New developments in breast cancer treatment

Up until a few years ago, breast cancer treatment had been limited. Broadly speaking, medical therapy for breast cancer is divided into:

1. Neoadjuvant (before operation) and Adjuvant (after operation) treatment

a. These treatments are for early breast cancers, which are resectable.

b. The aim is for cure by preventing breast cancer recurrence.

c. Neoadjuvant treatment can improve surgical outcomes and allow for an early evaluation of the effectiveness of systemic therapy.

d. Modality includes systemic treatment such as chemotherapy, hormonal blockade and Herceptin for HER2 positive disease.

e. Adjuvant radiotherapy for high-risk disease to minimise local recurrence.

2. Treatment for metastatic disease 

a. The aim is to improve quality and prolong life.

b. Modality involves systemic treatment as in Neoadjuvant and Adjuvant treatment.

c. Radiotherapy for palliation.

During the last decade, important developments were made to improve the treatment of breast cancer. These were either newer chemotherapy with less side effects, and new molecules, which enhance the effect of chemotherapy or hormonal blockade. Novel monoclonal antibodies were made and there were also genetic and molecular advances, which can help us to decide whether our patients would benefit from adjuvant chemotherapy. In addition, and most importantly, improvement in supportive care greatly improves the quality of life when patients are on therapy.

Here are some examples of the advances in breast cancer treatment:
PARP inhibitor in combination with chemotherapy

Cancer is the uncontrolled division or growth of abnormal cells. Chemotherapy kills cancer by damaging cellular DNA during the phase of mitosis (replication of cancer cells).

Naturally, the body repairs DNA damages by using PARP, which is an enzyme important in DNA damage repair. PARP can interfere with chemotherapy because we want chemotherapy to cause DNA damages, which will lead to killing of the cancer cells. PARP inhibitor will prevent DNA repair, and therefore, it will render chemotherapy more effective in killing of cancer cells.

This combination of chemotherapy plus PARP inhibitors had shown promise in BRCA mutated breast and ovarian cancer, as well as in squamous cell lung cancer, usually caused by cigarettes smoking. Large (Phase III) global clinical trials are available in South Africa and eligible patients should enquire about this potentially effective combination treatment.

HER2 blockers

Approximately 20% of breast cancer overexpressed HER2, which is a receptor expressed on breast cancer cells. Overexpression of HER2 is associated with an increased risk of recurrence and a worse prognosis.

When HER2 is overexpressed, there are many HER2 receptors on the cell surface, and this creates lots of opportunities for dimerisation (coming together of HER2 and other cell surface receptors). Dimerisation triggers a process called phosphorylation inside the cell, which drives the signalling pathway inside the cell to divide and grow.

Blocking HER2 therefore will stop dimerisation and ultimately leading to switching off the signalling pathway inside the breast cancer cells, leading to cancer cell death. This form of treatment is called targeted treatment, as we are targeting HER2 receptors specifically on the surface of the breast cancer cells, instead of killing cells in random in chemotherapy.

Targeting HER2 can be achieved by monoclonal antibodies or by small molecules called tyrosine kinase inhibitors.

Trastuzumab (Herceptin) is a monoclonal antibody against HER2. In HER2 overexpressed breast cancer, one year treatment with trastuzumab has been consistently shown to improve survival in the adjuvant setting. Trastuzumab has also been proven to be effective in HER2 positive metastatic breast cancer.

In addition to trastuzumab, other novel HER2 directed treatments are available:

1. Ado-trastuzumab emtansine (T-DM1 / Kadcyla) is an antibody-drug conjugate composed of trastuzumab and linked to a microtubule inhibitor, DM1. Once trastuzumab binds to the HER2 receptor, DM1 is delivered into the breast cancer cell and kills the breast cancer cell from within. It works like a “suicide bomber” on a cellular level. This treatment can be considered in patients who have progressed on or soon after trastuzumab or lapatinib treatment.

2. Pertuzumab (Perjeta) is another monoclonal antibody that Inhibits HER2 dimerisation by binding to a different HER2 domain, different from the site of binding of trastuzumab. When pertuzumab is combined with trastuzumab (dual HER2 blockade), a more complete inhibition of HER2 occurs, which leads to a more effective blockade of the signalling pathway. This has been demonstrated in the CLEOPATRA trial, where adding Pertuzumab to Trastuzumab plus chemotherapy (docetaxel) was shown to significantly improve the response and survival, compared to Trastuzumab plus docetaxel in HER2 positive metastatic breast cancer.

