De-Escalation: Reducing Breast Cancer Treatments

Breast cancer researchers are often focused on finding new and better treatments and prevention strategies for the disease.

However, some breast cancer research has another goal: to reduce the amount and intensity of treatment patients receive, while maintaining equally good cancer outcomes.

This is a research area for Professor Julia White.

Professor White is a tenured Professor of Radiation Oncology and Koltz Sisters Chair for Cancer Research at The Ohio State University.

“I think it’s important for us as providers to clarify that de-escalation doesn’t mean we’re backing off on therapy,” said Professor White.

“For so long, breast conservation has automatically meant you’re going to get surgery, a lumpectomy and breast radiation.”

“But from our knowledge of breast cancer biology, certain patients can be cured, or their cancer control is completed by just having the surgery portion.”

Professor White said de-escalation can be incredibly beneficial for certain patients, but the issue is identifying those patients who can benefit from this ‘right-sizing’ of treatment.

However clinical trials which use multi-gene assays or genomic tests of breast cancer tissue, can help to identify biologically which patients are going to have a low event rate in the breast after breast conserving surgery.

This means some patients could safely avoid radiation therapy.

“You’ll always get a lower reduction in breast risk when you radiate.”

“But if your likelihood of recurrence is so low then adding the radiation for women might not give a meaningful difference to them.”

“So, as we de-escalate or right-size breast conservation, we’re going to see who needs both lumpectomy and radiation and who is OK with just a lumpectomy.”

“So, de-escalation is really for breast cancer that is hormone sensitive, stage one. Meaning the lymph nodes are negative, in women who are post-menopausal and committed to taking their endocrine therapy.”

Current Research Into The De-Escalation In Breast Conserving Therapy

There is an increasing number of de-escalation clinical trials, including the Breast Cancer Trials EXPERT clinical trial.

EXPERT is investigating whether a genomic test of breast cancer tissue can be used to identify women with early breast cancer who can safely avoid radiation therapy after breast cancer surgery and the potential side effects of this treatment.

Professor White said in the US, where she practices, there are two groups of de-escalation trials.

“One is really for post-menopausal stage one breast cancer, in patients who are between the ages of 50 and 70.”

“Over age 70, the approach is de-escalation.”

“Under the age of 70, between 50 and 70, the trials are really focused on using a multi-gene assay, using an immunohistochemistry assay or using recurrence score.”

This is how researchers can determine if a patient needs further treatment after surgery, like radiation therapy.

Why De-Escalation Research Is Important

Professor White said de-escalation trials are about investing in patient’s wellbeing.

“It’s maybe not the most scientifically sexy clinical trials, we’re not identifying a new targeted agent, but we need to know how to take care of women.”

“When you look at breast cancer screening studies, the most common breast cancer stage that is picked up at breast cancer screening is stage one.”

“So, over 50% of newly diagnosed breast cancers are stage one and most of these occur in post-menopausal women and most of them are hormone sensitive,” she said.

“So, the impact is tens of thousands of women annually.”

“So, it’s really incumbent on us right now to run clinical trials that we can guarantee the next generation that we’ll know how to take care of them and that’s what we’re doing by investing in de-escalation trials.”

Breast Cancer Patients Have An Increased Risk Of Cardiovascular Disease

If you have received a breast cancer diagnosis you are at a higher risk of cardiovascular disease than those without.

According to Professor Bogda Koczwara, there are a number of reasons for why this is.

Professor Koczwara is a medical oncologist and Senior Staff Specialist at Flinders Medical Centre.

She said a key reason is the risk factors for both diseases overlap to a significant extent.

“So, the same risk factors that give you cancers also give you cardiovascular disease,” she said.

“We know if you have cancer, you’re more likely to develop cardiovascular disease.”

“And we’ve just recently learned that if you’ve got cardiovascular disease, you’re more likely to develop cancer.”

Professor Koczwara said researchers suspect that the mechanisms for development of cardiovascular disease and cancer are likely to be overlapping.

“I think that requires further research, but it relates to tissue damage, premature aging, and perhaps cancer and cardiovascular disease are somewhat different manifestations of very similar overarching processes.”

“The final thing is cancer treatments seem to impact on the body in such a way that they may accelerate cardiovascular disease, either through direct impact on the heart muscle or through impact on vasculature.”

“But more anti-cancer drugs for breast cancer than not, have some form of side effect that relates to cardio-vascular health.”

How You Can Help Protect Your Heart Health

There are important considerations practitioners should take when treating breast cancer patients to protect heart health according to Professor Koczwara.

“The first thing to do is to recognise that patients with cancer also have other conditions and to recognise there is maybe an interaction between those conditions.”

