Simultaneous Quantification of Aromatase Inhibitors and Estrogens in Postmenopausal Breast Cancer Patients

Context Currently there are no assays that can simultaneously quantify serum levels of the third generation aromatase inhibitors (AI); letrozole, anastrozole, and exemestane, and the ultralow levels of estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing an LC-MS/MS method for simultaneous assessment of letrozole, anastrozole, exemestane and 17-hydroxy-exemestane as well as subpicomolar levels of estradiol and estrone. Methods Internal standards, calibrators, serum samples and quality controls were in fully automated steps transferred to a deepwell plate for a two-step liquid-liquid-extraction. The extracts were reconstituted and analytes were separated chromatographically using two serially coupled columns, then subject to MS/MS in ESI mode. The method was thoroughly validated and is traceable to two accredited estrogen-methods. Results Measurement range for estrone and estradiol was 0.2 – 12 000 pmol/L and 0.8 – 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had precision ≤ 13 %, and accuracies within 100 ± 8 %. As proof-of-concept, AI and estrogen levels were determined in sera from postmenopausal breast cancer patients under treatment. Conclusions We present here an assay suitable for the simultaneous measurement of serum levels of all third generation AIs and ultralow levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below threshold of detection for most routine assays, but still require suppression.

Aromatase Inhibitors and Contralateral Breast Cancer in BRCA Mutation Carriers: A long-term Follow-up

Background: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. Methods: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004-2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow up was 11.5 years. Risk of CBC was evaluated as time to event. Results: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs %6.5 (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p=0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. Conclusions: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

The Role of Aromatase Enzyme in Hormone Related Diseases and Plant-Based Aromatase Inhibitors as Therapeutic Regimens

: Medicinal plants have a long history of use as food and remedy in traditional and modern societies, as well as have been used as herbal drugs and sources of novel bioactive compounds. They provide a wide array of chemical compounds, many of which can not be synthesized via current synthesis methods. Natural products may provide aromatase inhibitory activity through various pathways and may act clinically effective for treating pathologies associated with excessive aromatase secretion including breast, ovarian and endometrial cancers, endometriosis, uterine fibroid, benign prostatic hyperplasia (BPH), prostate cancer, infertility, and gynecomastia. Recent studies have shown that natural products with aromatase inhibitory activity, could also be good options against secondary recurrence of breast cancer by exhibiting chemopreventive effects. Therefore, screening for new plant-based aromatase inhibitors may provide novel leads for drug discovery and development, particularly with increased clinical efficacy and decreased side effects.

GnRHa as a Treatment for Letrozole-Resistent Recurrent Adult Granulosa Cell Tumors: A Case Report and Literature Review

Background: The optimal management of Recurrent Ovarian granulosa cell tumors was still unknown, Hormone therapy maybe an alternative for chemotherapy-resistant cases. the reaction rate for aromatase inhibitors was highest, how to treat the progressed case after aromatase inhibitors was challenging. Case presentation: Here we report a case of Recurrent Ovarian granulosa cell tumors treated with Diphereline and achieved clinical cure. A 46-year-old woman presented with third recurrence after primary treatment. She developed tumor progression and drug-induced nephritis after 6 cycles of combined treatment of cisplatin and paclitaxel for the second recurrence and failed to benefit from chemotherapy ,after the third Optimal cytoreduction and tumor progression after 6 months Letrozole treatent. The implementation of experimental treatment with Diphereline achieved Good therapeutic effect.Conclusion: Hormone therapy maybe an alternative to recurrent granulosa cell tumors, Gonadotropin-releasing hormone agonistsas maybe a rescued treatment for Aroatase inhibitor-resistant cases