Abstract OT1-03-04: The importance of central pathology pCR review in an international multicenter neoadjuvant study in HER2 positive early breast cancer - Results of the ABP 980 LILAC trial
Authors: Kolberg Hanz-Christian , Colleoni Marco , Demetriou Georgia Savva , Santi Patricia , Tesch Hans , Fujiwara Yasuhiro , Hanes Vladimir 
Published: March 2020

Abstract
Pathological complete response (pCR) after neoadjuvant therapy is an accepted surrogate endpoint for breast cancer registration trials and is a strong prognostic biomarker especially in high-risk tumor biology. The LILAC study, a comparative trial for the trastuzumab biosimilar ABP 980, was the first international multicenter neoadjuvant breast cancer trial using local and central pathology review for pCR. Here we report concordance between local and central review for the most commonly used pCR definitions. This study included 725 patients with early HER2-positive breast cancer, comparing neoadjuvant ABP 980 and trastuzumab reference product (RP) in combination with anthracycline and taxane-containing chemotherapy. Equivalence of both arms was defined at a significance level of 0.05 by comparing the 2-sided 90% confidence interval (CI) for the risk difference (RD) of pCR between ABP 980 and RP within a predefined margin (-13%, 13%) using definition 2 as described below. pCR was evaluated in local laboratories and in a central laboratory blinded to the local result. The purpose of the independent, central review was to reduce the inter-pathologist variability and provide a more consistent assessment. Central review was performed by 2 independent pathologists; in cases of discordance the specimen was reviewed and decided by a third pathologist (adjudicator). The pCR definition in the primary analysis was no invasive breast cancer in breast and axillary nodes, regardless of ductal carcinoma in situ (DCIS). No invasive tumor in the breast was pCR definition 1, no invasive breast cancer in breast and axillary nodes regardless of DCIS was pCR definition 2, and no invasive breast cancer in breast and axillary nodes and absence of DCIS was pCR definition 3. The RDs and CIs were evaluated for local and central pCR review for all 3 pCR definitions. The results of the neoadjuvant LILAC study have been reported previously, demonstrating no clinically meaningful differences between ABP 980 and RP in HER2-positive early breast cancer. Of the 696 subjects who underwent surgery and had specimens evaluable for pCR review by the local pathologists, 669 specimens were available for central review. Rates of pCR in the local review were 51.1% (ABP 980) and 45% (RP) for definition 1, 48% (ABP 980) and 40.5% (RP) for definition 2, and 37.7% (ABP 980) and 29.6% (RP) for definition 3. The corresponding pCR rates in the central review were 51.3% and 47.3% for definition 1, 47.8% and 41.8% for definition 2, and 29.9% and 26.1% for definition 3. The CI for RD was within the predefined margins for pCR definition 1 in local and central review, whereas it exceeded the prespecified margin in local review for pCR definitions 2 and 3. In the central review the CI was within the margin for the pCR definitions 2 and 3, with the difference between local and central pathology review 1.6% for pCR definition 2 and 4.4% for pCR definition 3, respectively. RDs (90% CI) for all 3 pCR definitions are shown in the Table. The LILAC study demonstrated that a central pathology review for pCR is feasible in a large, international, multicenter neoadjuvant breast cancer trial. Our results show that concordance between local and central pathology can decrease with increasing complexity of the pCR definition. Based on the results, it may be justified to include a central pathology review in neoadjuvant multicenter breast cancer trials with strict pCR definitions.
Citation Format: Hanz-Christian Kolberg, Marco Colleoni, Georgia Savva Demetriou, Patricia Santi, Hans Tesch, Yasuhiro Fujiwara, Vladimir Hanes. The importance of central pathology pCR review in an international multicenter neoadjuvant study in HER2 positive early breast cancer - Results of the ABP 980 LILAC trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-04.