Alessandro Troiani

 

“We all know our time is going to come eventually, but we rarely think about it, until we’re faced with the possibility of it.”

This quote was taken from the testimonial of a patient who is referred to as PR in this article. PR was diagnosed with invasive breast cancer at the age of 51 and her cancer is currently in remission. PR and the sister of another breast cancer patient, who is referred to in this article as BT, a woman who was diagnosed with two different breast carcinomas at the age of 61, have kindly agreed to share their experiences for this article.

Breast cancer, which is also known as carcinoma or neoplasm of the breast, is the most common type of cancerous tumour. Breast cancer represents about a third of all cancers that arise in women worldwide. This article is written in support of Breast Cancer Awareness and aims to both inform on the latest in breast cancer research and to support fundraising efforts for both new and ongoing research into treatments. While Breast Cancer Awareness month is the month of October and this article is written in support of Breast Cancer Awareness month, PMM also aims to continue to promote awareness of breast cancer well beyond October and encourages the sharing of knowledge and information about cancer throughout the year.

This article provides straightforward and comprehensive information on breast cancer, including the main causes and risk factors, as well as information on both available treatments and novel treatments that are currently in development. It includes testimonials from the two patients mentioned above and their relatives, who have chosen to share their experiences in order to provide first-hand insight and hope to others. This post is aimed at increasing awareness amongst young people as well as patients and their family members that would like to enhance their understanding of the condition, its burden, and possible interventions. While this article focuses on female breast cancer, it is important to note that breast cancer can also affect men.

 

PR’s daughter told us that following her mother’s breast cancer diagnosis, she has been looking into her own risk of developing breast cancer. However, she has found a great deal of conflicting information online. Statistics and graphs can be quite daunting if you are trying to understand your risk of developing breast cancer, as many of them include confusing terms and units. This article will explain the main causes and risk factors for breast cancer.

What causes breast cancer?

The main causes of breast cancer are changes or defects (mutations) in the deoxyribonucleic acid (DNA) in our cells. DNA forms the genes that provide the “code” that allows our cells to make the proteins needed for all cellular functions. Different types of mutations can arise in our DNA and while some mutations can arise spontaneously, others can be inherited. When genes are damaged, the resulting proteins can be defective, non-functional, and/or unstable. Certain mutations can cause cells to behave in unpredictably and abnormally, causing them to multiply rapidly or to use more energy than normal cells do. In the case of carcinomas, such mutations are usually found in genes that regulate the cell cycle and metabolism, and therefore mainly affect proteins that play roles in cell replication and energy production. The loss of control of the cell cycle and replication in cancerous cells can result in the formation of a group or groups of large, abnormal cells that can invade the surrounding spaces and tissues. Small numbers of cells can also detach from the original site of the tumour and begin to form tumours at other locations in the body and this spread and dissemination of cancer cells is known as ´metastasis´.

The term “invasive” determines how advanced a tumour is. The term ´locally invasive´ is used to refer to masses of cells that begin to take up space in neighbouring tissues that are in close proximity to the original site of the tumour. Metastasis indicates a more severe stage of the disease as multiple tumours may be found in different locations throughout the body, and can be much more difficult to treat effectively.

Breast cancer mutations can either be inherited or can occur spontaneously. Inherited mutations, which are also known as familial, are mutations that are usually inherited from a parent, while sporadic cases are mainly due to other factors such as ultraviolet ligh, components of diet, and certain toxins that may be present in the environment. Approximately 5% to 10% of all breast cancer cases diagnosed worldwide are caused by familial mutations. Approximately 30% of these cases are due to mutations in the BRCA1 and BRCA2 genes and/or related genes (1) (we will explore these in more detail later). In certain cases, relatives of a patient with breast cancer may decide to undergo genetic testing to determine whether they have inherited mutations in these genes. Based on the information that they receive, relatives may choose to subsequently undergo surgery to remove breast tissue as a preventive measure. The chance (penetrance) of developing breast cancer if this mutation is inherited, is around 42% for BRCA1 and 55% for BRCA2 mutations (2).

