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Context.--Repeated surgery is necessary for 20% to 40% of breast conservation surgeries owing to the unavailability of any adjunctive, accurate, and objective tool in the surgeon's hand for real-time margin assessment to achieve the desired balance of oncologic and cosmetic outcomes. Objective.--To assess the feasibility of using a multispectral autofluorescence imaging device for discriminating malignant neoplasm from normal breast tissue in pathology as a critical step in the development of a device for intraoperative use, and to demonstrate the device's utility for use in processing and prioritizing specimens during frozen section and in the pathology grossing room. Design.--We performed a preliminary assessment of our device, called the TumorMAP system, on 172 fresh tissue blocks from 115 patients obtained from lumpectomy specimens at the time of initial gross examination and compared the device results with gold standard pathology evaluation. Results.--The preliminary results demonstrate the potential of our device in detecting breast cancer in fresh tissue samples with a sensitivity of 82%, a specificity of 91%, a positive predictive value of 84%, and a negative predictive value of 89%. Conclusions.--Our results suggest that the TumorMAP system is suitable for the detection of malignant neoplasm in freshly excised breast specimens and has the potential to evaluate resection margins in real time. doi: 10.5858/arpa.2022-0228-OA, There are approximately 300 000 women per year in the United States alone who are diagnosed with breast cancer, (1) and a significant number of patients undergo breast-conserving surgery (BCS) [...]

Circulating tumor cells (CTC) and more recently, CTC clusters are implicated as a fundamental mechanism by which tumor cells break away from the primary site and travel to distant sites. Enumeration of CTC and CTC clusters represents a new approach to prognosis, prediction, and response to therapy in patients with early and metastatic breast cancer. Several recent studies have shown the predictive importance of monitoring CTCs levels in progression-free and overall survival in breast cancer patients. This review will focus on CTC enumeration and characterization in breast cancers. We will provide a historical perspective and clinical background of CTC detection in peripheral blood. The current methodologies for studying CTCs and newer technologies for CTC detection will be reviewed together with the current state of the art of CTCs as a biomarker in risk stratification and prognostication in breast cancers. Currently, there is an FDA approved CTC assessment method for clinical use. While CTC enumeration, is a marker for prognostication and survival, molecular characterization of CTC, may be more accurate in monitoring response to treatment due to tumor heterogeneity rather than the tumor phenotype at the primary or metastatic sites. [ABSTRACT FROM AUTHOR]

Introduction: Automated image analysis provides an objective, quantitative, and reproducible method of measurement of biomarkers. Image quantification is particularly well suited for the analysis of tissue microarrays which has played a major pivotal role in the rapid assessment of molecular biomarkers. Data acquired from grinding up bulk tissue samples miss spatial information regarding cellular localization; therefore, methods that allow for spatial cell phenotyping at high resolution have proven to be valuable in many biomarker discovery assays. Here, we focus our attention on breast cancer as an example of a tumor type that has benefited from quantitative biomarker studies using tissue microarray format. Areas covered: The history of immunofluorescence and immunohistochemistry and the current status of these techniques, including multiplexing technologies (spectral and non-spectral) and image analysis software will be addressed. Finally, we will turn our attention to studies that have provided proof-of-principle evidence that have been impacted from the use of these techniques. Expert opinion: Assessment of prognostic and predictive biomarkers on tissue sections and TMA using Quantitative immunohistochemistry is an important advancement in the investigation of biologic markers. The challenges in standardization of quantitative technologies for accurate assessment are required for adoption into routine clinical practice. [ABSTRACT FROM AUTHOR]

