Effects of Vaginal Estrogen on Serum Estradiol During Aromatase Inhibitor Therapy in Breast Cancer Patients with Vulvovaginal Atrophy: a Prospective Trial

Purpose: This study aimed to analyze changes in serum estradiol (E2) levels during concurrent vaginal estradiol therapy and adjuvant letrozole in postmenopausal breast cancer (BC) patients with vulvovaginal atrophy (VVA). Secondary objectives included assessing the effects of therapy on vaginal atrophy, quality of life (QoL) and menopause-related symptoms.

Methods: Postmenopausal patients undergoing adjuvant letrozole therapy and experiencing VVA symptoms were treated with vaginal estradiol for 12 weeks. Gynecologic examination and symptom screening were conducted at baseline and after 12 weeks. Serum E2 levels were analyzed at baseline, and at two, four, eight, and 12 weeks. E2 levels were measured using both a routine liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and a highly sensitive (hsE2-MS) LC-MS/MS method.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Intravaginal estrogen during adjuvant letrozole

Detailed Description

The study was conducted between November 2020 and May 2024 at the Comprehensive Cancer Center, Helsinki University Hospital, Finland. Eligible patients were postmenopausal women (> 50 years old) with early-stage hormone receptor-positive BC treated with adjuvant letrozole for at least six months and developed symptoms of AV during this period. Exclusion criteria included premenopausal status, recent use of local estrogen therapy within the previous three months, irregular use of letrozole, and metastatic disease.

VVA diagnosis was based on patient-reported symptoms, with gynecologic examinations, including speculum examination with transvaginal sonography, performed for all participants at baseline. Vaginal Pap smears were used to determine the vaginal maturation index (VMI) by assessing the proportions of parabasal, intermediate and superficial cells in the vaginal wall, along with other cytological findings according to the Bethesda System for cervical cytology. Vaginal pH was measured using litmus paper placed on the vaginal wall until moistened, serving as an indicator of VVA.

Eligible patients were treated with Vagifem® (17β-estradiol hemihydrate) 10 μg vaginal tablets for 12 weeks. Patients were instructed to insert one vaginal tablet daily using the provided applicator for 14 consecutive days, followed by one tablet twice weekly (Monday and Thursday evenings). Blood samples were collected at baseline, prior to the initiation of study treatment, and at two, four, eight, and 12 weeks thereafter, within 24 to 60 hours of vaginal tablet administration. Serum was separated by centrifugation within 1 hour of collection and the samples were stored at -80°C until analysis.

Patients completed the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires to assess QoL, with higher scores indicating better QoL or less QoL related symptoms, and the Women's Health Questionnaire (WHQ), where higher scores indicated greater distress and dysfunction, at baseline and after 12 weeks. Menopause-related symptoms were assessed using a structured 19-item questionnaire, while sexual function was evaluated with the McCoy Female Sexuality Questionnaire, which was completed by only half of the patients due to its limitation to sexually active participants. Higher scores on both questionnaires indicated greater severity or frequency of symptoms.

A follow-up gynecologic examination and oncology consultation were conducted at the end of the study to assess the patients' response to topical estradiol therapy. Patients who maintained serum E2 levels below LLOQ (< 5 pmol/L) and benefited from the therapy were considered for continued treatment off-study.

The primary objective was to analyze changes in serum E2 levels using two LC-MS/MS methods during concurrent adjuvant AI therapy and intravaginal estradiol treatment. Serum E2 levels were measured using both a routine LC-MS/MS method (Sciex Citrine™ Triple Quad™ LC-MS/MS system, E2-MS, HUSLAB, LLOQ 10 pmol/L) and a highly sensitive LC-MS/MS method (hsE2-MS, LLOQ 5 pmol/L, CV < 20%, LOD 1 pmol/L). The hsE2-MS method allowed for the detection of very low serum E2 concentrations, even below the LLOQ, within the range of 1-5 pmol/L, providing a precise assessment of the effect of letrozole and vaginal estrogen on E2 levels.

The intervention was considered unsuccessful if persistent elevation of E2 (> 5pmol/L in two consecutive tests) was observed after treatment initiation.

The local ethics committee of the Helsinki University Hospital approved the study protocol (No. 118). Informed consent was obtained from all participants included in the study. The trial was registered in the Helsinki and Uusimaa Hospital District Clinical Trials Register with EudraCT Number 2019-001234-34.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00290
    • HUS Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Eligible patients were postmenopausal women (> 50 years old) with early-stage hormone receptor-positive BC treated with adjuvant letrozole for at least six months and developed symptoms of AV during this period.

Exclusion Criteria:

• Exclusion criteria included premenopausal status, recent use of local estrogen therapy within the previous three months, irregular use of letrozole, and metastatic disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intravaginal estradiol during adjuvant letrozole; Eligible patients were treated with Vagifem® (17β-estradiol hemihydrate) 10 μg vaginal tablets for 12 weeks. Patients were instructed to insert one vaginal tablet daily using the provided applicator for 14 consecutive days, followed by one tablet twice weekly (Monday and Thursday evenings).

Drug: Intravaginal estrogen during adjuvant letrozole; Postmenopausal patients undergoing adjuvant letrozole therapy and experiencing VVA symptoms were treated with vaginal estradiol for 12 weeks. Gynecologic examination and symptom screening were conducted at baseline and after 12 weeks. Serum E2 levels were analyzed at baseline, and at two, four, eight, and 12 weeks. E2 levels were measured using both a routine liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and a highly sensitive (hsE2-MS) LC-MS/MS method.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum estradiol level	The primary objective was to analyze changes in serum E2 levels using two LC-MS/MS methods during concurrent adjuvant AI therapy and intravaginal estradiol treatment. ). Blood samples were collected at baseline, prior to the initiation of study treatment, and at two, four, eight, and 12 weeks thereafter, within 24 to 60 hours of vaginal tablet administration. Serum E2 levels were measured using both a routine LC-MS/MS method (Sciex Citrine™ Triple Quad™ LC-MS/MS system, E2-MS, HUSLAB, LLOQ 10 pmol/L) and a highly sensitive LC-MS/MS method (hsE2-MS, LLOQ 5 pmol/L, CV < 20%, LOD 1 pmol/L). The hsE2-MS method allowed for the detection of very low serum E2 concentrations, even below the LLOQ, within the range of 1-5 pmol/L, providing a precise assessment of the effect of letrozole and vaginal estrogen on E2 levels.	12 weeks

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2020
• Primary Completion (Actual): October 10, 2024
• Study Completion (Actual): October 10, 2024

Study Registration Dates

• First Submitted: October 21, 2024
• First Submitted That Met QC Criteria: October 21, 2024
• First Posted (Actual): October 23, 2024

Study Record Updates

• Last Update Posted (Actual): October 23, 2024
• Last Update Submitted That Met QC Criteria: October 21, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: breast cancer, adjuvant, letrozole, estradiol, vulvovaginal atrophy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Pathological Conditions, Anatomical; Skin Diseases; Breast Diseases; Breast Neoplasms; Atrophy; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Letrozole; Estrogens
• Other Study ID Numbers: 2019-001234-34

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The datasets generated and/or analyzed during the current study are not publicly available due to the restrictions outlined in the consent form. However, they are available from the corresponding author on reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No