Publications by authors named "David J Dabbs"

116 Publications

Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management.

Histopathology 2021 Apr 16;78(5):759-771. Epub 2020 Dec 16.

Department of Histopathology, The University of Nottingham and the Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.

Aims: Although rare, malignant sarcomatoid breast tumours without evidence of epithelial differentiation comprise a diagnostic challenge with management implications. Earlier studies have generally considered these to be primary breast sarcomas; however, supporting evidence is lacking and management remains variable. This study aimed to provide an evidence-based approach to improve the consistency of diagnosis and management for such cases.

Methods And Results: A large series (n = 140) of metaplastic breast carcinoma (MBC) diagnosed in Nottingham over 18 years was analysed. Only cases with available data on immunohistochemical expression of cytokeratins (CKs) were included. The prevalence and pattern of expression for various CKs were assessed and details of tumours negative for CKs were collected. A diagnostic approach based on our experience is provided. Forty-seven cases (34%) showed foci of conventional type invasive breast carcinoma or ductal carcinoma in situ (DCIS), while 93 cases (66%) were diagnosed as MBC based on morphology and/or CK expression. Ninety-seven cases (69%) were negative for one or more CKs, with 18 cases (13%) negative for five or more CKs. Eight cases (6%) lacked expression of all CKs tested. Further examination showed evidence of carcinomatous nature in five cases, and three were diagnosed as MBC following extensive diagnostic work-up and based on our experience.

Conclusion: This study suggests that MBC represents a spectrum of neoplasms, with some lacking CK expression. Sarcomatoid neoplasms of the breast lacking evidence of carcinomatous morphology and CK expression may represent an extreme end of differentiation that can be considered as carcinomas rather than sarcomas for management purposes (following extensive work-up).
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http://dx.doi.org/10.1111/his.14290DOI Listing
April 2021

Best Practice (Efficient) Immunohistologic Panel for Diagnosing Metaplastic Breast Carcinoma.

Appl Immunohistochem Mol Morphol 2021 Apr;29(4):265-269

Department of Pathology, University of Pittsburgh Medical Center (UPMC) Magee-Women's Hospital, Pittsburgh, PA.

Immunohistochemistry (IHC) plays a key role in the diagnosis of metaplastic breast carcinomas (MBCs), particularly the spindle cell variant. The most efficient immunopanel has yet to be developed. We studied the immunoprofile of 45 MBCs including 23 matrix-producing MBCs, 11 squamous cell carcinomas, 6 spindle cell carcinomas, and 5 mixed-subtypes (2 cases including spindle cell components). Representative sections from mastectomy or core biopsy specimens were subject to IHC using a list of antibodies including OSCAR, a recently developed antibody against pooled cytokeratins. The staining was interpreted as positive when >1% of tumor cells demonstrated unequivocal staining. As a result, OSCAR showed similar sensitivity to AE1/AE3 and CAM 5.2 (89.1% vs. 89.4% vs. 89.4%) for MBCs, but the former showed more diffuse pattern of staining, particularly in spindle cell carcinomas. High molecular weight cytokeratin CK14, CK5, and CK17 were positive in 91.3%, 87.2%, and 73.3% of MBCs, respectively. CK7 was much less likely to be positive in spindle cell carcinomas (37.5%) than in other variants of MBCs (97.4%). P63 and CK14 were the most useful markers for spindle cell carcinomas, positive in 87.5% and 85.7% of cases, respectively. GATA 3 was positive in 63% MBCs, and nonspecific staining for vimentin and smooth muscle actin were common. Random combination of up to 3 antibodies against keratins including p63 showed sensitivities ranging from 80.9% to 97.9%. Our results suggested the combination of OSCAR, CK14 and p63 is the most efficient panel (sensitivity 97.9%) for diagnosing MBCs.
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http://dx.doi.org/10.1097/PAI.0000000000000873DOI Listing
April 2021

Prosigna® breast cancer assay: histopathologic correlation, development, and assessment of size, nodal status, Ki-67 (SiNK™) index for breast cancer prognosis.

Mod Pathol 2021 01 1;34(1):70-76. Epub 2020 Aug 1.

Department of Pathology, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.

The Prosigna® assay is a United States Food and Drug Administration (US-FDA) cleared molecular test for prognostic use in hormone receptor-positive stage I/II breast cancer in postmenopausal women. We analyzed histopathologic features of 79 cases with Prosigna® assay results and found a significant correlation between tumor size, grade, and Ki-67 labeling index with Prosigna® score (0-40, 41-60, and 61-100) and Prosigna® risk categories. Since the Prosigna® risk stratification is influenced by lymph node status, we designed an index that included lymph node status and the two most correlated variables (size and Ki-67 labeling index). This was termed the size, nodal, and Ki-67 (SiNK™) index and is calculated as follows: (size in mm) + (pN × 10) + (Ki-67 labeling index). The SiNK™ index was divided into ≤40 and >40 to test its prognostic significance in a well-characterized dataset of 106 ER+/HER2-negative stage I-II invasive breast cancers treated with standard multi-modality therapy with long term follow-up (average 101 months follow-up). Patients with SiNK™ ≤40 showed significantly improved distant recurrence-free survival (96% distant recurrence-free survival in SiNK™ ≤40 compared to 81% in SiNK™ >40; log-rank test p value: 0.0027). SiNK™ provides strong prognostic information in ERo+/HER2-negative breast cancers. SiNK™ index is simple to calculate using data from routine pathology reports. This should be further evaluated in larger datasets.
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http://dx.doi.org/10.1038/s41379-020-0643-8DOI Listing
January 2021

Magee Equations™ and response to neoadjuvant chemotherapy in ER+/HER2-negative breast cancer: a multi-institutional study.

