Abstract P2-09-07: Low levels of HER2 extracellular domain (ECD) compared to intracelluar domain (ICD) in NeoALTTO may segregate benefit from lapatinib and trastuzumab in breast cancer
Authors: Rimm DL , Carvajal-Hausdorf D , Harbeck N , Fumagalli D , Rodrik-Outmezguine V , delaPena L , deAzambuja E , Huober J , Baselga J , Piccart M , Holmes E , Pusztai L 
Published: February 2018

Abstract
Background: Preclinical models suggest that in some HER2 overexpressed breast cancer cases, the extracellular domain of HER2, containing the binding region for trastuzumab (T) is not present due to proteolytic cleavage. Previous measurement of HER2 ECD and ICD in HeCOG 10/05 suggested that breast cancer cases that have low levels of ECD show decreased benefit from adjuvant T therapy (Carvajal et al, 2015). These cases may be more likely to show benefit from lapatinib(L), a small molecular tyrosine kinase inhibitor. NeoALTTO, an international multi-institutional trial comparing pre-surgical treatment with L vs T vs both, showed that pCR rates were around 25-30% for L or T but increased to 50% for both. This cohort allows us to test the hypothesis that patients with low ECD may benefit more from L than T.
Methods: ECD and ICD were measured 382 cases using quantitative immunofluorescence (QIF) with domain specific antibodies (SP3, Spring biosciences for ECD and CB11, Biocare for ICD). Slides were stained and scanned, then measured using the AQUA method of QIF. All fields of view were scored and FOVs were averaged to generate a QIF score for each case. Index TMAs were used to standardize all autostainer runs and to define the QIF score cut-point that is equivalent to the clinical cut-point for the index TMA cases. Each case was then assigned to one of three groups; 1) High ECD and ICD, 2) Low ECD but High ICD, and 3) low ICD.
Results: In the lapatinib arm, both group 1 and 2 showed a pCR rate of 25% (p&gt;0.99), but in the trastuzumab arm, Group 1 pCR rate was 34% compared to 19% for group 2 (p=0.38). In the combination arm, group 1 showed a pCR rate of 59% compared to 29% for group 2 (p=0.046). In a logistic regression model for pCR, after adjustment for treatment arm and HR status the ECD/ICD status shows a significant predictive value (p = 0.002). Although this study is not powered for event free survival (EFS), at 6 years of follow up we found that patients in group 2 on the lapatinib arm show 92% EFS compared to 69% EFS in group 1 (p=0.17). The opposite trend is seen in both trastuzumab arms where EFS for group 1 on T showed 70% vs 62% for group 2 (p=0.57) and 77% vs 71% on the T+L arm (p=0.74). In a Cox regression model for EFS after adjustment for treatment arm and HR status, the ECD/ICD status is not significant (p=0.88)
Conclusions: Cases with low levels of ECD compared to ICD appear benefit less than those with high levels of both ECD and ICD as assessed by pCR from treatments containing T. In contrast, those same patients also appear to benefit more, as assessed by EFS, on the L arm. These observations are consistent with the hypothesis that this assay could stratify benefit from L vs T based on the status of the ECD. Further assessment using this assay on the ALTTO cases is currently underway and may help confirm this observation.
Citation Format: Rimm DL, Carvajal-Hausdorf D, Harbeck N, Fumagalli D, Rodrik-Outmezguine V, delaPena L, deAzambuja E, Huober J, Baselga J, Piccart M, Holmes E, Pusztai L. Low levels of HER2 extracellular domain (ECD) compared to intracelluar domain (ICD) in NeoALTTO may segregate benefit from lapatinib and trastuzumab in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-07.