The BRACE Clinical Trial

Dr Ross Jennens is a member of Breast Cancer Trials and is a Medical Oncologist at the Epworth Hospital in Melbourne.

He has been involved in the conduct of a number of clinical trials including the TEXT clinical trial, which produced practice changing results in the treatment of young women with breast cancer.

But with rise of COVID-19 in our community, Dr Jennens is now one of 4,000 health professionals in Australia who are participating in the BRACE clinical trial.

This study aims to test the BCG vaccine, which was developed to prevent tuberculosis and is commonly used as a treatment for people with bladder cancer, to see if it can provide an immune system boost to protect people from COVID-19 symptoms.

We asked Dr Jennens how this Australian trial was developed and what’s involved for health workers.

Understanding the Likelihood of Breast Cancer Recurrence Rates

Fear of recurrence – that is, the fear your breast cancer will come back – is a common issue facing women who’ve had early stage breast cancer. Fortunately, Australia has one of the best survival rates of breast cancer in the world, with 91% of women surviving at least five years past their diagnosis. New Zealand is not far behind with 88% of women surviving five years past their first diagnosis.

This information may come as a relief for those diagnosed with early stages (stage 1-3) of the disease, as many recurrences appear within five years after the initial treatment, the exception being ER positive breast cancer, as many recurrences will occur after the first five years as within the first five years. The rate of recurrence is not the same for all breast cancer types or patients. Understanding the risk of recurrence for your type of breast cancer may help to ease some anxiety.

What Is Breast Cancer Recurrence?

Breast cancer recurrence means that the cancer was diagnosed when limited to the breast and/or armpit lymph nodes, then treated, and at some time later has come back.

Breast cancer recurrence occurs in three main ways:

• Local recurrence: the breast cancer that was previously treated returns within the breast or armpit lymph nodes.
• New primary breast cancer: an unrelated new breast cancer occurs in one or the other breast.
• Distant recurrence: The previously treated breast cancer returns in other parts of the body, such as the bones, liver or lungs.

Breast cancer recurrence occurs if:

• Cells from the original breast cancer diagnosis break away and hide nearby in the breast (called local recurrence) or spread elsewhere in the body (called distant recurrence); AND
• Treatment, including surgery, chemotherapy, radiotherapy and/or hormone therapy have not gotten rid of all these cancer cells from the body.

These cells can begin to grow right away or can remain dormant for many years before beginning to grow and travel further through the body.

Many breast cancer recurrences are detected in the five years after diagnosis, especially after triple negative breast cancer. However, recurrence can occur more than 20 years after the first diagnosis.

Breast cancer survivors are at risk for developing new cancers for a number of reasons – whatever caused the original cancer could still be having an effect, either on second primaries in the same organ, or on related cancers in other organs. This can be due to genetic predisposition, as is sometimes the case with breast cancer.

What are the Breast Cancer Recurrence Rates for Australia and New Zealand?

Unfortunately, Australia and New Zealand don’t keep track of breast cancer recurrence rates, so it is hard to state the chance of breast cancer returning for the whole population of those diagnosed with breast cancer.

Your individual chance of breast cancer returning depends on a number of factors including the type of breast cancer, tumour size, genetic factors and treatment types.

See more on risk factors for breast cancer recurrence.

What Types of Breast Cancer have the Highest Recurrence Rates?

A study published in the Journal of Clinical Oncology found the rate of recurrence for all breast cancers was highest in the first five years from the initial cancer diagnosis at 10.4%. Specifically, the risk was highest between the first and second years after the initial diagnosis.

During the first five years after the initial diagnosis, patients with oestrogen receptor (ER) positive breast cancer had lower rates of recurrence compared with those with ER negative disease. However, beyond five years, patients with ER positive disease had higher rates of recurrence.

Who Is At Risk Of Breast Cancer Recurrence?

Everyone who has received a breast cancer diagnosis is at risk of recurrence, however the risk differs markedly depending on a number of factors listed below.

• Lower risk recurrence: Some breast cancer, when diagnosed very early when small and without lymph node involvement, have an excellent prognosis and are very unlikely to recur.
• Greater risk of recurrence: Larger cancers, with lymph node involvement or with a more invasive behavior, unfortunately have a higher risk of returning.

