Advances in breast cancer research from ASCO 2011

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Published: 20 Jun 2011
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Dr David Miles - Mount Vernon Hospital, London, UK
Dr David Miles outlines his highlights from the 2011 ASCO congress. The first of these is a trial demonstrating that adding regional nodal irradiation to whole-breast irradiation significantly improves disease-free survival in women with node-positive or high-risk node-negative breast cancer treated with breast-conserving surgery and adjuvant therapy. A second key study from the 2011 meeting revealed that in postmenopausal women who are at increased risk of developing breast cancer, chemoprevention with the aromatase inhibitor exemestane reduces risk by 65 percent compared with placebo. Dr Miles concludes by discussing chemoprevention research that has not produced the data that had been expected and talking about some recent developments in the role of bevacizumab.

ASCO 2011 Annual Meeting, June 3-7 2011, Chicago

Advances in breast cancer research from ASCO 2011

Dr David Miles – Mount Vernon Hospital, London, UK

 

What are the things, the beacons of light, that have popped out for you in the various sessions, particularly breast, which of course you’re the big expert in?

Whether I’m the big expert or not, I’m not completely sure, Gordon.

That’s my line.

I’ve been to the majority of the breast sessions and I think it’s fair to say that in some ways ASCO 2011 has been about struggling new technology and, to some extent, establishment of old technology and the utility of it. So in many respects perhaps the highlights for me are more in terms of radiation oncology, about which I know very little, and, of course, the concept of chemoprevention. So in an era of molecular targeted therapies and gene expression arrays and the rest of it, actually it’s the Canadians who come riding over the hill with clinical studies which are potentially practice changing, using what we might call relatively old technology. So, for example, Tim Whelan presented this morning on the contribution of regional nodal irradiation in addition to the breast irradiation that, of course, we use for breast conserving therapy. A lot of background on this, as you know of course, in the European arena suggesting a potential benefit but doing a study there of around nearly 2,000 patients where extending the field of radiotherapy to include internal mammary nodes, apex of the axilla SCF.

Ipsilateral internal mammary?

Correct. So using these extended fields has yielded, not only, as predicted, improvement in local recurrence, but actually improvement in distant recurrence. And actually, unlike the mantra that we get from the early breast cancer trial, this overview about one life saved per four local recurrences, actually at a relatively short follow-up they are already seeing a trend towards overall survival for which the study was originally powered. This is a study done in the context of patients who are having modern adjuvant systemic therapy, so 90% of patients having chemo, appropriate endocrine treatment, aromatase inhibitors etc. So seeing real benefits there even as early as five years where conventionally when we look at the Lancet overview articles as they come out on a quinquennial basis, we expect to see these survival effects much, much later. So I think it wasn’t potentially a result that Tim Whelan was expecting but it’s potentially practice changing.

But it’s a good result and it’s an interesting result. Tell me, just clarify for me please, David, the status of the axilla in these patients. What was the entry criteria? Sentinel node? They presumably had not had a lymph node dissection for clearness.

They were patients who could be up to three nodes affected. 

That’s an interesting result because that’s a common group of patients.

Yes, and in many respects one gathered that the IDNC for this study had called a slightly altered analysis because increasingly, in the UK for example, post-mastectomy we’re looking at radiotherapy more for the one to three node positive group. There is clearly the SUPREMO trial going on but the feeling is that this is the way that we need to move and in many respects this is another bit of evidence in that respect.

A good study then. And anything more from the Canadians?

No, as I was just implying, Paul Goss, king of aromatase inhibitors, obviously now in Boston, but looking at chemoprevention using exemestane. Obviously we’ve got the tamoxifen prevention studies licensed in the US; concerns, obviously, about venous thrombosis, secondary effects on the endometrium, hence this MAP.3 exemestane study really showing something. So this is obviously in post-menopausal women, patients being selected by increasing age being a factor, Gail score being a factor, but showing really a 65% reduction in the risk of development of a new primary breast cancer.

Contralateral?

This is chemoprevention, this is patients with no established disease.

So this is not your adjuvant exemestane?

No, this is…

What’s the exemestane study around? There’s quite a bit of aromatase inhibitors data on the contralateral.

As with tamoxifen…

So a 65% reduction?

In risk of development of a new breast cancer. Now obviously the numbers that are developing are relatively small so in terms of a number needed to treat calculation it’s speculated that, say, for one prevented over a five year period then you’re treating around 26 patients. What was interesting, and such is the information technology these days, is that when that, as he was presenting it, it was being published on line in The New England Journal together with Nancy Davison doing an editorial which he also quoted in his talk. So the key point here, the message, if you like, is what are we waiting for? If these preventative trials are so good then what are we waiting for? We’ve got IBIS-II coming down the track, again with another aromatase inhibitor. So this is potentially practice changing but what we’ve failed to take into account perhaps, and of course Paul Goss was presenting the data on toxicity and, inevitably, with the AIs you have total body pain, you have the arthralgias, you have the sexual problems that these women experience. And I think we’ve got to try to come to terms with that or help our patients to come to terms with that if this is going to be a really serious prospect. But it ought to be practice changes when you look at the numbers but I think the reality may be somewhat different.

