Ki67 and response to hormonal therapy
Highlights from the 32nd San Antonio Breast Cancer Symposium, 9-13 December 2009, Texas, USA
In postmenopausal patients with T2/3 tumors who wish to preserve their breasts, neoadjuvant endocrine treatment may be recommended. Treatment can shrink the tumor, frequently making the patient a good candidate for breast conservation therapy, and can also allow assessment of response to the therapeutic agent. A problem arises, however, when the tumor does not respond to the drug during the ~4 months of neoadjuvant treatment, resulting in a delay in switching to chemotherapy, which may adversely affect the chance of achieving breast conservation therapy and the overall outcome.
The Preoperative Endocrine Prognostic Index (PEPI) is based on the independent prognostic effects of tumor size, nodal status, estrogen receptor status, and Ki67 level, and is used to predict long-term outcomes after the completion of neoadjuvant endocrine treatment.
Because these markers are measured in the surgical sample after the completion of the neoadjuvant therapy, the prognostic information becomes available only after 4 months of treatment. An alternative approach, based on measuring the Ki67 level in a tumor biopsy sample taken only 2 to 4 weeks after beginning neoadjuvant therapy, was described by Matthew Ellis, MD, PhD, from Washington University.
A Ki67 cut-off of 10% was determined by comparing Ki67 data with the PAM50 intrinsic subtype profile, essentially making Ki67 values ≤10 or >10 surrogates for the LumA and LumB molecular subtypes of breast cancer. This cut-off was applied to the baseline and early on-treatment Ki-67 data in 2 trials, comparing that data with Ki67 values from the surgical samples. In the preoperative letrozole phase 2 trial, in which the patients received 4 to 6 months of neoadjuvant letrozole therapy, these cut-off points measured on 4-week biopsy samples predicted low- and high-risk groups of patients that were significantly correlated with recurrence-free survival at 60 months. Only 1/20 patients with a PEPI score of 0 (very low risk) had a Ki67 value >10, whereas 10/36 patients in this PEPI category had a Ki67 value ≤10. Similar results were seen with 2-week biopsies taken from patients in the IMPACT trial. In the ACOSOG Z1031 trial, where patients are being randomized to receive exemestane, letrozole, or anastrozole as neoadjuvant therapy, an amendment has been activated whereby all patients will be biopsied at 2 to 4 weeks after the initiation of treatment for measurement of Ki67 levels. Those designated as high risk will be switched to either chemotherapy or surgery. Those classified as low risk will continue with aromatase inhibitor therapy until surgery, after which a decision about adjuvant chemotherapy will be made based on PEPI score and pathologic stage. A remaining problem in implementing Ki67 assessment in early biopsies is standardizing measurement; this problem is currently being addressed by BIG/NABCG.
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