PIK3CA mutation predicts resistance to anti-HER2 treatment and chemotherapy

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Published: 19 Dec 2013
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Dr Sibylle Loibl - German Breast Cancer Group

Dr Loibl talks to ecancertv at SABCS 2013 about her study "PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer".

Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer, PIK3CA mutations being the most common.

Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2 positive breast cancer.

The team investigated the frequency and prognostic associations of PIK3CA mutations in HER2 positive and triple negative primary breast cancer treated with neoadjuvant therapy.

Patients with PIK3CA mutant HER2 positive / HR negative breast cancer are resistant to chemotherapy and dual anti-HER2 treatment. Other treatment options are needed to be tested in this group.

2013 San Antonio Breast Cancer Symposium (SABCS)

PIK3CA mutation predicts resistance to anti-HER2 treatment and chemotherapy

Dr Sibylle Loibl - German Breast Cancer Group

We investigated the PIK3CA mutation, this is the second most common mutation in breast cancer and it’s about 20% of early breast cancers harbour this mutation; it seems to be a little more common in hormone receptor positive disease. We looked at that because it’s described that it plays a role in resistance to anti-HER2 treatment and that there might be a difference in response to lapatinib and trastuzumab or the combination even and now we are treating patients with a combined therapy we want to know if all of those patients really benefit from the double combination. Therefore we started performing this mutation analysis with extracting the DNA from the tumour and sequencing it to detect the mutations and we found, actually, that patients who harbour the tumours, who harbour the mutation, have a significantly lower chance of achieving a pathological complete response to a double HER2 blockade compared to those with a wild-type tumour. This was especially interesting for those who had a HER2 positive and hormone receptor positive tumour. These tumours, if they harbour the mutation they had a very low chance of obtaining a pathological complete response to chemotherapy and double HER2 blockade. The PCR rate was as low as 6.3% compared to 30% in the group without a mutation. This is a chance of selecting the patients according to the PIK3CA mutation status.

If we look at the different treatments according to the mutation then it seems that those with a PIK3CA  mutation derived no special benefit from an anti-HER2 treatment; they have the same PCR irrespective of trastuzumab, lapatinib or the double combination. But if we look at the wild-type cohort they actually have an increased PCR starting from lapatinib which was as low as 18% to trastuzumab with 30% and the double combination of 36%.

We need new therapies and there are therapies underway targeting the PIK3CA. There are PIK3CA inhibitors but we don’t know yet if they work especially in mutated tumours or if they work irrespective of a PIK3CA mutation. But we are conducting currently a clinical trial in early breast cancer with HER2 positive disease and stratifying the patients according to their PIK3CA mutation status and treating them in a double blind placebo controlled trial. They all receive trastuzumab with or without the PIK3CA mutation inhibitor for six weeks then they receive, in addition to this treatment, paclitaxel for an additional twelve weeks and then they will be operated. According to the PCR rate we will know if there is a difference for this drug overall in HER2 positive patients and if the PCR rate is different in those with or without the mutation, the PIK3CA mutation. This is an international trial, this is run under the umbrella of the Breast International Group with sites all over the world.