Retesting for Human epidermal growth factor receptor-2 (HER2) in post-neoadjuvant therapy resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. We identified 104 patients with localized HER2 IHC 3+ breast cancer who received neoadjuvant trastuzumab(T)/pertuzumab(P) containing chemotherapy at Yale Cancer Center between 2012 and 2022. Patients were divided into 3 cohorts by response and HER2 IHC in the residual disease: Cohort 1 pathologic complete response (pCR), Cohort 2 pre-treatment IHC 3+/post treatment IHC 1+/2+, and Cohort 3 pre-treatment IHC 3+/post-treatment IHC 3+. Kaplan-Meier survival analysis was performed to assess recurrence free survival at 36 months. The overall pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had residual disease (RD). Among patients with RD, 58.9% (23/39) remained IHC 3+ and 41.1% (16/39) had reduced HER2 expression IHC1+ or 2+. In patients with HER2 IHC 3+ RD, 26% (6/23) developed local recurrence or distant metastasis while none of patients with post NAT HER2 IHC 1+ or 2+ RD had relapse (p = 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis revealed superior disease-free survival in patients with reduced HER2 IHC expression compared to those with remained IHC 3+ (log rank p = 0.004). We conclude that reduced HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates in HER2 IHC 3+ breast cancer. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to stratify patients in adjuvant trials and identify patients who may benefit from more intensive adjuvant therapy and post therapy surveillance. • Retesting of HER2 post neoadjuvant therapy of HER2 + breast cancer is not widespread practice currently. • In patients with HER2 3+ IHC, reduced HER2 expression post neoadjuvant therapy was associated with lower recurrence rates compared to those with preserved 3+ IHC expression. • Reassessment of HER2 expression post neoadjuvant therapy could help risk stratify patients post neo adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Oncotype Dx is a genetic test that has been incorporated into the 2017 AJCC breast cancer staging system for ER positive, HER2‐negative, lymph node‐negative patients to predict the risk of recurrence. Recent data suggest that immunohistochemistry (ER, PR, HER2, and Ki‐67) and histologic subtype may identify patients that will not benefit from Oncotype Dx testing. Methods: A total of 371 patients underwent Oncotype Dx testing at our institution from 2012 to 2016. Oncotype recurrence score was categorized as low‐ (ORS = 0‐10), intermediate‐ (11‐25), or high risk (26‐100). Invasive carcinomas were categorized based on histologic subtype as "favorable" (mucinous, tubular, cribriform, tubulolobular, and lobular) and "unfavorable" (ductal, mixed ductal and lobular, and micropapillary carcinoma). All cases were estrogen receptor positive and HER2‐negative. Clinical and histologic predictors of low‐risk ORS were assessed in univariate and multivariate logistic regression. Results: A total of 371 patients were categorized by ORS as low risk (n = 85, 22.9%), intermediate risk (n = 244, 65.8%), and high risk (n = 42, 11.3%). The histologic subtypes with the highest percentage of high‐risk ORS were invasive micropapillary (n = 4/17, 23.5%), pleomorphic lobular (n = 2/10, 20%), and ductal carcinoma (n = 28/235, 11.9%). Low‐grade invasive carcinomas with favorable histology rarely had a high‐risk ORS (n = 1/97, 1%). In a simple multivariable model, favorable histologic subtype (OR = 2.39, 95% CI: 1.10 to 5.15, P = 0.026), and histologic grade (OR = 1.76, 95% CI: 1.07 to 2.90, P = 0.025) were the only significant predictors of an ORS less than 11 in estrogen receptor positive, HER2‐negative, and lymph node‐negative patients. Conclusion: We question the utility of performing Oncotype Dx in subtypes of invasive carcinoma that are associated with excellent prognosis. We propose that immunohistochemistry for ER, PR, and HER2 is sufficient for patients with low‐grade invasive carcinomas and can be used as a surrogate for Oncotype Dx. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to compare costs associated with excision of routine cavity shave margins (CSM) versus standard partial mastectomy (PM) in patients with breast cancer. Background: Excision of CSM reduces re-excision rates by more than 50%. The economic implications of this is, however, unclear. Methods: Between October 21, 2011 and November 25, 2013, 235 women undergoing PM for Stage 0–III breast cancer were randomized to undergo either standard PM (“no shave”, n = 116) or have additional CSM taken (“shave”, n = 119). Costs from both a payer and a hospital perspective were measured for index surgery and breast cancer surgery–related care through subsequent 90 days. Results: The 2 groups were well-matched in terms of baseline characteristics. Those in the “shave” group had a longer operative time at the initial surgery (median 76 vs 66 min, P < 0.01), but a lower re-excision rate for positive margins (13/119 = 10.9% vs 32/116 = 27.6%, P < 0.01). Actual direct hospital costs associated with operating room time ($1315 vs. $1137, P = 0.03) and pathology costs ($1195 vs $795, P < 0.01) were greater for the initial surgery in patients in the “shave” group. Taking into account the index surgery and the subsequent 90 days, there was no significant difference in cost from either the payer ($10,476 vs $11,219, P = 0.40) or hospital perspective ($5090 vs $5116, P = 0.37) between the “shave” and “no shave” groups. Conclusions: Overall costs were not significantly different between the “shave” and “no shave” groups due to significantly fewer reoperative surgeries in the former. [ABSTRACT FROM AUTHOR]

Two unusual examples of secondary tumors arising in adenolipomas were diagnosed in a 16-year-old girl and a 27-year-old woman, each of whom presented with asymmetric enlargement of the right breast. In both instances, a significant secondary lesion was associated with the adenolipoma. In the first case, a cyst appeared to have arisen in a fibroadenoma within the adenolipoma, which had apparently undergone infarction during a recent pregnancy and postpartum period. There was micropapillary duct epithelial hyperplasia of the cyst lining epithelium. In the second case, an adenofibroma with atypical lobular hyperplasia was present within the adenolipoma. [ABSTRACT FROM AUTHOR]

