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Aims: To examine our hypothesis that a higher number of touching tumour-infiltrating lymphocytes (TILs) in low-risk ductal carcinoma in situ (DCIS) detected in a setting such as an active surveillance clinical trial correlates with upgrading to high-grade DCIS (HG-DCIS) in the subsequent excisional biopsy. Methods and results: The clinical inclusion criteria of the Comparison of Operative versus Monitoring and Endocrine Therapy (COMET) trial were applied to women who were mammographically screened between 2007 and 2017. In the core needle biopsy, touching TILs were assessed by counting the number of TILs touching the ductal basement membrane or away from it by one lymphocyte thickness. The highest number of TILs around a single involved duct and the average number among involved ducts were recorded. DCIS was graded as low or intermediate. Twenty-six of 129 (20.2%) cases had upgrading [14 (10.9%) to pure HG-DCIS, and 12 (9.3%) to invasive carcinoma, two of them with concurrent HG-DCIS]. An increased average number of touching TILs and intermediate-grade DCIS correlated with upgrading to HG-DCIS in 11 of 16 (68.8%) cases, and a decreased average number of touching TILs and low-grade DCIS correlated with no upgrading in 89 of 113 (78.8%) cases [accuracy of 0.775; area under the curve (AUC) of 0.746]. An increased highest number of touching TILs and intermediate-grade DCIS correlated with upgrading to HG-DCIS in 12 of 16 (75%) cases, and a decreased highest number of touching TILs and low-grade DCIS correlated with no upgrading in 82 of 113 (72.6%) cases (accuracy of 0.7287; AUC of 0.734). A highest number of touching TILs of =10 correlated with upgrading to invasive carcinoma and/or HG-DCIS (P = 0.018). Conclusions: Intermediate-grade and touching TILs may be good variables to examine in the COMET trial and to correlate with the risk of upgrading. [ABSTRACT FROM AUTHOR]

The NanoString GeoMx digital spatial profiling is a new multiplexed platform that quantifies the abundance of tumor‐ and immune‐related proteins in a spatially resolved manner. We performed DSP for the simultaneous assessment of 52 analytes within spatially resolved tissue compartments defined by pan‐cytokeratin expression. We compared protein targets between 94 African American/Black and 65 European American/White cases, tumor and stromal tissue compartments, estrogen receptor alpha (ER)‐positive and ER‐negative cases, and explored potential biomarkers of survival. Of 33 analytes with robust signal for analysis, results were highly replicable. For a subset of markers, correlative analyses between DSP analytes and traditional immunohistochemistry scores revealed moderate to very strong associations between the two platforms. Similarly, DSP analytes and gene expression scores were concordant for 21 of 25 markers with overlap between the two datasets. Several analytes varied by ER status, and across the 25 immune markers surveyed, 14 had a significant inverse association with ER expression. B7 homolog 3 (B7‐H3; encoded by CD276) was the only analyte to show a significant difference by race, being lower in both the tumor and stromal compartments in Black women. DSP markers that were associated with survival included CD8, CD25, CD56, CD127, EpCAM, ER, Ki‐67, and STING. We conclude that DSP is an efficient tool for screening tumor‐ and immune‐related markers in a simultaneous fashion and yields results that are concordant with established immune profiling assays. DSP immune analytes were inversely associated with ER expression, in agreement with a substantial body of previous work that documents higher immune infiltration in ER‐negative breast cancers. This technology revealed that scores of the B7‐H3 protein were significantly lower in breast cancers from Black women compared with White women, an intriguing finding that requires replication in independent and racially diverse female populations. [ABSTRACT FROM AUTHOR]

Abstract Background Over-expression of HER2 in a subset of breast cancers (HER2+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of HER2+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients. Methods A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in HER2+ patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in HER2+ patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI). Results TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 HER2+ patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p < 0.0004). This association with outcome was confirmed using 75 HER2+ patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p < 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p < 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts. Conclusions Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in HER2+ breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with HER2 targeted therapy.

Background: African American/Black women with breast cancer have poorer survival than White women, and this disparity persists even after adjusting for non-biological factors. Differences in tumor immune biology have been reported between Black and White women, and the tumor immune milieu could potentially drive racial differences in breast cancer etiology and outcome.Methods: We examined the association of CD8+ cytotoxic T cells with clinical-pathological variables in the Women's Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We evaluated 688 invasive breast tumor samples (550 Black, 138 White) using immunohistochemical staining of tissue microarray slides. CD8+ T cells were scored for each patient tumor sample with digital image analysis.Results: Black women had a significantly higher percentage of high-grade, estrogen receptor (ER)-negative, and triple-negative tumors than White women and significantly higher CD8+ T cell density (median 87.6/mm2 vs. 53.1/mm2; p < 0.001). Within the overall population and in the population of Black women only, CD8+ T cell density was significantly higher in younger patients and patients with high-grade and ER/PR-negative tumors. No significant associations were observed between CD8+ T cell density and overall survival or breast cancer-specific survival in the overall population, or when Black patients were analyzed as a separate group. However, when stratified by subtype, Black women with triple-negative breast cancer and high CD8+ T cell density showed a trend towards better overall survival in comparison with patients with low CD8+ T cell density (HR = 0.51; 95% CI 0.25-1.04).Conclusions: Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups. [ABSTRACT FROM AUTHOR]