“That would mean, taking sufficient history to recognise patients risk factors and comorbidities, and factoring that into decision making process.”

Professor Koczwara said breast cancer patients should consider if they have any modifiable risk factors to protect their health.

“We know already that common risk factors for cardiovascular disease which also adversely impact breast cancer outcomes are obesity, inactivity, smoking, and they need to be managed.”

“Their management would be beneficial in terms of improving breast cancer outcomes, but it would also be beneficial in terms of improving cardiovascular outcomes.”

Professor Koczwara said if your oncologist or treating physician is concerned about your heart health or risk factors, there is services and programs available which you can be referred to.

She also said it is important for your physician to revisit these issues on a regular basis.

“Sometimes patients might not be in the right headspace to deal with those issues at the beginning, at the time of the initial diagnosis, and they may wish to return to those issues later.”

“Sometimes they might be eager to do something that is good for their health at the beginning and that should also be accommodated.”

“So, I think the key message is that the vision for supporting women with breast cancer and patients with breast cancer, goes beyond just providing anti-cancer treatment.”

Am I More At Risk Of Heart Issues If I Have Breast Cancer In My Left Breast?

Professor Koczwara said this is not a silly question to ask.

“The answer is yes, because you’re quite likely to have radiation treatment on the left side and the left sided radiation treatment would increase the risk of potential complications, in contrast to the right sided treatment.”

“If you don’t have radiation treatment, if you don’t have local treatment, then the risk is not magnified.”

However, Professor Koczwara said this is only one risk factor, that is safely managed, and patients should focus on how to best manage risk factors related to overall health.

“I think you should be more concerned about your cardiac health if you’re obese, if you have high blood pressure, if your lipids are elevated, if you’re inactive etc.”

“The site of radiotherapy is only one part of that story and these days with appropriate precautions for radiation treatment, a radiation oncologist would argue that the risk is not that great but I think you need to consider all the risk factors and manage them, because many of them are modifiable.”

What is the Androgen Receptor?

The Androgen Receptor regulates the development and growth of the prostate.

In prostate cancer, androgens bind to androgen receptors inside the cancer cells, which causes the cancer cells to grow. However, it has a very different effect in women with breast cancer.

Professor Wayne Tilley is the Director of the Dame Roma Mitchell Cancer Research Laboratories at the University of Adelaide, South Australia, and is an expert in the field of breast and prostate cancer.

He was a pioneer in investigating AR expression and function in breast cancer and cloned the human androgen receptor (AR) gene.

“The androgen receptor gene is being cloned for this androgen receptor protein, which is on the X chromosome. The androgen receptor protein is in men and is absolutely required for normal virilisation or masculinisation of males and has many vital functions,” said Professor Tilley.

“But because it’s critical for the development of the prostate, when cancers occur in the prostate this same receptor protein also drives their growth.”

However, what interests researchers is that the androgen receptor has been found to have a more positive effect in women.

“What’s intriguing is that the androgen receptor in women is a good player, whereas it’s a bad player in the prostate.”

“So this androgen receptor gene is the master regulator of a lot of processes in the body; metabolism, cell growth, division, differentiation and one of the things we’re trying to understand is what are the other factors, the other proteins in a tumour cell, or even in a normal cell, that might be instructive, that will allow us to understand how you can switch an androgen receptor in prostate cancer from being a bad player, to looking more like androgen receptor in a breast cancer.”

How Could The AR Gene Be Used In Breast Cancer Treatment?

Professor Tilley said the challenge to finding a way to make this switch from ‘bad player’ to ‘good player’ is that the androgen receptor gene doesn’t play by itself.

“There are hundreds of other factors in a cell that interact with the androgen receptor, so it’s like a symphony and depending on the components of that symphony, the androgen receptor might function quite differently.”

“So, we’re putting an enormous amount of effort into understanding what are those other factors that interact with the androgen receptor that can switch it from being a bad player like it is in prostate cancer, to being a good player like it is in breast cancer.”

“We are attempting to understand how to take advantage of that and maybe coming up with a very novel treatment for prostate cancer by switching this bad player to a state that’s more like in the normal development of the male, where it actually induces differentiation and inhibits cell growth.”

Online Support For Breast Cancer

Receiving face-to-face psychological care while going through breast cancer treatment is not for everybody.

However, it is still important to look after your mental health during this time and it’s important to note that it is common to struggle mentally throughout this time.

Clinical Psychologist and Cancer Council South Australia Senior Research Fellow, Dr Lisa Beatty, said those undergoing treatment for cancer often are undergoing psychological distress.

“We know that approximately 30 to 40% of women, after their diagnosed with breast cancer, will have what we call clinically significant distress, where it is impacting on their ability to either enjoy their lives or stopping them from getting out and doing things, impacting on their functioning.”