Mod Pathol 2021 01 13;34(1):77-84. Epub 2020 Jul 13.

John A. Burns University of Hawaii Cancer Center, Honolulu, HI, USA.

Magee Equations™ (ME) are multivariable models that can estimate oncotype DX recurrence score. One of the equations, Magee Equation 3 (ME3) which utilizes only semi-quantitative receptor results has been shown to provide chemopredictive value in the neoadjuvant setting in a single institutional study. This multi-institutional study (seven institutions contributed cases) was undertaken to examine the validity of ME3 in predicting response to neoadjuvant chemotherapy in estrogen receptor positive, HER2-negative breast cancers. Stage IV cases were excluded. The primary endpoint was the pathologic complete response (pCR) rate in different categories of ME3 scores calculated based on receptor results in the pre-therapy core biopsy. A total of 166 cases met the inclusion criteria. The patient age ranged from 24 to 83 years (median 53 years). The average pre-therapy tumor size was 3.9 cm, and axillary lymph nodes were confirmed positive by pre-therapy core biopsy in 85 of 166 cases (51%). The pCR rate according to ME3 scores was 0% (0 of 64) in ME3 < 18, 0% (0 of 46) in ME3 18-25, 14% (3 of 21) in ME3 > 25 to <31, and 40% (14 of 35) in ME3 score 31 or higher (p value: <0.0001). There were no distant recurrences and no deaths in the 17 patients with pCR. In the remaining 149 cases with residual disease, ME3 score of >25 was significantly associated with shorter distant recurrence-free survival and showed a trend for shorter breast cancer-specific survival. The results of this multi-institutional study are similar to previously published data from a single institution (PMID: 28548119) and confirm the chemo-predictive value of ME3 in the neoadjuvant setting. In addition, ME3 may provide prognostic information in patients with residual disease which should be further evaluated.
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http://dx.doi.org/10.1038/s41379-020-0620-2DOI Listing
January 2021

Differential Regulation and Targeting of Estrogen Receptor α Turnover in Invasive Lobular Breast Carcinoma.

Endocrinology 2020 09;161(9)

Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee Womens Research Institute, Pittsburgh, Pennsylvania.

Invasive lobular breast carcinoma (ILC) accounts for 10% to 15% of breast cancers diagnosed annually. Evidence suggests that some aspects of endocrine treatment response might differ between invasive ductal carcinoma (IDC) and ILC, and that patients with ILC have worse long-term survival. We analyzed The Cancer Genome Atlas dataset and observed lower levels of ESR1 mRNA (P = 0.002) and ERα protein (P = 0.038) in ER+ ILC (n = 137) compared to IDC (n = 554), and further confirmed the mRNA difference in a local UPMC cohort (ILC, n = 143; IDC, n = 877; P < 0.005). In both datasets, the correlation between ESR1 mRNA and ERα protein was weaker in ILC, suggesting differential post-transcriptional regulation of ERα. In vitro, 17β-estradiol (E2) decreased the rate of degradation and increased the half-life of ERα in ILC cell lines, whereas the opposite was observed in IDC cell lines. Further, E2 failed to induce robust ubiquitination of ERα in ILC cells. To determine the potential clinical relevance of these findings, we evaluated the effect of 2 selective estrogen receptor downregulators (SERDs), ICI 182,780 and AZD9496, on ERα turnover and cell growth. While ICI 182,780 and AZD9496 showed similar effects in IDC cells, in ILC cell lines, AZD9496 was not as effective as ICI 182,780 in decreasing ERα stability and E2-induced proliferation. Furthermore, AZD9496 exhibited partial agonist activity in growth assays in ILC cell lines. Our study provides evidence for a distinct ERα regulation by SERDs in ILC cell lines, and therefore it is important to include ILC models into preclinical and clinical testing of novel SERDs.
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http://dx.doi.org/10.1210/endocr/bqaa109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438704PMC
September 2020

The healthcare value of the Magee Decision Algorithm™: use of Magee Equations™ and mitosis score to safely forgo molecular testing in breast cancer.

Mod Pathol 2020 08 17;33(8):1563-1570. Epub 2020 Mar 17.

Departments of Pathology, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.

Magee Equations™ are multivariable models that can estimate oncotype DX® Recurrence Score, and Magee Equation 3 has been shown to have chemopredictive value in the neoadjuvant setting as a standalone test. The current study tests the accuracy of Magee Decision Algorithm™ using a large in-house database. According to the algorithm, if all Magee Equation scores are <18, or 18-25 with a mitosis score of 1, then oncotype testing is not required as the actual oncotype recurrence score is expected to be ≤25 (labeled "do not send"). If all Magee Equation scores are 31 or higher, then also oncotype testing is not required as the actual score is expected to be >25 (also "do not send"). All other cases could be considered for testing (labeled "send"). Of the 2196 ER+, HER2-negative cases sent for oncotype testing, 1538 (70%) were classified as "do not send" and 658 (30%) as "send". The classification accuracy in the "do not send" group was 95.1%. Of the 75 (4.9%) discordant cases (expected score ≤25 by decision algorithm but the actual oncotype score >25), 26 received endocrine therapy alone. None of these 26 patients experienced distant recurrence (average follow-up of 73 months). The Magee Decision Algorithm accurately identifies cases that will not benefit from oncotype testing. Such cases constitute ~70% of the routine clinical oncotype requests, an estimated saving of $300,000 per 100 test requests. The occasional discordant cases (expected ≤25, but actual oncotype score >25) appears to have an excellent outcome on endocrine therapy alone.
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http://dx.doi.org/10.1038/s41379-020-0521-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384988PMC
August 2020

Immunohistochemical Markers With Potential Diagnostic, Prognostic, and Therapeutic Significance in Uterine Carcinosarcoma: A Clinicopathologic Study of 43 Cases.