The majority of breast cancer cases are not caused by inherited mutations, but are influenced by secondary factors. These factors can include ethnicity, age, and onset of puberty (3). A study (4) has shown that European and White American women are slightly more likely to be diagnosed with breast cancer than African American women. However, the reverse is true for women aged below 45. Generally, the incidence rate of breast cancer, which is defined as the number of cases of the disease divided by the total population, rises exponentially between the ages of 35 and 65, meaning that, as one gets older, the chances of developing breast cancer increase faster in this age group than in other age groups (5). Other factors that can influence the risk of getting breast cancer are age at first menstruation (<12 years of age) and delayed menopause (>55 years) (3). Having a first degree relative with breast cancer, even if they do not have a familial mutation, is also related to an increased risk.

Certain habits and other contributing characteristics can increase the likelihood of developing breast cancer. These are called modifiable habits and may be habits that have become part of our day-to-day life. Studies suggest that behaviours such as frequent smoking or alcohol use can significantly increase a women’s risk of breast cancer, and even more so, if these activities begin between the first menstruation and the first pregnancy (6)(7). When the harmful substances that are present in cigarette smoke and/or the alcohol enter the bloodstream, they can reach the cells that compose the breast tissue and cause damage to the DNA in those cells. On the other hand, increased physical activity in women of all ages is associated with a reduction in the risk of developing breast cancer (8). Physical activity can also reduce the risk of tumour recurrence following cancer treatment. As a result, many breast cancer patients do decide to make lifestyle changes and PR is one of them. She told us, “I was never an active person, but since the procedure, my family and I have definitely become more active, and I have also changed my diet to consume less meat and dairy products.” Breastfeeding has also been associated with a 30% reduced risk of developing both breast and cervical cancer. An additional factor that has been found to be correlated with a slightly increased incidence of breast cancer studies is hormone replacement therapy (HRT) following the onset of menopause (9). During menopause, there is a reduction in the levels of certain hormones such as estrogen. HRT replaces these hormones and can help to alleviate some of the physical and psychological symptoms that are associated with menopause. It is important to mention and discuss risk factors such as any family history of breast cancer with your doctor if you are considering HRT. For example, since BT’s sister’s tumour was sensitive to estrogen, she decided to stop her HRT. She told us, “I immediately interrupted my hormone replacement therapy, as I am a first degree relative of the patient and she was on the same therapy for 10 years before the diagnosis.”

 

Classification of breast cancer types

Due to the large variety of cells and genes that may be involved in breast cancer, this condition has been classified into different types and groups, based on the tissue affected, the gene(s) responsible, and the degree of invasiveness. Below, we describe the main types of breast cancer, their similarities and differences, and the main types of underlying genetic mutations that are involved. Grading is a method that is also known as the TNM grade. The TNM acronym comes from the words Tumour, Node, and Metastasis. Health professionals use TNM grading to describe the specific stage of a tumour´s development. The more advanced a tumour is, the higher its TNM score. TNM scores are assigned based on the evaluation of three main criteria. These are as follows: tumour size, lymph involvement, and metastasis.


Table 1: Table explaining TNM grading of tumours and range of possible values

Staging, which is different from grading, is a simplified version of the above. Stage 1 includes T1N0/1M0, while stage 4 includes any cancers with M1, and so on. For example, following scans and biopsies, patient PR´s tumour was assigned a score of T1N0M0 and she was told that her cancer was a stage 1 breast cancer. For more information about the grading and stages of cancer, please visit the CancerUK website.

Breast cancer can originate in a variety of different types of cells and the particular type of cell normally determines the type of cancer. Lobular carcinomas develop from the cells that are involved in milk production, which form lobes and lobules on the areas around the nipple. Ductal breast cancers arise in the tubules (also known as ducts) that bring the milk from the lobes to the nipple. It is not always possible to precisely determine which cell type the tumour originates from, especially if the tumour is invasive, but where it is possible to determine, this knowledge can help to inform the surgery and treatment that the patient is offered (10).


