Pooled Analysis Finds HER2-Low–Positive Breast Cancer Could Be Identified as New Breast Cancer Subgroup by IHC Testing

Distinct from HER2-zero tumors, HER2-low–positive tumors can be recognized as a new subgroup of breast cancer that can be identified via standardized immunohistochemistry (IHC), according to a pooled analysis of patient data published in Lancet Oncology.

Hormone receptor (HR) positivity was observed in 64.0% of patients with HER2-low–positive tumors compared with 36.7% of patients with HER2-zero tumors (P< .0001). HER2-low-positive tumors also had a significantly lower pathological complete response (CR) rate (29.2%) than HER2-zero tumors (39.0%; P = .0002).

“For a long time, the biological model of breast cancer has been based on the subtypes [HR]­positive HER2­-negative, HER2-­positive, and triple-­negative breast cancer,” the investigators wrote. “Our study supports the view that additional clinically relevant subtypes of breast cancer exist.”

The pooled analysis pulled patient data from 4 clinical trials: the phase 3 GeparSepto trial (NCT01583426) assessing nanoparticle-based paclitaxel vs solvent-based paclitaxel plus neoadjuvant chemotherapy for early breast cancer; the phase 3 GeparOcto study (NCT02125344) examining neoadjuvant dose intensified approaches for high-risk early breast cancer; the phase 2 GeparX trial (NCT02682693) which utilized denosumab as part of a neoadjuvant regimen in several types of breast cancer; and the phase 3 Gain­2 study (NCT01690702), utilizing nab-paclitaxel as a treatment for high-risk early breast cancer. Recruitment for these trials that comprised the analysis’s cohort took place between July 30, 2012 and March 20, 2019.

Pathological CR based on review of local histopathological reports was the pooled analysis’ primary end point. Key secondary end points included Disease-free survival (DFS) and overall survival (OS).

The median follow­ups were 46.6 months overall (IQR, 35.0-52.3) excluding GeparX, 50.0 months (IQR, 45.9-54.4) in GeparSepto, 45.6 months (IQR, 40.0-50.8) in GeparOcto, and 30.2 months (IQR, 22.8-34.1) in Gain­2.

A total of 2310 patients were included in the pathologic CR analysis, 47.5% of whom had HER2-­low-­positive tumors and 52.5% had HER2­zero tumors.

In the HR-positive subgroup, pathological CR was lower among patients with HER2-low–positive tumors (17.5%) compared with HER2-zero tumors (23.6%; P = .024), although it was not significantly lower in the HR-negative subgroup (50.1% vs 48.0%; P = .21).

Three-year DFS was significantly longer among patients with HER2-low–positive tumors (83.4%; 95% CI, 80.5%-85.9%) compared with patients who had HER2-zero tumors (76.1%; 95% CI, 72.9%-79.0%; stratified log-rank test P = .0084). A similar trend for 3-year OS was seen in patients with HER2-low–positive tumors (91.6%; 95% CI, 84.9%-93.4%) compared with HER2-zero tumors (85.8%; 95% CI, 83.0%-88.1%; stratified log-rank test P = .0016).

The clinical trial cohort heterogeneity was a limiting factor for this pooled analysis, according to the research team. Moreover, differences DFS results might become more evident with longer follow-up for this group of patients.

“In breast cancer, these new subtypes can be distinguished by standardized pathological assessment of hormone receptors and HER2 with particular focus on HER2-­low­-positive tumors. This approach will result in a much more complex biological landscape of breast cancer subtypes and will also offer new targeted therapeutic options for improvement of breast cancer outcome,” the investigators concluded.

Reference

Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021;22(8):1151-1161. doi:10.1016/S1470-2045(21)00301-6