Imaging and Management of Fibroepithelial Lesions of the Breast: Radiologic-Pathologic Correlation.

Fibroepithelial lesions (FELs) are among the most common breast masses encountered by breast radiologists and pathologists. They encompass a spectrum of benign and malignant lesions, including fibroadenomas (FAs) and phyllodes tumors (PTs). FAs are typically seen in young premenopausal women, with a peak incidence at 20-30 years of age, and have imaging features of oval circumscribed hypoechoic masses. Although some FA variants are especially sensitive to hormonal influences and can exhibit rapid growth (eg, juvenile FA and lactational adenomas), most simple FAs are slow growing and involute after menopause. PTs can be benign, borderline, or malignant and are more common in older women aged 40-50 years. PTs usually manifest as enlarging palpable masses and are associated with a larger size and sometimes with an irregular shape at imaging compared with FAs. Although FA and FA variants are typically managed conservatively unless large and symptomatic, PTs are surgically excised because of the risk of undersampling at percutaneous biopsy and the malignant potential of borderline and malignant PTs. As a result of the overlap in imaging and histologic appearances, FELs can present a diagnostic challenge for the radiologist and pathologist. Radiologists can facilitate accurate diagnosis by supplying adequate tissue sampling and including critical information for the pathologist at the time of biopsy. Understanding the spectrum of FELs can facilitate and guide appropriate radiologic-pathologic correlation and timely diagnosis and management of PTs. Published under a CC BY 4.0 license. Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.

Intraoperative evaluation of sentinel lymph nodes in patients with breast cancer treated with systemic neoadjuvant therapy.

AIMS: Touch preparation (TP) and frozen section (FS) are the two methods routinely used in the intraoperative evaluation (IOE) of sentinel lymph nodes (SLNs) to detect metastases in patients with breast cancer. Both methods are extremely sensitive and specific in the primary surgery (non-neoadjuvant systemic therapy (non-NST)) setting. Since NST introduces unique challenges in the IOE of SLNs, the aim was to determine the accuracy of TP and FS in the IOE of SLNs in the NST setting and compare the results with the non-NST setting and to examine factors that contribute to any differences. METHODS: We analysed 871 SLNs from 232 patients (615 SLNs from NST and 256 SLNs from non-NST settings) between 2016 through 2019. RESULTS: In the NST group, TP alone (n=366) had a sensitivity of 45.7% and specificity of 99.7%; FS alone (n=90) had a sensitivity of 83.3% and specificity of 100%. When both TP and FS (n=135) were used, the sensitivity was 80.3% and the specificity was 98.6%.In the non-NST group, TP alone (n=193) had a sensitivity of 66.7% and specificity of 100%; FS alone (n=22) had a sensitivity and specificity of 100%; and combined TP and FS (n=34) had a sensitivity and specificity of 100% and 96%, respectively. CONCLUSIONS: Evaluating SLNs intraoperatively in the NST setting can be challenging secondary to therapy-related changes. In the NST setting, FS has higher sensitivity and specificity compared with TP for the IOE of SLNs and should be the preferred method.

Mediastinal Myxofibrosarcoma Harboring Loss-of-Function MSH2 Variant in a Patient With Lynch Syndrome: A Case Report and Literature Review.

Myxofibrosarcoma is a malignant fibroblastic neoplasm that commonly arises in the extremities, with mediastinum being a very rare location. The development of sarcomas is uncommon in patients with Lynch syndrome. We present a Lynch syndrome patient with synchronous cecal adenocarcinoma and mediastinal myxofibrosarcoma with both harboring the same loss-of-function MSH2 alteration (c.2634 + 1G > A splice region variant). Metastatic myxofibrosarcoma in the left chest wall developed 6 months after the initial diagnosis. The clinical presentation, imaging findings, histopathology, and molecular studies along with differential diagnoses are presented and discussed.

Case Report of Fibro-Adipose Vascular Anomaly (FAVA) with Activating Somatic PIK3CA Mutation.