Figure 1: Diagram showing a simplified version of the breast tissue. https://nbcf.org.au/about-breast-cancer/diagnosis/breast-cancer-anatomy/

The most common type of breast cancer, which accounts for 60-70% of all breast cancers, is invasive ductal cell carcinoma. In the UK, this type of breast cancer is referred to as Not Special Type (NST). Unfortunately, this type of breast cancer is usually discovered at a later stage of tumour development. Other types of breast cancer include Ductal Carcinoma in Situ (DCIS) and Lobar Carcinoma In Situ (LCIS). These types of breast cancer are still contained within the original tissue where they originated. However, left untreated, these types of cancer can develop into invasive ductal and lobar carcinomas (11).

Triple-negative breast cancer is a particular sub-type of breast cancer that accounts for approximately 15% of breast cancers cases diagnosed. “Triple” refers to three different cellular receptors that are commonly found on breast tumour cells. Receptors are structures that are found on the surface of cells and which allow signalling between cells. c. “Negative” refers to the absence of the receptors (hormone epidermal growth factor receptor 2 (HER2), estrogen receptors, and progesterone receptors) on the surface of cancer cells. The lack of these prevents the use of specific chemical treatments developed for breast cancer, as these drugs are designed to bind to the receptor and thereby inhibit the growth of tumour cells. (12) Rarer subtypes of breast neoplasms include inflammatory breast cancer (an aggressive form of breast cancer), angiosarcomas of the breast (which involve the blood vessels in the breast tissue) and the special types, which involve cells that are less predominant in breast tissue.

With regards to mutations, as mentioned previously, the two main types of mutations are inherited and sporadic mutations. Inherited mutations are classified based on the likelihood that they will be transmitted to future generations. High and medium penetrance mutations are mutations that give a person an increased risk (above 40%) of developing breast and ovarian cancer, and are usually found within the previously mentioned BRCA1 and BRCA2 genes. The role of these genes is to regulate cell replication by preventing DNA damage.

The DNA in our cells can be damaged by numerous factors including toxins, radiation, trauma to the cell structure, or as a result of mistakes made during cellular division. Cells have developed multiple mechanisms, such as the DNA damage response, to prevent and repair these mutations, and the BRCA genes play important roles in DNA repair (13). Multiple mutations in a gene that result from ineffective DNA repair can lead to the formation of non-functional cells that die, or to the development of tumour cells that are still able to function, but which replicate in an uncontrolled manner.

Mutations can occur within the coding part of the BRCA gene or within genes that encode (code for) proteins that contribute to the function of BRCA. Examples of the latter are CHK2 and ATM gene mutations. The majority of mutations in the BRCA gene lead to the protein being truncated (shortened) and therefore unable to function properly. The actual risk of developing breast cancer with a BRCA1 mutation is 46-60%, while for BRAC2, it is 43-45%. Breast cancers for which a BRCA1 mutation has been identified, are associated with earlier onset (occurring in younger women) and are more commonly found to be estrogen receptor-negative when compared to cancers due to mutations in the BRCA2 gene. However, breast cancers due to BRCA1 mutations are less common within the general population (14).

In non-familial breast cancer, mutations in the BRCA genes are highly uncommon. In these cases, the tumour cells normally arise due to an initial mutation that is followed by further small changes to the DNA. The two most common mutations that give rise to sporadic breast cancers occur in the PIK3CA and TP53 genes. The PIK3CA gene is responsible for the production of a protein that regulates the cell cycle, reproduction, and metabolism, while the TP53 gene codes for a protein that has an important role in repairing damage to DNA. This protein, which is known as p53, determines the degree of damage that has occurred within the DNA. If this damage is too great, then a process that leads to the death of the cell (apoptosis) will be activated. If the damage can be repaired, then p53 will activate the necessary processes for DNA repair. Even a small mistake within the PIK3CA and TP53 genes can impair their function. Mutations are detected within the PIK3CA gene in approximately 15-40% of breast cancer cases and are normally found in cells biopsied from estrogen resistant tumours. An abnormal p53 protein has been associated with a worse prognosis and such tumours can be resistant to certain cancer treatments (1, 15). The role of these mutations in ovarian and breast cancer continues to be studied. It is currently thought that the over-stimulation of breast and ovarian tissues by estrogen and progesterone during the menstrual cycle may make these mutations arise.

