SABCS 2012

Neratinib shows beneficial effects in the treatment of HER2 mutated breast cancer

Professor Ron Bose – Washington University School of Medicine, St Louis, USA

We looked at the information that was available on 1,500 patients and we identified 25 patients out of that who had HER2 mutations. We then took these HER2 mutations and tested them in the laboratory and we went through a very extensive process of testing thirteen different mutations, putting them in a variety of laboratory systems to see what they did. The majority of these mutations turned on HER2 functioning in an inappropriate manner, in a pro-cancerous manner, and they result in cancer-like growth of cells in the lab.

What do the results show?

Those results show us that these are mutations that are likely to drive the growth of human cancers. We tested a variety of drugs against these mutations and we have laboratory results that show that the drug neratinib is the most potent drug for these mutations. So, based on that, we are now launching a clinical trial in four sites in the US to screen patients for HER2 mutations and then if they have these mutations to treat them with neratinib.

What other drugs were investigated?

The three drugs that we looked at extensively are trastuzumab, which is brand name Herceptin, lapatinib, which is brand name Tykerb, and neratinib. We saw evidence of drug resistance with lapatinib with some of these mutations and that’s a reason that we didn’t choose that drug. We also looked carefully at trastuzumab and it had some effect in the laboratory but it was not as dramatic as neratinib. The jury is still out as to what the effectiveness of trastuzumab is going to be in patients but, for the purposes of clinical trial, we need to start with one drug before we go to combinations; so we have to walk before we can run. So we’re starting with a one drug clinical trial and we want to see how effective that is for this new population of breast cancer patients.

Is there potential to further investigate patients that were resistant?

We’re looking further into the resistant patients so we’re concerned about what are the details of resistance. There is always the possibility of resistance down the line so that is something that we’re going to keep watch for. If this trial is successful we want to broaden the patients that we are going to treat with neratinib, so we would start with metastatic patients and then, if it is successful for metastatic patients, we would consider patients who are newly diagnosed with breast cancer.

What are the implications of this research?

There are two implications of this research: first off, that we are finding real ways to translate genome sequencing results into patient treatment. This is opening a new era for cancer treatment, an era where we can take genome sequencing information and say this is how a patient should be treated. A more specific implication of this is that we are defining a small population of breast cancer patients that we think are going to behave more aggressively, that we have existing drugs for but we never knew before how to identify them. We think we can identify them now and give them better treatment.

Is the cost of sequencing a concern?

Those are certainly a concern. The costs of genome sequencing are coming down. I think that what we’ll see in the next two to five years is moderate sized panels of genes that could be sequenced on a patient for costs that are comparable with MRI scans or PET scans. So the radiology tests that are used in the US and elsewhere, this could be kind of a comparable version with that.