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- Title
Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ: A Randomized Clinical Trial.
- Authors
Khan, Seema A.; Mi, Xinlei; Xu, Yanfei; Blanco Jr, Luis Z.; Akasha, Azza M.; Pilewskie, Melissa; Degnim, Amy C.; AlHilli, Zahraa; Amin, Amanda L.; Hwang, E. Shelley; Guenther, Joseph Michael; Kocherginsky, Masha; Benante, Kelly; Zhang, Shanshan; Helland, Thomas; Hustad, Simon Steinar; Gursel, Demirkan B.; Mellgren, Gunnar; Dimond, Eileen; Perloff, Marjorie
- Abstract
Key Points: Question: Does transdermal delivery of the tamoxifen metabolite 4-hydroxytamoxifen produce antiproliferative effects in ductal carcinoma in situ lesions that are noninferior to those produced by oral tamoxifen citrate? Findings: In a placebo-controlled, randomized phase 2B presurgical clinical trial with 100 participants, noninferiority of 4-hydroxytamoxifen gel applied to the breast skin compared with oral tamoxifen was not demonstrated. Breast tissue concentrations of tamoxifen metabolites for 4-hydroxytamoxifen were similar in both groups, but the oral tamoxifen group demonstrated significantly higher levels of endoxifen. Meaning: In this study, local transdermal therapy with 4-hydroxytamoxifen did not suppress proliferation as effectively as full-dose oral tamoxifen, likely owing to the additional presence of substantial amounts of endoxifen in the oral tamoxifen group. This phase 2 randomized clinical trial compares oral tamoxifen with transdermal 4-hydroxytamoxifen gel among women undergoing surgery for estrogen receptor–positive ductal carcinoma in situ. Importance: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. Objective: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. Design, Setting, and Participants: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor–positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. Intervention: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. Main Outcomes and Measures: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. Results: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (−16 [95% CI, −22 to −9.4]) than with 4-hydroxytamoxifen gel (−1.8 [95% CI, −5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P <.001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. Conclusions and Relevance: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. Trial Registration: ClinicalTrials.gov Identifier: NCT02993159
- Publication
JAMA Surgery, 2023, Vol 158, Issue 12, p1265
- ISSN
2168-6254
- Publication type
Article
- DOI
10.1001/jamasurg.2023.5113