I had the opportunity at ASCO 2018 to talk about the escalation and escalation of therapy in patients with HER2 positive breast cancer in the adjuvant setting. In the session we reviewed some clinical aspects of patients with early stage breast cancer that is HER2 positive, emphasising all the advances that we’ve made in the last decade improving the outcomes of these patients, highlighting the importance of trastuzumab as a key component in the treatment of our patients.
Something that we’re facing as a challenge right now is a group of patients that despite these great therapies still relapse and that forces us to try to optimise our regimens and try to identify the patients that we can escalate in treatment and separate them from those that we can de-escalate therapies. So in this talk it was really dividing the strategies to escalate therapy and the strategies to de-escalate.
The key strategy, right now, to escalate treatment is adding new molecules. Today we have access to two new drugs that have been approved by the FDA in the last year – pertuzumab and neratinib. Pertuzumab is a humanised monoclonal antibody that has shown incredible success and great efficacy in the metastatic setting. The APHINITY trial, a large adjuvant trial that evaluated the role of pertuzumab in this patient population showed at four years an increase in disease free survival of 1.7% and that led to the approval of pertuzumab in the adjuvant setting.
Neratinib is an oral molecule, easy administration, it’s a tyrosine kinase inhibitor. This molecule has actually moderate activity in the metastatic setting. In early stage breast cancer it was evaluated in the ExteNET clinical trial. Patients that had completed trastuzumab based chemotherapy were then randomised to receive this molecule or placebo. What this trial demonstrated was about a 2.3% improvement in disease free survival. This drug also got approved by the FDA.
So in both cases these drugs are now available but as clinicians we are facing the challenge of identifying who are the patients that benefit from these drugs since the improvements in outcomes are relatively small. We still don’t have mature data in terms of overall survival so we’re very likely going to start using these drugs in patients that are high risk. The ASCO adjuvant guidelines for management of patients with breast cancers were updated last week, I invite you all to read this document. I had the privilege to be part of this panel and the recommendation from the ASCO guideline panel was that we may use these molecules in patients that are high risk, of course encouraging clinicians to engage in a shared decision-making process. These drugs make, indeed, treatments more complex, make them longer, it makes them more expensive and more toxic since these molecules are associated with important toxicities, particularly neratinib. In the PIVOTAL clinical trial it was associated with important rates of diarrhoea.
So that’s one strategy that we have. Another strategy is to try to identify patients that are higher risk, meaning those that have residual disease after neoadjuvant chemotherapy, and there are clinical trials ongoing targeting this population.
Talking briefly about de-escalation of care, one of the groups where we can really evaluate this approach is those patients that tend to have better outcomes and therefore we may not need to give them very toxic regimens. So we’re trying to identify regimens that are less toxic. Right now it’s standard practice in patients with node negative tumours to use combinations like weekly paclitaxel in combination with trastuzumab. Trastuzumab as suggested by the APT trial led by the Dana Farber group. We are looking into less toxic regimens, for example evaluating the role of TDM-1 in this patient population.
Another very relevant question in terms of de-escalation of care is the duration of trastuzumab-based therapy. Traditionally we’ve used one year of adjuvant trastuzumab in these patients but the question of duration continues to be relevant. There’s going to be data presented at this meeting that is going to be key to maybe identifying patients that could benefit or could have equivalent outcomes with shorter regimes. The question of duration is going to be particularly relevant in the future as we have the doublet agents. Maybe if we have two agents we can do shorter regimens. So it’s an area that is evolving rapidly, the algorithms are going to continue to change. We hopefully will have effective and practical biomarkers in the future to identify the patients that need more treatment so that way we can give them the therapies that they need and spare the toxicities to other patients. Hopefully we’re going to truly engage our patients in a shared decision-making process so that we can inform them of the benefits that sometimes can be minimal and the sometimes not too minimal side effects but again, hopefully, with the end goal of improving our patients’ outcomes.