Symptoms and diagnosis

Being aware of the most common symptoms and signs of breast cancer can help patients to detect changes earlier and to seek medical advice while any potential tumour is still at an early stage of development, and is easier to treat effectively (16). The symptoms that a patient may notice can differ from patient to patient and can vary depending on the type of cancer.  

The most common breast cancer symptoms include the following:

  • A lump or thickening on your breast or armpit
  • Changes to the size or shape of the breast, especially if over a short time and unilateral (one side only)
  • Pain in the breast
  • Fluid leaking when not breastfeeding
  • Changes to the nipple
  • Skin changes

(17)


Figure 2: Diagrams showing some of the possible symptoms and changes to look out for with regards to breast cancer. https://www.medicalnewstoday.com/articles/327488#early-signs

Inflammatory breast cancer has its specific symptoms. The breast tissue may become red, inflamed, and swollen and may feel warm to the touch. This type of cancer is also more likely to be painful and involve changes in the skin. This is because the tumour is blocking smaller lymphatics, the vessels the connect the lymph nodes, that usually help drain toxins from the breast, and this blockage leads to the accumulation of fluid within the breast tissue. Changes in the skin can be due to Paget’s disease of the nipple. This condition resembles eczema in its appearance (see the picture below) and usually affects the nipple or the areola, causing the skin to break out and to become red, painful and itchy. It is usually associated with breast neoplasms and, if so, it is common to find a lump below the nipple. (17)


Figure 3: Photo of a nipple affected by Paget’s disease. https://www.nhs.uk/conditions/pagets-disease-nipple/

It is important to note that each of these symptoms can also be due to conditions other than cancer. For example, cysts can cause lumps and skin changes may be due to eczema. However, you should always see a doctor for a medical examination if you experience any of these symptoms and are concerned. Being breast-aware can help you to recognize any unusual changes in the breast. An important part of this is regular self-examination of the breast and surrounding areas, which includes visual (done using a mirror) and palpation (18). BT shared that when her sister first realised something was wrong, “She felt and noticed in the mirror that her left breast was slightly larger than the other one, but did not feel a lump at the time”. It is important to examine your breasts at a similar stage of your menstrual cycle each month, for example at the end of menstruation, as some women experience changes in their breasts at different stages of the cycle. You may find this video by the City of Hope Hospital helpful if you wish to learn the proper technique.

A study done in Chile (19) has shown that patients that self-diagnosed are more likely to have a more advanced stage and grade of the tumour than patients that are diagnosed through screening. This highlights the importance of having a medical examination and also of having regular mammograms. Mammograms are X-rays of the breasts, done from above and the side, which detect and changes in the density of the breast tissue. The high incidence of breast cancer has led more than 22 countries to begin national breast mammograms programs for early detection of any suspicious tissue within the breast as well as sending patients for further testing where relevant. Early diagnosis allows for treatment to begin at an earlier stage, which in turn, allows for a better prognosis.

Screening programs differ from country to country. In some countries, mammograms may be offered every year or every three years. Some programs invite patients while others require patients to sign up for this service themselves. In the UK, women between the ages of 50 and 70 are routinely invited for a mammogram once every three years. Please check your local health services online information on Breast Cancer Screening to find out more.

It is important to note, however, that mammograms are not always reliable as they can give false negatives (when no breast cancer is detected when there is in fact cancer present) or ambiguous results. Breast Ultrasound (US) is a scan that is performed to visualize better a mass in the breast found through palpation or mammography. The device used emits sound waves to detect the density of structures within the breast tissue, and tumours are usually denser than the breast tissue, thus visible on the US. These are slightly more accurate and can lead to the next stages of diagnosis, as PR’ story demonstrates: “I had been doing ultrasound scans every six months since my mother died of breast cancer; a mass was found and aspirated and that is when the whole thing started.” – PR.

If breast cancer is suspected, there are a few more tests you should be aware of, explained in the table below.