Int J Gynecol Pathol 2021 Jan;40(1):84-93

Uterine carcinosarcomas (UCS) are rare and highly aggressive tumors. Although it is currently accepted that the majority of UCS are metaplastic carcinomas, their aggressive behavior is unparalleled to that of any other high-grade endometrial neoplasms. Therefore, the search for the distinct immunohistochemical and molecular features that could help in the development of new treatment strategies continues. We evaluated the expression of PDL-1, growth hormone releasing hormone receptor, p53, WT1, PAX-8, estrogen receptor, HNF-1, and mismatch repair proteins in 43 UCS. Tumors were selected from the archives of the Magee-Womens Hospital University of Pittsburgh Medical Center Department of Pathology. Seventeen were stage I, 4 were stage II, 15 were stage III, and 7 were stage IV. The median age was 67 yr and median overall survival was 3.2 yr. Immunostaining for PAX8, HNF-1, and estrogen receptor showed statistically significant difference between epithelial and stromal components. Expression of p53 was significantly associated with clinical high stage, but other markers did not correlate with stage or survival. Immunostaining for programmed death ligand-1 was strongly positive in 30 UCS (70%), including 24 cases with tumor cell positivity, 12 cases with tumor cell and tumor-infiltrating immune cell positivity, and 6 cases with tumor-infiltrating immune cell positivity only. Of 27 tumors tested for mismatch repair expression, 12 (44%) showed loss of expression, 7 of which were PDL-1 positive. Growth hormone releasing hormone receptor was positive in 38 tumors (88%) and predominantly expressed in the epithelial component. The range of positivity for programmed death ligand-1 and growth hormone releasing hormone receptor suggests a possible potential adjuvant treatment that may be considered for UCS.
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http://dx.doi.org/10.1097/PGP.0000000000000662DOI Listing
January 2021

Follow-up outcomes of benign vascular lesions of breast diagnosed on core needle biopsy: A study of 117 cases.

Breast J 2019 05 18;25(3):401-407. Epub 2019 Apr 18.

Department of Pathology, Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Benign vascular lesions of breast are uncommon findings on core biopsy and surgical excision has been recommended to rule out a more serious lesion. However, a recent study suggested that excision may be spared for vascular lesion without atypia. The aim of this study was to assess the follow-up outcomes in lesions yielding benign vascular lesions on core biopsy. We retrospectively reviewed 117 patients with diagnosis of hemangioma (106 patients) and atypical hemangioma (11 patients) on core biopsy at our institution over an 18-year period. Majority of benign vascular lesions were followed-up clinically and/or radiologically. Surgical excision was performed on 18 patients (16.9%) with benign hemangiomas and all 11 patients (100%) with atypical hemangiomas. Upon excision, the majority of patients (82.8%, 24/29) retained benign final pathology and five patients (17.2%) were atypical hemangioma. There was no upgrade on excision. All patients had a benign course regardless whether the lesions were excised or not. Our findings support the recent study that benign vascular lesion of breast may not require surgical excision.
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http://dx.doi.org/10.1111/tbj.13233DOI Listing
May 2019

Isolated Flat Epithelial Atypia on Core Biopsy Specimens Is Associated With a Low Risk of Upgrade at Excision.

Am J Clin Pathol 2019 04;151(5):511-515

University of Pittsburgh Medical Center, Pittsburgh, PA.

Objectives: We present a retrospective review of 111 breast core biopsy specimens with flat epithelial atypia (FEA) and corresponding excision to better understand rates of upgrade following this diagnosis.

Methods: In total, 252 breast core biopsy specimens were identified. Cases were excluded if biopsy slides or excision results were unavailable, for ipsilateral carcinoma or other findings warranting excision, or biopsy performed for indications other than mammographically detected calcifications. Coincident atypical lobular hyperplasia was not excluded. Diagnoses were confirmed by breast pathologists, and mammographic images were reviewed.

Results: Ultimately, 111 biopsy specimens with FEA were included. In subsequent excisions, one (1%) of 111 showed invasive carcinoma, 20 (18%) atypical ductal hyperplasia, 20 (18%) lobular neoplasia, 31 (28%) FEA, and 39 (35%) no atypical findings.

Conclusions: FEA on core biopsy specimens is associated with a low rate of upgrade to invasive carcinoma. Close follow-up may be a reasonable alternative to excision for isolated FEA on core needle biopsy specimens.
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http://dx.doi.org/10.1093/ajcp/aqy175DOI Listing
April 2019

Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response to neoadjuvant chemotherapy.

Mod Pathol 2019 06 5;32(6):807-816. Epub 2019 Feb 5.

Division of Breast and Gynecologic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Metaplastic breast carcinoma is a rare heterogeneous category of breast cancer, often associated with a poor prognosis. Clinical-pathologic studies with respect to varied morphologic subtypes are lacking. There is also a dearth of studies assessing the response of metaplastic breast carcinoma to neoadjuvant chemotherapy. Cases of metaplastic breast carcinoma diagnosed between 2007 and 2017 were identified. Various clinical-pathologic variables were tested for association with survival. Patients who underwent neoadjuvant chemotherapy were assessed for pathologic response. Median age at diagnosis with metaplastic breast carcinoma was 64 years. With a median follow-up of 39 months, 26 patients (27%) recurred (24 distant and 2 loco-regional). The overall survival rate of the cohort was 66% (64/97). A number of variables were associated with survival in univariable analysis; however, in multivariable analysis, only lymph node status and tumor size (pT3 vs. pT1/2) were significantly associated with all survival endpoints: recurrence-free survival, distant recurrence-free survival, overall survival and breast cancer-specific survival. Twenty-nine of 97 (30%) patients with metaplastic breast carcinoma received neoadjuvant chemotherapy. Five (17%) patients achieved pathologic complete response. Matrix-producing morphology was associated with higher probability of achieving pathologic complete response (p = 0.027). Similar to other breast cancer subtypes, tumor size and lymph node status are prognostic in metaplastic carcinomas. The pathologic complete response rate of metaplastic breast carcinoma in our cohort was 17%, higher than previously reported. Although the matrix-producing subtype was associated with pathologic complete response, there was no survival difference with respect to tumor subtypes.
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http://dx.doi.org/10.1038/s41379-019-0208-xDOI Listing
June 2019

