Current research and developments in genetic cancer with Prof Lindeman

18 Aug 2021

Professor Geoffrey Lindeman is a clinician-scientist focusing on breast stem cell biology, hereditary breast cancer and translational breast cancer research. He is heavily involved with the implementation and delivery clinical studies, including studies related to BRCA1 and BRCA2 mutation carriers.

Professor Lindeman joins Pink Hope’s BPLD campaign to shine a light on current research and developments in the genetic breast and ovarian cancer space. He believes in the importance of starting conversations around hereditary cancer risk to ensure risks can be appropriately managed. Here’s what he had to say…

Professor Lindeman, how long have you worked in research, and what changes have you seen over the years?

I’ve worked in this field for over 20 years. There have been remarkable advancements over this time, including improved screening, treatment and prevention options. These advances have played out to deliver better outcomes for women, most notable through better survival rates. When I first began in research, the five-year survival rate for breast cancer was about 75%. This is now more than 91%.

In terms of BRCA1 and BRCA2, not much known. The two genes were first discovered in the early- to mid 1990’s through genetic studies in high risk families containing multiple family members who had been diagnosed with breast and/or ovarian cancer. In Australia, identification of BRCA mutation carriers became possible shortly after their discovery - towards the end of the ’90s. Over subsequent years, the area became turbocharged with research activity. The roles of these important ‘tumour suppressor’ genes was deciphered through laboraroty research, while improved ways of identifying, screening and managing BRCA mutation carriers were defined in the clinic. On example includes the discovery of a novel class of drugs (called parp inhibitors) that have become part of routine care in some settings for BRCA mutation carriers.

A new field of cancer care evolved that has become an accepted part of mainstream clinical practice. When BRCA1 and BRCA2 were first discovered, genetic testing was slow and cumbersome. Obtaining a genetic test result could take twelve months or longer and was also very costly so the ‘right’ patient had to be selected. Nowadays results can be available within a clinically relevant timeframe for patients with newly diagnosed cancer – within a 2-week turnaround time if needed. In parallel, other breast and ovarian cancer predisposing genes have been identified that have also been incorporated into clinical practice.

Laboratory research played a crucial role in helping to shed light on the molecular and cellular changes that go awry that lead to breast or ovarian cancer in mutation carriers. These have led to promising treatment and prevention approaches for mutation carriers. This continues to be ‘work in progress’, underpinning the importance of supporting research.

In the clinic, we have seen the establishment of multidisciplinary familial cancer centres that helped deliver services to families affected by breast and ovarian cancer. Screening technologies have improved, as have surgical and medical interventions. As a result of research in this area, we are much better at calculating an individual’s cancer risk, there are better scanning tests available, and there have been substantial improvements in therapy for women diagnosed with cancer. These is still much to do, however, including in the area of cancer prevention.

What trials and research are you currently working on?

Our group has an interest in both hereditary and ‘sporadic’ (non-hereditary) forms of breast cancer. Fundamentally, we are interested in defining the type of cell in the breast that goes awry and gives rise to breast cancer. We wish to identify the first steps that lead to cancer in breast duct cells, and undertand how female hormones and surrounding ‘stromal’ cells (including immune cells) impact on this process. If we can understand that, discoveries that inform the treatment and prevention of breast cancer should be possible.

Several years ago, we discovered the culprit cell which likely gives rise to breast cancer in women with a faulty BRCA1 gene. Having identified the target ‘progenitor’ cell, we next found a way of switching those cells off in our laboratory models - using a drug called denosumab that was already available in the clinic.

We are currently conducting a small study in Melbourne (BRCA-D) that is helping to understand how denosumab affects breast cell growth in BRCA1 and BRCA2 mutation carriers who are electing to have preventive breast surgery (mastectomies) to reduce their breast cancer risk. For this women are treated for a short time with denosumab and we study its effect on breast tissue, 

Our pre-clinical work and BRCA-D has led to an exciting international prevention study called BRCA-P. This is a large randomised prevention study trial of about 2,900 BRCA1 mutation carriers across 7 countries. Its purpose is to test the safety and effectiveness of denosumab (compared to placebo) and determine if breast cancer can be prevented in women with a faulty BRCA1 gene. The study has now opened across 15 sites in Australia, so should be available to suitable participants, where-ever they live.