Fibro-adipose vascular anomaly (FAVA) is a recently described complex and painful benign lesion found in young adults and the pediatric population composed of intramuscular vascular, fibrous, and adipose tissues. A previous report has identified the presence of somatic mosaic mutations in the gene for the catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) in cases of FAVA. Herein, we present a case of FAVA found in a 23-year-old male patient who presented with chronic wrist pain associated with a mass, and we identified an associated somatic activating mutation (H1047R) in PIK3CA. We briefly review the relevant literature surrounding the identification and histology of FAVA, the known mutational spectrum, downstream signaling pathways, and relevant treatment modalities. Our case highlights the association between FAVA and somatic mosaic activating PIK3CA mutations.

Radiologic-Pathologic Correlation of Fibroepithelial Lesions: A Pictorial Review.

Fibroepithelial lesions (FEL) of the breast encompass a spectrum of masses ranging from benign to malignant. Although these lesions are on the same biologic spectrum, differences in their clinical behaviors necessitate different management approaches. While imaging features are nonspecific, small size (less than 3 cm), oval shape, circumscribed margins, growth in diameter less than 20% in six months, and homogeneous echotexture on US favor fibroadenoma (FA). Conversely, larger size (3 cm or larger), rapid growth, irregular shape, noncircumscribed margins, and heterogeneous echotexture suggest possible phyllodes tumor (PT). Histopathologically, increased stromal cellularity, stromal atypia, and mitotic activity characterize PT, while FA typically lack these features. In this review, we summarize the imaging and pathology characteristics of nonmalignant FEL, including simple, juvenile, and complex FA, and benign and borderline PT and highlight the collaborative role of radiologists and pathologists in informing diagnosis and clinical management.

Pathophysiology and Molecular Imaging of Diabetic Foot Infections.

Diabetic foot infection is the leading cause of non-traumatic lower limb amputations worldwide. In addition, diabetes mellitus and sequela of the disease are increasing in prevalence. In 2017, 9.4% of Americans were diagnosed with diabetes mellitus (DM). The growing pervasiveness and financial implications of diabetic foot infection (DFI) indicate an acute need for improved clinical assessment and treatment. Complex pathophysiology and suboptimal specificity of current non-invasive imaging modalities have made diagnosis and treatment response challenging. Current anatomical and molecular clinical imaging strategies have mainly targeted the host's immune responses rather than the unique metabolism of the invading microorganism. Advances in imaging have the potential to reduce the impact of these problems and improve the assessment of DFI, particularly in distinguishing infection of soft tissue alone from osteomyelitis (OM). This review presents a summary of the known pathophysiology of DFI, the molecular basis of current and emerging diagnostic imaging techniques, and the mechanistic links of these imaging techniques to the pathophysiology of diabetic foot infections.

Conventional and advanced MR imaging insights of synovial sarcoma.

OBJECTIVES: Synovial sarcomas commonly involve extremities. The purpose of this study was to systematically assess and describe the appearance of pathologically proven synovial sarcomas on conventional MR sequences, diffusion weighted imaging and dynamic contrast enhanced imaging. METHODS: In this cross-sectional retrospective study, fifteen pre-operative MRIs were analyzed separately by two musculoskeletal radiologists and a fellow. MRI features of synovial sarcomas were evaluated in a systematic fashion on conventional and advanced MR sequences. RESULTS: The tumors demonstrated heterogeneous appearance on conventional MR sequences. Peritumoral edema was absent in four of 15 (27%) lesions including grade 2 and grade 3 tumors. Average minimum ADC was 0.8 × 10-3 mm2/s and average mean ADC was 1.2 × 10-3 mm2/s. There was avid early arterial phase enhancement on contrast imaging. Average relative enhancement of the tumors was 5.7 times compared to the adjacent skeletal muscle. CONCLUSION: Synovial sarcomas demonstrate avid early arterial phase post-contrast enhancement on contrast images, low ADC values, and heterogeneous appearance on conventional MRI sequences. Peritumoral edema may be absent in such tumors despite being high grade tumors.

Clinical Non-Small Cell Lung Cancer Staging and Tumor Length Measurement Results From U.S. Cancer Hospitals.

