Why a clinical trial for metastatic breast cancer?

Today breast cancer affects one in eight Australian women in their lifetime. 

Despite the overall survival rates for breast cancer increasing to more than 84% today, the prognosis for late stage breast cancer is still only 32% according to Australia’s National Breast Cancer Foundation.  And more than one third of women with early breast cancer will go on to develop metastatic breast cancer later in life, sometimes 10 to 15 years down the track. 

In a culture faced on survivorship, those patients with metastatic breast cancer will be in treatment for the rest of their lives and can feel isolated and misunderstood – or often simply too exhausted to look at fresh options available to them.  

What is heartening for women living with “Mets” in Australia though, is that unlike some cancers where survival has not changed in decades, the outlook is constantly improving with studies showing significantly improved survival rates since the 1990s. 

This is expected to grow exponentially in the coming decade with researchers creating entirely new paradigms in the way we treat breast cancer – firstly with immunotherapy in recent years, and now with targeted epigenetic therapies such as the Epi-PRIMED trial, the first global trial of its kind –  which is a unique “combination therapy” of chemotherapy and epigenetics.

How does Epi-PRIMED work?

Currently, Abraxane is a chemotherapy drug of choice for any woman with advanced breast cancer in Australia, where other treatments have failed.  In the Epi-PRIMED trial, Abraxane is used in combination with an older-class of a standard antidepressant drug called Nardil. 

When used in combination, these two drugs have a powerful synergy whereby Nardil inhibits the pivotal enzyme, Lysine-Specific Demethylase1 (LSD1), which is responsible for stem cell cancer proliferation.  By blocking this enzyme with an inhibitor drug, rogue stem cells can be prevented from “reseeding” from the primary tumour to other locations in the body. Data from animal studies consistently shows that this blocking strategy is most effective at lowering the cancer stem cell burden when combined with standard chemotherapy.

What have the preliminary results found?

The animal studies to date have both shown consistently that the cancer stem cells can be reprogrammed by blocking LSD1.  When reprogrammed, chemotherapy is able to clear them from the body. “Obviously these are very early studies, but even in a small group of metastatic breast cancer patients,  and even after 12 months, there are an encouraging number who remain in remission,” says Professor Sudha Rao, who is Chief Scientific Officer of EpiAxis as well as Professor of Molecular and Cellular Biology at the University of Canberra.  

Cancer stem cells, which are known to be resistant to current therapies, remain dormant in the body even after successful chemotherapy and are difficult to treat.  “If further clinical trials vindicate these early findings, we hope within 5 years women diagnosed with metastatic breast cancer will be able to live with it as a “chronic” rather than terminal disease, just as we have seen with HIV.”

“Whilst the trial is focused initially on the prevention of metastatic breast cancer, we hope to pursue other cancer stem cell mediated diseases such as ovarian, pancreatic, colon, melanoma, lung and liver at a later stage.”

What are the side effects?

To date side effects have included dizziness or headaches, drowsiness, and diarrhoea. 

“But we could say that these side effects are “golfball sized”, compared to the “football sized” benefits of long-term survival, if the findings of the early research are further confirmed in larger studies,” says Professor Rao.

Professor Rao says the trial is also designed specifically for women with HER2 negative breast cancers, including triple negative breast cancers. “We decided to focus on this group because currently there are far more options for HER2 positive breast cancers and HER2 positive cancers are generally more responsive to targeted treatments. “  

Professor Rao adds there is a “substantial unmet clinical need” when it comes to fighting recurrent, metastatic breast cancer.

“This is the major cause of death in women with breast cancer. We aim to address that unmet need with this novel targeting of breast cancer stem cells, which are often resistant to conventional systemic anti-cancer therapies and contribute to the failure of those therapies in patients.” 

Who is eligible for Epi-PRIMED?