What Factors Contribute To The Risk of Breast Cancer Recurrence?

Whilst it is never completely certain that breast cancer has been cured, there are many treatments available that reduce the risk of recurrence. There are also a number of risk factors that can contribute to the rate of breast cancer recurrence.

• Your age at first diagnosis: Younger women, particularly those who had their first diagnosis under the age of 35, have a greater risk of breast cancer. This is because those diagnosed at a young age are more likely to have aggressive features in their breast cancer. Additionally women diagnosed with breast cancer before menopause have a greater risk of recurrence.
• Tumour size: Women who have a larger breast tumour have a greater risk of recurrence.
• Lifestyle factors: Excess weight is associated with a higher risk of postmenopausal breast cancer and is also associated with a higher risk of breast cancer recurrence and death. Smoking has also been shown to increase the risk of recurrence. Women who exercise regularly (at least half an hour per day of moderate intensity exercise, 5 days per week) appear to have a lower rate of breast cancer recurrence.
• Lymph node involvement: If cancer is found in lymph nodes at the time of the original breast cancer diagnosis, there is an increased risk of breast cancer recurrence. This is the strongest prognostic factor, and the more nodes involved, the higher the risk of recurrence.

How Does The BRCA1 or BRCA2 Gene Mutation Affect My Risk Of Breast Cancer Recurrence?

Women with a BRCA1 or BRCA2 gene mutation and who have already been diagnosed with breast cancer, have a higher-than-average chance of new primary breast cancers than those without this genetic mutation. The rate of local or distant recurrence depends on the type and stage of the original breast cancer, and is no different from a non-BRCA-mutated breast cancer.

For women with a BRCA1 or BRCA2 gene mutation, the rate of contralateral breast cancer, or cancer in the opposite breast to the original cancer, 10 years after diagnosis of the first cancer is about 10-30 percent, compared to about 5-10 percent for women diagnosed with breast cancer who do not have a BRCA1 or BRCA2 gene mutation.

Women who have a BRCA1 or BRCA2 gene mutation and have received a breast cancer diagnosis should talk to their treatment team about their options to reduce their risk of breast cancer recurrence.

What Are The Signs Of Breast Cancer Recurrence?

If you have a local recurrence or new primary breast cancer, you may find symptoms similar to an initial breast cancer.

These include:

• A new lump in the breast, armpit area or around the collarbone
• A change in breast size or shape
• Changes to the nipple, such as sores or crusting, an ulcer or inverted nipple
• Clear or bloody nipple discharge
• Changes to the skin including redness, puckering or dimpling (an ‘orange peel’ appearance)
• Breast tenderness or pain

If your breast cancer has spread to other parts to the body, known as distant recurrence, there are a number of possible symptoms, including:

• Fatigue
• Breathlessness
• Pain in your bones
• Unexpected weight loss or change in appetite
• Severe or ongoing headaches
• Nausea

However, symptoms will vary depending on where the secondary cancer presents, and some primary and secondary cancers may not present any obvious symptoms. Sometimes breast cancer recurrence is identified on a scan or blood test that was done for a reason other than the cancer itself.

If you have any health concerns or symptoms that are new or persistent, speak with your GP or treating physician.

Should I Have Scans Or Blood Tests To Check For Breast Cancer?

After a diagnosis of early stage breast cancer, any remaining breast tissue should be evaluated with scans (such as mammogram or ultrasound) regularly. The frequency is often annually but is best discussed with your specialist(s).

Current guidelines and evidence recommend against routine CT or bone scans, or blood tests, to look for recurrence of cancer in patients who do not have any symptoms or other concerns that need to be followed up on. These tests have not been shown to improve outcomes and cause unnecessary ‘scanxiety’. If you do have concerning symptoms (such as those mentioned above), then you should bring them to the attention of your healthcare team to be checked out.

Am I Still At Risk Of Breast Cancer Recurrence If I Have Had A Mastectomy?

Yes. You are still at risk of breast cancer recurrence if you have had a bilateral mastectomy (surgical removal of both breasts). Undergoing a bilateral mastectomy drastically reduces your chances of local or contralateral breast cancer recurrence as almost all of the breast tissue has been removed. However, there is still a chance that residual breast tissue or cancer cells could recur on the chest wall.