RATIONALE AND OBJECTIVES: Examine the accuracy of clinical non-small cell lung cancer staging and tumor length measurements, which are critical to prognosis and treatment planning. MATERIALS AND METHODS: Compare clinical and pathological staging and lengths using 10,320 2016 National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) and 559 2010-2018 non-SEER single-institute surgically-treated cases, and analyze modifiable causes of disagreement. RESULTS: The SEER clinical and pathological group-stages agree only 62.3% ± 0.9% over all stage categories. The lymph node N-stage agrees much better at 83.0% ± 1.0%, but the tumor length-location T-stage agrees only 57.7% ± 0.8% with approximately 29% of the cases having a greater pathology than clinical T-stage. Individual T-stage category agreements with respect to the number of pathology cases are Tis, T1a, T1b, T2a, T2b, T3, T4: 89.9% ± 10.0%; 78.7% ± 1.7%; 51.8% ± 1.9%; 46.1% ± 1.3%; 40.5% ± 3.1%; 44.1% ± 2.2%; 56.4% ± 4.7%, respectively. Most of the single-institute results statistically agree with SEER's. Excluding Tis cases, the mean difference in SEER tumor length is ∼1.18 ± 9.26 mm (confidence interval: 0.97-1.39 mm) with pathological lengths being longer than clinical lengths except for small tumors; the two measurements correlate well (Pearson-r >0.87, confidence interval: 0.86-0.87). Reasons for disagreement include the use of family-category descriptors (e.g., T1) instead of their subcategories (e.g., T1a and T1b), which worsens the T-stage agreement by over 15%. Disagreement is also associated with higher tumor grade, larger resected specimens, higher N-stage, patient age, and periodic biases in clinical and pathological tumor size measurements. CONCLUSIONS: By including preliminary non-small cell lung cancer clinical stage values in their evaluation, diagnostic radiologists can improve the accuracy of staging and standardize tumor-size measurements, which improves patient care.

Secondary Angiosarcoma With C-MYC Amplification Following Prophylactic Bilateral Mastectomy and Autologous Breast Reconstruction: Report of a Case and Review of the Literature.

In this article, we report a very rare case of secondary angiosarcoma in a young woman with no prior history of breast cancer who had bilateral prophylactic mastectomies with autologous reconstruction due to a strong family history of breast cancer and BRCA1 gene variant of uncertain significance. The surgery was complicated by recurrent fat necrosis requiring several excisions and additional reconstruction followed by the development of localized lymphedema and subsequent angiosarcoma in the reconstructed breast 10 years later. The angiosarcoma was high grade with prominent epithelioid features associated with abundant tumor-infiltrating lymphocytes. Amplification of C-MYC locus 8q21.24 was demonstrated by fluorescence in situ hybridization study. We postulate that chronic trauma from several surgeries including tissue hypoxia and impaired lymphatic drainage may have provided a milieu for angiogenesis and mutagenic transformation. Amplification of C-MYC locus 8q21.24 was most likely a strong oncogenic driver of angiosarcoma. To the best of our knowledge, this is the first report of its kind in the literature.

Neurofibroma in the Breast: Diagnosis and Management Considerations.

Neurofibroma (NF) of the breast is an uncommon benign entity that occurs sporadically or in association with neurofibromatosis type 1 (NF1). Sporadic NF of the breast is very rare and can present at any age. Neurofibroma of the breast associated with NF1 is more common. Neurofibroma commonly presents as oval, circumscribed masses that overlap with many benign entities. The histopathologic diagnosis of NF of the breast can present a management dilemma for the breast radiologist. An NF that is not associated with NF1 has good post-resection prognosis if superficial, sporadic, and solitary. However, NF of the breast diagnosed in an otherwise healthy patient should prompt evaluation for NF1 and formal genetic risk assessment. Patients diagnosed with NF1 have a higher lifetime risk for developing breast cancer and therefore may benefit from both initiating screening mammography at a younger age and supplemental screening MRI.

