Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

Molecular characterization of breast cancer needle core biopsy specimens by the 21-gene Breast Recurrence Score test.

BACKGROUND AND OBJECTIVE: Recent COVID-19 pandemic guidelines recommend genomic assessment of core biopsies to help guide treatment decisions in estrogen receptor (ER)-positive early-stage breast cancer. Herein we characterize biopsy and excisional breast cancer specimens submitted for 21-gene testing. METHODS: US samples submitted to Genomic Health for 21-gene testing (01/2004-04/2020) were assessed by pathologists and analyzed by a standardized quantitative reverse transcription-polymerase chain reaction. Predefined cutoffs were: ESR1 (positive ≥6.5), PGR (positive ≥5.5), and ERBB2 (negative <10.7). ER status by immunohistochemistry (IHC) and lymph node status were determined locally. Median and interquartile range were reported for continuous variables, and total and percent for categorical variables. Distributions were assessed overall, by age, and by nodal involvement. RESULTS: Of 919 701 samples analyzed, 13% were biopsies and 87% were excisions. Initial assay success rates were 94.5% (biopsies) and 97.3% (excisions). ER IHC concordance with central ESR1 was 96.8% (biopsies) and 97.6% (excisions). Biopsy and excisional medians were: Recurrence Score results 16 (each); ESR1 10.2 (each); PGR 7.7 and 7.6; ERBB2 9.4 and 9.2, respectively. CONCLUSIONS: Biopsy submissions for 21-gene testing are common and consistently generate results that are very similar to the experience with excisions. The 21-gene test can be performed reliably on core biopsies.

Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657).

PURPOSE: Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging-residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)-have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined. METHODS: Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation. RESULTS: Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies. CONCLUSIONS: These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.

Mesothelial Inclusions in Pelvic Lymph Nodes Initially Diagnosed as Metastatic Prostate Cancer; the Utility of Second Opinions and Genomic Testing in the Setting of Unexpected Results.

Benign mesothelial inclusions in pelvic lymph nodes may be mistaken for metastatic disease in the setting of pelvic malignancy. In this case-report a patient with Low-Risk prostate cancer (confirmed by biopsy and genomic testing) underwent radical prostatectomy with pelvic lymph node dissection. The initial pathological diagnosis was organ-confined Gleason 3 + 3 = 6 cancer with metastasis to a pelvic lymph node. Upon review of the pathological specimen and immunohistochemical staining the lymph node tissue concerning for metastatic disease was recharacterized as mesothelial in origin. This case illustrates the importance of second opinions and immunohistochemistry for unexpected or unusual pathological findings.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue.

Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.

Lymph node content of supraclavicular and thoracodorsal-based axillary flaps for vascularized lymph node transfer.

OBJECTIVE: Microvascular transfer of lymph node flaps has recently gained popularity as a treatment for secondary lymphedema often occurring after axillary, groin, or pelvic lymph node dissections. This study aimed to delineate the lymph node contents and pedicle characteristics of the supraclavicular (SC) and thoracodorsal (TD)-based axillary flaps as well as to compare lymph node quantification of surgeon vs pathologist. METHODS: SC and TD flaps were dissected from fresh female cadavers. The surgeon assessed pedicle characteristics, lymph node content, and anatomy. A pathologist assessed all flaps for gross and microscopic lymph node contents. The κ statistic was used to compare surgeon and pathologist. RESULTS: Ten SC flaps and 10 TD flaps were harvested and quantified. In comparing the SC and TD flaps, there were no statistical differences between artery diameter (3.1 vs 3.2 mm; P = .75) and vein diameter (2.8 vs 3.5 mm; P = .24). The TD flap did have a significantly longer pedicle than the SC flap (4.2 vs 3.2 cm; P = .03). The TD flap was found to be significantly heavier than the SC flap (17.0 ± 4.8 vs 12.9 ± 3.3 g; P = .04). Gross lymph node quantity was similar in the SC and TD flaps (2.5 ± 1.7 vs 1.8 ± 1.2; P = .33). There was good agreement between the surgeon and pathologist in detecting gross lymph nodes in the flaps (SC κ = 0.87, TD κ = 0.61). CONCLUSIONS: The SC and TD flaps have similar lymph node quantity, but the SC flap has higher lymphatic density. A surgeon's estimation of lymph node quantity is reliable and has been verified in this study by comparison to a pathologist's examination.