Breast Cancers With Magee Equation Score of Less Than 18, or 18-25 and Mitosis Score of 1, Do Not Require Oncotype DX Testing: A Value Study.

Am J Clin Pathol 2019 02;151(3):316-323

Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA.

Objectives: To investigate use of Magee equations (MEs) to determine which breast cancer cases can be excluded from Oncotype DX testing.

Methods: A prospective value study was carried out using data from pathology reports.

Results: If all three MEs scores were less than 18 or 31 or higher, the cases were labeled do not send for testing. If any or all scores were 18 to 25, cases were labeled do not send if mitosis score was 1. Of the total 205 cases, 146 (71%) were labeled do not send; of these, the correct call was made in 143 (98%) cases. Two of the three discordant cases had associated nontumor factors, likely resulting in higher scores.

Conclusions: Cases with ME scores less than 18, or 18 to 25 and mitosis score 1, do not require Oncotype DX testing, an estimated saving of US$280,000 per 100 clinical requests.
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http://dx.doi.org/10.1093/ajcp/aqy148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360636PMC
February 2019

Breast cancer global tumor biomarkers: a quality assurance study of intratumoral heterogeneity.

Mod Pathol 2019 03 16;32(3):354-366. Epub 2018 Oct 16.

Faculty of Computer Science, Bialystok University of Technology, Bialystok, Poland.

Biomarker analysis of invasive breast carcinoma is useful for prognosis, as surrogate for molecular subtypes of breast cancer, and prediction of response to adjuvant and neoadjuvant systemic therapies. Breast cancer intratumoral heterogeneity is incompletely studied. Comprehensive biomarker analysis of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 labeling index was performed on each tissue block of 100 entirely submitted breast tumors in 99 patients. Invasive carcinoma and in situ carcinoma was scored using semiquantitative histologic score (H-score) for ER and PR, HER2 expression from 0 to 3+, and percentage positive cells for Ki67. Core biopsy results were compared with surgical excision results, invasive carcinoma was compared with in situ carcinoma, and interblock tumoral heterogeneity was assessed using measures of dispersion (coefficient of variation and quartile coefficient of dispersion). Overall concordance between core biopsy and surgical excision was 99% for ER and 95% for PR. Mean histologic score of ER was significantly lower in invasive carcinoma between core biopsy and surgical excision (p = 0.000796). Intratumoral heterogeneity was higher for PR than for ER (mean coefficient of variation for ER 0.08 stdv 0.13 vs. PR 0.26 stdv 0.41). Ki67 labeling index was significantly higher in invasive carcinoma as compared with associated ductal carcinoma in situ on surgical resection specimen (p ≤ 0.0001). Ki67 hotspots were identified in 47% of cases. Of 52 HER2 negative cases on core biopsy, 10 were scored as equivocal on surgical resection. None (0/10) were amplified by Her-2/neu fluorescence in situ hybridization. Overall, biomarkers on core biopsy showed concordance with the surgical excision specimen in the vast majority of cases. Biomarker expression of in situ closely approximates associated invasive carcinoma. Intratumoral heterogeneity of PR is greater than ER. Biomarker expression on diagnostic core biopsy or single tumor block is representative of breast carcinoma as a whole in most cases and is appropriate for clinical decision-making.
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http://dx.doi.org/10.1038/s41379-018-0153-0DOI Listing
March 2019

High Fidelity of Breast Biomarker Metrics: A 10-Year Experience in a Single, Large Academic Institution.

Appl Immunohistochem Mol Morphol 2018 Nov/Dec;26(10):697-700

Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA.

Purpose: Recommendations for standardization of breast biomarkers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) led to the creation of American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines to provide continuous guidance. Included in these recommendations is the "ongoing assay assessment procedures." We report these biomarker metrics as there is a dearth of published information on this topic.

Materials And Methods: ER, PR, and HER2 positivity rates of all newly diagnosed, recurrent, and metastatic invasive breast cancers on core biopsies, and repeated testing on resection specimen by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) were collected from April 1, 2008 to December 31, 2017.

Results: The positivity rates of ER, PR, and HER2 over almost 10 years of monitoring showed high fidelity. Total ER-positive rate was 83.6% (81.4% to 86.8%), ER+/PR+ was 71.7% (68.6% to 75.5%), ER+/PR- was 17.6% (11.0% to 15.0%), ER-/PR- was 16.0% (13.5% to 18.2%), and ER-/PR+ was 0.6% (0.2% to 1.0%). The HER2-positive rate was 13.7% (10.2% to 17.4%) including 9.9% (7.3% to 11.9%) by IHC and 3.8% (1.9% to 5.9%) by FISH reflexed from IHC 2+ results. FISH amplification rate of HER2 IHC 2+ cases was 11.0% (5.8% to 19.2%). Annual quality-assurance check for HER2 IHC/FISH percent positive and percent negative agreement (as defined by Food and Drug Administration) was 96% to 100%.

