Abstract P2-13-42: Effect of young age at diagnosis on clinical outcomes and efficacy of anti-HER2 targeted therapy in patients with HER2-positive early breast cancer: Results from the APHINITY trial
Authors: Lambertini Matteo , Fielding Shona , Loibl Sibylle , Janni Wolfgang , Clark Emma , Franzoi Maria Alice , Fumagalli Debora , Caballero Carmela , Arecco Luca , Salomoni Sharon , Ponde Noam F , Poggio Francesca , Kim Hee Jeong , Villarreal-Garza Cynthia , Pagani Olivia , Paluch-Shimon Shani , Ballestrero Alberto , Mastro Lucia Del , Piccart Martine , Bines Jose , Partridge Ann H. , de Azambuja Evandro 
Published: March 2022

Abstract
Background: The poor prognostic value of young age at diagnosis appears to vary according to breast cancer (BC) subtype, although this has been studied mainly in hormone receptor-positive (HR+) disease, with limited data in HER2-positive BC and short follow-up. Limited evidence exists on the benefit of anti-HER2 therapy in young women with BC. Considering that age has historically been a rationale for overtreatment, further research efforts to better investigate the prognostic and predictive value of age are needed. This exploratory analysis conducted within the APHINITY trial aimed to investigate the prognostic and predictive value of young age in patients with HER2-positive early BC treated with modern chemotherapy and concurrent anti-HER2 targeted treatment. Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in patients with HER2-positive early BC investigating the benefit of adding pertuzumab to adjuvant chemotherapy plus trastuzumab. For the purpose of the present analysis, 40 years of age at enrolment was used as the cut-off to distinguish between young (≤40 years) and older (&gt;40 years) cohorts. Invasive disease-free survival (IDFS) was the primary endpoint. IDFS irrespective of treatment arm and the benefit of adding pertuzumab were evaluated in all patients by comparing the young and older cohorts and then according to centrally-assessed hormone receptor status. Univariate and multivariable Cox proportional hazard models were used to assess the prognostic and predictive value of age on IDFS as a continuous and dichotomous variable (≤40 years and &gt;40 years). A STEPP analysis was also conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. Results: Out of 4,804 patients in the ITT population, 768 (16.0%) were ≤40 years at enrollment. Patients in the young cohort were less overweight/obese (29.3% vs. 50.4%), underwent mastectomy more frequently (63.2% vs. 52.6%), had higher rates of node positive (66.4% vs. 61.8%) and HR+ (71.7% vs. 64.9%) BC as compared to those in the older cohort (all p&lt;0.05). Among patients with HR+ BC that received adjuvant endocrine therapy in the young cohort (n=498), 132 (26.5%) underwent ovarian function suppression while 324 (65.1%) received tamoxifen alone. Overall median follow-up was 74 months (IQR 62-75 months). 6-year IDFS was 88% and 89% in the young and older cohorts, respectively. In univariate and multivariable analyses, young age was not prognostic as dichotomous (unadjusted HR 1.06; 95% CI 0.84-1.33; adjusted HR 1.07; 95% CI 0.84-1.35) nor as continuous (unadjusted HR 1.00; 95% CI 1.00-1.01) variables. The lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No significant interaction was observed between age and treatment effect (Pinteraction=0.605). The addition of pertuzumab improved IDFS for both patients in the young (6-year IDFS 89% vs. 87%; adjusted HR 0.86; 95% CI 0.56-1.32) and older (6-year IDFS 91% vs. 88%; adjusted HR 0.75; 95% CI 0.62-0.92) cohorts. By analyzing the potential predictive value of age according to hormone receptor status, similar results were observed. The STEPP analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations. Conclusions: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate prognostic or predictive value in long-term follow-up, irrespective of hormone receptor status and anti-HER2 treatment modalities. These results may help to improve the care of young women with BC, highlighting that, in the current era of precision medicine, age alone is not a reason to expect a different disease outcome or treatment benefit.
Citation Format: Matteo Lambertini, Shona Fielding, Sibylle Loibl, Wolfgang Janni, Emma Clark, Maria Alice Franzoi, Debora Fumagalli, Carmela Caballero, Luca Arecco, Sharon Salomoni, Noam F Ponde, Francesca Poggio, Hee Jeong Kim, Cynthia Villarreal-Garza, Olivia Pagani, Shani Paluch-Shimon, Alberto Ballestrero, Lucia Del Mastro, Martine Piccart, Jose Bines, Ann H. Partridge, Evandro de Azambuja. Effect of young age at diagnosis on clinical outcomes and efficacy of anti-HER2 targeted therapy in patients with HER2-positive early breast cancer: Results from the APHINITY trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-42.