Abstract PD12-06: Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial
Authors: Hurvitz Sara A , Fresco Rodrigo , Afenjar Karen , Stroyakovskiy Daniil , Huang Chiun-Sheng , Wildiers Hans , Jung Kyung Hae , Boileau Jean-François , Campone Mario , Martín Miguel , Valero Vicente , Sparano Joseph A. , Symmans W. Fraser , Fasching Peter A. , Thompson Alastair M. , Harbeck Nadia , López-Valverde Vanesa , Song Chunyan , Boulet Thomas , Restuccia Eleonora , Slamon Dennis J. 
Published: February 2021

Abstract
Background: Cytotoxic chemotherapy (CT) in combination with trastuzumab and pertuzumab (HP) is standard of care for patients (pts) diagnosed with HER2-positive early breast cancer (EBC). While highly effective, the toxicity associated with CT is challenging. In KRISTINE/TRIO-021, neoadjuvant T-DM1 was combined with pertuzumab (KP) and compared to standard TCHP. Pts. received six cycles of neoadjuvant treatment followed by adjuvant therapy (KP or HP). Pts. in the KP arm were allowed to receive standard adjuvant CT. Pathologic complete response (pCR) rate was significantly lower with KP versus TCHP and more pts. had disease progression prior to surgery with KP, resulting in a meaningfully lower event-free survival rate vs. the control (85.3% vs 94.2%). However, 3-year invasive disease-free survival was numerically similar in both arms. Neoadjuvant KP demonstrated less toxicity than standard CT, although treatment discontinuation was higher post-surgery. Association of KP and TCHP with treatment-related amenorrhea (TRA) in premenopausal EBC pts. has not been ascertained. Methods: All pts. with premenopausal status at study entry (those not meeting the menopause definition based on National Comprehensive Cancer Network Guidelines v3, 2012) and with menstrual period documented within 3 months of randomization, were independently evaluated for presence or absence of TRA by two reviewers. TRA, a prespecified exploratory endpoint of KRISTINE, was defined as cessation of menstruation for &gt;12 months in the absence of treatment with ovarian suppression or other interventions that can induce amenorrhea. Pts. were followed from the time of study entry through the 3-year follow up period after surgery. For cases with inconsistent determination between the two reviewers, a third reviewer adjudicated. TRA rates were calculated per arm, hormone-receptor (HR) status, adjuvant CT and age group. Proportions were compared by estimating the odds ratio (OR) and the 95% confidence interval. Results: Of 444 pts. enrolled, 205 were excluded based on being post-menopausal per NCCN guidelines. Of 239 pts. remaining, 56 were excluded due to insufficient data. The median age of pts. included was 40 years (range: 22-53) for TCHP and 42.5 (range: 23-52) for KP. TRA was observed in 55% (50/91) of pts. treated with TCHP compared to 30% (28/92) treated with KP (OR=2.79; 95% CI 1.52-5.12). In pts. with HR-positive EBC, TRA occurred in 62% with TCHP vs 35% for KP (OR=2.998; 95% CI 1.44-6.25). In those with HR-negative EBC, TRA was observed in 42% with TCHP vs. 21% with KP (OR=2.77; 95% CI 0.88-8.72). In the KP arm, TRA was observed in 38% (8/21) of pts. treated with standard adjuvant CT vs. 28% (20/71) of those that did not (OR 1.57; 95% CI 0.57-4.36). For women age ≤ 40, the rate of TRA was 38% with TCHP vs. 17% with KP (OR=3.00; 95% CI 1.05-8.60). For those &gt; 40 years, TRA was observed in 74% treated with TCHP vs. 39% of those with KP (OR=4.50; 95% CI 1.88-10.73). Conclusion: The rate of TRA with standard TCHP is nearly double that observed with KP, suggesting that targeted CT with an antibody-drug conjugate regimen is associated with less gonadal toxicity. Rates of TRA are higher in women over the age of 40 for each treatment arm however KP is associated with lower rate of TRA in each age group. Association of TRA with efficacy outcomes (pCR, iDFS) will be presented.
Citation Format: Sara A Hurvitz, Rodrigo Fresco, Karen Afenjar, Daniil Stroyakovskiy, Chiun-Sheng Huang, Hans Wildiers, Kyung Hae Jung, Jean-François Boileau, Mario Campone, Miguel Martín, Vicente Valero, Joseph A. Sparano, W. Fraser Symmans, Peter A. Fasching, Alastair M. Thompson, Nadia Harbeck, Vanesa López-Valverde, Chunyan Song, Thomas Boulet, Eleonora Restuccia, Dennis J. Slamon. Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD12-06.