Conclusions: This longitudinal active assessment of 9564 breast biomarker cases shows the achievement of high fidelity of breast biomarker results when following the ASCO/CAP guidelines. Continuous monitoring of breast biomarkers may minimize assay analytical drift and assure quality clinically relevant results.
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http://dx.doi.org/10.1097/PAI.0000000000000697DOI Listing
September 2019

Pathologist's health-care value in the triage of Oncotype DX testing: a value-based pathology study of tumour biology with outcomes.

Histopathology 2018 Oct 6;73(4):692-700. Epub 2018 Aug 6.

Department of Pathology, Pittsburgh, PA, USA.

Aims: Pathologists provide expert tissue assessment of breast cancer, yet their value to guide the appropriate use of breast cancer gene expression profile tests (GEPT) is underutilised. The specific aims of this study are to report morpho-immunohistological characteristics of breast tumours with Oncotype DX (ODx) recurrence scores (RS) of 10 or fewer (ultra-low risk) and 25 or fewer (low risk) in order to determine if pathologists can identify prospectively patient tumours that do not require ODx testing.

Methods And Results: Oncotype DX cases with RS < 10 from 2005 to 2010 comprised 441 of 2594 (17%) of clinical cases; this cohort had 5 years' follow-up and was treated with endocrine therapy alone. Tumours were analysed for tumour type, Nottingham grade, mitosis score (MS) semi-quantitative (H-score) hormone receptor content and Magee equation 3. Knowledge derived from this data set was used to develop algorithms in order to identify prospectively tumours with RS of 10 or fewer or 25 or fewer. Thirty-four per cent of tumours were low-grade special types, while the remainder were enriched with high hormone receptor content with MS of 1. These algorithmic selection criteria identified correctly all patient cases below the chemotherapy cut-point, i.e. RS < 25, indicating that these oncotype test orders were an unnecessary cost.

Conclusions: This unique study demonstrates that (i) pathologists add great value to triage breast cancer for GEPT; and (ii) can identify prospectively low-grade tumour biology with high sensitivity and high specificity for those cases which do not require chemotherapy (RS < 25) using MS and hormone receptor content.
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http://dx.doi.org/10.1111/his.13690DOI Listing
October 2018

Low Estrogen Receptor (ER)-Positive Breast Cancer and Neoadjuvant Systemic Chemotherapy: Is Response Similar to Typical ER-Positive or ER-Negative Disease?

Am J Clin Pathol 2018 May;150(1):34-42

Division of Breast and Gynecologic Pathology, Department of Pathology, Pittsburgh, PA.

Objectives: Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)-negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and 98 high ER+ (30%) tumors.

Methods: Human epidermal growth factor receptor 2-positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded.

Results: The pCR rate of low ER+ tumors was similar to the pCR rate of ER- tumors (37% and 26% for low ER and ER- respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER- and low ER+ cases compared with moderate and high ER+ cases.

Conclusions: Low ER+ breast cancers are biologically similar to ER- tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy.
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http://dx.doi.org/10.1093/ajcp/aqy028DOI Listing
May 2018

Prognostic Significance of Modified Residual Disease in Breast and Nodes (mRDBN) Algorithm After Neoadjuvant Chemotherapy for Breast Cancer.

Am J Clin Pathol 2018 Mar;149(4):332-343

Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA.

Objectives: We hypothesized that prognostic accuracy of the residual disease in breast and lymph nodes (RDBN) method, which is calculated using residual tumor size, nodal involvement, and tumor grade, may be improved by incorporating residual tumor cellularity.

Methods: Cases included 614 patients who underwent neoadjuvant therapy for breast cancer. Tumor size was adjusted for residual cellularity of invasive carcinoma and used to calculate modified RDBN (mRDBN) and compared with unmodified gross tumor size (gRDBN).

Results: RDBN could be calculated in 428 cases. Relative risks of recurrence and death were significantly higher for RDBN-3 and RDBN-4 compared with RDBN-1. Kaplan-Meier analysis showed significant differences in disease-free survival and overall survival for estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative and ER-positive/HER2-negative subgroups (P < .0001).

Conclusions: Both mRDBN and gRDBN provide prognostic information, particularly in HER2-negative carcinoma; however, mRDBN showed better stratification of RDBN-3 and RDBN-4 patients.
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http://dx.doi.org/10.1093/ajcp/aqx168DOI Listing
March 2018

Invasion in breast lesions: the role of the epithelial-stroma barrier.

Histopathology 2018 Jun 13;72(7):1075-1083. Epub 2018 Feb 13.

Department of Histopathology, Nottingham City Hospital NHS Trust, Nottingham University, Nottingham, UK.

Despite the significant biological, behavioural and management differences between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast, they share many morphological and molecular similarities. Differentiation of these two different lesions in breast pathological diagnosis is based typically on the presence of an intact barrier between the malignant epithelial cells and stroma; namely, the myoepithelial cell (MEC) layer and surrounding basement membrane (BM). Despite being robust diagnostic criteria, the identification of MECs and BM to differentiate in-situ from invasive carcinoma is not always straightforward. The MEC layer around DCIS may be interrupted and/or show an altered immunoprofile. MECs may be absent in some benign locally infiltrative lesions such as microglandular adenosis and infiltrating epitheliosis, and occasionally in non-infiltrative conditions such as apocrine lesions, and in these contexts this does not denote malignancy or invasive disease with metastatic potential. MECs may also be absent around some malignant lesions such as some forms of papillary carcinoma, yet these behave in an indolent fashion akin to some DCIS. In Paget's disease, malignant mammary epithelial cells extend anteriorly from the ducts to infiltrate the epidermis of the nipple but do not typically infiltrate through the BM into the dermis. Conversely, BM-like material can be seen around invasive carcinoma cells and around metastatic tumour cell deposits. Here, we review the role of MECs and BM in breast pathology and highlight potential clinical implications. We advise caution in interpretation of MEC features in breast pathology and mindfulness of the substantive evidence base in the literature associated with behaviour and clinical outcome of lesions classified as benign on conventional morphological examination before changing classification to an invasive lesion on the sole basis of MEC characteristics.
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http://dx.doi.org/10.1111/his.13446DOI Listing
June 2018

Effects of Hydrochloric Acid and Formic Acid Decalcification on Breast Tumor Biomarkers and HER2 Fluorescence In Situ Hybridization.

