Abstract
To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [(18)F]-3'deoxy-3'-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer. This was a prospective unblinded study in 20 patients with American Joint Committee on Cancer (AJCC) stage II-IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan 2 weeks after initiating the first or second cycle of docetaxel. PET variables were compared with anatomic response midtherapy (after 3 cycles). Average and maximum tumor standardized uptake values at 60 minutes (SUV(60,av) and SUV(60,max)) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 × 10(-5) m(2)/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P = 0.0003 for SUV(60,av) and P = 0.0002 for SUV(60,max)). Reduction in tumor SUV(60,av) was associated with target lesion size changes midtherapy (Pearson R for SUV(60,av) = 0.64; P = 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV(60,av) in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, K(i)). Docetaxel significantly reduced K(i) by 51.1% (±28.4%, P = 0.0009). Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response midtherapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non-FLT-PET response.
Highlights
Taxanes are some of the most commonly used drugs in the treatment of breast cancer today
Reduction in tumor SUV60,av was associated with target lesion size changes midtherapy (Pearson R for SUV60,av 1⁄4 0.64; P 1⁄4 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity)
Patients This was a prospective, unblinded, single institution study in patients with American Joint Committee on Cancer (AJCC) stage II–IV breast cancer, including primary breast cancer being unresponsive to first-line chemotherapy, or metastatic disease progressing on previous therapy
Summary
Taxanes are some of the most commonly used drugs in the treatment of breast cancer today. The cytotoxic activity of taxanes is promoted by stabilizing cellular microtubule assembly [1, 2]. This leads to inhibition of mitotic cell division Docetaxel is approved for the treatment of patients with locally advanced or metastatic breast and non–small cell lung cancer [4] who have undergone anthracycline-based chemotherapy and failed because of tumor progression or relapse. The drug has shown effectiveness against tumors resistant to anthracyclines or paclitaxel [5, 6] and good response rates (55%–68%) in the neoadjuvant setting [7, 8], at the expense of well-known myelosuppressive and other toxicities
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