Genomic heterogeneity in peritoneal implants: A differential analysis of gene expression using nanostring Human Cancer Reference panel identifies a malignant signature.

OBJECTIVES: Peritoneal implants of ovarian borderline serous tumors are diagnostically challenging. Distinguishing invasive from non-invasive cases is crucial for patient management. This study aims to develop a molecular signature to distinguish invasive implants with malignant potential from those with benign. METHODS: Archival formalin-fixed paraffin embedded tissues were retrieved from 3 institutions, with consensus histologic review. Lesions were classified as a non-invasive implant (n = 10), invasive implant (n = 9) or high grade (HG) peritoneal metastasis from HG serous ovarian carcinoma (n = 4). The nCounter® GX Human Cancer Gene Reference Assay was used to profile expression of 230 cancer genes and 6 control genes. The DEGs in HG peritoneal metastases compared to non-invasive implants were identified using T-tests performed in the NanoString Diff package, then used to cluster cases using the Eisen cluster 3.0 package. Lasso in glmnet package was used to select the subset of genes that most strongly correlate with a malignant potential. RESULTS: 37 genes were downregulated and 16 genes were upregulated in HG peritoneal metastases. Using this 53-gene signature, one of nine of the invasive implants clustered with the HG peritoneal metastasis. Expression of ABCB1, CDC2, CDKN1A, FAT1, MMP9, MSH2, NQO1 and TOP2A were sufficient to indicate malignant potential of implants. The HG peritoneal metastasis and one invasive implant exhibited a high malignant likelihood (>92%) whereas the non-invasive implants and eight invasive implants displayed a low malignant likelihood (≤0.1%). CONCLUSIONS: Invasive implants are heterogenous and often morphologically indistinguishable lesions with transcriptomes that may be classified as malignant or not. Additional research is needed to determine the importance of these genes as drivers and/or surrogates of malignant potential, and their utility for triaging invasive implants.

Conventional MR and diffusion-weighted imaging of musculoskeletal soft tissue malignancy: correlation with histologic grading.

AIM: To evaluate proven soft tissue musculoskeletal malignancies blinded to their Fédération Nationale des Centres de Lutte Contre le Cancer histologic grades to identify the predictive values of conventional MR findings and best fit region of interest (ROI) apparent diffusion coefficient (ADC) measurements. MATERIALS AND METHODS: Fifty-one consecutive patients with different histologic grades were evaluated by four readers (R1-4) of different experience levels. Quantitatively, the maximum longitudinal size, tumor to muscle signal intensity ratios, and ADC measurements and, qualitatively, the spatial location of the tumor, its signal alterations, heterogeneity, intralesional hemorrhage or fat, and types of enhancement were assessed. Intraclass correlation, weighted kappa, ANOVA, and Fisher exact tests were used. RESULTS: There were 22/51 (43%) men (mean age ± SD = 52 ± 16 years) and 29/51 (57%) women (mean age ± SD = 54± 17 years), with the majority of tumors 38/51 (75%) in the lower extremities. Histologic grades were I in 8/51 (16%), II in 17/51 (33%), and III in 26/51 (51%), respectively. The longitudinal dimensions were different among three grades (p = 0.0015), largest with grade I. More central enhancements and deep locations were seen in grade III tumors (p = 0.0191, 0.0246). The ADC mean was significantly lower in grade III than in grade I or II (p < 0.0001 and p = 0.04). The ADC min was significantly lower in grade III than in grade I (p = 0.02). Good to excellent agreements were seen for T1/T2 tumor/muscle ratios, longitudinal dimension, and ADC (ICC = 0.60-0.98). CONCLUSION: Longitudinal tumor dimension, central enhancement, and ADC values differentiate histology grades in musculoskeletal soft tissue malignancy with good to excellent inter-reader reliability. KEY POINTS: • The longitudinal tumor dimension of grade III malignancy is smaller than that of grade I (p < 0.0001), and higher-grade tumors are located deeper (p = 0.0246). • The ADC mean is significantly lower in grade III than in grade I or grade II (p < 0.0001 and p = 0.04). • The ADC minimum is significantly lower in grade III than in grade I (p = 0.02).

