Neoadjuvant HER2 Inhibitor Therapy and Effect of Molecular Heterogeneity on Response in HER2-Positive Breast Cancer


Get Permission

Lisa A. Carey, MD

[Pathologic complete response] to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pathologic complete response rates.

—Lisa A. Carey, MD, and colleagues

In the phase III CALGB 40601 trial, reported in the Journal of Clinical Oncology by Lisa A. Carey, MD, of University of North Carolina at Chapel Hill, and colleagues, pathologic complete response rate was not significantly increased by adding neoadjuvant trastuzumab (Herceptin) plus lapatinib (Tykerb) vs trastuzumab alone to paclitaxel in women with stage II or III HER2-positive breast cancer—although significant benefit was observed with dual inhibition in patients with hormone receptor–positive disease.1 Tumor and microenvironment heterogeneity significantly affected pathologic complete response rates.

Study Details

In the trial, 305 patients underwent tumor biopsy followed by randomization between December 2008 and February 2012 to neoadjuvant paclitaxel at 80 mg/m2 once weekly for 16 weeks with trastuzumab at a loading dose of 4 mg/kg in week 1 and at 2 mg/kg thereafter and lapatinib at a dose that was reduced from 1,000 mg/d early in accrual to 750 mg/d (n = 118), trastuzumab alone (n = 120), or lapatinib alone (n = 67). The paclitaxel/lapatinib arm was closed early (based on reports of inferiority and greater toxicity with lapatinib-only regimens).

The primary endpoint was pathologic complete response in the breast. Correlative endpoints consisted of molecular features identified by gene expression–based assays.

Pathologic Complete Response Rates

The pathologic complete response rates were 56% (95% confidence interval [CI] = 47%–65%) in the trastuzumab/lapatinib group vs 46% (95% CI = 37%–55%) in the trastuzumab group (P = .13). Pathologic complete response rates were 41% vs 41% among 139 patients in the two groups with hormone receptor–positive disease and 79% vs 54% (P = .01) among 82 with hormone receptor–negative disease. The pathologic complete response rate in the early-terminated lapatinib group was 32%, including rates of 29% in 37 hormone receptor–positive patients and 37% in 27 hormone receptor–negative patients (P = .09).

HER2 Inhibitor Therapy

■ The addition of trastuzumab/lapatinib vs trastuzumab alone to paclitaxel did not signi cantly increase pathologic complete response rate. ■ On multivariate analysis, intrinsic subtype, HER2 amplicon gene expression, TP53 mutation signature, and IgG immune cell signature were independently associated with pathologic complete response.

Multivariable Analysis

Pathologic complete response rates varied significantly by intrinsic subtype (P < .001), with the rate being approximately twice as high in HER2-enriched tumors (70%) compared with luminal A (34%) and luminal B (36%) subtypes, irrespective of treatment group or hormone receptor status.

In multivariable analysis, treatment group (trastuzumab/lapatinib vs trastuzumab and trastuzumab vs lapatinib groups; P = .077), intrinsic subtype (P = .0264), increased HER2 amplicon gene expression (P = .0252), TP53 mutation signature (P = .0119), and IgG immune cell signature (P = .0024) were independently associated with pathologic complete response, with no significant association of hormone receptor status and pathologic complete response observed.

ESR1 and ERBB2 gene expression were highly associated with pathologic complete response as continuous variables. In an exploratory multivariate analysis including these genes, factors independently associated with pathologic complete response were ESR1 (P = .0139), ERBB2 (P < .001), TP53 signature (P = .014), IgG signature (P = .0112), and treatment group (P = .0114), whereas no significant association was found for intrinsic subtype overall, HER2 amplicon signature, or hormone receptor status.

Post-treatment residual disease was mostly luminal A (69%), found in 25%, 15%, and 7% of specimens that were luminal A, luminal B, and HER2-enriched on pretreatment assessment.

The investigators concluded: “[Pathologic complete response] to dual HER2-targeted therapy was not significantly higher than single HER2 targeting. Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pathologic complete response rates. These factors should be considered when interpreting and designing trials in HER2-positive disease.” ■

Disclosure: CALGB 40601 was supported by grants from the National Cancer Institute, Breast Cancer Research Foundation, Susan G. Komen, and GlaxoSmithKline. Dr. Carey has received research funding from GlaxoSmithKline and Genentech/Roche. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

  1. Carey LA, Berry DA, Cirrincione CT, et al: Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. November 2, 2015 (early release online).

 


Advertisement

Advertisement



Advertisement