Yesterday I made a presentation on the treatment of HER2 positive early breast cancer patients. These patients have now a relatively good prognosis because of availability of trastuzumab, an anti-HER2 antibody, given concomitantly with chemotherapy. We do have now new anti-HER2 treatments which can be added to trastuzumab so the question is when is it necessary to increase the burden, the treatment, for those patients who are still at high risk of relapse and is it possible to decrease, on the other side, the burden of treatment for those patients who still have a very good chance of being cured with available therapies.

So my talk was focussed specifically on two trials which have shown that the addition of two other anti-HER2 treatments, either neratinib, a tyrosine kinase inhibitor, or pertuzumab, another anti-HER2 monoclonal antibody. Both of these trials have shown that there is a statistically significant improvement in disease free survival in comparison to the classic treatment consisting of trastuzumab for one year plus chemotherapy. But unfortunately in both trials the percentage of patients who actually benefitted from the addition of the new anti-HER2 treatment was relatively low. So you treat a lot of patients to benefit the few and, of course, you induce additional toxicities, especially diarrhoea with neratinib and to a lesser extent also with pertuzumab and even slightly more increasing the incidence of cardiac events. So it will be necessary to define more precisely who are the patients who actually need more. We do have data to identify these patients – from the neratinib trial it is clear that the patients with a hormone receptor positive tumour benefitted more by the addition of neratinib in comparison to those patients with hormone receptor negative disease. So the first message is patients with high tumour burden, node positive disease, and hormone receptor positive disease might be considered for additional treatment with neratinib in addition to trastuzumab and chemotherapy.

From the APHINITY trial also we do have some data indicating that the patients with again node positive disease and, on the opposite, those with hormone receptor negative disease might derive a greater benefit from the addition of pertuzumab. So here again we can define a patient population, those with node positive disease and those with hormone receptor negative disease, where the addition of pertuzumab might be of value.

On the other side we do know that fortunately the vast majority of these patients nowadays are cured by chemo and trastuzumab given for one year and we also know that unfortunately a proportion of these patients might experience unpleasant side effects, particularly cardiac toxicity. So is it possible for at least some of these patients to reduce the burden of treatment? There are trials which have explored the possibility to reduce the chemotherapy burden by avoiding especially anthracyclines which are the most toxic component of the chemotherapy regimens. These trials do demonstrate that it is possible to avoid anthracyclines and still maintain a very good disease free survival by giving a no anthracycline containing chemotherapy regimen plus one year of trastuzumab.

There are also trials which explore the possibility to reduce the duration of exposure to trastuzumab by giving trastuzumab either for six months instead of the classic one year administration, or even shorter treatment periods such as nine weeks. There are five randomised trials, relatively large randomised trials, of course these trials have been designed as non-inferiority trials and it’s highly difficult to demonstrate non-inferiority. In fact, four out of the five trials have not been able to demonstrate non-inferiority with shorter trastuzumab administration versus one year trastuzumab. Only one trial, a trial from the UK, the PERSEPHONE trial comparing six months versus one year of trastuzumab has been able to show statistically that six months is not inferior to one year. But overall all these trials have clearly shown that there are subgroups of patients with a lower risk of relapse which means patients with smaller tumour size and node negativity where there is essentially no difference at all by giving one year or shorter treatment durations. On the other side there is a significant reduction in the risk of cardiac events.

So the key message is that we now know that for low risk patients if there are some cardiac risk factors, either baseline or during the administration of trastuzumab, you can safely stop the administration of trastuzumab without compromising the efficacy of the treatment. This message is also important for those patients living in countries with limited resources, there are a lot of patients unfortunately worldwide who do not have access to trastuzumab because of financial constraints, so for these patients it’s a good message the fact that you can give shorter, so cheaper, trastuzumab administration with still very good clinical results.