Frequency of breast cancer subtypes among African American women in the AMBER consortium.

BACKGROUND: Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. METHODS: Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression. RESULTS: Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%). CONCLUSIONS: Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.

Pathologic Findings of Breast Lesions Detected on Magnetic Resonance Imaging.

CONTEXT: - Breast magnetic resonance imaging (MRI) is now used routinely for high-risk screening and in the evaluation of the extent of disease in newly diagnosed breast cancer patients. Morphologic characteristics and the kinetic pattern largely determine how suspicious a breast lesion is on MRI. Because of its high sensitivity, MRI identifies a large number of suspicious lesions. However, the low to moderate specificity and the additional cost have raised questions regarding its frequent use. OBJECTIVES: - To identify the pathologic entities that frequently present as suspicious enhancing lesions and to identify specific MRI characteristics that may be predictive of malignancy. DESIGN: - One hundred seventy-seven MRI-guided biopsies from 152 patients were included in the study. The indication for MRI, MRI features, pathologic findings, and patient demographics were recorded. The MRI findings and the pathology slides were reviewed by a dedicated breast radiologist and breast pathologists. RESULTS: - Seventy-one percent (126 of 177) of MRI-guided breast biopsies were benign, 11% (20 of 177) showed epithelial atypia, and 18% (31 of 177) showed malignancy. The vast majority (84%; 62 of 74) of MRI lesions with persistent kinetics were benign. However, 57% (17 of 30) of lesions with washout kinetics and 65% (62 of 95) of mass lesions were also benign. CONCLUSIONS: - Magnetic resonance imaging detects malignancies undetected by other imaging modalities but also detects a wide variety of benign lesions. Benign and malignant lesions identified by MRI share similar morphologic and kinetic features, necessitating biopsy for histologic confirmation.

Unusual skull tumors with psammomatoid bodies: a diagnostic challenge.

AIM: We describe a series of three diagnostically challenging, histologically similar fibro-osseous skull masses. METHODS: The cases were identified in our archives among 50,000 neuropathology specimens. A comprehensive review of the histological, immunohistochemical, ultrastructural, and imaging features as well as the clinical outcome was performed. RESULTS: The routine histology was similar in all 3 cases and showed spindle cell proliferations with frequent calcospheres or psammomatoid bodies. There was no evidence of an underlying subdural component. Immunohistochemistry for the meningioma markers EMA and SSTR2A raised the possibility of intraosseous meningioma, as all 3 lesions were convincingly positive for epithelial membrane antigen (EMA) and 1 lesion was convincingly positive for the somatostatin receptor subtype 2A (SSTR2A); weak, questionable positivity for SSTR2 was present in the remaining 2 cases. In addition, electron microscopy was available in 1 case and showed features consistent with meningioma. CONCLUSIONS: Overall, the findings were most consistent with intraosseous meningioma. Primary intraosseous meningiomas are rare lesions that may present a diagnostic challenge. It is important to consider meningiomas in the differential diagnosis, as extradural meningiomas are associated with an increased risk of recurrence and may occasionally undergo malignant transformation.
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Primary cutaneous histiocytoid carcinoma with distant metastasis.

Distinguishing primary cutaneous adnexal carcinoma from metastatic carcinoma of unknown primary can be a diagnostic challenge due to the frequent overlap of histologic and immunohistochemical features. A 58-year-old man presented with a tender, indurated plaque on axillary skin. Biopsy revealed infiltrating atypical cells throughout the dermis, without connection to the epidermis. Tumor cells had a histiocytoid appearance and displayed mild pleomorphism. The tumor was discohesive and had areas with a single file pattern. Signet ring cells were also present. Cells were reactive with CK7, CK5/6, p63, GATA3, GCDFP-15 and Her 2-neu. Additional studies were negative, including TTF-1, CDX2, E-cadherin, mammaglobin, estrogen receptor and progesterone receptor. Thorough clinical and radiologic evaluation failed to identify an occult primary extracutaneous malignancy; however, regional lymphadenopathy, widespread osteoblastic lesions and multiple subcentimeter liver hypodensities were noted. Considering the clinical and histopathologic features, the diagnosis of primary cutaneous histiocytoid carcinoma with distant metastasis was favored.