The incidence of involved intramammary lymph node (intra‐MLN) with breast carcinoma (BC) is rare. Its clinical significance and impact on the clinical decision making is unclear. A total of 113 BC cases with at least one positive intra‐MLN were collected from 11 academic institutions. The inclusion criteria were subsequent axillary lymph node dissection, and the availability of information on T‐stage, size of node metastasis, extranodal extension status, biomarkers status, and clinical follow‐up. Stage 4 cases and/or neo‐adjuvant treated patients were excluded. AJCC TN‐stage was calculated twice, with and without intra‐MLN. Five‐year overall survival (OS) and relapse (local and/or distant)‐free survival (RFS) were calculated and correlated with the clinicopathologic variables. Excluding intra‐MLN, TN‐stage correlated with OS (P =.016) but not with RFS (P =.19). However, when intra‐MLN was included, TN‐stage correlated with both OS (P <.001) and RFS (P =.016). In the multivariate analysis, when intra‐MLN was excluded, only radiation therapy (RT) correlated with RFS (HR = 0.19, 95% CI: 0.054‐0.66, P =.009). However, when intra‐MLN was included in the TN‐stage both RT (HR = 0.13, 95% CI: 0.04‐0.45, P =.001) and TN‐stage 3 (HR = 8.92, 95% CI: 1.47‐54, P =.017) correlated with RFS. Tumor multifocality was the only variable correlated with OS when the intra‐MLN involvement was excluded. When intra‐MLN was included, multifocality became insignificant but TN‐stage 3 correlated with OS (HR = 8.59, 95% CI: 1.06‐69.71, P =.044). Positive intra‐MLN is an independent factor in predicting both RFS and OS. [ABSTRACT FROM AUTHOR]

Background: Non-hematopoietic malignancies first presented as an axillary mass constitute a unique clinical presentation. We investigated the incidence of various types of malignancies and aimed to define clinicopathologic variables that may assist in the diagnosis, with focus on occult breast carcinoma (OBC). Design: We reviewed the pathology reports of cases with non-hematopoietic malignancies of the axillary region in our institution between 2000 and 2016. We included patients who presented first with axillary mass and with the absence of a known primary. We recorded patients' age and gender, tumor characteristics including size, histologic type, number of positive lymph nodes, and the clinical management. Then we focused on BC which were divided into OBC or primary BC (PBC). Results: There were 100 cases that met our criteria (28 melanoma, 7 sarcoma and 65 carcinoma). For carcinoma cases, there were 42 BC (19 OBC, 17 PBC, and 6 possible OBC), 17 non-BC, and 6 carcinoma of unknown primary (CUP). Tumors found incidentally were more likely to be of breast primary (p = 0.01). Larger tumor size (in mm) favored melanoma or sarcoma over BC, non-BC carcinoma or CUP with median and range 61 (15, 180), 60 (23, 80), 30 (15, 75), 31 (17, 90), 26 (20, 55), respectively (p < 0.001). There were no differences in the histopathologic findings or clinical presentation. Conclusions: More than half of the patients with axillary malignancy have a tumor of non-breast origin. Therefore, clinical and pathologic studies are warranted to identify the primary site. [ABSTRACT FROM AUTHOR]

Background: Forkhead box protein A1 (FOXA1) promotes luminal differentiation, and hypermethylation of the gene can be a mechanism of developing estrogen receptor-negative (ER-) breast cancer. We examined FOXA1 in breast tumor and adjacent normal tissue in relation to reproductive factors, particularly higher parity and no breastfeeding, that are associated with ER- tumors. Methods: We performed IHC for FOXA1 in breast tumors (n = 1,329) and adjacent normal tissues (n = 298) in the Women's Circle of Health Study (949 Blacks and 380 Whites). Protein expression levels were summarized by histology (H) scores. Generalized linear models were used to assess FOXA1 protein expression in relation to reproductive factors by ER status. Results: ER-positive (ER+) versus ER- tumors had higher FOXA1 protein expression (P < 0.001). FOXA1 expression was higher in tumor versus paired adjacent normal tissue in women with ER+ or non-triple-negative cancer (both P < 0.001), but not in those with ER- or triple-negative cancer. Higher number of births (1, 2, and 3+) was associated with lower FOXA1 protein expression in ER+ tumors [differences in H score, or β = -8.5; 95% confidence interval (CI), -15.1 to -2.0], particularly among parous women who never breastfed (β = -10.4; 95% CI, -19.7 to -1.0), but not among those who breastfed (β = -7.5; 95% CI, -16.9 to 1.8). The associations for ER- tumors were similar, although they were not statistically significant. Conclusions: In this tumor-based study, higher parity was associated with lower FOXA1 expression in ER+ tumors, and breastfeeding may ameliorate the influence. [ABSTRACT FROM AUTHOR]

