Combined therapy offers promise for aggressive breast cancers

'Triple negative’ cancers are particularly difficult to treat and offer a poor prognosis. Now there’s hope for some individuals with these aggressive cancers in the form of a combination therapy developed at the Walter and Eliza Hall Institute (WEHI) in Melbourne.

These cancers are so-called because they test negative for oestrogen, progesterone and HER2 receptors, and cannot be treated with hormone therapy or trastuzumab, or Herceptin, a common monoclonal antibody treatment. Up to 20 per cent of all breast cancers are ‘triple negative’.

The researchers at WEHI, led by Professors Geoff Lindeman and Jane Visvader along with colleagues Dr Samantha Oakes and Dr François Vaillant, have found that by combining a conventional chemotherapy with another anti-cancer drug, a BH3 mimetic, can see improved results.

The BH3 mimetic in question is ABT-737, which inhibits the protein Bcl-2, which is known to play a role in apoptosis, or programmed cell death. Bcl-2 proteins act to ‘protect’ the cells after they have been damaged by chemotherapy drugs, and prevent the cancer cells from dying.

“ABT-737 targets proteins from the Bcl-2 family, which are found at high levels in up to 70 per cent of breast cancers,” Lindeman said.

“We have shown that breast tumours that have high levels of Bcl-2 respond well to treatment with ABT-737 when used in combination with a conventional chemotherapy drug.”

ABT-737 and navitoclax, another Bcl-2 mimetic, are not yet available for patient treatment, but navitoclax is currently in phase II clinical trials to establish its efficacy in treating some types of leukaemia and lymphoma. Navitoclax is being jointly developed by Abbott and Genentech.

Visvader said combined treatment with ABT-737 and docetaxel, a commonly used chemotherapy drug for treating breast cancer, in mice transplanted with human breast cancer cells improved tumour response and survival rates, when compared to docetaxel as a single agent.

ABT-737 alone was not effective in treating cancers with high levels of Bcl-2, nor was it effective in treating cancers that did not express Bcl-2.

“The research suggests that these agents make the cancer cells more vulnerable to chemotherapy,” Visvader said. “We are particularly excited that the research shows a good response in Bcl-2-expressing breast cancer, including basal-like breast cancer, which is often the most aggressive and hardest to treat.”

Dr Lindeman said the research could lead to the development of new treatment regimens that make resistant and difficult-to-treat breast cancers more vulnerable to conventional chemotherapy treatments.

“We have had a good result in pre-clinical models of disease, but we are still a way off this being used in humans,” said Lindeman, who is also an oncologist at The Royal Melbourne Hospital.

“We hope that these results could see a clinical trial of navitoclax for treating breast cancer with high Bcl-2 levels within the next few years.”

The research was published today in the Proceedings of the National Academy of Sciences USA.