Despite a remarkable increase in the depth of our understanding and management of breast cancer in the past 50 years, the disease is still a major public health problem worldwide and poses significant challenges. The palpability of breast tumors has facilitated diagnosis and documentation since ancient times. The earliest descriptions of breast cancer date back to around 3500 BC. For centuries to follow, theories by Hippocrates (460 BC) and Galen (200 AD), attributing the cause of breast cancer to an “excess of black bile” and treatment options including the use of opium and castor oil, prevailed. Surgical resection was introduced in the 18th century. With the advent of modern medicine, we have come a long way. Yet, at present, breast cancer is the second most common cancer (after lung cancer) in the two sexes combined, and the most common one in women globally, affecting 1 in 7 women (not to forget that men are not spared either). Despite the awareness about this cancer type increasing each day, going by the global statistics, we can safely say that the pink ribbon is here to stay. So, let us take a more detailed look at breast cancer to understand where we presently stand.
What Causes Breast Cancer?
Breast cancer, like other cancers, is a multifactorial disease caused by an interaction between an environmental factor and a genetically susceptible host.
Normal cells undergo programmed cell death when they are no longer needed. Until then, they are protected by several protein clusters and pathways, like the PI3K/AKT pathway and the RAS/MEK/ERK pathway. Sometimes the genes along these pathways are mutated, leading to continuous cell proliferation and cancer. Also, mutation in the gene that encodes the PTEN protein that normally turns off the PI3K/AKT pathway can lead to cancer.
An important aspect is that of hereditary breast-ovarian cancer syndrome, a familial tendency to develop these two cancers. The most common of these are related to the BRCA (BRCA1 and BRCA2) mutations, which confer a lifetime risk of breast cancer of 60-85%. These mutations can be inherited or occur after birth.
Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure. Also, the loss of GATA-3, a transcription factor which directly controls the expression of estrogen receptor (ER) and other genes related to epithelial differentiation, leads to loss of cell differentiation and poor prognosis.
The risk factors are diverse, including lifestyle (e.g., consumption of alcohol, high-fat diet, tobacco, sitting for prolonged periods, late childbirth, exposure to radiation and some chemicals, etc.), genetics, and some other medical conditions.
Are there Different Types of Breast Cancer?
Well, breast cancer can be categorized based on multiple factors, viz. histopathology, grade, stage, receptors status. These classifications greatly influence the prognosis.
• Histopathology – Based on its tissue type, breast cancer can be classified into ductal or lobular carcinoma, and carcinoma in situ or invasive carcinoma.
• Grade – Considering that cancer cells increasingly lose differentiation that is required for normal functioning, they can be categorized as low-grade (well-differentiated), intermediate-grade (moderately differentiated), and high-grade (poorly differentiated).
• Stage – This is determined based on the TNM staging system (size of tumor, whether it has spread to the lymph nodes, and whether it has metastasized) –
Stage 0: precancerous or marker condition.
Stages 1-3: within the breast or lymph nodes.
Stage 4: metastatic cancer.
• Receptor Status – The presence or absence of some hormone receptors on the surface, cytoplasm or nucleus of the breast cancer cells have consequence for the prognosis, viz. estrogen (ER), progesterone (PR), and human epidermal growth factor (HER2). The cancer type that lacks all three are called triple negative breast cancer (TNBC).
How is Breast Cancer Diagnosed?
Together, physical examination of the breasts, mammography, and fine-needle aspiration can be used to diagnose breast cancer with a good degree of accuracy. Other options for biopsy include a core biopsy or vacuum-assisted breast biopsy or an excisional biopsy. Where available, imaging studies may be employed as part of the staging process in select cases to look for signs of metastatic cancer. However, in cases of breast cancer with low risk for metastasis, the risks associated with PET scans, CT scans, or bone scans outweigh the possible benefits, as these procedures expose the person to a substantial amount of potentially dangerous ionizing radiation. With respect to regular screening, Cochrane states that, due to recent improvements in breast cancer treatment, and the risks of false positives from breast cancer screening leading to unnecessary treatment, "it therefore no longer seems beneficial to attend for breast cancer screening" at any age.
How is Breast Cancer Treated?
Various treatment modalities are available for breast cancer management, with a more advanced cancer requiring more aggressive treatment. In general, these are surgery, radiation, and medication.
• Surgery – The standard surgery options include mastectomy (removal of the whole breast), quadrantectomy (removal of one-quarter of the breast), and lumpectomy (removal of a small part of the breast including the lump). Post tumor removal, a person can opt for breast reconstruction surgery or prosthesis.
• Radiation – Radiotherapy can be given externally or internally during or after the surgery to target the microscopic tumor cells that may escape surgery, thus reducing the probability of recurrence.
• Medication – Different kinds of medications may be used as adjuvant (during or after surgery) or neoadjuvant (before surgery) therapy. The currently used types are –
Hormonal therapy: Some breast cancers which require hormones like estrogen to grow have their receptors which can be detected. They are treated with either receptor blockers (tamoxifen) or hormone production blockers like aromatase inhibitors (e.g., anastrozole). These are taken for long durations.
