In 2018, the American Society of Clinical Oncology updated its guidelines to recommend that women with node-positive breast cancer (BC) receive extended endocrine therapy (ET) (including an aromatase inhibitor [AI]) for up to a total of 10 years of adjuvant endocrine treatment to prevent BC recurrence.

The preferred options for extended ET in the guidelines include taking an AI for up to a total of 10 years, receiving 2 to 3 years of tamoxifen followed by 7 to 8 years of an AI, or administrating 5 years of tamoxifen followed by 5 years of an AI. Currently,  three AIs are commercially available: anastrozole, exemestane, and letrozole.

In women who were premenopausal at the time of initial BC treatment and whose menses stopped during chemotherapy or upon the initiation of tamoxifen, switching to an AI may cause reactivation of ovarian function, thereby increasing the risk of BC recurrence.

This prospective trial aimed to determine how using routine, standard direct immunoassay (DIA) monitoring of estradiol (E2) levels compared with highly sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) monitoring in women who switched from tamoxifen to letrozole. Specifically, investigators wanted to determine whether E2 levels as determined by LC-MS/MS were below the lower limit of quantification (LLOQ), i.e., <5 pmol/L; failure to achieve this low level may be indicative of “AI failure.” DIA is not able to detect levels this low.

In total, 71 women aged 40 to 60 years (median age 51 years) who were diagnosed with early hormone receptor-positive BC with either lymph node metastases or other high-risk factors for cancer recurrence and who had been treated with 5 years of adjuvant tamoxifen therapy were screened for this study. Of these patients, 48 were postmenopausal and 23 were premenopausal. The  latter group did not undergo any further review. Two postmenopausal women had missing data and were excluded, leaving 46 postmenopausal women for final analysis.

Follicle stimulating hormone (FSH) and E2 levels were measured by standard DIA. Postmenopausal status was confirmed by a FSH >20 IU/L and an E2 <200 pmol/L as well as transvaginal ultrasound findings. Women considered postmenopausal were switched to letrozole for 5 years and peri- and premenopausal women continued on the tamoxifen for 5 more years. FSH levels and E2 levels were measured at 3 and 12 months during letrozole treatment using both DIA and LC-MS/MS. If E2 levels did not decrease to undetectable serum levels as determined by LC-MS/MS, i.e., < 5 pmol/L while on letrozole at 3 or 12 months, this was deemed “AI failure.”

E2 levels, as measured by LC-MS/MS, were below LLOQ in 39 (85%) women at 3 months and 12 months. Additionally, two of these women had undetectable levels at baseline that remained suppressed throughout the study. Of the remaining seven (15%) postmenopausal women with AI failure, four women’s E2 levels rose above 5 pmol/L at 3 months and three women’s levels increased to >5 pmol/L at 12 months.

Five women (11%) had vaginal bleeding while on letrozole. Three of these women had been deemed to have AI failures since their E2 levels were >5 pmol/L on letrozole and vaginal bleeding was possibly due to ovarian recovery. They were subsequently switched back to tamoxifen. In the case of the other two women without AI failure, the vaginal bleeding was secondary to endometrial polyps.

Baseline variables including age, body mass index, ovarian volume, antral follicle count, endometrial thickness, and E2 and FSH levels as determined by DIA were not predictive of AI failure in logistic regression. Further, FSH and E2 using DIA did not discriminate between AI failure and AI nonfailure at 3 and 12 months and poorly correlated with levels obtained using LC-MS/MS.

Since transitioning from tamoxifen to an AI is considered safe only if there is evidence of permanent menopause, pharmacists who counsel on ET should be aware of the limitations of laboratory testing when it is being utilized to guide drug therapy.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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