If you have had a single mastectomy (surgical removal of one breast), you are still at risk of developing cancer in the breast that remains.

It must be noted that having a mastectomy or bi-lateral mastectomy does not reduce your risk of developing cancer in other parts of your body (distant recurrence).

How Can I Prevent Breast Cancer Recurrence?

There is no definitive way to prevent breast cancer from coming back. However, treatments such as surgery, chemotherapy, radiotherapy, targeted therapy (eg trastuzumab for HER2-positive breast cancer) and/or hormone therapy (for hormone receptor positive breast cancer) do reduce the risk of recurrence, depending on the type and stage of the cancer. These can be discussed with your treatment team.

Understanding the risk factors for breast cancer recurrence and participating in regular breast screening through BreastScreen in Australia and BreastScreen Aotearoa in New Zealand can help to pick up any breast changes. Discussion with your healthcare team can help to catch any changes or abnormalities early and act on them.

Rebecca’s Experience During the COVID-19 Pandemic

Although life may feel like it is beginning to return to normal for some with COVID-19 restrictions beginning to lift, there are pockets of our society who still need to remain extra vigilant and cannot relax back into this new normal. This includes those who are immunocompromised, like breast cancer patients.

Rebecca Angus is a member of the Breast Cancer Trials Consumer Advisory Panel (CAP).

CAP members use their experience of breast cancer to provide input and insight into Breast Cancer Trials research, ensuring a consumer perspective is provided from the very early planning stage of clinical trials.

In this Breast Cancer Trials blog, Rebecca writes about why it is important to still remain safe and socially distant for those who are immunocompromised, how her breast cancer experience has prepared her for COVID-19 and what it is like to work in healthcare during this time.

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It has been two years since my diagnosis and the commencement of breast cancer treatment. Regardless of the COVID-19 pandemic, we are celebrating my breast cancer survival and life.

Today I am at home, practising social distancing and watching my son play in the backyard. This morning I went to visit my general practitioner for my flu vaccine and monthly Zoladex injection. My annual scans are due in a few weeks; managing breast cancer does not stop during the COVID-19 pandemic.

I am currently working in healthcare as a full-time Podiatrist and making most of my precious moments at home with my family. Trying to stay healthy and exercising regularly. My health is still and always will be at the forefront of my mind.

For those with chronic illness, COVID-19 impacts on our daily lives. I honestly cannot imagine how challenging it would be at present for those newly diagnosed with breast cancer, enduring chemotherapy, immunotherapy, or participating in clinical trials.

COVID-19 has reminded me of my health vulnerabilities. While no longer undergoing chemotherapy, radiation treatment, episodes of hospitalisation and neutropenia, I still do not want to test the waters with contracting COVID-19. This human body has lived through an enormous amount of treatment!

Working in an essential healthcare service during COVID-19 pandemic means I have face to face exposure to patients on a routine basis. This will continue until my oncologist instructs me that it is unsafe to do so.

A breast cancer diagnosis and treatments have adverse financial effects on patients. At present, I am trying to balance my health with my financial responsibilities. Hoping that it will not affect our financial stability as it has previously done in the past.

My social distancing measures include driving to work and avoiding public transport. My son is dropped off to his early learning centre at the door. I bring my lunch from home and do not leave the office until I go home. At work, we have been minimising our contact with patients when appropriate to do so. As soon as the family arrives home, we shower and change our clothes.

Practising infection control and hand hygiene has always been a big part of my work life and staying healthy during breast cancer treatment. Cleaning and disinfecting surfaces at home and work regularly. At work, I wear N95 masks, eye protection, gloves and gown. Washing my hands regularly and encouraging anyone I come into contact with to wash their hands.

This includes washing hands with soap and water more frequently, and for at least 20 seconds.

It is better to use soap and water at home and use alcohol-based hand sanitizer when you are mobile. It is also important to moisturise your skin daily, especially those women on breast cancer treatment or who have been affected by lymphoedema. I also avoid touching my face at work, in public or at home.

Breast cancer patients and those on chemotherapy practice social distancing and isolation as a standard precaution. So, adjusting to the COVID -19 pandemic may be a relatively smooth transition. My family have been adopting some of our breast cancer treatment rituals again.