Feasibility of the internal mammary lymph node flap as a vascularized lymph node transfer: A cadaveric dissection study.

BACKGROUND: We performed cadaveric dissections to examine the feasibility of an internal mammary-based lymph node flap as a donor site for vascularized lymph node transfer. METHODS: Internal mammary vessels and adjacent nodes were dissected in ten fresh cadaver specimens. Surgeon inspection and palpation identified the number of nodes in the specimen. Specimens were examined macro- and microscopically by a pathologist for correlation of lymph node counts. Kappa statistic correlated surgeon- and pathologist-reported node counts. RESULTS: Surgeon- and pathologist-reported node counts were moderately correlated (kappa 0.57). Inspection and palpation correctly predicted node presence or absence in 80% of specimens. Sixty percent of flaps contained between 1 and 3 nodes, with a mean of 2.0 nodes when nodes were present. CONCLUSIONS: Inspection and palpation predicts the presence or absence of nodes in 80% of flaps. Nodes were present in 60% of internal mammary-based flaps, and one to three nodes can be transferred. © 2015 Wiley Periodicals, Inc. Microsurgery 36:485-490, 2016.

Breast DCE-MRI Kinetic Heterogeneity Tumor Markers: Preliminary Associations With Neoadjuvant Chemotherapy Response.

The ability to predict response to neoadjuvant chemotherapy for women diagnosed with breast cancer, either before or early on in treatment, is critical to judicious patient selection and tailoring the treatment regimen. In this paper, we investigate the role of contrast agent kinetic heterogeneity features derived from breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting treatment response. We propose a set of kinetic statistic descriptors and present preliminary results showing the discriminatory capacity of the proposed descriptors for predicting complete and non-complete responders as assessed from pre-treatment imaging exams. The study population consisted of 15 participants: 8 complete responders and 7 non-complete responders. Using the proposed kinetic features, we trained a leave-one-out logistic regression classifier that performs with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 under the ROC. We compare the predictive value of our features against commonly used MRI features including kinetics of the characteristic kinetic curve (CKC), maximum peak enhancement (MPE), hotspot signal enhancement ratio (SER), and longest tumor diameter that give lower AUCs of 0.71, 0.66, 0.64, and 0.54, respectively. Our proposed kinetic statistics thus outperform the conventional kinetic descriptors as well as the classifier using a combination of all the conventional descriptors (i.e., CKC, MPE, SER, and longest diameter), which gives an AUC of 0.74. These findings suggest that heterogeneity-based DCE-MRI kinetic statistics could serve as potential imaging biomarkers for tumor characterization and could be used to improve candidate patient selection even before the start of the neoadjuvant treatment.

Pharmacokinetic Tumor Heterogeneity as a Prognostic Biomarker for Classifying Breast Cancer Recurrence Risk.

