IMPAKT Breast Cancer Conference 2013

Integrating breast cancer genomics and proteomics

Dr Gordon Mills - University of Texas MD Anderson Cancer Center, Houston, USA

Gordon, thanks for coming in today and you’ve actually been giving the keynote lecture here, but I want to ask you about the flagship projects that you’re doing at the moment. You’ve got some projects in triple negative breast cancer at the MD Anderson, can you tell me what’s up your sleeve, what are you launching at the moment?

The MD Anderson Cancer Center has taken a bold and aggressive initiative to really make a difference in terms of outcomes in a series of cancers called our Moon Shot Program. One of those programmes focusses on breast and ovarian cancer and the first moon shot will be to implement a comprehensive programme around abnormalities in BRCA1 and BRCA2. We know today that if patients are tested with triple negative breast cancer or high grade serous ovarian cancer with no known family history, at least 12%, and maybe as many as 15%, of them will have an unexpected germline abnormality. We will then preform an active outreach to their family members, bringing them to MD Anderson for counselling and testing where appropriate and then implementing aggressive screening and prevention. This alone will change the outcome for breast and ovarian cancer in a way we haven’t done before.

Right. How easy is it to do that testing and checking up on what these factors are?

The testing right now is fairly easy, it can be done at a commercial source. The main commercial source right now is Myriad Genetics and, indeed, they are donating testing free for all of these patients as part of this overall programme. And, in addition, they will test all of the family members without charge.

What are the factors you look for?

We’re looking right now very easily for the family in germline inherited abnormalities in BRCA1 and BRCA2. And, at least for the family members, that’s the key test to find those that are at high risk for developing cancer and implement an aggressive prevention programme.

In the prevention programme what are you able to do and how effective is that?

The real effective therapy is surgical. It’s prophylactic surgery to remove ovaries or to remove the breast in the appropriate individual at the right time. We know that that works; that decreases the chance that these individuals will develop cancer by at least 80%. At the same time we’re developing programmes for much less aggressive interventions that we will work with women early on. Things like removing just the tip of the fallopian tube is probably sufficient to prevent what we call ovarian cancer that probably starts in the fallopian tube rather than the ovary. So there are alternatives that work, there are alternatives that are effective and there are alternatives that we talk about pre-therapy, pre-cure, prevention in a way that will decrease the mortality from a disease that we’ve had little impact on otherwise.

And quite apart from prevention you have got some new treatments coming along, haven’t you too?

Yes, not only will patients be tested for germline abnormalities but also for acquired or somatic abnormalities. That will bring the number up to close to 20% of patients without a family history unselected will have an abnormality in BRCA1 or BRCA2. Further, we have a series of assays that look for defects in the function of BRCA1 and 2, or their pathway, not just the genes themselves, which may happen in as many as 50% of triple negative breast cancers and high grade serous ovarian cancers. This is exciting because there are therapies that are emerging and present. These signal sensitivity to drugs like cisplatinum that are already available, or carboplatinum, platinum analogues. But more importantly there’s a series of PARP inhibitors specifically targeting the effects of BRCA1 or 2 or cells that have defects in BRCA1 or 2 functions that are sensitive to these inhibitors and clinical trials are showing remarkable results in patients with abnormalities in BRCA1 and BRCA2.

How much difference to outcomes do you think you might be able to make using, on the one hand, more conventional agents like platinum and also, perhaps, the PARP inhibitors?

Well, if we just start with the fact that you’re preventing cancers, this should be a 5% decrease in mortality off the top and that’s a pretty impressive number. What will happen in terms of long-term outcomes with the use of the PARP inhibitors I think still has to be determined but early studies in BRCA1 and BRCA2 mutant ovarian cancer shows incredible improvements in relative risk for recurrence and overall survival. Where that will go, many in long term, and which patients will benefit, I think, is where we are at now in terms of developing trials and answering those questions.

So one of your flagship programmes involves shooting for the moon, as it were, with the BRCA1 and going for a really big step forwards. But we live in a genomic age, do you see other genetic factors which could also, perhaps, influence the future of breast cancer?

