Jason Aboudi Mouabbi

Strategies are needed to avoid chemotherapy in early stage HER2-positive (HER2 + ) breast cancer (BC). We conducted a neoadjuvant therapy trial with zanidatamab, a dual HER2-directed bispecific antibody, in patients with 1-3 cm, node-negative HER2 + BC. Primary endpoint was pathologic complete response (pCR). Secondary endpoints were radiographic response by ultrasound and magnetic resonance imaging. US and MRI, pathologic response by residual cancer burden (RCB), rate of adverse events, feasibility of accrual and biomarkers of response. Fifteen patients with HER2 IHC 3 + , and 5 with HER2 IHC 2 + /ISH + BC were enrolled. Patients received zanidatamab 20 mg/kg every 2 weeks for 6 (n = 11) or 10 doses (n = 9). Fourteen patients also received endocrine therapy. At 6 weeks, there was a significant decrease in tumor size and volume. At surgery, six patients (30%) had pCR, meeting the prespecified pCR target, and four had limited RCB (RCB-1; 20%). Treatment was well tolerated. All patients with pCR had HER2 IHC 3+ tumors, ERBB2 amplification on WES, PAM50 HER2-high subtype, and a trend towards higher HER2 mRNA expression (p = 0.06). In conclusion, de-escalation to HER2-targeted therapy alone may be feasible. Further research is needed to refine patient selection. This study is registered at ClinicalTrials.gov (NCT05035836).

Background: HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 antibody–drug conjugate trastuzumab deruxtecan over standard chemotherapy in patients with metastatic breast cancer (MBC) defined as HER2-low. More recently, the DESTINY-Breast06 trial confirmed this benefit in hormone receptor-positive and HER2-ultralow (less than 1+, but with ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining) cases, prompting re-evaluation of HER2 diagnostic thresholds and treatment strategies. Methods: Eligible patients were women with HER2-low or HER2-0 MBC evaluated at MD Anderson between January 2006 and January 2019. HER2-low was defined as either (1) IHC 1+ or (2) IHC 2+ and negative on fluorescence in situ hybridization. Multivariate logistic regression was used to evaluate distinct clinicopathologic features of patients with HER2-low status. Overall survival (OS) was estimated by the Kaplan–Meier method. Multivariate Cox proportional hazards regression was applied to assess the effects of covariates of interest on OS across different HER2 groups. Results: We included 3834 women: 2637 (69%) with recurrent and 1197 (31%) with de novo MBC; HER2-low disease was present in 1575 (60%) and 712 (59%), respectively. In de novo cases, higher nuclear grade was associated with HER2-low status (grade 2 vs. 1, OR = 2.02, p = 0.007; grade 3 vs. 1, OR = 1.87, p = 0.015), while recurrent cases were associated with ER-positivity (OR = 1.96, p < 0.001) and prior adjuvant radiotherapy (OR = 0.79, p = 0.007). Median OS was 3.2 years (95% CI 3.0–3.5). In de novo disease, Black race (HR = 1.48), metaplastic (HR = 3.15) or other non-ductal/lobular histologies (HR = 2.36), and grade 3 (HR = 1.67) predicted worse OS, whereas Hispanic ethnicity (HR = 0.74) and Other races (HR = 0.57), higher ER (HR = 0.48–0.41) and PR (HR = 0.72–0.53), and HER2-low status (HR = 0.77) conferred improved outcomes. In recurrent disease, Black race predicted worse OS (HR = 1.21, 95% CI 1.05–1.39), while Other race (HR = 0.78, 95% CI 0.62–0.97), higher ER (HR = 0.69–0.44) and PR (HR = 0.73–0.73), and HER2-low (HR = 0.89) were protective. HER2 discordance between primary and metastatic sites occurred in 38.8% of recurrent and 13.1% of de novo cases. Conclusions: HER2-low status was significantly associated with longer OS compared to HER2-0 status in both recurrent and de novo MBC cases. These real-world data help establish the prevalence of HER2-low status and its distinct outcomes. The discrepancy in HER2-low status between the primary tumor and metastatic sites highlights the potential for changes in HER2 expression over time, exploring the interaction between HER2-low breast cancer and the tumor microenvironment and emphasizing the importance of monitoring and reassessing HER2 status at various stages to guide treatment decisions effectively and the need for more quantitative and reproducible HER assays.

Supplementary Table 3: Difference in rates of HER2 loss and HER2 score decrease according to prior therapies.

Supplementary Table 1: Changes in HER2 status after treatment with T-DXd in patients with paired pre- and post-treatment biopsies

Supplementary Table 2: Details of patients with increased HER2 IHC score

Purpose:Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) that is HER2 positive [immunohistochemistry (IHC) score of 3+ or in situ hybridization (ISH) positivity] or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2-overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 status might change following T-DXd therapy.Experimental Design:We retrospectively reviewed patients with MBC who received T-DXd at the University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC.Results:We included 41 patients with MBC who received treatment with T-DXd and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients [32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)] following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd.Conclusions:HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Reevaluation of HER2 status following T-DXd treatment should be considered prior to alternate HER2-targeted therapies that require HER2 overexpression for efficacy.

Supplementary Table 4: Sites of biopsy in included patients (including patients with HER2 0 at baseline) and correlation to HER2 loss

Purpose: Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) that is HER2 positive [immunohistochemistry (IHC) score of 3+ or in situ hybridization (ISH) positivity] or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2-overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 status might change following T-DXd therapy. Experimental Design: We retrospectively reviewed patients with MBC who received T-DXd at the University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC. Results: We included 41 patients with MBC who received treatment with T-DXd and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients [32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)] following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd. Conclusions: HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Reevaluation of HER2 status following T-DXd treatment should be considered prior to alternate HER2-targeted therapies that require HER2 overexpression for efficacy.