Association of Peritumoral Radiomics With Tumor Biology and Pathologic Response to Preoperative Targeted Therapy for HER2 (ERBB2)–Positive Breast Cancer | Breast Cancer | JAMA Network Open | JAMA Network
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    Original Investigation
    April 19, 2019

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

    Author Affiliations
    • 1Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
    • 2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
    • 3Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, Connecticut
    • 4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
    • 5Department of Radiology, Boston Medical Center, Boston, Massachusetts
    • 6Department of Radiology, Boston University School of Medicine, Boston, Massachusetts
    • 7Department of Hematology and Medical Oncology, The Cleveland Clinic, Cleveland, Ohio
    • 8Department of Diagnostic Radiology, The Cleveland Clinic, Cleveland, Ohio
    • 9Program in Women’s Oncology, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
    • 10Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
    • 11Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California
    • 12National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • 13Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio
    • 14Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio
    • 15Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, Ohio
    JAMA Netw Open. 2019;2(4):e192561. doi:10.1001/jamanetworkopen.2019.2561
    Key Points español 中文 (chinese)

    Question  Can quantitative imaging features extracted from the tumor and tumor environment on breast magnetic resonance imaging characterize tumor biological features relevant to outcome of targeted therapy?

    Findings  In this diagnostic study of 209 patients, among HER2 (ERBB2)-positive breast cancers, an intratumoral and peritumoral imaging signature capable of discriminating the response-associated HER2-enriched molecular subtype was identified. When evaluated among recipients of HER2-targeted therapy, this signature was found to be associated with response to neoadjuvant chemotherapy.

    Meaning  Quantitative analysis of the tumor and its surroundings may provide valuable cues into breast cancer biological features and likelihood of response to targeted therapy.


    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.