“We also know that of those, when offered, only less than 30% of distressed people with cancer actually take up the offer of help in face to face interventions like going and seeing a psychologist.”

Dr Beatty said online tools have been created to help bridge this gap caused by limited access to mental health workers and for those who are not comfortable seeking face to face support.

She said the online tool she co-created covers similar topics that are covered in face to face sessions.

“This was done very much in consultation with women with breast cancer,” she said.

“We went and met with a lot of women, did a series of focus groups to work out what are the most commonly experienced issues that come up for them and then we ended up creating a series of topics, or modules, around those commonly experienced issues.”

“Some of them might be on the common physical symptoms that they might be experiences, the emotional distress, body image changes and also navigating issues with family and friends is a big one too and transitioning into survivorship.”

Dr Beatty said the online modules provide strategies and activities to help target symptoms and help to improve their mental health.

What Online Mental Health Tools Are Available?

Dr Beatty is the co-creator of Finding My Way.

Finding my way is an online self-help coping program that offers information, suggestions and support for women and men who have recently been diagnosed with a cancer being treated with the aim of cure.

It was developed as part of a clinical trial for anyone who was currently going through cancer treatment or had been diagnosed in the past six months.
“Anyone with a diagnosis can just log on and start the program.”

“It’s a very simple registration process, you just have to create an account and you’ll get directed to the initial welcome video which will guide you through how to use the program.

“Because it is actually targeting not just a psychological disorder, but it is targeting some of the most commonly experienced issues, there’s going to be something in there for everybody, you don’t have to have depression or anxiety diagnosed by a GP or some else to benefit from the program.”

Why Do People Choose Online Mental Health Support?

Dr Beatty said there are a number of reasons why someone would choose to access online support for their mental health.

“Geography definitely is a huge barrier and some services simply don’t have face to face programs, but we definitely know that there’s still unfortunately a big stigma around mental health,” she said.

“We also know that screening is not routinely done yet, even though there is increasing recognition of the importance of it.”

“But screening for anxiety, distress, depression, isn’t routinely done and even when it is, there are many people out there that just don’t feel comfortable going to see someone face to face and actually have a preference for trying to be able to sort through things on their own.”

Dr Beatty said through qualitative feedback, they found using their online tool was a positive first step for those struggling through their diagnosis.

“It was that useful first step that broke down that barrier and patients were more comfortable to go and seek help when it was needed.”

“But for a lot of people they also found that they got enough that they needed out of the program itself, that it actually was the thing that stopped them from needing to go on to additional face to face support.”

If you are experiencing difficulties with your mental health throughout your diagnosis, talk to your treatment team or GP about your mental health options.

What Is Genetic Testing?

Genetic testing involves looking for a fault or mutation in genes that cause a high risk of developing breast and ovarian cancer within a family. These mutations are often found in the BRCA1, BRCA2, and PALB2 genes. Genetic testing for breast cancer testing is done on a blood sample, usually starting with an affected family member. If a gene mutation is detected, other family members can be tested. This is known as predictive genetic testing.

Genetic testing is typically offered through a cancer clinic if appropriate, and a referral to a familial cancer clinic is arranged to consider genetic testing. Before testing occurs, you are counselled about the process to understand the potential implications.

Associate Professor Judy Kirk is a cancer geneticist at the Familial Cancer Service at Westmead Hospital.

She says genetic testing is looking for a mistake in the gene that causes a high risk of breast and ovarian cancer within a family.

“It’s testing that’s done on blood, in a family with a pretty strong family history of breast cancer where we would start by testing an affected family member.”

“Usually, we test a woman who’s had either breast or ovarian cancer, and we search a number of different genes to try and find a fault or mutation, that’s passed down through the family that causes that high risk,” she said.

“When we do that, there are a number of different genes that we can test and the ones that relate to breast cancer are two genes we’ve known about now for over 20 years. One of them is called BRCA1, the breast cancer one gene, and the other called BRCA2, the breast cancer two gene, and more recently it’s been found that mutations in another gene, known as PALB2 also cause a higher risk of breast cancer.”

Who Should Consider Genetic Testing?

Genetic testing for breast cancer is a crucial tool in identifying individuals at risk. You may consider it if you meet any of the criteria below:

• Personal History of Cancer: According to Harvard Medical School, individuals with a personal history of breast or ovarian cancer, especially if diagnosed at age 50 or younger. Males with breast cancer at any age should consider testing.
• Family History of Cancer: Individuals with two or more close family members (parents, siblings, and/or children) with a history of breast or ovarian cancer should consider testing.
• Known BRCA1 or BRCA2 Gene Mutations: If there is a family history of BRCA1 or BRCA2 gene mutations, genetic testing is recommended.
• Ashkenazi Jewish Heritage: Individuals of Ashkenazi Jewish descent are at a higher risk.