Appl Immunohistochem Mol Morphol 2019 03;27(3):223-230

Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA.

Biomarker analysis of metastatic breast carcinoma (MBC) is routinely recommended by ASCO/CAP guidelines, and establishing a diagnosis of MBC often requires immunohistochemistry (IHC). The reliability of breast tumor biomarkers and breast-specific markers on decalcified tissues has not been extensively studied. We performed IHC studies on breast tumors exposed to hydrochloric acid (HCl) and formic acid (FA) decalcification solutions, and HER2 fluorescence in situ hybridization on a subset of these tumors to establish a protocol for handling bone specimens with suspicion for MBC. Fifteen fresh cases of primary breast carcinoma and 8 HER2+ paraffin-embedded core biopsy cases were studied. Fresh tissue was divided into 5 fragments to approximate a bone core biopsy. One fragment (control) was fixed in 10% neutral buffered formalin. The remaining fragments were also exposed to FA or HCl decalcification for 1 or 5 hours. All fragments were embedded in 1 block and tested with an IHC panel. The known HER2+ cases were exposed to either 1 or 5 hours of FA, and HER2 fluorescence in situ hybridization was also performed. Results were interpreted as follows: H-scores for estrogen receptor, progesterone receptor, and GATA-3 were assigned from 0 to 300; HER2, cytokeratin 7, gross cystic disease fluid protein-15, Pax-8, TTF-1, cytokeratin 20, and mammaglobin were scored from 0 to 3+; and Ki67 from 0% to 100%. Mean scores were compared using the t test or Wilcoxon test for paired samples. No significant differences in mean score were seen between NF and 1 hour FA for any IHC immunoreactivity. After 5 hours of FA, only Ki67 average score was significantly less than NF. Mean scores for estrogen receptor, progesterone receptor, HER2, Ki67, and GATA-3 were significantly lower than NF in the tissue after either 1 or 5 hours of HCl. Mean scores for gross cystic disease fluid protein-15, mammaglobin, and cytokeratin 7 staining were not significantly lower than NF after 1 or 5 hours of HCl.
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http://dx.doi.org/10.1097/PAI.0000000000000564DOI Listing
March 2019

Cervical Carcinoma With Divergent Neuroendocrine and Gastrointestinal Differentiation.

Int J Gynecol Pathol 2018 Sep;37(5):488-491

Department of Pathology, Magee Womens Hospital of UPMC, Pittsburgh, PA (K.R.V., D.J.D.).

Neuroendocrine carcinomas of the uterine cervix are rare tumors with aggressive behavior. They comprise <4% of cervical carcinomas. They may coexist with both adenocarcinoma and squamous cell carcinoma of cervix. Signet ring carcinoma of cervix is a rarer entity and less than 20 cases have been described in the literature. We present a case of a 34-year-old female who presented with systemic thrombosis, splenic mass and a cervical mass which on biopsy showed divergent differentiation of primitive large cell neuroendocrine carcinoma with signet ring cells. The cervical tumor was positive for human papilloma virus 16/18 by in situ hybridization, confirming cervical origin of the tumor. This unusual presentation and morphology needs to be recognized and appropriately evaluated when patients present with tumors of unknown origin in metastatic sites.
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http://dx.doi.org/10.1097/PGP.0000000000000438DOI Listing
September 2018

Magee Equation 3 predicts pathologic response to neoadjuvant systemic chemotherapy in estrogen receptor positive, HER2 negative/equivocal breast tumors.

Mod Pathol 2017 08 26;30(8):1078-1085. Epub 2017 May 26.

Division of Breast and Gynecologic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Magee Equations were derived as an inexpensive, rapid alternative to Oncotype DX. The Magee Equation 3 utilizes immunohistochemical and FISH data for estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki-67 for its calculation (24.30812+ERIHC × (-0.02177)+PRIHC × (-0.02884)+(0 for HER2 negative, 1.46495 for equivocal, 12.75525 for HER2 positive)+Ki-67 × 0.18649). We hypothesize that Magee Equation 3 scores from pre-therapy core biopsy can predict response to neoadjuvant systemic chemotherapy. A prospectively-maintained database of patients who received neoadjuvant systemic therapy from 2010 to 2014 at a single institution was retrospectively reviewed. Pathologic complete response was defined as absence of invasive tumor in the breast and regional lymph nodes. Of the 614 cases, tumors with missing immunohistochemical results and those that were ER negative or HER2 positive were excluded. This resulted in 237 ER positive, HER2 negative/equivocal tumors that formed the basis of this study. Magee Equation 3 scores were divided into 3 categories similar to Oncotype DX, ie, 0 to <18 (low), 18 to <31 (intermediate), and 31 or higher (high) scores. The pathologic complete response rate for low, intermediate and high Magee Equation 3 scores was 0%, 4%, and 36%, respectively. Patients with high Magee Equation 3 scores were 13 times more likely to achieve pathologic complete response compared to those with Magee Equation 3 scores less than 31 (95% CI 5.09-32.87, P<0.0001). For patients that did not achieve pathologic complete response, high Magee Equation 3 correlated with higher recurrence rate, with the majority occurring in patients with positive lymph nodes in the resection specimen. Magee Equation 3 score ≥31 predicts pathologic complete response in the neoadjuvant setting and for tumor recurrence, when pathologic complete response is not achieved. These results show the utility of Magee Equation 3 in predicting patients who will benefit from chemotherapy but warrant prospective multi-institutional validation.
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http://dx.doi.org/10.1038/modpathol.2017.41DOI Listing
August 2017

Magee equations and oncotype DX-a perspective.