 



Table 2: Possible diagnostic tests

Figure 5: Diagram explaining how fine needle aspiration is performed, with Ultrasound guidance. https://www.cancer.org/cancer/breast-cancer/screening-tests-and-early-detection/breast-biopsy/fine-needle-aspiration-biopsy-of-the-breast.html
Figure 6: Result of a positive MRI scan. https://www.cancernetwork.com/view/mri-improves-breast-cancer-screening-older-brca-carriers

Figure 7: Diagram demonstrating the position adopted by patients within the MRI machine for better visualisation of the breast tissue. https://www.mayoclinic.org/tests-procedures/breast-mri/multimedia/breast-mri/img-20007363

Treatments

Due to the increasing number of breast cancer cases diagnosed each year (just in the UK, the average between 2016 and 2018 was above 55,000 cases/year) (5) and thank to the advances in medical research, multiple options for treatments now exist to aid breast cancer patients, and they continue to evolve to provide better prognosis and quality of life to the affected. Currently, the most effective treatment option for most cancerous tumours is surgery. For breast cancer, this involves the removal of the breast tissue (mastectomy) to prevent the further spread of the cancer cell to the rest of the breast and other organs.

A total or radical mastectomy is a surgery in which the entire breast tissue is removed. This is considered to be the best option for patients who have more advanced stages of breast cancer, for example where cancer has already spread to the lymph nodes (stage 3 and above) (20). The spread of cancer to the lymph nodes is checked via a biopsy of the sentinel lymph nodes which are located in the armpit region. This surgery usually includes a reconstruction of the breast, as it might be necessary to remove the nipple as well, which is what BT’s sister had to endure: “Due to the delay in the diagnosis, a total mastectomy was done, together with the removal of several affected lymph nodes.”

 


Figure 8: Diagram representing the position of the lymphnodes most likely to be affected by a breast cancer spreading. https://breastendocrine.com.au/axillary-surgery/sentinel-lymph-node-biopsy

Partial mastectomy and lumpectomy are options for less advanced stages of breast cancer when only part of the breast is affected. These types of surgery would only remove a smaller portion of the breast tissue; thus it would not be necessary to remove the nipple (nipple-sparing surgery). To reduce the chance of recurrence, mastectomies are usually combined with other, non-surgical options of treatment. Neo-adjuvant therapies are given before surgery, to reduce the size of the tumour and possible complications that may arise. Adjuvant therapies are given after the mastectomy. Adjuvant radiotherapy uses X-rays to kill off any cancer cells that may be left in breast tissue following a mastectomy, in an attempt to reduce the risk of recurrence. If a tumour is localised, radiotherapy may be offered in place of surgery. Radiotherapy can cause side effects and the most common are described in table 3. Others can be more severe, such as breathing problems, but are rare. Due to some of the damages that radiotherapy might have, breast reconstruction may be done after.

 


Table 3: table displaying some of the possible side effects of radiotherapy and their incidence. (12)

 


Table 4: Table displaying different types of chemotherapy drugs with a brief description of how they act (21-23)

Chemotherapy uses “cancer-killing” drugs to control the growth and replication of cancer cells as well as to prevent metastasis. There are many different types of chemotherapeutic drugs. Table 4 describes some of the main chemotherapeutics that are currently being used to treat breast cancer.

Multiple medications are often used in combination to increase the overall effectiveness of treatment. However, as some of these drugs can interfere with fundamental metabolic processes within the many different types of cells and tissues of the body, this can lead to toxicity resulting in a range of side effects. Such side-effects can include hair loss (which is usually temporary), nausea, vomiting, bruising, bleeding gums, nosebleeds, and other gastrointestinal problems. This can make the patients extremely tired and weak. You can visit ChemoCare’s webpage to read on how to manage them.

Chemotherapy is normally given in cycles of treatment that often require the patient to visit the hospital several times a week to receive treatment. The drugs are usually being given intravenously (injected or infused into the bloodstream). Depending on the particular treatment, the treatment is normally then stopped for a few weeks to allow the body to recover before the next cycle of treatment. Patient BT’s sister, for example, received 5-6 cycles every 30-40 days, with the overall treatment duration being about six months.

In the case of breast carcinomas, chemotherapy may be given alongside hormone therapy. This treatment course is normally given to patients that have an oestrogen receptor-positive (ER+) tumour, meaning that their cancer cells are responsive to growth signals sent via the hormone oestrogen. This means that controlling the levels of this oestrogen in these patients can potentially slow down the growth of tumours or prevent new tumours from forming in these patients. Below are the two main options.


