Neoadjuvant endocrine therapy: clinical and biological issues
- IE Smith1
© BioMed Central Ltd 2007
Received: 23 May 2007
Published: 19 June 2007
Neoadjuvant endocrine therapy is being increasingly used with two aims: to downstage cancers and reduce the need for mastectomy; and to establish short-term clinical and/or biological surrogate endpoints predicting for long-term outcome.
The results of key randomised trials addressing these issues are reviewed.
In the P24 trial for patients not suitable for conservative surgery, neoadjuvant letrozole was shown to achieve a significantly greater clinical overall response rate than tamoxifen (56% versus 36%, P < 0.001) and a significantly better incidence of breast-conserving surgery (45% versus 35%, P = 0.02). In the IMPACT trial, neoadjuvant anastrozole was compared with tamoxifen and the combination (three arms, equivalent to adjuvant ATAC). No significant difference in clinical overall response was seen between the three arms although breast-conserving surgery was considered feasibly significantly more often with anastrozole (46%) than with tamoxifen (22%) or with the combination (26%) (P = 0.03). In the PROACT trial, neoadjuvant anastrozole achieved a higher clinical overall response rate than tamoxifen (50% versus 40%) but this difference was not significant (in the endocrine therapy alone group – excluding patients also treated with chemotherapy). Breast-conserving surgery was achieved significantly more often with anastrozole (43% versus 31%, P = 0.04).
The optimum duration of neoadjuvant endocrine therapy prior to surgery has not been established but circumstantial evidence suggests that it is at least 4 months, and probably longer.
In the P24 trial and the IMPACT trial, patients with higher levels of ER expression had a significantly higher chance of clinical response. Likewise in both trials, aromatase inhibitors appeared strikingly more effective than tamoxifen in the subgroup of patients with HER2-positive, ER-positive tumours.
In the IMPACT trial, the change in proliferation rates after 2 weeks of treatment as measured by Ki67 was significantly greater for anastrozole than for tamoxifen or the combination, reflecting results in the adjuvant ATAC trial, and suggesting that Ki67 might be a better marker for long-term outcome than clinical response. Likewise, long-term follow-up of the IMPACT trial showed that the absolute level of Ki67 suppression after 2 weeks of neoadjuvant endocrine therapy significantly correlated with long-term disease-free survival outcome, and more so than baseline pre-treatment Ki67. Changes in expression of >2,800 genes were observed after 2 weeks of aromatase inhibitor therapy.
These results suggest that neoadjuvant endocrine therapy is an effective clinical strategy to reduce the need for mastectomy in postmenopausal women with large hormone receptor-positive breast cancer. Short-term changes in molecular markers may be superior to clinical response in predicting long-term outcome, and this hypothesis is being further tested in a large prospective randomised trial.