Breast Cancer Res Treat 2017 07 9;164(1):245-246. Epub 2017 Apr 9.

Magee-Womens Hospital of University of Pittsburgh Medical Center, 300 Halket Street, Pittsburgh, PA, 15213, USA.

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http://dx.doi.org/10.1007/s10549-017-4235-3DOI Listing
July 2017

Male Breast Cancer.

Am J Clin Pathol 2017 01;147(1):110-119

From the Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, PA.

Objectives: A clinicopathologic study with an emphasis on tumor immunohistochemical profile is presented.

Methods: Sixty-one cases of male invasive breast cancers were studied. Median age of the cohort was 65 years.

Results: Ninety-seven percent were estrogen receptor positive+ and 10% human epidermal growth factor receptor 2 positive. The individual diagnostic marker positivity was 98% for GATA-binding protein 3, 95% for androgen receptor, 90% for progesterone receptor, 88% for deleted in pancreatic cancer 4, 75% for gross cystic disease fluid protein 15, 72% for cytokeratin 7, 55% for mammaglobin, and 15% for vimentin and Wilms tumor protein 1. Caudal type homeobox 2 protein, cytokeratin 20, Napsin A, paired box gene 8, prostate-specific antigen, thyroid transcription factor 1, and uroplakin II were negative in all cases. Survival analyses showed tumor stage, receptor status, and Nottingham prognostic index to be prognostic. The overall survival was 70%, but the breast cancer–specific survival was 92% (mean follow-up, 59 months); 33% developed second malignancy. The immunohistochemistry profile was similar to female breast cancers.

Conclusions: The second malignancies in this cohort affected overall survival and suggest the possibility of other germline mutations in addition to BRCA2 in male patients with breast cancer.
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http://dx.doi.org/10.1093/ajcp/aqw207DOI Listing
January 2017

Intratumor Heterogeneity Affects Gene Expression Profile Test Prognostic Risk Stratification in Early Breast Cancer.

Clin Cancer Res 2016 Nov 16;22(21):5362-5369. Epub 2016 May 16.

Women's Cancer Research Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Womens Research Institute, Pittsburgh, Pennsylvania.

Purpose: To examine the effect of intratumor heterogeneity (ITH) on detection of genes within gene expression panels (GEPs) and the subsequent ability to predict prognostic risk.

Experimental Design: Multiplexed barcoded RNA analysis was used to measure the expression of 141 genes from five GEPs (Oncotype Dx, MammaPrint, PAM50, EndoPredict, and Breast Cancer Index) in breast cancer tissue sections and tumor-rich cores from 71 estrogen receptor (ER)-positive node-negative tumors, on which clinical Oncotype Dx testing was previously performed. If the tumor had foci of high Ki67 (n = 26), low/negative progesterone receptor (PR; n = 13), or both (n = 5), additional cores were obtained. In total, 181 samples were processed. Oncotype Dx recurrence scores were calculated from NanoString nCounter gene expression data.

Results: Hierarchical clustering using all GEP genes showed that majority (61 of 71) of tumor samples clustered by patient, indicating greater interpatient heterogeneity (IPH) than ITH. We found a strikingly high correlation between Oncotype Dx recurrence scores obtained from whole sections versus tumor-rich cores (r = 0.94). However, high Ki67 and low PR cores had slightly higher but not statistically significant recurrence scores. For 18 of 71 (25%) patients, scores were divergent between sections and cores and crossed the boundaries for low, intermediate, and high risk.

Conclusions: Our study indicates that in patients with highly heterogeneous tumors, GEP recurrence scores from a single core could under- or overestimate prognostic risk. Hence, it may be a useful strategy to assess multiple samples (both representative and atypical cores) to fully account for the ITH-driven variation in risk prediction. Clin Cancer Res; 22(21); 5362-9. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093028PMC
November 2016

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer.

Appl Immunohistochem Mol Morphol 2017 07;25(6):392-398

Departments of *Pathology, Division of Breast & Gynecologic Pathology ‡Oncology, Magee-Womens Hospital †Pathology, Division of Molecular & Genomic Pathology §Magee-Womens Research Institute & Foundation, The University of Pittsburgh Medical Center, Pittsburgh, PA.

Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53 (n=21), PIK3CA (n=20), and FGFR1 (n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (∼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited.
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http://dx.doi.org/10.1097/PAI.0000000000000322DOI Listing
July 2017

Biomarker assessment and molecular testing for prognostication in breast cancer.

Histopathology 2016 Jan;68(1):70-85

Magee-Women's Hospital, UPMC, Pittsburgh, PA, USA.

Current treatment of breast cancer incorporates clinical, pathological and molecular data. Oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) define prognosis and identify tumours for targeted therapy, and remain the sole established single-molecule biomarkers defining the minimum breast cancer pathology data set. Ki67 remains one of the most promising yet controversial biomarkers in breast cancer, implemented routinely in some, but not all, pathology departments. Beyond the single-molecule biomarkers, a host of multigene expression tests have been developed to interrogate the driver pathways and biology of individual breast cancers to predict clinical outcome more accurately. A minority of these assays have entered into clinical practice. This review focuses on the established biomarkers of ER, PR and HER2, the controversial but clinically implemented biomarker Ki67 and the currently marketed gene expression signatures.
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http://dx.doi.org/10.1111/his.12795DOI Listing
January 2016

Phyllodes tumours of the breast: a consensus review.