One of the things that we will be doing is implementing an integrated programme in breast and ovarian cancer where every single tumour will be collected, will be tested for what we call actionable genes. All of the genes that appear to be targetable therapeutically affect patient outcomes in a broad and concentrated manner. We will also look in extreme depth at what is going on with these genes to capture heterogeneity. And finally, for every patient that goes on to a clinical trial that has an unusual response, either unusually good or unusually bad, we plan to obtain repeat biopsies and characterise those in depth to ask why that specific patient had the type of outcome that they did. The goal is then to be able to broaden that across all of the patients that we see.

You’re painting a very exciting vision of the future but, of course, most doctors have patients waiting to be seen and, with treatments that are available now, what would you say to doctors at the moment about applying some of these ideas and how much hope they give? Or is there anything that can be applied now?

I think that most of these are in clinical trials. I think that the PARP inhibitors are going to be approved soon, at least in certain circumstances of maintenance for those patients that enter complete response. The other that I think is becoming more and more exciting, even in triple negative breast cancer, is neoadjuvant therapy and characterising what that neoadjuvant therapy has done at the first step and that is by asking whether patients have entered a complete pathological response or not with that therapy, those that do have an incredible outcome, even if they have triple negative breast cancer, normally a bad disease. For those that don’t have complete pathologic remission we don’t have active on-going therapy that is approved, however, these patients probably should be directed to clinical trials almost immediately. Their chance of recurring is extremely high and that’s the population that we’re going to characterise the genetics in so that for each of those patients we will have an idea of what’s next for them. So we are pre-planning or pre-expecting recurrences and making sure that we have all of our information available and ready to go when and if that happens.

So you’re quite hopeful about using neoadjuvant therapy as a means of predicting what happens to patients? How else would you integrate proteomics and genomics into everyday practice, if you were to sum this up for ordinary doctors?

The other that is coming is that we have very good markers not for triple negative breast cancer but for the much more common and, frankly, more people die from luminal breast cancers. Both RNA testing, tests like genomic health, MammaPrint, identify those women that really will do well with just hormonal manipulation alone and don’t need chemotherapy and another group that has high risk and will benefit from chemotherapy up front. There’s a new proteomic marker that we are exploring that will be going into prospective clinical trials probably in the next few months. The retrospective trials are, again, extremely promising in identifying many women who currently would receive chemotherapy because they’re considered high risk who are at sufficiently low risk that chemotherapy isn’t needed up front. So I think the exciting side of luminal breast cancers or the ER-positive breast cancers is less therapy, less toxic therapy, and on the triple negative breast cancer side is really the fact that we have something that works up front, neoadjuvant therapy, and now combined with an active approach for those individuals who don’t achieve a complete response to that chemotherapy, potentially by clinical trials but eventually by approved and effective therapies.

And your bottom line message for busy cancer doctors coming from this meeting here in Brussels would be what?

Is that breast cancer is many different diseases and we must embrace that concept, understand up front whether patients have ER-positive breast cancers with the many different therapies that are appropriate and working, HER2-positive therapy with some really exciting new results with TDM1 and pertuzumab that I think are going to change what was the worst and most aggressive disease or type of breast cancer into potentially one of the best behaved, the best outcomes. And then finally that triple negative breast cancer remains a challenge but we’re making real and significant head roads. Triple negative breast cancer is many different types of cancer and I think the next step is to embrace that concept, split them into different groups, initiate trials for each of those groups. That’s going to require worldwide collaborations because this takes breast cancer, the most common cancer in women, and almost turns it into an orphan disease because each one of these types of breast cancer are different, will not respond to the same type of management or the same type of therapy. So embracing that concept of many different diseases being clustered and clumped as one for many years will improve outcomes.

And one of the places to come to find out about all of this is the MD Anderson.

The MD Anderson Cancer Center really has decided that it is time to ask the question, if a concerted effort, taking the knowledge that we’ve gained from the Cancer Genome Atlas, the International Cancer Genomics Consortia, multitudes of biological and biochemical studies and putting that together into a concerted effort will make a difference rapidly and effectively.

Gordon, you’ve made a difference rapidly and effectively to our thinking. Thank you very much indeed.

Thank you.