In the first instance, a genetic test is done on a family member who has been affected by breast cancer. If the immediately affected family member has died or cannot be tested, other family members can still choose to be tested.

The information gained from the test can only be used for that individual tested and cannot tell us about the entire family. If no genetic fault is found in the tested individual, it is reassuring but does not rule out the possibility of a genetic fault in the family. Each family member would need to undergo genetic testing to understand their own risk.

Genetic testing for breast cancer is typically offered only through a cancer clinic where benefits and possible consequences of genetic testing will be discussed with the individual.

Genetic testing is a complex process and should always be undertaken with appropriate counselling and an understanding of the potential implications.

“I originally got tested for the BRCA mutation after my Auntie was diagnosed with breast cancer. She was 47. And then when my cousin turned 30 and she was diagnosed with breast cancer in 2013. So, all of my family started getting tested at that point which included myself and in 2015 I found out I carried the gene mutation,” Skye said. Learn more about Skye’s story. 

What is a ‘Strong Family History’?

Associate Professor Kirk said a ‘strong family history’ is when there are two or more affected family members on one side of the family. Sometimes, individuals may not know this information, or their family may be predominantly male. In these cases, other factors are considered:

• Early age at breast cancer diagnosis.
• Presence of triple-negative breast cancer.
• High-grade, invasive epithelial ovarian cancer.

“Inherited gene mutations are not necessarily more common on the mother’s side of the family. Both sides of the family are equally more important in assessing risk”, she said.

What Happens if you Test Positive for the BRCA Gene?

If your test results identify a mutation in the BRCA gene, a personalised risk management plan is developed. Individuals with the BRCA1 gene mutation would typically commence their breast screening from age 30 in a specialised risk management clinic. This offers the expertise as well as the access to breast MRI for screening in addition to mammography or ultrasound. Additionally, these individuals are also given the option of risk-reducing surgery to remove all breast tissue, which is chosen by approximately 30% of high-risk women.

The BRCA 1 or 2 gene mutations also increase the risk of developing ovarian cancer. As there is no screening test for ovarian cancer, the best option is to consider surgery to remove the ovaries and fallopian tubes once a woman has finished their family by about the age 30.

“They usually start it in a risk management clinic where there’s special expertise and the availability of breast MRI for screening rather than simply mammography ultrasound and of course, those women are also given the opportunity risk reducing surgery for the breast tissue, which is taken up by maybe about 30% of high-risk women,” Associate Professor Kirk said.

“Many choose to have screening, but I think the more important thing is that these women, if they have a BRCA1 or BRCA2 mutation, are also at very high risk of ovarian cancer.”

“So it’s very important to identify these women because we can save lives from cancer if we look after them appropriately.”

Genetic Counselling

Genetic counselling typically involves:

• Risk Assessment: Genetic counselling begins with a risk assessment based on your personal and family history of breast cancer. This can help determine your likelihood of having an inherited BRCA gene mutation.
• Education: Genetic counsellors provide information about inherited gene changes that can increase breast cancer risk, such as BRCA1 and BRCA2 gene mutations.
• Testing Considerations: Genetic counsellors discuss the pros and cons of genetic testing, helping you understand what genetic testing can and cannot tell you before these tests are done. It is important to understand the implications for insurance and impacts on other family members.
• Support: Genetic counsellors provide resources and support to help you and your family make informed decisions about genetic testing.

What is the Life Expectancy of Someone with the BRCA Gene?

Individuals with BRCA1 or BRCA2 mutations have an increased risk of developing certain cancers, particularly breast and ovarian cancers. However, having a BRCA gene mutation does not directly affect life expectancy.

The specific impact on life expectancy depends on various factors, including the individual’s overall health, access to medical care, early detection, and the effectiveness of preventative measures taken.

Where Can I Get Genetic Testing in Australia?

If you have a strong family history and would like to be tested, Associate Professor Kirk said to contact your local familiar cancer clinic.

“Most of this genetic testing is done through specialist clinics, either private or public and the genetic testing is covered by the system either Medicare or by the state health departments where it’s quite likely that we’ll find something, perhaps an over 10% chance that we’re going to find something.”

“If the chance is less than that, it tends not to be covered by the system and in that case the patient can pay for that testing,” she said.

“Again, it’s usually done through a specialist familiar cancer service, so that they understand the limitations of the testing in that circumstance and the implications of insurance and for other family members etc.”

“So, they’re fully informed before the testing about what could be expected, what genes are going to be tested and what could be the impact of finding something or finding nothing in some situations.”