The 2012 CTRC-AACR San Antonio Breast Cancer Symposium, 4-8 December

Validation of genomic grade index histological grading in invasive breast cancer

Professor Christos Sotiriou – Jules Bordet Institute, Brussels, Belgium

It’s about the genomic grade index, which is a signature that aims to better characterise histological grade in breast cancer that we have developed in 2006. So this presentation is the clinical validation of that signature but not based on microarray experiments but based on an RT-PCR or they can use it from using paraffin and better fixed material to this end. So we clinically validated the performance of that PCR based assay using material from the BIG-1-98 trial and patients enrolled in the monotherapy arms, either Tamoxifen or letrozole. The signature was developed in the beginning to better characterise the histological grading, particularly for grade 2 which for those particular patients is the grey zone for grading. So we know, for example, that grade 1 patients do very, very well; grade 3 patients do poor, badly, where the grade 2 patients which have this intermediate grade we don’t know how, they have intermediate behaviour and we don’t know how we have to treat them. So the idea of that signature is that you apply that signature for those histological grade 2 tumours and then you can split them either in patients that resemble grade 1 or grade 3. So another way to say it is that we try to improve this grey zone of histological grading by applying this signature.

The problem with that signature is that in 2006 when we developed that it was developed based on frozen material so we had to use a microarray experiment which is not something that we can use in routine clinical practice. So that’s why the idea was to transfer this microarray based signature to an RT-PCR based signature. This we have done a year ago that we have presented in the same meeting in San Antonio and then this year in San Antonio we wanted to clinically validate the performance of that assay in the BIG-1-98 study.

So what we found is that basically we found that almost 40% of the patients having the genomic grade 1 signature, so the signature that resembles histological grade 1 patients, they have an excellent ten years distant relapse free interval. So, for example, 99% of these patients are distant recurrence free after ten years of follow up, which is really excellent. So the idea is that by applying the signature to ER positive, node negative endocrine altered patients, if they have this good profile we may avoid giving chemotherapy because they have an excellent outcome with endocrine therapy alone.

Could the implications be a difference in therapies?

The implication is that particularly for grade 2 patients that we don’t know how to treat them, if we have to give chemo or not, so you can apply the signature and in those patients that have the good profile you might actually suggest not giving chemotherapy whereas for those patients that have the poor, bad profile of that signature then you should definitely recommend chemotherapy. So I think it’s good for patients because, as I said before, for the histological grade 2 patients we don’t know how to treat them because they have this intermediate outcome. So for those particular patients and for those with node negative disease, if you apply that we can actually clearly identify the patient that may actually do very, very, very well with endocrine therapy alone and from that patients that you might actually need to suggest chemotherapy.

In that particular study also we compared another proliferation marker, which is the Ki67, and actually we found that Ki67 performed very well as well, actually, as the signature. The only difference is that the Ki67 in the BIG-1-98 trial was centrally reviewed by a very, very good pathologist which is unfortunately not the case for everyday clinical practice. So the message is that if you have a good pathologist Ki67 is as good as the signature but we know that in real life unfortunately Ki67 isn’t that reliable and then this signature may help to better identify the patients that may need, or not, chemotherapy.

After my presentation there was a whole session about Ki67 issues looking at the possibility, the clinical,analytical issues and other issues. This is the problem with Ki67, it’s a rough marker of proliferation so you lose the quantification that you may have with a gene signature such as, for example, the genomic grade index that we have defined.