3. Lapatinib (Tykerb) is a tyrosine kinase inhibitor, which blocks HER2 and EGFR receptors. It targets the receptors directly, stopping phosphorylation and downstream signalling, ultimately leading to cancer cell death. This treatment can be considered in combination with chemotherapy or hormonal blockade (if estrogen receptor positive) in the HER2 positive metastatic setting, after progression on trastuzumab-based treatment.

new developments

Hormonal blockade, mTOR inhibitor & CDK inhibitor 

In breast cancers that are estrogen receptor (ER) positive, depleting estrogen will stop the cancer from growing. Hormonal blockade using tamoxifen and aromatase inhibitors (e.g. anastrazole, letrozole and exemestane) are well studied both adjuvantly and in metastatic settings, and are effective and is commonly used in clinical practice.

Sometimes, these estrogen receptors can become resistant to the hormonal blockade, leading to breast cancer recurrence. Everolimus (Afinitor), an mTOR inhibitor, in combination with exemestane or tamoxifen, can restore the sensitivity of estrogen receptors, allowing another line of treatment of hormonal manipulation in ER positive and HER2 negative metastatic breast cancers.

Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6). These kinases are important in regulating the cell cycle (the cellular process of making new cells). Palbociclib reduces proliferation of breast cancer cells by inhibiting certain phases in the cell cycle. Palbociclib plus letrozole has been shown to improve progression free survival significantly (almost double) compared to letrozole alone, and can be considered in the first-line treatment of metastatic ER-positive, HER2-negative breast cancer.

Promising future of immunotherapy

Immunotherapy in the form of anti-CTLA4 and anti-PD1/PDL1 treatment (checkpoint inhibitors) has been having major success in lung cancer and melanoma recently.  These treatments are also showing promises in Hodgkin’s lymphoma, head and neck cancer, stomach cancer, mesothelioma, bladder cancer, kidney cancer and certain type of colon cancer, to name a few.

In a specific type of breast cancer, the triple negative breast cancer (estrogen receptor, progesterone receptor and HER2 negative), anti-PD1 treatment with pembrolizumab is showing exciting promises and long duration of response in metastatic setting.  Side effects are mild and larger clinical studies (Phase III) are now being conducted globally (including South Africa) to compare this form of treatment versus traditional chemotherapy.

Oncotype DX (21-gene recurrence score)

The 21-gene recurrence score (RS) is a prognostic assay. It is a genetic / molecular test of the breast tumour plus mathematical analysis and calculation to predict distant relapse despite five-year of tamoxifen therapy. The result of this calculation is known as the recurrence score.

It is indicated for women with node-negative, ER-positive breast cancer to determine the prognosis and to predict who is most likely to benefit from adjuvant chemotherapy.

In general, the prognosis for low RS score is very favourable with 5 years of adjuvant tamoxifen, that the absolute benefit of chemotherapy is very low. Intermediate or high RS score usually indicates a higher chance of recurrence and adjuvant chemotherapy should be discussed with the patient to reduce the risk of recurrence together with the use of hormonal blockade for 5 years.

This information can be very useful as an additional guide to both patients and doctors to choose or omit adjuvant chemotherapy in early breast cancer.

Molecular testing such as the Oncotype DX testing helps us to understand the molecular / genetic landscape of breast cancers. Not only does molecular technology like this help guide and inform us about the risk of recurrence, it can perhaps in the near future, locate an important gene which could be responsible for metastasis (spreading of cancer to other sites), and predict and guide what treatment the patient should receive (biomarker development).

Prevention of hair loss

Hair loss is transient and reversible during chemotherapy. However, it is often distressing to many women suffering from breast cancer. Although there are some chemotherapy agents that cause no or minimal hair loss, most breast cancer chemotherapy will cause major hair loss.

Scalp cooling causes vasoconstriction of blood vessels and limits absorption of chemotherapy by slowing down the metabolic rate of hair follicles. Problems patients may encounter from the process of scalp cooling includes patient discomfort from the cooling cap, headache, and long duration of treatment (cooling before, during and after chemotherapy infusion).

The success of scalp cooling for preventing hair loss is variable between patients, chemotherapy regimens and dosage of drugs. The success rate (no wig requirement) is usually between 40-60%, and it varies between different oncology units.

Other advances in cancer treatment that are beyond the scope of this article are new class of anti-nausea medications, aiming to prevent nausea altogether, bisphosphonate and denosumab to decrease the skeletal related events such as fractures associated with bone metastasis, and G-CSF prophylaxis and rescue treatment in chemotherapy-induced febrile neutropenia (a condition associated with severe infection after chemotherapy).

Finally, although these treatments and advances hold great promise, choosing any of these treatments will depend on the correct clinical indications. Patient preference, concerns regarding toxicities, and drug availability are also important factors to consider. Some of the new treatments may not be available yet in South Africa, but there are often clinical trial opportunities to allow early access to these treatments. Occasionally, compassionate programmes are available.

Please consult your oncologists who will guide you through these treatment options. And, keep watching the space for exciting new developments in cancer diagnosis and treatment!

Written By Dr Sze Wai Chan.

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