The Prognostic and Treatment Predictive Value of Proliferation and TIMP-1 in Breast Cancer

Sammanfattning: Breast cancer is the most common tumour form and the second leading cause of death in solid tumours in women in the Western world. Despite improvements in the treatment, a considerable number of patients will relapse and die from their breast cancer. At the same time, a substantial number of patients will be over-treated, as they would have been cured by surgery and radiotherapy alone. In the metastatic setting, only 50% of patients will respond to chemotherapy, but there are no established factors predictive of response to chemotherapy. Therefore there is a need for identification of new prognostic and treatment predictive factors. In paper I, the chemotherapy predictive value of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) was assessed in 162 metastatic breast cancer patients. It was found that increasing tumour levels of TIMP-1, reaching borderline significance, were associated with a decreasing probability of response to CMF or anthracycline-containing chemotherapy. Proliferation, either in the form of single factors or as the main common denominator in different genetic profiles, has been shown to be of independent prognostic value in addition to the already established prognostic factors. In papers II, and IV the proliferation factors Ki67, Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), cyclin B1, and cyclin A were found to add prognostic value in a retrospective cohort of 237 node-negative premenopausal breast cancer patients, specifically in estrogen receptor (ER) positive patients, and in patients with histological grade 2. Also, in paper IV, when combining two proliferation factors, when either one or two factors were high, the prognostic value was strengthened. Paper III is a prospective Swedish multicenter validation study assessing the prognostic value of an index composed of the proliferation factor S-phase fraction (SPF), progesterone receptor status (PgR), and tumour size. 576 T1-2N0 breast cancer patients were included. High-risk was defined as ≥2 of the following: 1. tumour size >20mm, 2. PgR-negativity (in the absence of PgR-status, ER-negativity), and 3. high SPF (in the absence of SPF; Bloom-Richardson histological grade 3). High-risk patients had an almost five-fold risk of dying of breast cancer the first 5 years, and an increased risk of breast cancer death even after 15 years. Interestingly, an additional low-risk group was identified, 37% of the patients with no risk factors, who had an excellent 15-year survival rate. The index could therefore be helpful in decisions on risk and choice of adjuvant medical treatment.