Today I talked about neoadjuvant hormone therapy as a way to treat luminal type breast cancer in the early stage setting in a session that was really focused on a variety of different areas important to neoadjuvant therapy for breast cancer.

What were some of the main outcomes from this session?

Actually some of the talk I modelled after some of the points that my colleague Ingrid Mayer made at San Antonio when she gave a plenary talk about neoadjuvant endocrine therapy. The very interesting things that we’ve learned about neoadjuvant endocrine therapy, starting from the easiest, is that you can improve the rates of breast conserving surgery if you treat an endocrine responsive type tumour. Most of the studies were done in postmenopausal women, if not all. But there’s so much more to neoadjuvant endocrine therapy. What we’ve understood when we gave chemotherapy to everybody, so one size fits all as neoadjuvant therapy, is that the patients who had very low proliferative hormone receptor positive disease that people refer to as luminal A like, those patients didn’t have high rates of pCR, in fact overall they were less than 5%. But then the interesting thing about these patients is that the lack of pCR didn’t translate into a worse outcome as it does with triple negative disease, more proliferative hormone receptor positive disease and HER2 positive disease. So in this subgroup of tumours which represent a large subset of breast cancer, particularly in older women, what we saw was that the failure to achieve a pCR didn’t correlate with outcome.

So then if you look a little bit further into this field you find that what we’ve discovered are several things. One is that there are some early biologic markers of endocrine sensitivity – one is a fall in Ki67 – and some of the studies have used a definition in fall of Ki67, a marker of proliferation, to less than 2% or 2.7% and termed that complete cell cycle arrest. It turns out that tumours that actually drop their Ki67 and at the time of surgery, based on the score that Matt Ellis developed called the PEPI score, have actually less positive nodes, low Ki67 and very strong hormone receptors, that those patients have a very good outcome based on this PEPI score that’s very much weighted on these biologic as well as pathologic features.

So that’s one really important area of trying to figure out whether hormone therapy is working. And because we know the features of the cancer, including proliferation at the time of surgery, help to determine outcome, it means that not just getting more breast conserving surgery but you could also reduce the number of women who need chemotherapy simply based on the amount of tumour they have at the time of diagnosis. So that also personalises therapy and reduces toxicity.

Then a third area is really if you could figure out if one therapy is better than another by looking at these short-term endpoints. So Ki67 has now been used to try and evaluate whether adding treatment x to a hormone treatment, a targeted therapy, is better than just giving the hormone therapy alone. What’s interesting is the drop in Ki67, if it’s a big drop, has actually correlated where response doesn’t with studies that are positive in the metastatic setting or in the adjuvant setting even. Very interesting. So it’s a very interesting way to look at the addition of targeted agents or different treatments compared to the standard to see whether or not they’re better because then you could take that information and put it into a registration style phase III trial either in the early or late stage setting.

So a number of studies have been done adding CDK4/6 inhibitors most recently and showing a drop in Ki67 but no difference in response. So, current studies are really looking at longer durations of the combination therapy to see whether or not we can really change response and, of course, in the long term change outcome in those patients. So now you have all sorts of reasons why neoadjuvant endocrine therapy could be helpful for a patient and for drug development as well. The next thing is really being sure that people are comfortable with the treatment, understand that a longer duration corresponds with better response and better chance of pCR in endocrine responsive disease and then understanding how to identify those patients. It may be that gene expression tests are going to be used even more in the future to try and identify those patients and we certainly use those now in the clinic.

Do you have any predictions about changes in the clinical landscape in the near future?

What I’d really like to see may or may not happen but what I’d like to see is that this is a way for us to further evaluate new targeted agents added to endocrine therapy without using the endpoint of pCR like we use for chemotherapy based regimens where we add a targeted agent but instead using the endpoint of a change in biologic characteristics or drop in Ki67 and/or the PEPI score. There’s one randomised study going on run by Cynthia Ma within the co-operative group that is looking in the neoadjuvant setting at the Ki67, taking patients off who have an early failure to drop Ki67 and giving them chemotherapy and then continuing to follow the ones that drop through until their surgery and using the PEPI score to then determine postoperative therapy. I think that that trial will be a model for the basis of which we can use to study novel agents moving forward.

Any additional thoughts on the conference?

I think it’s a fabulous conference. There’s a tremendous amount of material presented which means that the conference is really packed but there’s a lot of opportunity for conversation during the events that bring everybody together which is nice and in the breaks as well. The coverage is quite broad and complete; there is a nice mix of people from the region as well as from further international speakers like myself. The conference not only helps tremendously with education and brings the most current data to the population who may not be able to travel to all of the meetings all over the world or read every single paper but also applies it clinically and fosters collaboration for the future with the larger Middle Eastern region and the international community of breast cancer doctors.