Abstract PD15-07: Effect of pertuzumab plus neoadjuvant trastuzumab-based chemotherapy in early-stage HER2-positive breast cancer according to BluePrint molecularly defined breast cancer subtypes
Authors: Liefaard Marte C , van der Voort Anna , Sanders Joyce , Vonk Shiva , Horlings Hugo M , Siesling Sabine , de Munck Linda , van Leeuwen-Stok Elise , Kleijn Miranda , Mittempergher Lorenza , Kuilman Midas M , Lips Esther H , Sonke Gabe S 
Published: March 2022

Abstract
Background: The addition of pertuzumab to neoadjuvant trastuzumab-containing chemotherapy significantly improves pathological complete response (pCR) rates in patients with HER2-positive breast cancer. However, effects on long-term survival outcomes have been modest. While prior studies suggest that only a subset of patients benefits most from the addition of pertuzumab, a reliable biomarker for response prediction has not been established. BluePrint is an 80-gene molecular subtyping test that classifies breast tumors as Basal-, Luminal- or HER2-subtype. Recent data shows that some tumors have more than one activated pathway and can be classified as dual subtype. Secondary analyses from the Aphinity trial (NCT01358877) suggest that pertuzumab benefit is largely restricted to patients with single-activated HER2-type tumors and less pronounced in patients with other single- or dual-activated subtypes. In this study, we evaluated BluePrint subtype as a biomarker for predicting response to trastuzumab-containing neoadjuvant chemotherapy with or without pertuzumab in a large nationwide cohort of patients. Methods: We collected data of all patients with stage II-III HER2-positive breast cancer who received neoadjuvant chemotherapy and trastuzumab between January 2013 and January 2016 from the Netherlands Cancer Registry. Pertuzumab was not reimbursed in the Netherlands during this period but was available to patients participating in the TRAIN2 clinical trial (NCT01996267). Pre-treatment biopsies were collected and tumor cell percentage was adequate in 404 patients who received pertuzumab and in 432 matched control patients who did not receive pertuzumab. Matching factors included treatment with anthracyclines (yes vs. no), age and hormone receptor status. BluePrint molecular subtypes were determined sucessfully through microarray in 680 patients. Pathological complete response (pCR) and overall survival (OS) were analyzed by treatment arm and BluePrint subtypes, using logistic and Cox regression analyses. Results: Microarray data was available for 334 patients who received pertuzumab and 346 patients who did not. Tumors were classified as single HER2 (77.6%), Luminal-HER2 (11.3%), single Luminal (8.4%), or other (2.6%). Overall, pCR rate was 65.0% in patients who received pertuzumab and 38.9% in patients who did not. In patients with single HER2-type tumors, pCR rate was significantly higher with pertuzumab (77.0% vs. 46.0%, multivariate adjusted odds ratio [aOR] 3.92, 95% confidence interval [CI] 2.60 - 5.98). In patients with other subtypes, pCR rate was lower overall and not significantly different with or without pertuzumab (23.5% vs. 13.5%, aOR 2.50, 95% CI 0.98 - 6.89). In addition, multivariate Cox regression analyses showed a significant OS benefit with pertuzumab in patients with single HER2-type tumors (adjusted hazard ratio [aHR] 0.33, 95% CI 0.16 - 0.67), but not in other subtypes (aHR 0.94, 95% CI 0.31 - 2.83). However, tests for interactions between pertuzumab and BluePrint subtypes were not significant. Conclusion: We confirmed the results of a prior secondary analysis of the Aphinity trial that the benefit of adding pertuzumab to (neo)adjuvant trastuzumab-based chemotherapy seems most pronounced in patients with a molecularly defined single-activated HER2-subtype. In other subtypes, pathological complete response rates and long-term outcomes are worse overall and no clear benefit of pertuzumab was seen, although tests for interaction between pertuzumab treatment and BluePrint subtype were not significant.
Citation Format: Marte C Liefaard, Anna van der Voort, Joyce Sanders, Shiva Vonk, Hugo M Horlings, Sabine Siesling, Linda de Munck, Elise van Leeuwen-Stok, Miranda Kleijn, Lorenza Mittempergher, Midas M Kuilman, Esther H Lips, Gabe S Sonke. Effect of pertuzumab plus neoadjuvant trastuzumab-based chemotherapy in early-stage HER2-positive breast cancer according to BluePrint molecularly defined breast cancer subtypes [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 PD15-07.