Breast cancer risk factor associations differ for pure versus invasive carcinoma with an in situ component in case-control and case-case analyses.

PURPOSE: Invasive ductal carcinoma (IDC) is diagnosed with or without a ductal carcinoma in situ (DCIS) component. Previous analyses have found significant differences in tumor characteristics between pure IDC lacking DCIS and mixed IDC with DCIS. We will test our hypothesis that pure IDC represents a form of breast cancer with etiology and risk factors distinct from mixed IDC/DCIS. METHODS: We compared reproductive risk factors for breast cancer risk, as well as family and smoking history between 831 women with mixed IDC/DCIS (n = 650) or pure IDC (n = 181), and 1,620 controls, in the context of the Women's Circle of Health Study (WCHS), a case-control study of breast cancer in African-American and European-American women. Data on reproductive and lifestyle factors were collected during interviews, and tumor characteristics were abstracted from pathology reports. Case-control and case-case analyses were conducted using unconditional logistic regression. RESULTS: Most risk factors were similarly associated with pure IDC and mixed IDC/DCIS. However, among postmenopausal women, risk of pure IDC was lower in women with body mass index (BMI) 25 to <30 [odds ratio (OR) 0.66; 95 % confidence interval (CI) 0.35-1.23] and BMI ≥ 30 (OR 0.33; 95 % CI 0.18-0.67) compared to women with BMI < 25, with no associations with mixed IDC/DCIS. In case-case analyses, women who breastfed up to 12 months (OR 0.55; 95 % CI 0.32-0.94) or longer (OR 0.47; 95 % CI 0.26-0.87) showed decreased odds of pure IDC than mixed IDC/DCIS compared to those who did not breastfeed. CONCLUSIONS: Associations with some breast cancer risk factors differed between mixed IDC/DCIS and pure IDC, potentially suggesting differential developmental pathways. These findings, if confirmed in a larger study, will provide a better understanding of the developmental patterns of breast cancer and the influence of modifiable risk factors, which in turn could lead to better preventive measures for pure IDC, which have worse disease prognosis compared to mixed IDC/DCIS.

Performance of Three-Biomarker Immunohistochemistry for Intrinsic Breast Cancer Subtyping in the AMBER Consortium.

BACKGROUND: Classification of breast cancer into intrinsic subtypes has clinical and epidemiologic importance. To examine accuracy of IHC-based methods for identifying intrinsic subtypes, a three-biomarker IHC panel was compared with the clinical record and RNA-based intrinsic (PAM50) subtypes. METHODS: Automated scoring of estrogen receptor (ER), progesterone receptor (PR), and HER2 was performed on IHC-stained tissue microarrays comprising 1,920 cases from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Multiple cores (1-6/case) were collapsed to classify cases, and automated scoring was compared with the clinical record and to RNA-based subtyping. RESULTS: Automated analysis of the three-biomarker IHC panel produced high agreement with the clinical record (93% for ER and HER2, and 88% for PR). Cases with low tumor cellularity and smaller core size had reduced agreement with the clinical record. IHC-based definitions had high agreement with the clinical record regardless of hormone receptor positivity threshold (1% vs. 10%), but a 10% threshold produced highest agreement with RNA-based intrinsic subtypes. Using a 10% threshold, IHC-based definitions identified the basal-like intrinsic subtype with high sensitivity (86%), although sensitivity was lower for luminal A, luminal B, and HER2-enriched subtypes (76%, 40%, and 37%, respectively). CONCLUSION: Three-biomarker IHC-based subtyping has reasonable accuracy for distinguishing basal-like from nonbasal-like, although additional biomarkers are required for accurate classification of luminal A, luminal B, and HER2-enriched cancers. IMPACT: Epidemiologic studies relying on three-biomarker IHC status for subtype classification should use caution when distinguishing luminal A from luminal B and when interpreting findings for HER2-enriched cancers.