The Epi-PRIMED trial is suitable for:

 

  • Women age 18-65 who have been diagnosed recently with any HER2 negative metastatic breast cancer or inoperable locally advanced breast cancer, including triple negative breast cancer.
  • Women who are fluent in written and spoken English and in a position to provide written informed consent 
  • Women who have a reasonable day to day functional status (ECOG Performance Status 0 or 1 as determined by their oncologist) 
  • Women with adequate liver function 
  • Women who live in NSW and can commit to 12-week regimen (travel costs covered). If you are travelling from areas outside of Sydney your travel costs will be covered, and your partner’s if necessary.
  • Women of child-bearing age must have a negative serum pregnancy test and agree to abstain from sex during the 12-week period OR practice reliable contraceptive regimen during the trial such as an intrauterine device or intrauterine system with a failure rate of <1% stated on the product label OR have a male partner who has had a vasectomy/sterilisation.

  • As the effect of these treatments on the developing foetus is unknown, pregnancy must be avoided during treatment. 

Who is not eligible for the Epi-PRIMED trial?

There are a number of exclusion criteria including:

  • Women who have been diagnosed with HER2-positive metastatic breast cancer 
  • Women with a concurrent condition that may limit decision-making capabilities (e.g. dementia) 
  • Women who are pregnant or lactating 
  • Women with a previous diagnosis of HIV, Hepatitis C, or Hepatitis B virus
  • Women with uncontrolled brain tumours, however controlled metastases are permitted, e.g. stable patients who are post 1-month completion of whole brain radiotherapy and not currently on steroids or anticonvulsants 
  • Current use of monoamine oxidase inhibitors (MOAI) or use of dextromethorphan 
  • Current use of CNS depressants such as selective serotonin re-uptake inhibitors as well as specific medication for pain management including pethidine, tramadol, fentanyl and methadone. Ask your doctor about switching your anti-depressant if you wish to go on the trial. 
  • Previous use of Abraxane
What is involved?
  • Generally, the trial involves coming to Sydney, Wollongong, or Canberra for one day, once a week, over three weeks to receive Abraxane, and the Nardil (phenelzine sulfate) that will be taken daily. 
  • Five patient cohort groups will receive a progressively increased dose of phenelzine sulphate and safety, and efficacy will be assessed weekly. 
  • The fourth week will be an evaluation week. 
  • The trial centres are in Liverpool Public Hospital, Southern Medical Day Care Centre in Wollongong and Canberra Region Cancer Centre.

All travel costs will be reimbursed, including travel costs of partner.
Patients will be able to be back home on the same day.

What does this trial mean in terms of real women?

Every woman’s cancer experience is different. Just as every cancer is different. 

Many Australians will remember Triple Negative breast cancer patient Natasha Stuart’s inspirational performance on The Voice 2019  – just months after chemotherapy.  

Natasha has triple negative breast cancer, a less common and aggressive form of breast cancer, that is often harder to treat than other breast cancers. 

Cancer too has its own song, and “gene expression” (epigenetics) is increasingly becoming the new way to change cancer’s “main melody”.

“If your DNA is the ‘unique song of you’, your epigenomes are the audio engineers that decide how that music will be played – which bits are loud, or edited out, whether the melody is dominant, or maybe if the drums are lost altogether,” says this report in ABC Science. 

Other scientists describe DNA (or your body’s genetic blueprint) as the hardware – and epigenetics as the software.

 “The epigenome sits in your cells with your genome – a set of instructions of sorts that decides which bits of DNA are activated or which genes are switched ‘on’ or ‘off’,” says Professor Rao.

“While you can’t change the body’s DNA we know that many things in our everyday life can change the way DNA acts – including diet, alcohol, physical activity and infectious diseases,” says Professor Rao. 

“It’s thought that these epigenetic changes can set off a certain cancer pathway. Similarly, we are looking at new ways to reverse this process and by making changes at an epigenetic level, to stop cancer in its tracks. To date we have found that Nardil changes the way specific proteins are expressed in cells. This in turn changes the cells from being aggressive and cancerous to quiet and quiescent.”

      

 

Professor Sudha Rao