Association of Peritumoral Radiomics With Tumor Biology and Pathologic Response to Preoperative Targeted Therapy for HER2 (ERBB2)-Positive Breast Cancer

Abstract

Importance: There has been significant recent interest in understanding the utility of quantitative imaging to delineate breast cancer intrinsic biological factors and therapeutic response. No clinically accepted biomarkers are as yet available for estimation of response to human epidermal growth factor receptor 2 (currently known as ERBB2, but referred to as HER2 in this study)-targeted therapy in breast cancer.

Objective: To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize HER2-positive tumor biological factors and estimate response to HER2-targeted neoadjuvant therapy.

Design, setting, and participants: In a retrospective diagnostic study encompassing 209 patients with breast cancer, textural imaging features extracted within the tumor and annular peritumoral tissue regions on MRI were examined as a means to identify increasingly granular breast cancer subgroups relevant to therapeutic approach and response. First, among a cohort of 117 patients who received an MRI prior to neoadjuvant chemotherapy (NAC) at a single institution from April 27, 2012, through September 4, 2015, imaging features that distinguished HER2+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with HER2+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated HER2-enriched (HER2-E) molecular subtype within HER2+ tumors (n = 42) was identified. The association of this signature with pathologic complete response was explored in 2 patient cohorts from different institutions, where all patients received HER2-targeted NAC (n = 28, n = 50). Finally, the association between significant peritumoral features and lymphocyte distribution was explored in patients within the BrUOG 211B trial who had corresponding biopsy hematoxylin-eosin-stained slide images. Data analysis was conducted from January 15, 2017, to February 14, 2019.

Main outcomes and measures: Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying HER2+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with HER2-targeting.

Results: In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated HER2-E tumors (maximum AUC, 0.85; 95% CI, 0.79-0.90; 9-12 mm from the tumor) compared with intratumoral features (AUC, 0.76; 95% CI, 0.69-0.84). A classifier combining peritumoral and intratumoral features identified the HER2-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to HER2-targeted therapy in both validation cohorts (AUC, 0.80; 95% CI, 0.61-0.98 and AUC, 0.69; 95% CI, 0.53-0.84). Features from the 0- to 3-mm peritumoral region were significantly associated with the density of tumor-infiltrating lymphocytes (R2 = 0.57; 95% CI, 0.39-0.75; P = .002).

Conclusions and relevance: A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of HER2+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.

Figure 1.. Experimental Design

eFigure 2 in the Supplement depicts the process of developing imaging signatures associated with receptor status (experiment 1) and HER2+ molecular subtype (experiment 2). HER2-E indicates HER2-enriched; HR, hormone receptor; pCR, pathologic complete response; PRC1, pathologic response cohort 1; PRC2, pathologic response cohort 2; and TN, triple negative.

Figure 2.. Peritumoral Signature of HER2-Enriched (HER2-E) Identifies Responders to HER2-Targeted Therapy

A, Co-occurrence of local anisotropy gradients (CoLlAGe) feature expression maps visualize the elevated disorder of local intensity gradient orientations within the peritumoral region of HER2-E relative to non–HER2-E breast cancers. B, Imaging signature of HER2-E is also associated with pathologic complete response (pCR) to anti-HER2 therapy, with rippled enhancement patterns detected intratumorally by Laws feature and elevated local peritumoral heterogeneity captured by CoLlAGe features 9 to 12 mm from the tumor characterizing both features. NAC indicates neoadjuvant chemotherapy. Radiomic feature values are unitless, thus the scale depicts relative expression values of radiomic features, standardized between 0 and 1.0 based on the range of their distribution. The blue color at 0 depicts the minimum observed feature value; the red color at 1.0 depicts the maximum observed feature value.

Figure 3.. Molecular Subtype Signatures Within the Peritumoral Region Associated With Lymphocyte Density and Distribution on Biopsy

A, Kurtosis of Gabor features 0 to 3 mm from the tumor on magnetic resonance imaging, associated with HER2-enriched (HER2-E) status was additionally associated with B, lymphocyte density within and 0-3 mm beyond the tumor on corresponding biopsy samples. Red and blue dots indicate lymphocytes and other nuclei, respectively. Green lines denote pathologist-annotated tumor boundaries (hematoxylin-eosin; inset original magnification ×100). C, When hematoxylin-eosin–stained images are down-sampled to approximate the imaging scale (original magnification ×100), midfrequency Gabor features computed on example hematoxylin-eosin images at that magnification possess spatial association with lymphocyte density. Radiomic feature values are unitless, thus the scale depicts relative expression values of radiomic features, standardized between 0 and 1.0 based on the range of their distribution. The blue color at 0 depicts the minimum observed feature value; the red color at 1.0 depicts the maximum observed feature value.