An international study involving Peter Mac patients is the first in the world to clinically characterise the therapeutic importance of a diverse set of mutations affecting the HER2 and HER3 proteins.

A paper describing the findings is published today in Nature. The study found the clinical response of cancers to the drug neratinib is likely determined through a combination of the type of mutation as well as the tissue in which the cancer has arisen.

As part of the SUMMIT clinical trial, patients with a wide range of cancers harbouring mutations in the ERBB2 or ERBB3 genes, which encode the HER2 and HER3 oncogenic proteins, were enrolled to undergo treatment with the pan-HER inhibitor neratinib. 

HER proteins sit on the surface of cells and when activated signal for the cell to undergo division. Mutations in these proteins can cause uncontrolled cell division leading to cancer.

While some mutations are well known to activate HER proteins, others remain uncharacterised. Usually only patients with functionally known mutations are enrolled into clinical trials.

The SUMMIT study was unique as it allowed patients with any mutation in HER2 or HER3 proteins to participate. 

“This more inclusive approach is powerful as it enables biological and therapeutic characterisation of untested mutations, as well as allowing more patients access to treatments that may offer clinical benefit,” says Prof Sherene Loi, study co-author and Peter Mac Consultant Medical Oncologist and research group leader.

“Classically, the biological impact of individual gene mutations have been characterised in the laboratory. A limitation to this approach is a lack of laboratory models that accurately recreate the complex biology of human cancer. Therefore, we cannot truly predict the impact of a mutation until we look to see what it does in a human”.

The trial encompassed 141 patients diagnosed with 21 different cancer types, most commonly breast, lung, bladder and colorectal cancer, with 31 unique HER2 mutations and 11 unique HER3 mutations.

They found that clinical benefit in response to neratinib was likely determined through a combination of the type of HER mutation as well as the tissue in which the cancer has arisen.

“For example, responses to neratinib were observed in many breast cancers across a variety of mutations, whereas response in lung cancer was limited to a specific mutation context. Other cancers such as bladder and colorectal cancers did not show any sensitivity to neratinib regardless of mutation type,” explains Prof Loi.

Importantly, the study also found that although HER3 mutations were predicted to be oncogenic in laboratory models, patients with HER3 mutant tumours did not show response to neratinib.

While responses to neratinib treatment as a single agent were overall lower than some other approved therapies, the SUMMIT trial demonstrates the opportunity to interrogate cancer biology at the bedside in a manner previously only possible at the bench.

“SUMMIT demonstrates how the clinical trial can become an important tool in refining our understanding of how human cancers biologically depend on mutant proteins,” says Prof Loi.