GOAL: Heterogeneity in cancer can affect response to therapy and patient prognosis. Histologic measures have classically been used to measure heterogeneity, although a reliable noninvasive measurement is needed both to establish baseline risk of recurrence and monitor response to treatment. Here, we propose using spatiotemporal wavelet kinetic features from dynamic contrast-enhanced magnetic resonance imaging to quantify intratumor heterogeneity in breast cancer. METHODS: Tumor pixels are first partitioned into homogeneous subregions using pharmacokinetic measures. Heterogeneity wavelet kinetic (HetWave) features are then extracted from these partitions to obtain spatiotemporal patterns of the wavelet coefficients and the contrast agent uptake. The HetWave features are evaluated in terms of their prognostic value using a logistic regression classifier with genetic algorithm wrapper-based feature selection to classify breast cancer recurrence risk as determined by a validated gene expression assay. RESULTS: Receiver operating characteristic analysis and area under the curve (AUC) are computed to assess classifier performance using leave-one-out cross validation. The HetWave features outperform other commonly used features (AUC = 0.88 HetWave versus 0.70 standard features). The combination of HetWave and standard features further increases classifier performance (AUCs 0.94). CONCLUSION: The rate of the spatial frequency pattern over the pharmacokinetic partitions can provide valuable prognostic information. SIGNIFICANCE: HetWave could be a powerful feature extraction approach for characterizing tumor heterogeneity, providing valuable prognostic information.

Circulating sex hormones and terminal duct lobular unit involution of the normal breast.

BACKGROUND: Terminal duct lobular units (TDLU) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009-2011). METHODS: We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n = 390): TDLU counts, median TDLU span, and median acini counts per TDLU. RRs (for continuous measures), ORs (for categorical measures), 95% confidence intervals (95% CI), and Ptrends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone-binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. RESULTS: Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18; 95% CI: 1.07-1.31; Ptrend = 0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80; 95% CI: 0.72-0.89; Ptrend < 0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61; 95% CI: 1.32-1.97; Ptrend < 0.0001) and testosterone (RRT3vsT1: 1.32; 95% CI: 1.09-1.59; Ptrend = 0.0043) were associated with higher TDLU counts. CONCLUSIONS: These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. IMPACT: Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis. Cancer Epidemiol Biomarkers Prev; 23(12); 2765-73. ©2014 AACR.

Terminal duct lobular unit involution of the normal breast: implications for breast cancer etiology.

BACKGROUND: Greater degrees of terminal duct lobular unit (TDLU) involution have been linked to lower breast cancer risk; however, factors that influence this process are poorly characterized. METHODS: To study this question, we developed three reproducible measures that are inversely associated with TDLU involution: TDLU counts, median TDLU span, and median acini counts/TDLU. We determined factors associated with TDLU involution using normal breast tissues from 1938 participants (1369 premenopausal and 569 postmenopausal) ages 18 to 75 years in the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Multivariable zero-inflated Poisson models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) for factors associated with TDLU counts, and multivariable ordinal logistic regression models were used to estimate odds ratios (ORs) and 95% CIs for factors associated with categories of median TDLU span and acini counts/TDLU. RESULTS: All TDLU measures started declining in the third age decade (all measures, two-sided P trend ≤ .001); and all metrics were statistically significantly lower among postmenopausal women. Nulliparous women demonstrated lower TDLU counts compared with uniparous women (among premenopausal women, RR = 0.79, 95% CI = 0.73 to 0.85; among postmenopausal, RR = 0.67, 95% CI = 0.56 to 0.79); however, rates of age-related TDLU decline were faster among parous women. Other factors were related to specific measures of TDLU involution. CONCLUSION: Morphometric analysis of TDLU involution warrants further evaluation to understand the pathogenesis of breast cancer and assessing its role as a progression marker for women with benign biopsies or as an intermediate endpoint in prevention studies.

Optically measured microvascular blood flow contrast of malignant breast tumors.

