Chicago, Illinois—Study findings to be presented at the 2019 ASCO Annual Meeting show that intratumor HER2 heterogeneity (ITH-HER2) evaluated routinely via pathology is a strong prognosticator of pathologic complete response (pCR) to treatment with a dual-HER2 targeted therapy.

“HER2 targeted therapy without chemotherapy may be insufficient to completely eradicate a HER2+ cancer in cases of significant [ITH-HER2],” explained Otto Metzger Filho, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and colleagues.

Dr Filho et al conducted a single-arm, phase 2 clinical trial of 164 patients with HER2-positive breast cancer given 6 cycles of trastuzumab emtansine plus pertuzumab before surgery. There were 2 patients who ultimately withdrew consent.

ITH-HER2, defined as ≥1 of the 6 areas demonstrating HER2-positivity via FISH in >5% and <50% of tumor cells or an area of tumor that tested HER2-negative, was assessed at baseline on ultrasound-guided core biopsies from 2 distinct areas of each tumor.

The primary end point of the study was the relationship between pCR (defined as residual cancer burden of 0) and ITH, stratified by estrogen receptor (ER) status.

Imaging revealed a median tumor size of 2.8 cm; 111 (69%) were ER-positive and 51 (32%) ER-negative. Ultimately, 8 patients discontinued treatment—6 because of disease progression and 2 because of toxicity.

Approximately 50% of patients had a pCR (residual cancer burden, 0), whereas 14% had residual cancer burden 1, 26% had residual cancer burden 2, and 11% had residual cancer burden 3. Of note, there were higher rates of 0 residual cancer burden observed in patients with ER-negative versus ER-positive tumors (65% vs 42%, respectively).

Findings also demonstrated that ITH-HER2 was detected in 10% of evaluable patients (n = 157), and that there was no pCR observed among cases classified as heterogeneous.

“The study met its primary endpoint by demonstrating a significant association between ITH-HER2 and pCR stratified by ER status,”Dr Filho et al said.

In addition, secondary analysis showed a significant link between ITH-HER2 and pathologic response defined as RCB 0 or 1, and exploratory analysis revealed higher rates of 0 residual cancer burden in patients with tumors centrally classified as HER2 3+ (56%) versus HER2 2+ (27%).

The relationship between ITH-HER2 and pCR preserved when patients were stratified by ER-status and HER2 ImmunoHistoChemistry (2+ vs 3+; P = .002).

“ITH-HER2 assessed by routine pathology evaluation is a strong predictor of pCR to a dual-HER2 targeted therapy regimen. If validated, ITH-HER2 may need to be considered in selection of pts for HER2-targeted regimens without chemotherapy in the curative setting,” Dr Filho and colleagues concluded.—Hina Khaliq

Filho OM, Viale G, Trippa L, et al. HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial. Presented at: the 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 502.