Neoadjuvant chemotherapy studies have firmly established that response, and particularly pCR, is a strong predictor of survival in breast cancer patients. However, in the subset of patients with ER+ HER2− disease treated with chemotherapy, pCR has limited value, as these patients often do well despite the absence of pCR because of effective adjuvant endocrine therapy (Buchholz et al, 2001
). Pathological CR is very uncommon in response to neoadjuvant endocrine therapy. In three relatively large studies with letrozole, the pCR rate was no more than 1% (Eiermann et al, 2001
; Baselga et al, 2009
; Olson et al, 2009
). Although residual cancer burden after neoadjuvant chemotherapy has been shown to predict distant relapse-free survival (Symmans et al, 2007
), the application of this measure to patients who underwent neoadjuvant endocrine therapy remains to be evaluated. To identify alternative post-treatment factors that predict breast cancer survival after neoadjuvant endocrine therapy, Dowsett et al (2007)
examined Ki67 expression before and after 2 weeks of endocrine therapy. Patients with higher Ki67 expression after 2 weeks of endocrine therapy had a significantly lower recurrence-free survival (Dowsett et al, 2007
). In a multivariable analysis conducted on the P024 trial (Ellis et al, 2008a
), four factors were determined to have independent prognostic value for relapse and death after relapse. These included pathological tumour size (T1/2 vs
T3/4), pathological node status (positive or negative) and two biomarkers in the surgical resection specimen, the natural logarithm of the Ki67 value and the ER status of the tumour. A prognostic score, the preoperative endocrine prognostic index (PEPI), was developed, which weighs each of these factors according to their associated hazard ratios (). The PEPI was then validated in an independent dataset from the IMPACT trial (Ellis et al, 2008a
). No relapses were recorded in either trial in patients with T1, N0 tumours with a PEPI score of 0 (residual tumour with Ki67 index of 2.7% – natural logarithm of 1 – or less with maintained ER expression) or in the rare patient with a pCR. These patients are not likely to benefit from adjuvant chemotherapy as endocrine therapy alone appears to adequately control their disease. These results supported an amendment to the Z1031 trial (Cohort B), in which chemotherapy was not recommended to patients in the pathological stage 1/0 PEPI 0 category. The acceptability of this advice will be assessed to see if this approach can be made a protocol mandate in the next phase of clinical trial development. In addition, patients with a high Ki67 proliferation index in a 2- to 4-week biopsy (>10%) are triaged to neoadjuvant chemotherapy or immediate surgery, as these tumours are exhibiting primary endocrine therapy resistance (Dowsett et al, 2007
). To determine the chemotherapy responsiveness of this group, the rate of pCR with neoadjuvant chemotherapy in the high on-treatment Ki67 group will be determined (). If this approach to tailoring neoadjuvant endocrine therapy is feasible, a larger, more definitive study will be considered.
Schema for ACOSOG trial Z1031 Cohort B.