Another area of focus it to test the effectiveness of ‘mainstream’ genetic testing of all women with recently diagnosed breast cancer. Over the last few years has has becoming clear that women with newly diagnosed breast or ovarian cancers can benefit from knowing whether or not they carry a faulty BRCA1 or BRCA2 gene. This can modify treatment approaches, and of course help inform genetic testing of relatives when a mutation is found. With colleagues in Melbourne, I’m involved in a clinical study, where women with newly diagnosed breast cancer undergo realtime testing at the time of diagnosis. We are trying to determine how often mutations will be found, whether it impacts on clinical management, and determine its acceptability for both patients and clinicians. This approach could help to identify unaffected family members, who would in turn benefit from more strategic management of their breast and/or ovarian cancer risk.

What hope do we have for families with hereditary cancer in the future?

These are really exciting times. As mentioned, things there have been remarkable developments over the last couple of decades. Clinicians and families can now have fast and relatively inexpensive access to genetic testing. If applied appropriately, this can be used to assist family members in managing their risks, and/or helping with treatment decisions for women diagnosed with cancer. This usually requires expert specialist input - we well placed in Australia through a collaborative network of Familial Cancer Centres and specialist clinicians to implement this care. With the increased activity in this area, more resourcing is almost certainly going to be needed, however.

For families, I believe there is a lot of hope on the horizon. We are becoming better at managing risk once a person is found to be a mutation carrier. Some interventions (like screening) can be straightforward, while others (such as mastectomy) can of course involve significant surgery. By conducting fundamental and clinical research, my hope is that we will define new less intrusive approaches. This includes the develpment of suitable prevention drugs that can switch off cancers even before they happen. This may seem to be too far down the horizon, but if  intensive research is done now, the outcomes could benefit the next generation of women.

How can families have those conversations around hereditary health, and what advice would you give?

The first and most important thing is not to be frightened of talking about your own experiences. Discuss it and get expert advice (not every internet search leads to a credible answer!). Raising the issue with family members before embarking on genetic testing helps people to think about how they might react, what it might mean for them and their immediate family. Its important to know that independent expert advice and support is available through Australia’s network of Familial Cancer Centres. 

It’s also important to remember that when an unaffected family members undergoes genetic testing, the identification of a mutation means that they are at increased risk of breast or ovarian cancer. It does not mean that they will develop cancer. With appropriate risk management, the odds can be substantially tipped in their favour. It’s really about having a conversation with experts around options and timing – something that will be different for different age groups.

How important are organisations like Pink Hope for those working in genetic cancer research?

These organisations are hugely important in addressing diverse issues in breast cancer. Pink Hope fills an important niche for young women with breast cancer and genetic cancers. It highlights genetic awareness, self-empowerment and advocacy for women.

Pink Hope helped to raise awareness on the importance of affordable and accessible genetic testing. This is becoming reality that will benefit families and shoulds assist research efforts in this area.

This year, we have chosen Professor Geoffrey Lindeman to be the face of “Resilience.” Here’s what it means to him…

I think 2021 has defined resilience for us all. It has been amazing to see how Australians have had to cope with the multiple challenges thrown at us from left field during the COVID pandemic.

From a researcher's perspective, resilience is the realisation that experiments fail more often than they work. Knowing that even a negative result is a lesson learnt. Either way, it can lead to new questions, eventually getting there – or at least to the next research question.

I also see the amazing resilience in breast cancer patients facing incredible challenges. They often have to pick themselves up of the floor and and find that extra bit of stamina to overcome adversity.

For mutation carriers, resilience can be turning this knowledge into a plus through empowerment by managing their risk, helping family members, and becoming involved research and advocacy.

To learn more about the BRCA P Trial, read here