In the recent article published by our German colleagues, von Minckwitz et al. (J Clin Oncol 2012) elegantly present the impact of pCR on the outcome of 6,377 patients enrolled in seven randomised trials of NAC (anthracycline-taxane-based), with a median follow-up of 46.3 months (range 0-127 months), 1,466 relapses (23%) and 775 deaths (12.2%). In this individual patients-based pooled analysis, the authors described the impact of pCR according to different breast cancer subtypes, but most importantly, the authors provide a definition of pCR, which seems to be the best to be used in future trials: pCR defined as no invasive and no in situ residuals in breast and nodes (ypT0ypN0).
In this study, the patient’s median age was 50.1 years (range 21-81 years), median tumour size was 4.0 cm (range 1.2-33 cm), oestrogen receptor (ER) positive was identified in 3,771 (62.4%), and HER2 negative in 3,060 (69.8%). Patients with ypT0ypN0 tumours experienced better DFS compared to patients with ypTisypN0 (presence of no invasive tumour) (HR 1.74; 95% CI 1.28-2.36, p<.001). HR for DFS and OS comparing patients achieving or not achieving pCR and according to different pCR definitions used, were higher for ypT0ypN0 (DFS HR 4.04, 95% CI 3.07-5.31; OS HR 7.39, 95% CI 4.45-12.3, respectively). Important to highlight is the fact that pCR was predictive for neither DSF nor OS in low proliferation subgroups such as lobular type, grade 1, and positive ER or PgR status, but predictive in ductal, grade 2-3 tumours and negative ER or PgR status. This is particularly important for highly aggressive tumour subtypes such as HER2 positive (non-luminal) and triple negative, where a significant prognostic value of pCR was demonstrated. Unfortunately, neither central assessment of surgical specimens nor Ki-67 tumour cell proliferation indices was available and, therefore, some imprecise categorisation of breast cancer subtypes may have occurred.
These findings corroborate with other published data also showing that patients with HER2 positive or triple negative breast cancers achieving pCR after NAC have a much better prognosis compared to their counterparts not achieving it. This is something to consider when designing future neoadjuvant trials with chemotherapy: who are the patients that should be included in those? For the moment, most of the evidence seems to lead toward the inclusion of patients with high proliferative features, particularly HER2 positive and triple negative tumours. One important point to discuss is that future research should also focus on patients not achieving pCR. Translational research should focus on residual disease in such patients and should try to better understand the mechanisms by which patients do not respond to NAC rather than looking for only those responding. Another important feature may be the inclusion of functional imaging such as PET-CT scan in the future trials. Some trials have showed that achieving metabolic complete response after 2 weeks of therapy may be correlated with pCR at surgery. If this approach is confirmed in future trials, the identification of patients most likely to achieve pCR could be done very early in the treatment, avoiding unnecessary therapies (and side-effects) to those patients who are not likely to respond to a given agent (or combination).
In summary, this article highlights the importance of a good definition of pCR in patients with breast cancer receiving NAC, but also enforces previous findings that pCR is correlated with outcomes in these patients. Moreover, not all patients (all comers) will benefit from NAC and the decision should be based on tumour biology, patients’ characteristics and desire, and discussion in a multidisciplinary team. Important, future neoadjuvant trials should use a common definition of pCR and should also focus on understanding those patients with residual disease after NAC. The identification of patients likely to achieve pCR after few weeks of therapy with the use of molecular imaging should also be sought through. This is the only way towards personalised medicine in the 21st century and to indirectly reward all women who were brave enough to participate in past clinical trials, helping the progress we have made in breast cancer research over the past years.