Breast cancer is the second most common cancer globally. According to the World Health Organisation (WHO), in 2022, there were 2.3 million people diagnosed with breast cancer and 670,000 deaths globally. Moreover, a report from the American Cancer Society identified a shocking trend that breast cancer incidence is increasing at a faster rate in younger women than in those over 50.

The report also highlighted a 1.4% increase in cancer incidence in women under 50 years old from 2012 to 2021 in comparison to a 1% increase in women over 50. This is a worrying trend as breast cancer has largely been viewed as a disease that predominately affects older women; however, this may now be changing.

The WHO is aiming to decrease the incidence and mortality rates for breast cancer across the globe using their WHO Global Breast Cancer Initiative (GBCI). The incentive aims to reduce breast cancer mortality by 25% by 2030 and 40% by 2040 in women under the age of 70 years old. They aim to do this by focusing on three main pillars, including health promotion for early detection, timely diagnosis, and comprehensive breast cancer management.

Researchers from the National University of Singapore (NUS) who recently published in the Open Access journal Cancers are contributing to this incentive by developing a non-invasive method to improve the effectiveness of a common chemotherapy method.

What is breast cancer?

Breast cancer is a disease caused by the unregulated growth of mutated cells in the breast tissue. The mutated cells divide and grow uncontrollably, forming cancerous tumours. Anyone can develop breast cancer; however, there are some genetic factors that can increase the risk, such as family history and ethnicity.

There are multiple types of breast cancer depending on the cell type affected by the mutation; this also identifies the location of the cancer. Moreover, the type of breast cancer can also be classified by the presence of hormone receptors on the outside of breast cancer cells, which can escalate the growth of cancerous cells. In addition, it can  also be classified based on the overproduction of human epithelial growth factor-2 (HER2), a growth factor protein that controls cell growth.

The treatment for breast cancer depends on the above factors as well as

• The size and location
• If it has metastasised to other areas of the body
• General health.

The treatments for breast cancer include surgery, chemotherapy, radiation therapy, hormonal therapy, and immunotherapy.

Chemotherapy was developed for the treatment of lymphoma in the 1940s using the cytotoxic substance nitrogen mustard, originally produced for chemical warfare during World War II. It kills or stops the growth of cancerous and fast-growing cells.

Since its discovery, a wide range of chemotherapies have been developed to treat all types of cancerous cells. In recent years, many therapies have been developed to mitigate the toxic effects of chemotherapy and increase tolerability. The researchers from the National University of Singapore (NUS) hoped to add a treatment option for patients being treated with the chemotherapeutic drug doxorubicin (DOX).

Doxorubicin for breast cancer treatment

Doxorubicin (DOX) is a common chemotherapy agent used to treat breast cancer. It can also be used for the treatment and management of other cancers such as ovarian, thyroid, bladder, lung, as well as for the clinical management of leukaemia, lymphomas, and sarcomas.

DOX can be used for the management of a variety of cancers because of its broad mechanism of action. This includes being able to intercalate between DNA base pairs, distorting the DNA structure, and disrupting DNA replication and repair mechanisms. More specifically, it effectively disrupts topoisomerase-mediated DNA repair and replication mechanisms, resulting in the inhibition of cell proliferation and promotes cell death (apoptosis).

Doxorubicin associated toxicity

DOX is effective at targeting heightened DNA replication, which is crucial for the progression of cancer. However, DOX also damages healthy tissue that has elevated levels of basal mitochondrial respiration needed for ATP production and energy generation. This includes healthy tissue such as cardiac muscle, which requires continuous high levels of ATP to efficiently pump blood around the body.

Skeletal muscles and central nervous tissue are also commonly damaged by DOX because of elevated basal levels of mitochondrial respiration. Because of this, DOX can cause a wide range of side effects, such as tissue damage and sometimes organ failure.

“The majority of women who undergo chemotherapy experience side effects from treatment, and in some cases, doses of chemotherapy need to be reduced, or in severe cases, stopped prematurely. Moreover, prolonged exposure to high-dose chemotherapy can also lead to drug resistance. This targeted approach represents an excellent opportunity to potentially improve treatment outcomes while preserving patients’ quality of life”. – Assistant Professor Joline Lim, author on paper.

The researchers aimed to investigate the use of pulsed electromagnetic fields (PEMFs) in combination with DOX treatment to mitigate the harmful effects of DOX on healthy tissue in breast cancer patients.

Pulsed electromagnetic fields to boost the efficiency of DOX

PEMFs are a non-invasive medical therapy that uses electromagnetic fields to treat a range of conditions. The treatment has been shown to activate the channel TRPC1 (transient receptor potential) in healthy breast tissue.

TRPC1 regulates cell cycle progression in healthy cells; however, elevated expression of this calcium channel has been associated with cancer progression in a variety of aggressive cancers. PEMF has been demonstrated to increase the vulnerability of breast cancer cells to DOX treatment. Moreover, it activates the TRPC-1 channel, directly targeting the cancerous cells and increasing DOX intake into the cells.

The researchers investigated this synergistic relationship of PEMFs and DOX treatment using mouse models as well as cancerous human breast tissue. DOX uptake in cancerous cells was assessed using innate autofluorescence following magnetic exposure. Furthermore, the cellular vulnerability of the cancerous cells was assessed by monitoring mitochondrial activity and cellular DNA content.

Pulsed electromagnetic fields elevating DOX efficiency and mitigating side effects

The researchers identified that 10 minutes of PEMF treatment improved the uptake of DOX into the cancerous cells. Moreover, the researchers identified that the PEMF treatment was most effective using low doses of DOX, reducing the potential toxicity and side effects associated with DOX. In addition, by directly targeting the breast cancer cells, healthy tissue was less sensitive to PEMF DOX cytotoxicity

“Importantly, when we increased the amount of TRPC1, we observed an increase in DOX uptake — this means that TRPC1 can be used as a viable therapeutic target for aggressive cancers,” said Mr Vinesh Krishnan Sukumar, author on the study.

The researchers conclude that this study could pave the way for selective non-invasive PEMF platforms to improve cancer outcomes with lower systemic levels of DOX.

“Our approach will be patented and form the foundation for a startup specialising in breast cancer treatment. We are currently in discussions with potential investors in Southeast Asia and the United States to translate this technology from bench to bedside,” – Associate Professor Franco-Obregón, author on paper.

If you’re interested in reading more research or submitting research in this area, please see the Cancers Special Issue: Advances and Novel Multidisciplinary Strategies for Breast Cancer.