Human epidermal growth factor receptor 2 (HER2) is a member of the human epidermal growth factor receptor family, encoded by the gene HER2 on 17q12-21.32 (1). Around 20% of invasive breast cancer cases overexpress or exhibit amplification of HER2 (HER2+ breast cancer). HER2+ breast cancer is known to be an aggressive disease, with a poor clinical outcome (2). Trastuzumab, a monoclonal antibody that targets HER2, has demonstrated efficacy against HER2+ primary and metastatic breast cancer, both as a single agent and combined with chemotherapy (3, 4). Treatments that include anti-HER2 reagent have become the standard of care for patients with early or advanced HER2+ breast cancer (5,6).Accurate detection of HER2 overexpression or gene amplification is crucial in determining patients' eligibility for anti-HER2 treatment and predicting disease prognosis. According to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, HER2 testing is performed using immunohistochemical (IHC) assessment of HER2 protein overexpression and in situ hybridization
Purpose The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline on HER2 testing in breast cancer permits reclassification of cases with HER2-equivocal results by FISH. The impact of such reclassification is unclear. We sought to determine the proportion of HER2-equivocal cases that are reclassified as HER2-negative and the impact of anti-HER2 therapy on survival in HER2-equivocal cases. Methods We reviewed medical records of breast cancer patients who had HER2 testing by fluorescence in stitu hybridization (FISH) and immunohistochemistry (IHC) performed or verified at The University of Texas MD Anderson Cancer Center during April 2014 through March 2018 and had equivocal results according to the 2013 ASCO/CAP guideline. The population was divided into 2 cohorts according to whether the biopsy specimen analyzed came from primary or from recurrent or metastatic disease. HER2 status was reclassified according to the 2018 ASCO/CAP guideline. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method, and the relationship between anti-HER2 therapy and clinical outcomes was assessed. Results We identified 139 cases with HER2-equivocal results according to the 2013 ASCO/CAP guideline: 90 cases of primary disease and 49 cases of recurrent/metastatic disease. Per the 2018 ASCO/CAP guideline, these cases were classified as follows: overall, HER2-negative 112 cases (80%), HER2-positive 1 (1%), and unknown 26 (19%); primary cohort, HER2-negative 85 (94%), HER2-positive 1 (1%), unknown 4 (4%); and recurrent/metastatic, HER2-negative 27 (55%) and unknown 22 (45%). Five patients in the primary-disease cohort and 1 patient in the recurrent/metastatic-disease cohort received anti-HER2 therapy. There was no significant association between anti-HER2 therapy and OS or EFS in either cohort (primary disease: OS, p = 0.67; EFS, p = 0.49; recurrent/metastatic-disease, OS, p = 0.61; EFS, p = 0.78. Conclusions The majority of HER2-equivocal breast cancer cases were reclassified as HER2-negative per the 2018 ASCO/CAP guideline. No association between anti-HER2 therapy and OS or EFS was observed. HER2-equivocal cases seem to have clinical behavior similar to that of HER2-negative breast cancers.
Background: The LAR subtype of triple negative breast cancer (TNBC) was defined using the Vanderbilt genomic signature in cell lines. The characteristics of this population remain unclear. Methods: We collected the clinicopathological, molecular and imaging characteristics of the LAR population who were enrolled in the ARTEMIS trial, a prospective trial to treat women with TNBC to receive neoadjuvant anthracycline therapy followed by experimental arms based on biomarker versus taxane. The ultrasonography-based response assessment was performed at baseline, after 2 and 4 cycles of anthracycline chemotherapy. The Vanderbilt genomic signature was used to classify the TNBC into the basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like and luminal androgen receptor (LAR) subtypes. The clinical data for this analysis included age, race, menopausal status, TNM stage and BRCA mutation status. Pathological and molecular characteristics included histologic subtype, nuclear grade, Ki67, vimentin expression, androgen receptor (AR) immunohistochemical (IHC) nuclear staining, stromal tumor infiltrating lymphocytes (TIL) percentage and residual cancer burden (RCB) at surgery. Results: Total 28 patients with the LAR signature were analyzed. The characteristics are showed in the table: AgeRaceno. (%)Clinical Stageno. (%)AR IHC StainingBRCA Mutationno. (%)Median (yr)55White19 (68)IA1 (4)Median (%)52No mutation16 (57)Distribution(%)no. (%)Asian3 (11)IIA6 (21)Distribution (%)no(%)Mutation present018-402 (7)Black2 (7)IIB10 (36)<259 (32)VUS1 (4)41-6012 (43)Hispanic3 (11)IIIA6 (21)25-505 (18)Test not indicated6 (21)>6014 (50)American Indian1 (3)IIIB051-751 (3,5)Unknown5 (18)IIIC5 (18)76-10012 (43)Not available1 (3,5)Menopauseno. (%)Histologic subtypeno. (%)Ki67Stromal TILno. (%)Vimentin expressionno. (%)Postmenopausal23 (82)IDC24 (87)Median (%)40<5%10 (36)< 1%24 (85)Perimenopausal2 (7)ILC2 (7)Distribution (%)no. (%)5% - <50 %16 (57)≥1%3 (11)Premenopausal3 (11)Apocrine Carcinoma1 (3)<205 (18)≥50%1 (3,5)N/A1 (4)Metaplastic carcinoma1 (3)≥2013 (46)N/A1 (3,5)N/A10 (36)T stageno. (%)Lymph node involvementno. (%)Nuclear gradeno. (%)Tumor reduction (%)no. (%)RCBno(%)T1c3 (11)Yes22 (79)11 (4)≥ 7012 (43)pCR-111 (39)T213 (46)No6 (21)26 (21)< 7014 (50)2-315 (54)T311 (39)321 (75)N/A2 (7)N/A2 (7)T41 (4)Experimental armno. (%)Enzalutamide8 (29)Atezolizumab4 (14)None16 (57) Relevant characteristics are: median age of 55 years, 82% postmenopausal, 89% breast tumor size > 2cm, 79% with lymph node involvement, no BRCA mutation detected, 75% nuclear grade III, 46% with Ki67 ≥ 20%, median AR IHC staining of 52%, 85% vimentin expression of <1%, 93% had stromal TIL <50%, 39% RCB 0-1 and 54% RCB 2-3. We found that 43% had ≥ 70% reduction in size after 4 cycles of AC. Univariate and multivariate analysis using characteristics did not reveal contributing factor to the RCB. Conclusion: The LAR subgroup harbors unique characteristics that require further confirmation in larger cohorts. Citation Format: James Crespo, Seth Sahil, Elizabeth Ravenberg, Lei Huo, Kenneth Hess, Lumarie Santiago, Beatriz Adrada, Gaiane Rauch, Damodaran Senthil, Rashmi Murthy, Jennifer Litton, Debu Tripathy, Naoto Ueno, Stacy Moulder, Bora Lim. Characterization of the LAR subtype triple negative breast cancer population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1409.
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