involves taking blood, skin, or saliva samples.
As biomarkers help to identify the subtypes of breast cancer, suitable treatments and medications can be implemented. Moreover, biomarkers can also help doctors monitor the effectiveness of the therapy and predict how likely cancer is to return; for example, TNBC is a more aggressive type and is more likely to return and further spread from the origin of cancer.
Mechanism of targeted therapy
In targeted therapy, drugs aim to inhibit the hormone receptors (or production of hormones) and mutated genes from functioning. The medications can come in the form of monoclonal antibodies, which can also be conjugated to drugs, inhibitors to proteins that synthesise mutated genes and promote cell growth.
Monoclonal antibodies refer to a large number of cloned antibodies that can bind to receptors and proteins, therefore stopping them from being stimulated. Drugs used in chemotherapy are directly attached to these antibodies, so when the antibodies bind to the specific protein in cancer cells, drugs can be released to kill the cancerous cells.
The key difference between chemotherapy and targeted therapy is that chemotherapy can kill all fast-growing cells, including normal cells; on the other hand, targeted therapy only targets specific proteins that facilitate the spreading of cancer.
Main types of targeted therapies
Hormonal therapy
- Drugs: Tamoxifen, Aromatase inhibitors, Fulvestrant
- Application: HR-positive breast cancer
These drugs are prescribed when the hormone receptors are present in cancer cells.
Tamoxifen works by blocking the receptors of estrogen and progesterone, which these hormones would usually bind to promote cell growth in breast tissue. Tamoxifen also has a preventative effect for people assigned female at birth. It is the only option for premenopausal people AFAB to pursue breast cancer prevention.
Aromatase inhibitors work by inhibiting the enzyme that is responsible for the synthesis of estrogen, aromatase, from functioning.
Fulvestrant also interacts with estrogen receptors. It inhibits estrogen receptors from forming and accelerates the degradation of the receptors; therefore, less estrogen signal can reach the receptors to trigger action.
HER2-targeted therapy
- Drugs: Trastuzumab, Pertuzumab, Lapatinib, Neratinib, T-DM1
- Application: HER2-positive breast cancer
In HER2 breast cancer, an excess amount of growth-promoting is produced, which increases the spread of cancer cells.
Both Trastuzumab and Pertuzumab are monoclonal antibodies and they both bind to the HER2 receptor. Trastuzumab stops the growth signal from reaching the receptor; on the other hand, Pertuzumab stops HER2 receptors from pairing with each other (dimerisation), which also promotes cell growth. Furthermore, for Trastuzumab, it can also trigger the body’s immune system to attack cells that have HER2 receptors.
T-DM1 is Trastuzumab, a monoclonal antibody, conjugated with a chemotherapy drug called DM1.
CDK4/6 inhibitors
- Drugs: Palbociclib, Ribociclib, Abemaciclib
- Application: HR-positive, HER2-negative breast cancer
CDK4 and 6 are proteins that facilitate cell division; they allow cells to progress through the cell cycle to enable successful cell synthesis, therefore blocking these proteins slows down the spread of cancer cells.
They are usually used along with hormone therapy, since they are suitable for HR+ breast cancer.
PARP inhibitors
- Drugs: Olaparib, Talazoparib
- Application: BRCA-mutated breast cancers
BRCA genes are important tumour-suppressing genes, so having mutations in these genes greatly increases the risk of developing breast cancer. It also helps with DNA damage repair.
PARP is a type of protein that also helps to repair damaged DNA. With both the gene and protein not functioning and inhibited, damaged DNA will not be repaired, and these damages will accumulate, leading to cancer cells dying, especially the cells with BRCA gene mutations.
PI3K inhibitors
- Drugs: Alpelisib
- Mechanism: Inhibiting the PI3K pathway
- Application: HR-positive, HER2-negative breast cancer with PIK3CA mutations
PI3K is a type of protein produced by the gene PIK3CA, and it regulates processes like cell growth and proliferation. When the gene is mutated, the protein is overly active, leading to uncontrolled cell growth; therefore, inhibiting PI3K protein will slow this down.
It is usually used along with hormonal therapy in patients with HR+ and PIK3CA mutation, because patients can build resistance to hormonal therapy drugs like fulvestrant, so by targeting another pathway, the anti-cancer treatment can continue.
Immunotherapy
- Drugs: Pembrolizumab, Atezolizumab
- Application: Triple-negative breast cancer (TNBC)
Triple negative breast cancer may be argued to be harder to treat than HR and HER breast cancer because there is no receptor to target.
Pembrolizumab is a PD-1 receptor inhibitor. PD-1 receptor is normally located on a type of white blood cell called T- cells, it is there to prevent T- cells from attacking the body’s cells; however cancer cells have exploted this feature: they have developed a protein called PDL-1, which can bind to PD-1 to stop it from attacking cancer cells. When Pembrolizumab is put in place, PDL-1 cannot bind to the receptor, so T-cells can attack cancer cells again.
Atezolizumab is a PDL-1 inhibitor that achieves the same effect. It binds to PDL-1 on cancer cells so they can’t stop T-cells from attacking them.
Advantages of targeted therapy
Targeted therapy is very personalised, apart from looking for specific biomarkers, a drug is chosen based on:
- Where the cancer is
- The size of the cancer and whether it has spread (the stage)
- How abnormal the cells look under the microscope (the grade)
- Your general health
This includes consideration of age, if the patient is pregnant and the state of health of your other organs. Doctors will also assess which drugs can be used together, to double the effect and also reduce the effect of resistance to therapy.
Challenges and limitations
Unfortunately, there are drawbacks to targeted therapy. Cancer cells can build resistance to targeted therapy over time. This means that cancer may be controlled for a while, but they will figure out a way to spread again. For example, over time, the structure of the hormonal receptors can change, resulting, inhibitors not being able to bind to these structures to stop their function.
Drugs can also be pumped out of the cells by efflux pumps, reducing the efficacy of the drugs over time
Summary
To sum up, targeted therapy has completely changed the way breast cancer is treated by providing more individualised and accurate methods than conventional therapies like radiation and chemotherapy. Targeted therapies lessen damage to healthy cells by concentrating on particular chemicals, receptors, or genetic abnormalities that promote the growth of cancer. This can reduce side effects. Nevertheless, there are several drawbacks to these treatments, including the limited efficacy in specific subtypes of breast cancer and drug resistance. Targeted therapy is a significant advancement, even with these restrictions, especially for malignancies that are hormone receptor-positive, HER2-positive, or have a BRCA mutation. Targeted therapies have the potential to become an even more crucial component of breast cancer treatment with ongoing research and innovation.
