Biomarkers and predictive factors of response to neoadjuvant treatment

Introduction

Neoadjuvant therapy provides a unique and powerful opportunity to derive biopsy material before, during and subsequent to the treatment of otherwise untreated breast cancers and, by measuring the expression of biomarkers in these, to study the biology of the disease in vivo. We have conducted such studies involving endocrine therapy or chemotherapy and have focused on the concept that measurement of change in expression of critical biomarkers shortly after starting therapy may be more closely associated with clinical outcome than before therapy.

Endocrine therapy

The IMPACT trial, in which over 300 ER⁺ patients were treated with tamoxifen or anastrozole or the combination, revealed that change in the proliferation marker Ki67 was greater with anastrozole than with either of the other arms, a result parallel to the drug's greater effectiveness in the far larger and longer ATAC adjuvant trial. In addition, Ki67 after 2 weeks was more predictive of recurrence-free survival than pretreatment Ki67 [1]. The value of on-treatment Ki67 as an index of long-term outcome is being studied in detail in the 4,000-patient Perioperative Endocrine Treatment for Individualised Care (POETIC) trial. The combination of on-treatment Ki67 with standard clinical features has allowed the derivation of a Preoperative Endocrine Therapy Index, which identified a group of patients with a very low likelihood of relapse on endocrine treatment alone [2]. Most recently we have created expression array data from over 100 patients treated with anastrozole. The quantitative expression of ER at a transcript level correlated strongly with the decrease in Ki67 and a Global Index of Dependence on Estrogen such that tumours with low ER showed little reaction to oestrogen deprivation. However, not all tumours with high ER expression showed high oestrogen dependence. Some of the less dependent tumours were HER2-positive but other mechanisms must account for the discordance in others. The POETIC trial should help to identify molecular factors associated with resistance to aromatase inhibitors.

Conclusion

Neoadjuvant chemotherapy is also associated with reduced levels of Ki67, although the mechanism in this case is likely to involve the selective apoptosis of highly proliferative cells as opposed to the cytostatic effect of endocrine therapy. In general those molecular features that are associated with poor long-term outcome are related to good response to neoadjuvant chemotherapy, and this complicates the use of the presurgical setting for study of treatment efficacy. Patients with high proliferation and ER negativity are more likely to show pathological complete response; the higher proliferation seen in ER-negative tumours appears to only partly explain the greater effectiveness seen in these cases. Those tumours with high Ki67 at the end of neoadjuvant therapy have a very poor outcome [3].