Superior suppression of serum estrogens during neoadjuvant breast cancer treatment with letrozole compared to exemestane.

PURPOSE: The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking. METHODS: Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC-MS/MS method established in our laboratory. RESULTS: Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women. CONCLUSION: To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane.

[Patient reporting of adverse drug reactions in Norway 2010-13]. / Melding av legemiddelbivirkninger fra pasienter 2010-13.

BACKGROUND: Since 1 March 2010, patients in Norway have had the opportunity to report adverse reactions to The Norwegian Medicines Agency. The purpose of this study was to review these reports. MATERIAL AND METHOD: The content of adverse reaction reports received from patients in the period from 1 March 2010 to 31 December 2013 was classified based on age, gender, suspected drug and suspected adverse reactions. The patient reports were compared to the adverse reaction reports received from health care professionals in the same period. RESULTS: A total of 755 reports from patients and 9629 reports from health care professionals were received during the period in question. The 20-39-year age group was most frequently represented in the patient reports. In the reports from health care professionals, the main age group was 0-9 years, followed by the 60-69-year age group. The drug group most often mentioned in the patient reports was drugs acting on the nervous system, and above all psychotropic drugs and analgesics, while vaccines dominated in the reports from health care professionals. Adverse mental and neurological reactions were most frequently reported by patients, while general symptoms and local reactions were most common in the reports from health care professionals. A total of 74 different adverse reactions were reported only by patients and not by the health care professionals. INTERPRETATION: Adverse drug reaction reports from patients are different from reports by health care professionals. Our findings indicate that the system with patient reporting functions as a supplement to reporting from health care professionals.