Crown Princess Mary Cancer Centre, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
Thanks to careful, persistent research, the outlook for women diagnosed with early HER2 positive breast cancer has improved markedly over the last two decades. The evolution of HER2-targeted treatments has been a game changer, and the pathology report that reads “HER2 amplified” is not as dreaded as it once was. Clinical trials have proven the safety and effectiveness of adjuvant trastuzumab, and longer term follow-up has been reassuring. However, now is a good time to reflect on these achievements and ask ourselves two questions: how can we do better, and can some patients get by with less treatment?
The development of trastuzumab as treatment for HER2 positive early breast cancer has been a triumph of post-enlightenment rationalism.1 From the demonstration that HER2 amplification conferred a poor prognosis, to developing an antibody to this receptor, to showing the effectiveness of this antibody in cell culture and mouse models, we came to testing trastuzumab in humans with metastatic breast cancer.
There we learnt useful lessons. There was unexpected cardiac toxicity, and the drug wasn’t very active in the absence of chemotherapy, but was very active in combination with a number of different chemotherapy types. Thus armed with useful knowledge and experience, we tested in the adjuvant setting with spectacular results.
Long term follow-up has been reassuring – this is a drug with low toxicity and sustained efficacy, even though it is combined with anthracycline and taxane chemotherapy.2 An 85% 10 year overall survival for a disease that was previously of poor prognosis is quite remarkable, and the outlook of many of our patients with lower risk than those in the trials must be even better. All the adjuvant trials were restricted to node positive or high risk early breast cancer, whereas we frequently see women with node negative disease and small tumours. This begs two clinically relevant questions: is there much room for improvement? And can we de-escalate?
Of course, we would always like to improve and we will soon see if the addition of adjuvant pertuzumab (as tested in the APHINITY trial – clinicaltrials.gov identifier NCT01358877) improves disease free survival. It would be surprising if it didn’t, but then we had a similar perspective about the addition of lapatinib, and the combination of lapatinib and trastuzumab did not materially improve outcomes.3 If pertuzumab does improve disease free survival, then the question will be by how much, because this is a very expensive drug, and very modest benefits may not be cost-effective.
In addition, we have a number of anti-HER2 drugs that are active in the metastatic setting, and because of cost each such drug cannot be tested in multi-thousand patient adjuvant trials. In the recent past, new drugs or combinations have been tested in the neoadjuvant setting to save time and money. However we have the unresolved problem of whether success there necessarily predicts for long term outcomes. This is a complex issue, but it remains unclear whether, just because a drug shrinks a primary tumour better than another drug it necessary follows that long term survival is better.4
The answer may be twofold. First in understanding HER2 biology better, we should be able to predict those who will do especially well with additional anti-HER2 therapies (or to paraphrase, will do badly if given chemotherapy and trastuzumab alone). Second, in the absence of persuasive biological reasoning, we may need to test these drugs in smaller cohorts of higher risk patients, and restrict use to such subgroups.
This raises the issue of de-escalation. Many of the patients we now treat with six months of chemotherapy and a year of trastuzumab would not have even been eligible for the adjuvant trials, as they often have small node negative tumours. It’s therefore likely that we are over-treating some of them. However proving that is probably not possible, and it’s a brave oncologist who ‘under-treats’ in today’s environment. But progress can and needs to be made.
Duration doesn’t seem to be the answer, at least with current biological understanding taken into account. With reference to all HER2 positive patients, two years of trastuzumab is not better than one,5 and it seems that six months is not quite as good as one year. However it appears extremely unlikely that the entirely empirical one year of treatment just happens to coincide with the biologically correct duration. The more reasonable explanation is that increased biological understanding is required as to which patients do not require therapy, which patients can be treated for only three months and which patients need longer treatment and more drugs.
Very helpful additional knowledge came from the study reported by Tolaney et al.6 Recognising that a randomised trial of trastuzumab versus not in women with small tumours would not be achievable, they devised a ‘shortcut’ treatment to test in a single arm trial. Women with node negative, small tumours (about half were less than 10mm) could elect to be treated with weekly paclitaxel and one year of trastuzumab, thus avoiding the toxicity and inconvenience of three months of anthracycline chemotherapy.
Over 400 women were accrued, and at an average four years’ follow-up there were only 12 events, and only two of these were distant recurrences. Obviously longer term follow-up would be reassuring, but it is not possible to immediately improve on present knowledge. Thus, although these patients may not have needed any treatment at all, they have at least avoided anthracyclines and had a shorter time on chemotherapy.
We therefore have a reasonably evidence-based de-escalation strategy to use, and indeed this regimen could always serve as a comparator arm in a randomised trial (perhaps compared to six months of trastuzumab), although the low event rate will always be a challenge.
Taking all relevant findings into account, much has been achieved in the adjuvant treatment of early breast cancer, although there is the natural desire to improve. As long as we deal with HER2 positive disease as a mono-identity however, logistics will make it difficult to test new agents in the adjuvant setting. There is an urgent need to understand HER2 biology more comprehensively so that we can more accurately identify those patients who would most benefit from the new drugs being tested and used in metastatic disease (as outlined in the next chapter), and those who need very little if any treatment.