Context.--The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. Objective.--To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. Design.--A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. Results.--Among 35 pathologists, the k statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathol-ogists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. Conclusions.--We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules. [ABSTRACT FROM AUTHOR]

Phyllodes tumor is an uncommon breast fibroepithelial neoplasm mainly found in middle-aged patients, presenting a morphologic continuum from benign to malignant. Juvenile papillomatosis represents a rare benign proliferative breast tumor primarily affecting young individuals and carries a potential elevated risk of subsequent breast cancer development. Juvenile fibroadenoma is a well-circumscribed biphasic neoplasm that often occurs in adolescent girls, characterized by a pericanalicular growth pattern with usual-type epithelial hyperplasia and gynaecomastia-like micropapillary proliferation. Herein, we present an unusual example of a 26-year-old woman with a left breast outer lower quadrant palpable mass. Ultrasonography identified a 5.9 cm lobulated hypoechoic solid mass with scattered small cysts. The preoperative biopsy initially diagnosed a fibroepithelial lesion, considering giant cellular fibroadenoma and phyllodes tumor in the differential. Subsequent complete excision revealed areas of benign phyllodes tumor features closely admixed with distinctive elements such as prominent multiple cysts exhibiting apocrine and papillary apocrine metaplasia, duct papillomatosis, and duct stasis characteristic of juvenile papillomatosis, and hyperplastic ductal epithelium with micropapillary projections demonstrating a pericanalicular growth pattern indicative of juvenile fibroadenoma. The diagnosis was conclusively established as a fibroepithelial lesion with combined features of benign phyllodes tumor, juvenile papillomatosis, and juvenile fibroadenoma. Further investigation uncovered a family history of breast cancer. Molecular analysis revealed a pattern of unique and overlapping mutations within these distinct histopathological areas. This unusual presentation with hybrid features within a single tumor is described for the first time in the literature along with the molecular signature of the individual components. [ABSTRACT FROM AUTHOR]

Introduction. MYC overexpression is a known phenomenon in breast cancer. This study investigates the correlation of MYC gene copy number amplification and MYC protein overexpression with coexisting genetic abnormalities and associated clinicopathologic features in breast cancer patients. Methods. The study analyzed data from 81 patients with localized or metastatic breast cancers using targeted next-generation sequencing and MYC immunohistochemical studies, along with pathological and clinical data. Results. Applying the criteria of MYC/chromosome 8 ratio ≥5, MYC copy number amplified tumors (n = 11, 14%) were associated with invasive ductal carcinoma (91% vs 68%, P = .048), poorly differentiated (grade 3, 64% vs 30%, P = .032), mitotically active (Nottingham mitotic score 3, 71% vs 20%, P = .004), estrogen receptor (ER)-negative (45% vs 12%, P = .008), and triple-negative (56% vs 12%, P = .013) compared to MYC non-amplified tumors. Among MYC-amplified breast cancer patients, those with triple-negative status showed significantly shorter disease-free survival time than non-triple negative MYC-amplified patients (median survival month: 25.5 vs 127.6, P = .049). MYC amplification is significantly associated with TP53 mutation (P = .007). The majority (10 of 11; 91%) of MYC-amplified tumors showed positive c-MYC immunostaining. Conclusion. Breast cancers with MYC copy number amplication display distinct clinicopathologic characteristics indicative of more aggressive behavior. [ABSTRACT FROM AUTHOR]

KIT Proto-Oncogene Receptor Tyrosine Kinase (KIT) is a transmembrane receptor tyrosine kinase which plays an important role in regulation of cell proliferation, survival and migration. Interestingly, the role of c-KIT in malignant transformation seems to be highly tissue-specific and it can act either as an oncogene or tumor suppressor gene. Here we analyzed the expression of c-KIT in normal breast tissues and tissues from different stages encompassing major steps of breast tumor development. Our study showed, that the c-KIT protein expression is gradually lost during the process of breast tissue transformation. The analysis of previously published datasets revealed that c-KIT expression in breast malignancies was downregulated at mRNA level. Because sequencing studies did not identify any recurrent mutations or copy number alterations, we proposed a potential epigenetic mechanism for the downregulation of c-KIT expression. In-silico analysis of the KIT promoter revealed the presence of CpG islands, therefore we performed bisulfite sequencing of normal breast epithelial tissues as well as breast tumor samples. We found, that KIT promoter is hypermethylated in breast tumors compared to normal breast tissues. Furthermore, treatment of breast cancer cell lines, that lack the expression of c-KIT, with methyltransferase inhibitor 5-Azacytidine (5Aza-2dC) resulted in increased expression of c-KIT mRNA. Collectively, our studies demonstrate that c-KIT expression is epigenetically downregulated during breast epithelium transformation and cancer development via KIT promoter hypermethylation. [ABSTRACT FROM AUTHOR]