Microvascular blood flow contrast is an important hemodynamic and metabolic parameter with potential to enhance in vivo breast cancer detection and therapy monitoring. Here we report on non-invasive line-scan measurements of malignant breast tumors with a hand-held optical probe in the remission geometry. The probe employs diffuse correlation spectroscopy (DCS), a near-infrared optical method that quantifies deep tissue microvascular blood flow. Tumor-to-normal perfusion ratios are derived from thirty-two human subjects. Mean (95% confidence interval) tumor-to-normal ratio using surrounding normal tissue was 2.25 (1.92-2.63); tumor-to-normal ratio using normal tissues at the corresponding tumor location in the contralateral breast was 2.27 (1.94-2.66), and using normal tissue in the contralateral breast was 2.27 (1.90-2.70). Thus, the mean tumor-to-normal ratios were significantly different from unity irrespective of the normal tissue chosen, implying that tumors have significantly higher blood flow than normal tissues. Therefore, the study demonstrates existence of breast cancer contrast in blood flow measured by DCS. The new, optically accessible cancer contrast holds potential for cancer detection and therapy monitoring applications, and it is likely to be especially useful when combined with diffuse optical spectroscopy/tomography.

Pretreatment vitamin D level and response to neoadjuvant chemotherapy in women with breast cancer on the I-SPY trial (CALGB 150007/150015/ACRIN6657).

Laboratory studies suggest that vitamin D (vitD) enhances chemotherapy-induced cell death. The objective of this study was to determine whether pretreatment vitD levels were associated with response to neoadjuvant chemotherapy (NACT) in women with breast cancer. Study patients (n = 82) were enrolled on the I-SPY TRIAL, had HER2-negative tumors, and available pretreatment serum. VitD levels were measured via DiaSorin radioimmunoassay. The primary outcome was pathologic residual cancer burden (RCB; dichotomized 0/1 vs. 2/3). Secondary outcomes included biomarkers of proliferation, differentiation, and apoptosis (Ki67, grade, Bcl2, respectively) and 3-year relapse-free survival (RFS). Mean and median vitD values were 22.7 ng/mL (SD 11.9) and 23.1 ng/mL, respectively; 72% of patients had levels deemed "insufficient" (<30 ng/mL) by the Institute of Medicine (IOM). VitD level was not associated with attaining RCB 0/1 after NACT (univariate odds ratio [OR], 1.01; 95% CI, 0.96-1.05) even after adjustment for hormone receptor status (HR), grade, Ki67, or body mass index (BMI). Lower vitD levels were associated with higher tumor Ki67 adjusting for race (OR, 0.95; 95% CI, 0.90-0.99). VitD level was not associated with 3-year RFS, either alone (hazard ratio [HzR], 0.98; 95% CI, 0.95-1.02) or after adjustment for HR, grade, Ki-67, BMI, or response. VitD insufficiency was common at the time of breast cancer diagnosis among women who were candidates for NACT and was associated with a more proliferative phenotype. However, vitD levels had no impact on tumor response to NACT or short-term prognosis.

Identification of intrinsic imaging phenotypes for breast cancer tumors: preliminary associations with gene expression profiles.

PURPOSE: To present a method for identifying intrinsic imaging phenotypes in breast cancer tumors and to investigate their association with prognostic gene expression profiles. MATERIALS AND METHODS: The authors retrospectively analyzed dynamic contrast material-enhanced (DCE) magnetic resonance (MR) images of the breast in 56 women (mean age, 55.6 years; age range, 37-74 years) diagnosed with estrogen receptor-positive breast cancer between 2005 and 2010. The study was approved by the institutional review board and compliant with HIPAA. The requirement to obtain informed consent was waived. Primary tumors were assayed with a validated gene expression assay that provides a score for the likelihood of recurrence. A multiparametric imaging phenotype vector was extracted for each tumor by using quantitative morphologic, kinetic, and spatial heterogeneity features. Multivariate linear regression was performed to test associations between DCE MR imaging features and recurrence likelihood. To identify intrinsic imaging phenotypes, hierarchical clustering was performed on the extracted feature vectors. Multivariate logistic regression was used to classify tumors at high versus low or medium risk of recurrence. To determine the additional value of intrinsic phenotypes, the phenotype category was tested as an additional variable. Receiver operating characteristic analysis and the area under the receiver operating characteristic curve (Az) were used to assess classification performance. RESULTS: There was a moderate correlation (r = 0.71, R(2) = 0.50, P < .001) between DCE MR imaging features and the recurrence score. DCE MR imaging features were predictive of recurrence risk as determined by the surrogate assay, with an Az of 0.77 (P < .01). Four dominant imaging phenotypes were detected, with two including only low- and medium-risk tumors. When the phenotype category was used as an additional variable, the Az increased to 0.82 (P < .01). CONCLUSION: Intrinsic imaging phenotypes exist for breast cancer tumors and correlate with recurrence likelihood as determined with gene expression profiling. These imaging biomarkers could ultimately help guide treatment decisions.