When attending appointments, we call the facility ahead to make sure that we are practising social distancing or opt for telehealth consultations when appropriate. We do not wait in doctors waiting rooms.

COVID-19 has separated individuals priorities in life. While the general public was stockpiling toilet paper, flour and rice at the shops. The first thought that came to me was: How is this going to impact my healthcare and the life-saving medication, which assists in preventing re-occurrence of breast cancer? Will I be able to continue to access the Neratinib medication program?

Breast cancer has certainly put what is essential in life into perspective!

At home, we have been trying to keep space between ourselves and others, limiting our exposure to people and avoid any unnecessary travel. All our food, clothing and other supplies are purchased online and delivered to home. Otherwise, my husband picks up supplies.

Self-isolation and social distancing can get lonely at times, especially when your undergoing chemotherapy.

Your family and friends are the foundation of your support network, and with the social distancing rules, it can make it difficult at times. Trying to find fun ways to interact with your loved ones is essential.

Social media, facetime or zoom chat your family and friends. Make sure you discuss your mental health concerns with your doctor, psychologist or access free online evidence-based tools such as Finding My Way or BCNA My Journey.

Keep your routine as best as possible, including getting exposure to plenty of fresh air and exercise. You can also access prescribed exercise physiology and physiotherapy apps. These can be designed by your health professional to be completed at home, under a Medicare plan. For further information, discuss this with your general practitioner.

Yoga and meditation DVD’s/ online resources were tools that I used during my treatment to assist in managing my mental health. I plan to continue to practise them during COVID-19.

Breast Cancer Trials needs to continue their life-saving work and clinical trials into breast cancer throughout COVID-19. I am sending love and support to those involved in clinical trials and oncology care. The true health care heroes are our researchers, doctors and nurses.

To the trial participants and their families. My thoughts are with you; please stay safe. Lastly, please stay home for breast cancer patients and their families.

Our research is still continuing during COVID-19.

You can help support our life-saving research during this difficult time here.

What Is A Clinical Trial?

Clinical trials are an important part of our health system and are necessary to find out if new treatments are more effective than those currently accepted as the best available standard of care. They are designed to answer a scientific question and compare whether a new treatment is better than the current treatment. In fact, the current treatments that are saving lives today are typically only available because clinical trials have shown that they are beneficial.

All new breast cancer treatments or prevention strategies must be rigorously tested through the clinical trials process before they are made widely available to the community. This includes chemotherapy and hormone treatments to prevent recurrence and save lives, mammograms and breast cancer surgeries.

Who Participates In A Clinical Trial?

People who participate in a clinical trial volunteer to do so. In terms of breast cancer clinical trials, participants have been diagnosed with breast cancer or in regard to prevention trials, are at higher than average risk of being diagnosed with breast cancer.

Participants in any clinical trials need to understand what is going to be involved. This is the process of informed consent, before signing onto a trial. The treating physician and clinical trial coordinator will go through this information with the potential participant. This will include an explanation of the trial protocol and provision of written participant information and consent forms. They will discuss the trials aims, potential side effects and what kind of trial it is. Potential participants are given time to read about it, ask questions, discuss with their friends, family and other health professionals before deciding to enter the trial.

Is It Safe To Participate In A Clinical Trial?

What Phases Are Involved During A Clinical Trial?

Clinical trials are generally conducted in four phases. Each phase is designed to answer certain scientific questions.

Phase One Clinical Trial

Phase 1 clinical trials are conducted to test a new biomedical intervention (treatment) for the first time in a small group of people (around 20 to 50 people) to evaluate the safety and side effects of the new treatment or intervention. Phase 1 trials are not usually randomised.

Phase Two Clinical Trial

If the treatment or intervention is proven successful in phase one, it is moved to a phase 2 study and tested in a larger group of people (generally several hundred) to give an indication of how effective it is and to further evaluate its safety.