And the uptake of tamoxifen, which is the only drug that’s ever been approved by the FDA for chemoprevention, is 5%, so there’s a lot more to be done down the line. Any other chemopreventive drugs? I’ve heard rumours about there might be a PARP that might be safe enough to use in BRCA1 or 2 mutated women. That’s interesting.

Well we can come on to the PARPs in a minute. My concern about the PARPs is that if you’re inhibiting some element of DNA repair then what is the potential for second malignancies? So just moving it on from old technologies like radiotherapy and endocrine treatment then we all knew from a press release earlier on in the year that the PARP inhibitor, iniparib, and again that was presented this morning, that was presented by Joyce O’Shaughnessy, as we know, that was on the back of a randomised phase II presented at ASCO this time last year with a great hue and cry, with a fantastic overall survival result for patients with metastatic disease; published in The New England Journal at the beginning of the year and then a month or two later all we get so far is a press release saying the confirmatory phase III trial hasn’t reached its endpoints. So the first chance for most of us to actually look at the data today and try and understand what’s going on here. The interesting point is that here we have this agent, iniparib, which is really now being described as an investigational agent. In fact, none other than Hilary Calvert has been telling us for some years that some of these drugs aren’t PARP inhibitors and we’ve got the Alan Ashworths of this world just standing there saying, it’s too small to be a PARP inhibitor. So really drawing back on this whole thing, so we heard, really, today that in toto really the trial is negative, interestingly there’s still the suggestion that in subsequent lines of therapy, second and third line, you’re seeing a similar effect. One of the aspects of it that I hadn’t realised was going to be presented but which was actually also quite useful, and that’s my comments about us catching up with this technology, is that although Joyce was presenting a group of patients thought to be, if you will, triple negative then what they did was to go back and look at some of these patients by gene expression array and find out actually, yes, some were the basal type but actually there were many luminal As, luminal Bs and HER2 types in there as well. So our understanding, our so-called targeting of this stuff, is not where it needs to be to ask more intelligent questions about these smarter agents that we’ve got coming through. We’re still really looking at patients by the criteria that we’ve had for decades and decades.

The St Gallen line is going to change that, I hope, and start addressing in public the fact that we’re looking at far more diseases than we actually believed. And the more sophisticated the technology the more subsets we’re going to have to deal with. But, on the other hand, it’s then up to the drug developers to take each of these subsets and go for them. If we have the sort of results that we’re getting with the ARC3 in lung and BRAF for the melanoma, where we started, that’s going to be quite optimistic. 

But it’s the preparedness then and I was overlooking somebody reading The New York Times, or one of the financial papers, saying actually this is going to present its own challenges in terms of the diagnostics for sure, and also in terms of pharma development. Because plucking out 4% with an ALK change in lung cancer is going to mean screening thousands and thousands to do your clinical trials. So we have to really rethink, we may have to rethink the development in its entirety.

Any other technology presented that you liked? Any imaging?

Imaging – did I catch up with any imaging? 

I haven’t seen any imaging but I just wondered if you had.

I don’t think I saw any imaging, I walked past a poster on PET standard uptake values and thought oh no, not again. No, I guess I’m just concentrating in therapeutic terms, really. Some good stuff from Frankie Holmes, from the Italian group, on dual blockade of HER2, actually dual blockade of HER2 without chemotherapy, with Jenny Chang, in a neoadjuvant setting with a very respectable looking path CR (?). But in many ways mentioning this stuff because I think much of what is exciting in breast this year is probably going to come out of San Antonio, really, in terms of the CLEOPATRA trial and tryphena (?) studies and Averil (?) studies with bevacizumab, for example. So that’s more a lead in to what might be happening later on in the year. The bevacizumab story, of course, deeply close to my heart; interesting data there because the German group had looked to the neoadjuvant setting and had passed out a group of patients triple negative who seemed to derive more benefit from bevacizumab and then Harry Bear comes along from NSABP looking at the B40 study, this was a study looking at the contribution of antimetabolites, didn’t do very much, versus the addition of bevacizumab which actually did improve the path CR rate overall, unlike the GBG study. But interestingly for the NSABP that was in the hormone receptor positive group. So you got two bits of information directly conflicting, so not completely clear. Again I think with bev, the technology is lagging behind the agent in some ways, we’ve completely failed to understand.

No biomarker that matters, have we?

Funny you should say that, but I think we do, I think we presented some data at San Antonio last year, again too late for this year but I think there is a way forward here and I think that we will be looking towards commitment studies with bevacizumab in breast. So I’m hoping. The interesting thing, as you know Gordon, we’re in a situation now where the FDA are not smiling on bevacizumab and actually the EMA have smiled on bevacizumab. My view, I’m clearly hugely biased, but I think that if we throw this agent away that’s going to be a bit of a mistake but we have to get our understanding a lot better and develop these things more intelligently and not like cytotoxics which is what we always do.

Just not quite like cytotoxics, that’s a good bottom line to finish on. David, thank you so much for your overview, very wise, very critical and quite constructive too. I really appreciate it, fantastic.

Not at all, thanks very much.