Abstract PS09-02: Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage HER2-positive Breast Cancer
Authors: Metzger Otto , Kim Se Eun , Tayob Nabihah , Viale Giuseppe , Yardley Denise , Prat Aleix , Abramson Vandana , Spring Laura , Waks Adrienne , Wrabel Eileen , DeMeo Michelle , Bardia Aditya , Dell'Orto Patrizia , Russo Leila , King Tari , Michor Franziska , Winer Eric , Polyak Kornelia , Tolaney Sara , Krop Ian 
Published: May 2024

Background:

Intratumor HER2 heterogeneity (ITH-HER2) predicates resistance to targeted anti-HER2-based therapy, and understanding its impact on response to HER2-directed therapies is particularly important with regimens that rely solely on targeted anti-HER2 therapies without chemotherapy.

Methods:

To determine the effect of ITH-HER2 on response to therapy, we conducted a single-arm phase II study in which patients (pts) with centrally confirmed HER2+ early-stage breast cancer received six cycles of preoperative T-DM1 plus pertuzumab. Baseline image-guided biopsies allowed central pathology evaluation of ITH HER2, defined as an area with HER2 amplification in &gt;5% but &lt; 50% of tumor cells or a HER2-negative area by FISH. The study met its primary endpoint by demonstrating inferior pathologic complete response (pCR) measured by Residual Cancer Burden (RCB) in the subset of ITH-HER2 pts. Single-cell ERBB2 FISH analysis identified the fraction of ERBB2 nonamplified cells as a factor associated with therapeutic resistance (Metzger et al. Cancer Discovery 2021). Secondary endpoints included event-free survival (EFS), invasive disease-free survival (iDFS), and breast cancer-specific survival (BCSS) by ITH-HER2 status and RCB scores.

Results:

163 pts were enrolled and received treatment in the study from Jan 2015 to Jan 2018. Central pathology evaluation of HER2 heterogeneity was successful in 96% (157/163) of cases, with 16 classified as ITH-HER2. RCB-0 or -I rate in the ITH-HER2 vs. not was (25% v. 67%, OR = 5.6, p = 0.002). Median follow-up, including all treated pts (n =163), was 65.4 months (IQR, 60.3-76.6). The 5yr EFS, iDFS, and BCSS were 91% [86.5% - 95.6%], 89.4% [84.5% - 94.5%], and 96% [92.9% - 99.2%], respectively. ITH-HER2 was associated with numerically inferior outcomes for EFS, iDFS, and BCSS (Table 1).

The subset of pts with non-ITH-HER2 at baseline (n= 141) and RCB-0 or -I (n = 95/141, 67%) had a 5-yr IDFS of 94.2% [89.3% - 99.3%]. A sensitivity analysis describing survival outcomes by chemotherapy use in the adjuvant setting will be presented at the meeting, along with translational research results evaluating the association of HER2DX assay with pCR and survival outcomes.

Conclusions:

The inferior pCR rates among cases classified as ITH-HER2 translated into numerically inferior outcomes for both EFS and iDFS. The number of events is small; therefore, our results are exploratory. Selecting pts whose tumors lack ITH-HER2 can increase the chances of achieving RCB 0/I with neoadjuvant TDM1 + pertuzumab. Neoadjuvant TDM1 + pertuzumab, followed by adjuvant HER2-directed therapy without classic chemotherapy agents, could represent an optimal regimen for non-ITH-HER2 pts experiencing RCB 0/I at the time of surgery and deserves further study.

Table 1. 5-year survival estimates by ITH-HER2

Citation Format: Otto Metzger, Se Eun Kim, Nabihah Tayob, Giuseppe Viale, Denise Yardley, Aleix Prat, Vandana Abramson, Laura Spring, Adrienne Waks, Eileen Wrabel, Michelle DeMeo, Aditya Bardia, Patrizia Dell'Orto, Leila Russo, Tari King, Franziska Michor, Eric Winer, Kornelia Polyak, Sara Tolaney, Ian Krop. Event-free Survival by Residual Cancer Burden (RCB) and Intratumor HER2 Heterogeneity after Neoadjuvant T-DM1 and Pertuzumab for Early-stage HER2-positive Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS09-02.