Compared to U.S. white women, African American women are more likely to die from ductal carcinoma in situ (DCIS). Elucidation of risk factors for DCIS in African American women may provide opportunities for risk reduction. We used data from three epidemiologic studies in the African American Breast Cancer Epidemiology and Risk Consortium to study risk factors for estrogen receptor (ER) positive DCIS (488 cases; 13,830 controls). Results were compared to associations observed for ER+ invasive breast cancer (n = 2,099). First degree family history of breast cancer was associated with increased risk of ER+ DCIS [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.31, 2.17]. Oral contraceptive use within the past 10 years (vs. never) was also associated with increased risk (OR: 1.43, 95%CI: 1.03, 1.97), as was late age at first birth (≥25 years vs. <20 years) (OR: 1.26, 95%CI: 0.96, 1.67). Risk was reduced in women with older age at menarche (≥15 years vs. <11 years) (OR: 0.62, 95%CI: 0.42, 0.93) and higher body mass index (BMI) in early adulthood (≥25 vs. <20 kg/m2 at age 18 or 21) (OR: 0.75, 95%CI: 0.55, 1.01). There was a positive association of recent BMI with risk in postmenopausal women only. In general, associations of risk factors for ER+ DCIS were similar in magnitude and direction to those for invasive ER+ breast cancer. Our findings suggest that most risk factors for invasive ER+ breast cancer are also associated with increased risk of ER+ DCIS among African American women. • Few studies of risk factors for ductal carcinoma in situ (DCIS) have evaluated associations for African American women. • We analyzed data from the African American African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. • Family history of breast cancer, reproductive factors, and anthropometric factors were associated with risk of ER+ DCIS. • In general, risk factor associations for ER+ DCIS were similar to those for ER+ invasive breast cancer. • Our findings support a common etiology and pathogenesis between ER+ DICS and ER+ invasive cancer in African American women. [ABSTRACT FROM AUTHOR]

Objectives: Women with atypical ductal hyperplasia (ADH), unlike those with ductal carcinoma in situ (DCIS), are denied eligibility for active surveillance clinical trials.Methods: We applied the inclusion criteria of the Comparison of Operative to Monitoring and Endocrine Therapy (COMET) trial to the cases of women (n = 165) at the Roswell Park Cancer Institute who had a diagnosis of ADH, ADH bordering on DCIS, or low- to intermediate-grade DCIS on core biopsy taken during screening mammography. Upgrade of lesions to high risk was based on invasive carcinoma, high-grade DCIS, or DCIS with comedo necrosis.Results: In total, nine (5.5%) lesions were upgraded: two (1.7%) reported ADH, one (5.9%) reported ADH bordering on DCIS, and six (19.4%) reported DCIS (P = .002); and two (1.6%) reclassified ADH vs seven (17.1%) reclassified DCIS (P < .001). In multivariate analysis, only increased number of foci had the potential to predict high risk (odds ratio: 1.39; P = .06).Conclusions: We conclude that ADH and ADH bordering on DCIS have lower upgrade rates than DCIS. We recommend opening an active surveillance clinical trial for women with these diagnoses. [ABSTRACT FROM AUTHOR]

* Context--Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein highly expressed in fetal tissue and malignant tumors but only rarely within adult benign tissues. The expression of IMP3 in esophageal adenocarcinoma (EAC) and its precursor lesions including distinctive type Barrett mucosa (BM, intestinal metaplasia) and esophageal columnar dysplasia (ECD) is largely unknown. Objective--To characterize the patterns of IMP3 expression in EAC and its precursor lesions. Design--Samples from 132 cases of EAC, 28 cases of ECD (16 high-grade dysplasia and 12 low-grade dysplasia cases), 28 cases of BM without dysplasia, and 138 cases of nonneoplastic esophageal mucosa without dysplasia or BM within formalin-fixed, paraffin-embedded tissue microarray blocks were examined. Tissues were stained with mouse monoclonal anti-IMP3 antibody. The intensity (1-3+) and percent (0%-100%) of positive cytoplasmic and/or membranous IMP3 staining cells were determined. Results--Most of EAC cases (93 of 132; 70%) showed cytoplasmic and membranous IMP3 staining. Poorly and moderately differentiated EAC showed statistically significant higher IMP3 expression compared with well-differentiated EAC (P < .001). A subset of ECD cases (7 of 28; 25%) was positive for IMP3, including 3 low-grade dysplasia cases (focal 1+ IMP3 staining) and 4 high-grade dysplasia cases (more diffuse 1-2+ IMP3 staining). No IMP3 staining was observed in any nonneoplastic esophageal mucosa and BM tissues without dysplasia. Conclusions--This study suggests that IMP3 may play a role in the carcinogenesis of EAC and has diagnostic utility in differentiating neoplastic and nonneoplastic lesions of the esophagus., Esophageal adenocarcinoma (EAC) has shown a rapid and steady increase in its incidence during the past 20 years in the United States and in some European countries, especially within the [...]