Computerized image analysis for identifying triple-negative breast cancers and differentiating them from other molecular subtypes of breast cancer on dynamic contrast-enhanced MR images: a feasibility study.

PURPOSE: To determine the feasibility of using a computer-aided diagnosis (CAD) system to differentiate among triple-negative breast cancer, estrogen receptor (ER)-positive cancer, human epidermal growth factor receptor type 2 (HER2)-positive cancer, and benign fibroadenoma lesions on dynamic contrast material-enhanced (DCE) magnetic resonance (MR) images. MATERIALS AND METHODS: This is a retrospective study of prospectively acquired breast MR imaging data collected from an institutional review board-approved, HIPAA-compliant study between 2002 and 2007. Written informed consent was obtained from all patients. The authors collected DCE MR images from 65 women with 76 breast lesions who had been recruited into a larger study of breast MR imaging. The women had triple-negative (n = 21), ER-positive (n = 25), HER2-positive (n = 18), or fibroadenoma (n = 12) lesions. All lesions were classified as Breast Imaging Reporting and Data System category 4 or higher on the basis of previous imaging. Images were subject to quantitative feature extraction, feed-forward feature selection by means of linear discriminant analysis, and lesion classification by using a support vector machine classifier. The area under the receiver operating characteristic curve (Az) was calculated for each of five lesion classification tasks involving triple-negative breast cancers. RESULTS: For each pair-wise lesion type comparison, linear discriminant analysis helped identify the most discriminatory features, which in conjunction with a support vector machine classifier yielded an Az of 0.73 (95% confidence interval [CI]: 0.59, 0.87) for triple-negative cancer versus all non-triple-negative lesions, 0.74 (95% CI: 0.60, 0.88) for triple-negative cancer versus ER- and HER2-positive cancer, 0.77 (95% CI: 0.63, 0.91) for triple-negative versus ER-positive cancer, 0.74 (95% CI: 0.58, 0.89) for triple-negative versus HER2-positive cancer, and 0.97 (95% CI: 0.91, 1.00) for triple-negative cancer versus fibroadenoma. CONCLUSION: Triple-negative cancers possess certain characteristic features on DCE MR images that can be captured and quantified with CAD, enabling good discrimination of triple-negative cancers from non-triple-negative cancers, as well as between triple-negative cancers and benign fibroadenomas. Such CAD algorithms may provide added diagnostic benefit in identifying the highly aggressive triple-negative cancer phenotype with DCE MR imaging in high-risk women.

Opportunities for molecular epidemiological research on ductal carcinoma in-situ and breast carcinogenesis: interdisciplinary approaches.

Most invasive breast cancers arise from ductal carcinoma in-situ (DCIS), a non-obligate precursor of invasive breast cancer. Given that the natural history of individual DCIS lesions is unpredictable, many women with DCIS receive extensive treatments, which may include surgery, radiation and endocrine therapy, even though many of these lesions may have limited potential to progress to invasion and metastasize. In contrast to valid concerns about overtreatment, the fact that invasive breast cancers outnumber DCIS lesions by more than three-to-one, suggests that many cancer precursors (particularly DCIS, but LCIS also) progress to invasion prior to detection. Thus, DCIS poses a dual problem of overdiagnosis among some women and failure of early detection among others. These concerns are heightened by the multifold increase in rates of DCIS in conjunction with widespread use of mammographic screening and access to outpatient radiologically-guided biopsies. Accordingly, methods are needed to both specifically detect and identify DCIS lesions with potential to progress to invasive cancer and to discover techniques to triage and conservatively manage indolent cases of DCIS.

