Association of Peritumoral Radiomics With Tumor Biology and Pathologic Response to Preoperative Targeted Therapy for <i>HER2 (ERBB2)</i>–Positive Breast Cancer
Authors: Nathaniel Braman, Prateek Prasanna, Jon Whitney, Salendra Singh, Niha Beig, Maryam Etesami, David D. B. Bates, Katherine Gallagher, B. Nicolas Bloch, Manasa Vulchi, Paulette Turk, Kaustav Bera, Jame Abraham, William M. Sikov, George Somlo, Lyndsay N. Harris, Hannah Gilmore, Donna Plecha, Vinay Varadan, Anant Madabhushi
Journal: JAMA Network Open (2019)

<h3>Importance</h3> 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<i>ERBB2</i>, but referred to as<i>HER2</i>in this study)–targeted therapy in breast cancer. <h3>Objective</h3> To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize<i>HER2</i>-positive tumor biological factors and estimate response to<i>HER2</i>-targeted neoadjuvant therapy. <h3>Design, Setting, and Participants</h3> 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<i>HER2</i>+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with<i>HER2</i>+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated<i>HER2</i>-enriched (<i>HER2</i>-E) molecular subtype within<i>HER2</i>+ 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<i>HER2</i>-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. <h3>Main Outcomes and Measures</h3> Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying<i>HER2</i>+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with<i>HER2</i>-targeting. <h3>Results</h3> In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated<i>HER2</i>-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<i>HER2</i>-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to<i>HER2</i>-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 (<i>R</i><sup>2</sup> = 0.57; 95% CI, 0.39-0.75;<i>P</i> = .002). <h3>Conclusions and Relevance</h3> A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of<i>HER2</i>+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.