Genetic pre-disposition to breast cancer


Professor Georgia Chenevix-Trench

21 October 2011

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Introduction: Hello I’m Carolyn Norrie from the NHMRC. I’m speaking today with Professor Georgia Chenevix-Trench. Hello and welcome Georgia.

Prof: Chenevix-Trench: Hello.

Interviewer: I understand that you’ve been working in the area of genetic pre-disposition to breast cancer for quite some time. What have been your main areas of investigation?

Prof: Chenevix-Trench: Well the last program grant focused very much on the characteristics of tumors from women who carry high risk predisposing mutations in the BRCA1 or BRCA2 genes. We have collected a very large number of these families through the National Consortium that’s called ConFab and we used tumors from these women in the last program grant to get a better understanding of the nature of their tumors. In particular we were able to look at some of the epigenetic changes that occur in these tumors and were surprised to find that tumors resulting from women with BRCA1 mutations had quite a distinct profile in the methylation of the DNA. We have also been working a good deal at a different class of genes which you might call intermediate genes, in particular one called ATM that Dr Kum Kum Khanna and I have worked on for a very long time and we have found that there are some rare mutations in this gene that have an intermediate risk of breast cancer associated with them.

Interviewer: So what you’re probably finding is that you’re going to be able to investigate genetic mutations where the family record of breast cancer is not quite so strong?

Prof: Chenevix-Trench: That’s correct, although not everybody who develops breast cancer has a clear family history; nonetheless it’s clear that the genetic basis is very strong. There are probably hundreds if not thousands of genes that underlie the risk for breast cancer and of course within and one particular family you’ll seldom get the two individuals who carry all the risk aliorts for those genes and so it won’t necessarily manifest itself in a very strong family history. But through the genome wide association revolution of the last five years or so and through the very large international collaborative projects that were part of, we’ve made enormous progress at identifying those genes which is important both for the long term clinical benefits that might result but also for understanding more about the pathways that underlie predisposition to breast cancer.

Interviewer: And this research also gives you information on how and why and when breast cancers spread throughout the body?

Prof: Chenevix-Trench: Not so much this sort of information. That’s something that we’ve come across from a rather different angle. Because Shaul Karni originally identified BRCA1 related tumors for having a distinctive basil phenotype and because he also noted that brain metastases are much more common in women who have basal breast tumors we really developed our interest in metastases from that and we began by looking at some matched pairs – a very rare collection of matched pairs of primary tumors and brain metastases taken from the same woman and they’re rare of course because people don’t always operate on brain metastases and through some expression analysis of those pairs we were able to implicate a molecule called HER3 which we think plays a role in brain colonization and we’ve also found quite a high frequency of mutations in a gene called EGFR somatic mutations that arise particularly in basal tumors that are likely to metastasize to the brain. So we came to our interest in metastases which will be a big focus of the next five years in a slightly circumtuitous route.

Interviewer: So how in the longer term do you see this research having clinical benefit?

Prof: Chenevix-Trench: Well I think there are two major areas. The first is that the genes that we found through these large consortia to play a role to predisposition to breast cancer individually have a very small role but collectively are probably going to be important in identifying women at risk. They’ll be particularly important in women who already carry a mutation in BRCA1 or BRCA2 because they start with a very high risk because of that mutation and very small additions in that risk because of these additional polymorphisms in other genes can have quite dramatic effects in predicting whether and when a woman might develop breast or ovarian cancer. So I think there’ll be clinical trials starting – I know at least of one that will be starting in Europe in the next year or two using this information to try and predict which women should have more or less mammographic screening for example. So that’s one area – the risk prediction area – and the other is that we hope through a much better understanding of how metastases develop particularly in women who have high grade, high risk, breast cancers that we’ll be able to develop more targeted therapy against brain metastases. This is likely to be combination therapy – it’s very unlikely that a single agent would be effective – but perhaps multiple agents in women with particularly high risk tumors might be able to delay the onset of brain metastases or regress them or at least halt them. We don’t expect again that there’ll be a magic bullet but if we could start to move into some clinical trials that would even allow us to extend life for women with brain metastases slightly then we would be very pleased for the results of the next program.

Interviewer: Professor Georgia Chenevix-Trench thank you for your time today.

Prof: Chenevix-Trench: No problem, thank you.

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