Table 5: Possible adjunct hormonal treatments (20)

In the case of PR, the chosen therapy was “surgery with adjuvant radiotherapy combined with aromatase inhibitors.” Being still pre-menopausal, she “opted for a hysterectomy (removal of the uterus) with oophorectomy (removal of ovaries) to start the AIs treatment.” Even in the case of Tamoxifen, pre-menopausal women may opt to undergo either a surgical procedure called ovarian ablation, or a non-invasive procedure called ovarian suppression. These procedures either remove or inhibit the function of the ovaries, as doing this has been associated with a better outcome for patients on Tamoxifen (25).

Immunotherapy is the latest type of therapy being used or trialled for the treatment of a wide range of medical conditions. This approach uses monoclonal antibodies or molecules generated in the lab through the modification of these. “Antibodies” are molecules that are produced by plasma immune cells that attach to specific receptors or other molecules that are present on the surface of harmful cells such as cancerous cells and foreign organisms to allow the body to identify them and destroy them. “Monoclonal” refers to the process of extracting immune cells, cloning them in a lab and then changing their genetic code to produce antibodies that will bind to specific receptors found on cells such as breast cancer cells.

As per the latest medical news (26), the drug abemaciclib has been approved by the FDA for adjuvant treatment of early-stage oestrogen/progesterone-positive, HER2-negative breast carcinomas. It was formerly used only for more advanced, metastatic cancers. The continuous effort to repurpose and create drugs is an essential part of the fight against breast cancer, and this recent advance should give new hope to all who are affected by the condition.

In the case of oestrogen/progesterone-negative, HER2-positive carcinomas, drugs such as trastuzumab, pertuzumab, and neratinib are given in combination with chemotherapy or surgery to increase the chances of survival from cancer (27). Each of these drugs is designed to bind the HER2 receptor and this binding leads to the inhibition of the cell’s metabolism and activity, thereby slowing down the growth and spread of cancerous tumours. In the UK, trastuzumab is normally the first choice of treatment for this type of breast cancer. However, this drug can cause a range of side effects that range in seriousness from nausea to arthralgia (joint pain) to heart muscle weakening (known as heart failure).

In the case of triple-negative breast cancer, in which the cancer cells lack all of the receptors, a different approach to treatment is needed. As cancer cells originate from our bodies, our immune systems do not target them for destruction. In addition, some types of tumour cells have a specific type of molecule present on their surface that is known as PD-L1. This molecule prevents attacks from the immune cells by inhibiting their ability to detect cancer cells. However, several monoclonal antibodies including pembrolizumab and atezolizumab have been developed to counteract this issue.

Other monoclonals such as bevacizumab, impede tumour development by reducing its ability to form blood vessels to supply it with nutrients. However, as these monoclonals are less precise and can bind to receptors or proteins in cells other than tumour cells, they can cause severe side effects (28). For this reason, these drugs are generally reserved for use in treating rarer cancers, the most advanced cases, or as a last resort.

Medical research in the field of oncology (the study of the biology and treatment of cancers) is continuing apace, with many different types of clinical trials being conducted every year. This is the case for many different types of cancer, including breast cancer and increasingly for the rarer types of breast cancer. New types of chemotherapies and immunological treatments are being approved every year, and patients can contribute to this research by participating in clinical trials, such as tucatinib (used in HER2+ cancers), which has recently been approved by the European Medicine Emergencies (29). With all clinical trials, it is important to carefully read all eligibility criteria and we encourage you to discuss eligibility for ongoing or upcoming clinical trials that you may be interested in participating in with your doctor.

Conclusion

Although a great deal of scientific information can be found on the internet, in many cases, this information is not easily accessible to the public. Furthermore, even when people are able to access scientific articles and publications, they often find it very difficult to understand and utilize the information that is contained within them. PMM aims to provide patients, relatives, and health professionals alike, with well-researched and clearly written information on a wide range of topics within medical innovation that is easy to follow and to understand. Below, you will find a list of references that you may wish to refer to for further information.

 

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