Patients with HER2 positive breast cancer derive less benefit from anti-HER2 drugs when they have PIK3CA mutations, according to Dr Evandro de Azambuja, medical director of the Br.E.A.S.T. Data Centre, Jules Bordet Institute in Brussels, Belgium. de Azambuja commented on the impact of PIK3CA mutations as new data in the neoadjuvant setting was presented at the ESMO 2014 Congress in Madrid, Spain.
De Azambuja said: “The results presented at ESMO 2014 are consistent with other trials in the neoadjuvant setting and suggest that there may be a resistance to anti-HER2 drugs when PIK3CA is mutated.”
The NeoALTTO trial found similar distributions of PIK3CA mutations in the whole population compared to the study presented by Guarneri at ESMO 2014. Both studies found that the pathological complete response (pCR) was lower in patients with PIK3CA mutations. The effect of PIK3CA mutations occurred in all treatment arms – lapatinib, trastuzumab, and lapatinib plus trastuzumab – but was most pronounced in the combination group, although this finding did not reach statistical significance in Guarneri’s study likely due to low patient numbers.
A study from the German Breast Group (GBG) which combined two neoadjuvant trials, GeparQuinto and GeparSixto, also found a significantly reduced pCR in patients with PIK3CA mutations. In particular, patients who were HER2 positive and hormone receptor positive had a much lower pCR when they had the PIK3CA mutation.
Trials of dual anti-HER2 blockade in the metastatic setting have produced similar findings to the neoadjuvant studies. Patients with PIK3CA mutations had much less benefit from trastuzumab alone or from trastuzumab and pertuzumab in the CLEOPATRA trial, and less benefit from lapatinib plus chemotherapy with capecitabine in the EMILIA trial.
De Azambuja said: “All of this data seems to be in line and shows that patients with the PIK3CA mutation derive less benefit from anti-HER2 drugs. This is an important pathway in the cells which leads to proliferation, cell survival and tumour growth. We already know that PIK3CA is a prognostic marker but now it also appears to predict response to treatment.”
The FinHER trial investigated the impact of PIK3CA mutations on HER2 positive breast cancer patients in the adjuvant setting who received trastuzumab or no trastuzumab. de Azambuja said: “PIK3CA mutations did not predict response to trastuzumab but patient numbers were very small and I think it’s a question of power. We need more data before we can be confident about whether or not PIK3CA status predicts response to treatment in the adjuvant setting.”
The ongoing NeoPHOEBE neoadjuvant trial in patients with HER2 positive breast cancer is randomising patients with PIK3CA wild type and PIK3CA mutations to receive the anti-HER2 drug trastuzumab either alone or in combination with a PI3K inhibitor for 6 weeks, both in addition of weekly paclitaxel for a further 12 weeks. de Azambuja said: “The results of this trial should provide a clear answer on whether PIK3CA status can be used to stratify patients to receive, or not receive, anti-HER2 drugs.”
The incidence of PIK3CA mutations varies according to the different breast cancer subtypes. The majority of research in this area has focused on the HER2 positive subtype. However, a number of trials are investigating the impact of PIK3CA mutations on endocrine therapy and PI3K inhibition in patients with hormone receptor positive and HER2 negative breast cancer in the neoadjuvant setting.
Commenting on the impact of the new data presented at ESMO 2014 on current practice, de Azambuja said: “This research adds to the scientific knowledge on PIK3CA mutations but at the moment will not change clinical practice. There is some evidence that when patients have genetic tests and are directed towards clinical trials focused on their mutation they derive more benefit from treatment. I think we will see more and more use of genetic testing for PIK3CA and other mutations to stratify patients to clinical trials, particularly in the neoadjuvant or metastatic settings. This is the way to move forward in clinical research.”