Fibroblast activation protein expression by stromal cells and tumor-associated macrophages in human breast cancer.

Fibroblast activation protein (FAP) has long been known to be expressed in the stroma of breast cancer. However, very little is known if the magnitude of FAP expression within the stroma may have a prognostic value and reflect the heterogeneous biology of the tumor cell. An earlier study had suggested that stromal FAP expression in breast cancer was inversely proportional to prognosis. We, therefore, hypothesized that stromal FAP expression may correlate with clinicopathologic variables and may serve as an adjunct prognostic factor in breast cancer. We evaluated the expression of FAP in a panel of breast cancer tissues (n = 52) using a combination of immunostain analyses at the tissue and single-cell level using freshly frozen or freshly digested human breast tumor samples, respectively. Our results showed that FAP expression was abundantly expressed in the stroma across all breast cancer subtypes without significant correlation with clinicopathologic factors. We further identified a subset of FAP-positive (or FAP(+)) stromal cells that also expressed CD45, a pan-leukocyte marker. Using freshly dissociated human breast tumor specimens (n = 5), we demonstrated that some of these FAP(+)CD45(+) cells were CD11b(+)CD14(+)MHC-II(+), indicating that they were likely tumor-associated macrophages (TAMs). Although FAP(+)CD45(+) cells have been demonstrated in the mouse tumor stroma, our results demonstrating that human breast TAMs expressed FAP were novel and suggested that existing and future FAP-directed therapy may have dual-therapeutic benefits targeting both stromal mesenchymal cells and immune cells such as TAMs. More work is needed to explore the role of FAP as a potential targetable molecule in breast cancer treatment.

Cutaneous metastatic breast carcinoma with clear cell features.

Breast carcinoma remains one of the most common sources of skin metastases in women. Cutaneous breast carcinoma metastases have variable clinical and histopathologic presentations that can make diagnosis challenging. We report a unique case of metastatic breast carcinoma with prominent clear cell features, thus mimicking a xanthomatous process. Dermatopathologists should be aware of this entity given its resemblance to other clear cell infiltrates and neoplasms.

Multi-field-of-view framework for distinguishing tumor grade in ER+ breast cancer from entire histopathology slides.

Modified Bloom-Richardson (mBR) grading is known to have prognostic value in breast cancer (BCa), yet its use in clinical practice has been limited by intra- and interobserver variability. The development of a computerized system to distinguish mBR grade from entire estrogen receptor-positive (ER+) BCa histopathology slides will help clinicians identify grading discrepancies and improve overall confidence in the diagnostic result. In this paper, we isolate salient image features characterizing tumor morphology and texture to differentiate entire hematoxylin and eosin (H and E) stained histopathology slides based on mBR grade. The features are used in conjunction with a novel multi-field-of-view (multi-FOV) classifier--a whole-slide classifier that extracts features from a multitude of FOVs of varying sizes--to identify important image features at different FOV sizes. Image features utilized include those related to the spatial arrangement of cancer nuclei (i.e., nuclear architecture) and the textural patterns within nuclei (i.e., nuclear texture). Using slides from 126 ER+ patients (46 low, 60 intermediate, and 20 high mBR grade), our grading system was able to distinguish low versus high, low versus intermediate, and intermediate versus high grade patients with area under curve values of 0.93, 0.72, and 0.74, respectively. Our results suggest that the multi-FOV classifier is able to 1) successfully discriminate low, medium, and high mBR grade and 2) identify specific image features at different FOV sizes that are important for distinguishing mBR grade in H and E stained ER+ BCa histology slides.