Phase Three Clinical Trial

Phase 3 clinical trials compare new treatments with the best currently available treatment (standard treatment). Phase 3 clinical trials study the efficacy of a treatment or intervention in large groups of people (several hundred to several thousand). They look at which treatments work best for the disease, how the treatment affects quality of life and learns more about side effects. A phase 3 clinical trial could compare the standard treatment with a new treatment, a different dose of the same treatment or a different way of giving the same treatment. These are usually randomised, meaning that participants are allocated to one of two or more treatment options at random, and neither they or their doctors get to choose which treatment. Determined This helps to remove any biases that could lead to false conclusions being made about the effectiveness of the new treatment. Importantly, with this type of trial, participants are given the current standard of care at a minimum, and the new treatment is hoped to be better than that standard care (or at the minimum, no worse).

Phase Four Clinical Trial

A phase 4 clinical trial is conducted after the new treatment or intervention has been approved and entered routine clinical practice. A phase 4 clinical trial aims to learn more about the side effects and safety of the new treatment, the long-term risks and benefits of the new treatment and how effective the treatment is when used in the general population over a longer period of time.

How Long Do Clinical Trials Take?

The length of a clinical trial is dependent on what kind of trial and treatment is being tested. This means each clinical trial timeline is different and we cannot say definitively how long each phase of a clinical trial will last. If you are considering signing on to a clinical trial, this information will be communicated to you by your treating doctor and the clinical trial coordinator. The following information is intended only as a guide and may not be relevant to your individual situation:

Phase 1 trials may last less than a year as these trials are testing in small groups and evaluate the safety of a new treatment or drug. However, if the patient is benefiting from the treatment, the patient may continue on the clinical trial and treatment for longer. This is dependent on individual circumstances.

Phase 2 trials may be longer than phase 1 trials as there are more participants, which means recruitment may take longer. Though recruitment may take longer, patients may be on the treatment for a similar time to those on a phase one trial.

Phase 3 trials, the most common phase trials, may take longer than phase 1 and 2 clinical trials, but the duration depends on the size of the clinical trial, what stage of cancer is being treated and what the determined end points for the clinical trials. For example, the large adjuvant clinical trials SOFT and TEXT have been going on for around a decade, with follow-up still occurring. This does not mean patients are still receiving active treatment, but it does mean researchers are still examining the benefit of the treatment patients received through follow-up consultations.

Phase 4 trials can last for a few years to more than a decade as it is testing the long-term risks and benefits of a new treatment in a larger population, over a longer period of time.

What Happens When A Clinical Trial Ends?

When a clinical trial has reached its determined end point, the researchers involved in the study will evaluate all the information collected. An analysis is also usually conducted during the clinical trial. All this information collected during and post- trial will help to determine if the treatment or intervention should continue to the next phase of the clinical trial, or if the treatment or intervention should be approved for use in the clinic by the relevant health authorities. Once a new treatment has been proven in a clinical trial, the addition of this treatment to the Pharmaceutical Benefits Scheme (PBS) in Australia and PHARMAC in New Zealand, is a separate process and can take several years.

There are a lot of factors that determine how long it will take for a safe and effective treatment to be approved for use in the clinic. Larger trials that have had thousands of participants will take longer to evaluate than smaller trials. This can take a number of years.

Participants are also usually involved in follow-up for years after their involvement in the active treatment part of a clinical trial. This means they are monitored for many years after their active involvement has finished, including when they have finished taking the treatment tested in the clinical trial. This follow-up could include filling in a survey each year or receiving check-ups with your treating doctor. This helps researchers study the long-term effects and efficiency of the treatment or intervention studied.

If you have participated in a clinical trial, the researchers should make the results of the study available to you directly when they become available. Results are generally presented in reports or published in scientific journals.

Can I Participate In Two Clinical Trials At Once?

Generally, researchers prefer clinical trial participants to be involved in only one clinical trial at a time. This is so they can clearly attribute the risks and benefits of each treatment or intervention to the clinical trial. There are exceptions; however, clinical trial participants can be involved in a therapeutic trial and a tumour banking trial, a quality of life or lifestyle intervention trial simultaneously. Your treating doctor will advise on what trials you can participate in.

Can I Discuss The Clinical Trial With My Family And Friends?

Yes!

Your doctor and clinical trial team will encourage you to discuss your participation in clinical trials with trusted loved ones so you can feel confident in your choice to participate. Additionally, the more people who are aware of and understand clinical trials the better. This helps to increase participation in clinical trials which helps to further breast cancer research and help to find new and better treatments and prevention strategies for the disease. You may also wish to discuss the trial with other health professionals such as your GP prior to participation.

