Distribution of 21-Gene Recurrence Scores Among Breast Cancer Histologic Subtypes Scott Kizy, MD; Jing Li Huang, MD; Schelomo Marmor, PhD, MPH; Anne Blaes, MD, MS; Jianling Yuan, MD, PhD; Heather Beckwith, MD; Todd M. Tuttle, MD, MS; Jane Yuet Ching Hui, MD, MS  Context.—The 21-gene recurrence score (RS) provides a probability of distant recurrence for estrogen receptor– positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancers. The utility of RS for rarer histologic subtypes of breast cancer is uncertain. Objective.—To determine the distribution of RS among various histologic subtypes using a population database. Design.—Women between the ages of 18 and 75 with estrogen receptor-positive, HER2-negative breast cancer and known RS results were identified using the Surveil- lance, Epidemiology, and End Results database. Recurrence scores were categorized into risk groups using both traditional and Trial Assigning Individualized Options for Treatment cutoffs. Multivariable logistic regression was used to determine factors associated with high-risk RS. Results.—We identified 45 618 patients with stage I to III, estrogen receptor–positive, HER2-negative breast cancer who had RS available. Overall, 3087 (7%) and 6337 (14%) of cancers were classified as high risk based on traditional and Trial Assigning Individualized Options for Treatment RS cutoffs, respectively. The proportion of high- risk RS ranged from 1% (tubular, 2 of 225) to 68% (medullary, 13 of 19) and 4% (tubular, 10 of 225) to 79% (medullary, 15 of 19) for traditional and Trial Assigning Individualized Options for Treatment cutoffs, respectively. Based on multivariable logistic regression (excluding medullary), subtypes other than invasive ductal carcinoma and papillary carcinoma were significantly associated with lower RS. The strongest predictors of a high-risk RS were higher tumor grade and negative progesterone receptor status. Conclusions.—We identified distinct distributions of RS among different histologic subtypes of breast cancer. Excluding medullary carcinoma, histologic subtypes other than invasive ductal carcinoma and papillary carcinoma all predict lower RS. (Arch Pathol Lab Med. 2018;142:735–741; doi: 10.5858/ arpa.2017-0169-OA) B reast cancer is a heterogeneous disease comprising several subtypes that differ in clinical and pathologic characteristics. 1,2 Invasive ductal carcinoma (IDC) is the most common histologic variant and accounts for 70% to 80% of cases. 3 Invasive lobular carcinoma (ILC) is the next most common subtype, affecting 15% of breast cancer diagnoses. 2 Several genomic and prognostic differences have been demonstrated between ILC and IDC. 4 Other histologic subtypes, including mixed ductal/lobular, tubular, mucinous, papillary, and medullary carcinoma, all have distinct clinical and biologic features. 1,2,5–7 Although breast cancer remains the most commonly diagnosed malignancy in women, 8 relatively little is understood about these less common subtypes. Underscoring the heterogeneity of breast cancer is the differential effectiveness of adjuvant chemotherapy. For patients with estrogen receptor (ER)–positive disease, clinical trials have shown improvement in disease-free and overall survival with adjuvant chemotherapy. 9 How- ever, approximately 85% of women with early-stage breast cancer treated with endocrine therapy alone remain disease free at 10 years. 9 Taken together, these results suggest that a majority of patients with ER-positive breast cancer may be overtreated, especially if chemotherapy is administered. To this end, genomic markers that help predict the risk of recurrence and benefit of adjuvant chemotherapy have been extensively researched. Oncotype DX (Genomic Health, Redwood City, California) is a 21- gene expression assay currently used in clinical practice to estimate the risk of distant recurrence. 10 This reverse transcriptase polymerase chain reaction-based test assess- es the expression of several cancer-related genes associated with tumor invasion and proliferation. 11 Patients are categorized based on recurrence score (RS) into low-risk, intermediate-risk, and high-risk groups. 12 The RS has been validated for predicting benefit from chemotherapy using retrospective analyses of the prospective NSABP B-20 and SWOG-8814 trials for ER-positive patients with node- Accepted for publication September 15, 2017. Published as an Early Online Release March 12, 2018. Supplemental digital content is available for this article at www. archivesofpathology.org in the June 2018 table of contents. From the Department of Surgery (Drs Kizy, Huang, Marmor, Tuttle, and Hui), the Division of Hematology, Oncology, and Transplanta- tion (Drs Blaes and Beckwith), and the Department of Radiation Oncology (Dr Yuan), University of Minnesota, Minneapolis. Dr Tuttle holds an advisory board position for Genomic Health. The other authors have no relevant financial interest in the products or companies described in this article. Presented at the American College of Surgeons; October 26, 2017; San Diego, California. Corresponding author: Jane Yuet Ching Hui, MD, MS, Department of Surgery, University of Minnesota, 420 Delaware St SE, Mayo Mail Code 195, Minneapolis, MN 55455 (email: jhui@umn.edu). Arch Pathol Lab Med—Vol 142, June 2018 Breast Cancer Subtypes and Oncotype DX RS—Kizy et al 735