Chemotherapy: These are mostly used for stage 2-4 breast cancer and ER- breast cancer. The medications are administered in combinations like “AC”, “CAT”, “CMF”, etc. for a period of 3-6 months.
Targeted therapy: The increasing amounts of information about the cancers have led to the design of targeted therapies, like monoclonal antibodies (e.g., herceptin), antibody-drug conjugates (e.g., kadcyla) and kinase inhibitors (e.g., tykerb) for HER2+ breast cancer, CDK4/6 inhibitors (e.g., ibrance), mTOR inhibitor (e.g., afinitor) and PI3K inhibitor (e.g., piqray) for hormone receptor-positive breast cancer, olaparib and talazoparib for BRCA gene mutations, and antibody-drug conjugate (e.g., trodelvy) for HER2- and hormone receptor-negative breast cancer.
Immunotherapy: These stimulate the person’s own immune system to recognize and destroy cancer cells more effectively, like immune checkpoint inhibitors (PD-L1 inhibitors, e.g., tecentriq).
Another important aspect of management of this disease is post treatment follow-up care, which may include regular tests, rehabilitation programmes and improvements in lifestyle.
Current Breast Cancer Research
Breast cancer research is a very active field with various aspects. The recent research focuses on the causes and risk factors, newer, safer, and more effective screening and diagnostic methods, and improvements in each modality of treatment.
Several studies are looking at the effect of exercise, weight gain or loss, and diet on risk.
Studies on the best use of genetic testing for breast cancer mutations continue.
Scientists are exploring how common gene variations (small changes in genes that are not as significant as mutations) may affect breast cancer risk. Gene variants typically have only a modest effect on risk, but when taken together they could possibly have a large impact.
Possible environmental causes of breast cancer have also received more attention in recent years. While much of the science on this topic is still in its earliest stages, this is an area of active research.
• Reducing Breast Cancer Risk –
Estrogen blocking drugs are typically used to help treat breast cancer, but some might also help prevent it. Tamoxifen and raloxifene have been used for many years to prevent breast cancer. More recent studies with another class of drugs called aromatase inhibitors (exemestane and anastrozole) have shown that these drugs are also very effective in preventing breast cancer
Other clinical trials are looking at non-hormonal drugs for breast cancer reduction. Drugs of interest include drugs for diabetes like metformin, drugs used to treat blood or bone marrow disorders, like ruxolitinib, and bexarotene, a drug that treats a specific type of T-cell lymphoma.
• New Lab Tests –
Circulating tumor cells (CTCs) are cancer cells that break away from the tumor and move into the bloodstream. Circulating tumor DNA (ctDNA) is DNA that is released into the bloodstream when cancer cells die. Researchers are investigating tests that measure the amounts of CTCs and ctDNA in the blood of women with breast cancer. Identifying and testing the CTCs and ctDNA in the blood is sometimes referred to as a “liquid biopsy.” This type of biopsy may offer an easier and less expensive way to test the tumor than a traditional needle biopsy, which comes with risks such as bleeding and infection.
Some studies have shown that in women with metastatic (Stage 4) breast cancer, a high level of CTCs might predict a poorer outcome compared to women with a lower level.
• New Imaging Tests –
Scintimammography (molecular breast imaging)
Positron emission mammography (PEM)
Electrical impedance imaging (EIT)
Elastography
New types of optical imaging tests
• Chemotherapy –
In 2019, the immunotherapy drug Atezolizumab (Tecentriq), was approved along with the chemotherapy drug nab-paclitaxel (Abraxane) for use in women with advanced triple negative breast cancer that makes the PD-L1 protein. Other potential targets for new breast cancer drugs have been identified in recent years. Drugs based on these targets, such as kinase inhibitors, are now being studied to treat triple-negative breast cancers, either by themselves, or in combination with chemotherapy. One example is the AKT inhibitor ipatasertib, which, when used with paclitaxel, shows promising results in treating women with TNBC as the first treatment. Another AKT inhibitor, capivasertib, is also showing encouraging results when given with paclitaxel.
• Combating Drug Resistance –
Research is on to tackle this common hurdle of cancer therapy.
• Supportive Care –
There are trials looking at different medicines to try and improve memory and brain symptoms after chemotherapy. Other studies are evaluating if certain cardiac drugs, known as beta-blockers, can prevent the heart damage sometimes caused by common breast cancer drugs such as doxorubicin and trastuzumab.
Breast cancer remains a serious public health issue worldwide. However, appreciable growth in our understanding of breast cancer in the past century has led to remarkable progress in the early detection, treatment, and prevention of the disease. The clinical focus is shifting more towards tailored therapy as more targets are characterized and novel highly innovative approaches are developed. The increasing focus on tailored therapy and the integration of cancer stem cell-based targeted therapies and immune therapies, together with existing therapeutic methods, hold promise for the cure of breast cancer. With news like CRISPR being able to hold back TNBC in mice, we are surely moving towards more hopeful days.