Will My Details Be Published To The Public?

No.

Patient privacy is of the utmost importance is the clinical trials process. Once you consent to take part in a clinical trial, your information will form part of the clinical trials records and be processed in line with the applicable laws that control clinical trials. This means that identifying information such as name, date of birth and address are removed from your information, and replaced with a code, so that the researchers analysing the information cannot identify you as an individual. In any case, the trial information is generally only meaningful when it is analysed as a group, not from any one participant on their own.

When participating in a Breast Cancer Trials clinical trial, your confidential health information will only be accessed by people involved in the clinical trial, including health care professionals and Breast Cancer Trials research staff who are all dedicated to upholding the rights of trial participants to privacy. Any identifying details are removed by your treating doctor or clinical trial coordinator prior to the data being send to the data repository, for example the Breast Cancer Trials database.

Responding To COVID-19

In this Breast Cancer Trials (BCT) members podcast, Professor Fran Boyle AM and Associate Professor Nicholas Wilcken discuss how those involved in breast cancer care and treatment have responded to the COVID-19 pandemic.

Professor Fran Boyle is a Medical Oncologist at North Sydney’s Mater Hospital, where she is the Director of the Patricia Ritchie Centre for Cancer Care and Research, and Professor of Medical Oncology at the University of Sydney. Professor Boyle has been involved in breast cancer clinical trials research for the past 20 years. She has chaired the BCT Board and is a current member of the BCT Scientific Advisory Committee.

Associate Professor Nicholas Wilcken is the Director of Medical Oncology at the Crown Princess Mary Cancer Centre Westmead, Senior Staff Specialist at Nepean Hospital and Associate Professor of Medicine at the University of Sydney. Associate Professor Wilcken was elected to the BCT Board of Directors in July 2016. He was the Chair of the BCT’s Scientific Advisory Committee from 2011 to March 2017.

The Importance Of Genetics In Breast Cancer

An individual’s genetic makeup is becoming increasingly important in how certain breast cancers are treated.

New treatments and prevention strategies are now being tailored to specific genetic make ups, especially those who have a known genetic mutation.

Associate Professor Judy Kirk is a Cancer Geneticist at the Familiar Cancer Service at Westmead Hospital.

She says there are two ways genetics will become more important in cancer genetic testing and personalising treatment.

“When we talk about genetic testing, sometimes we are talking about testing of the tumour to find the genetic changes in the tumour that have caused that cancer and to target the therapy for that cancer.”

“So that’s quite different to a fault in the gene that’s in every single cell in the blood that causes a higher risk of cancer.”

“Our understanding of both of those aspects of genetic testing is changing over time.”

She said what researchers know about how genetics affects cancer risk and treatment, has come a long way over the past couple of decades.

“We know when our clinic first started in 1994, we didn’t really know much.”

“We knew about two genes only at that point,” she said.

“We had very rudimentary testing, but it cost an awful lot of money and it took a long time to do.”

“Now the sequencing of these genes is much cheaper. So, it’s more available.”
She said now more funding and time is spent on interpreting the data found through testing.

“The more testing we do, the more we find changes in genes that are called unclassified variance.”

“They’re small changes that probably mean nothing but we’re not sure about that yet,” she said.

“The more genes you test the more you find and you can find in some studies, where they’ve tested lots of different genes in women with breast cancer, up to a third will have slight variations in genes that may or may not mean something.”

“So, there’s still uncertainty about some aspects of genetic testing. There’s a lot left to learn.”

Genetic Testing For Targeted Therapies

Associate Professor Kirk said that the information researchers already know about genetic abnormalities and mutations has helped to inform treatments in those with known BRCA1 and BRCA2 gene mutations.

“It’s already been shown that individuals who have a germline mutation or mutation in every single cell, a mutation in BRCA1 or BRCA2, certainly respond well to specific PARP inhibitors.”

“Now that also could be found by testing their tumour. Some people don’t have a mistake in every single cell, but there is a mistake in their tumour.”

Breast Cancer Trials currently has a clinical trial open for the prevention of breast cancer in women who have the BRCA-1 gene mutation.

You can find out more about BRCA-P and sign up for the BRCA-P mailing list here.