Histopathology 2016 Jan;68(1):5-21

Department of Pathology, Singapore General Hospital, Singapore.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.
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http://dx.doi.org/10.1111/his.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027876PMC
January 2016

Breast lesions of uncertain malignant nature and limited metastatic potential: proposals to improve their recognition and clinical management.

Histopathology 2016 Jan;68(1):45-56

Department of Histopathology, Nottingham City Hospital NHS Trust, Nottingham University, Nottingham, UK.

Breast lesions comprise a family of heterogeneous entities with variable patterns of presentation, morphology and clinical behaviour. The majority of breast lesions are classified traditionally into benign and malignant conditions and their behaviour can, in the vast majority of cases, be predicted with a reasonable degree of accuracy. However, there remain lesions which show borderline features and lie in a grey zone between benign and malignant, as their behaviour cannot be predicted reliably. Defined pathological categorization of such lesions is challenging, and for some entities is recognized to be subjective and include a range of diagnoses, and forms of terminology, which may trigger over- or undertreatment. The rarity of these lesions makes the acquisition of clinical evidence problematic and limits the development of a sufficient evidence base to support informed decision-making by clinicians and patients. Emerging molecular evidence is providing a greater understanding of the biology of these lesions, but this may or may not be reflected in their clinical behaviour. Herein we discuss some breast lesions that are associated with uncertainty regarding classification and behaviour, and hence management. These include biologically invasive malignant lesions associated with uncertain metastatic potential, such as low-grade adenosquamous carcinoma, low-grade fibromatosis-like spindle cell carcinoma and encapsulated papillary carcinoma. Other lesions of uncertain malignant nature remain, such as mammary cylindroma, atypical microglandular adenosis, mammary pleomorphic adenoma and infiltrating epitheliosis. The concept of categories of (1) breast lesions of uncertain malignant nature and (2) breast lesions of limited metastatic potential are proposed with details of which histological entities could be included in each category, and their management implications are discussed.
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http://dx.doi.org/10.1111/his.12861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987288PMC
January 2016

Developing in vitro models of human ductal carcinoma in situ from primary tissue explants.

Breast Cancer Res Treat 2015 Sep 18;153(2):311-21. Epub 2015 Aug 18.

Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, 300 Halket Street, Suite 2601, Pittsburgh, PA, 15217, USA.

Because there are currently no reliable predictors for progression of ductal carcinoma in situ (DCIS) to invasive disease, nearly all patients receive comprehensive therapy, leading to over-treatment in many cases. Few in vitro models for studying DCIS progression have been developed. We report here the successful culture and expansion of primary DCIS from surgical specimens using a conditional reprogramming protocol. Patients with percutaneous core-needle biopsy demonstrating DCIS were enrolled in a tissue banking protocol after informed consent was received. Fresh tissue was taken from lumpectomy or mastectomy specimens, mechanically and enzymatically dissociated, cultured in medium conditioned by irradiated mouse fibroblasts and supplemented with rho-associated protein kinase (ROCK) inhibitor, and characterized by immunocytochemistry. Out of 33 DCIS cases, 58% (19) were expanded for up to 2 months in culture, and 42% (14) were frozen immediately after mechanical dissociation for future growth. The cultures are almost exclusively composed of cytokeratin 8- and EpCAM-positive luminal and cytokeratin 14-, cytokeratin 5-, and p63-positive basal mammary epithelial cells, suggesting maintenance of heterogeneity in vitro. Furthermore, as assessed by luminal and basal marker expression, these cells retain their cellular identities both in the "conditionally reprogrammed" proliferative state and after conditioned media and ROCK inhibitor withdrawal. When grown to 100 % confluency, the cultures organize into luminal and basal layers as well as luminal compartments surrounded by basal cells. Primary cultures of DCIS derived directly from patient tissues can be generated and may serve as in vitro models for the study of DCIS.
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http://dx.doi.org/10.1007/s10549-015-3551-8DOI Listing
September 2015

A Comparison of Breast Cancer Multianalyte Assays With Algorithmic Analyses (MAAA) for Their Net Predictive/Prognostic Value.

Authors:
David J Dabbs

Clin Adv Hematol Oncol 2015 Jun;13(6 Suppl 6):14-24

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

In breast cancer, prognostic and predictive information has traditionally been ascertained using clinicopathologic measures, such as tumor size and grade, lymph node involvement, and the presence of protein biomarkers, including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)/neu. These parameters provide important prognostic and predictive information. Conventional clinicopathologic factors also help guide the use of adjuvant therapy. However, standard clinicopathologic factors have a limited ability to estimate prognosis, predict responses to chemotherapy, and help guide the selection of chemotherapeutic agents. In addition, clinical factors alone can be misleading in that they do not fully indicate whether chemotherapy is needed or if hormonal treatment in ER-positive patients is sufficient. Multianalyte assays with algorithmic analyses (MAAA) were developed toward the goal of personalized medicine, to supplement existing techniques and further inform the decision of whether to treat with adjuvant chemotherapy. Several gene expression profiling tests are now available for use in patients with breast cancer. In general, these tests provide an estimate of prognosis. In select instances, they may also be predictive for benefit from chemotherapy. This article reviews the latest studies evaluating the use of these tests.
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June 2015

Molecular drivers of lobular carcinoma in situ.

Breast Cancer Res 2015 Jun 4;17:76. Epub 2015 Jun 4.

Womens Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA.

Lobular carcinoma in situ (LCIS) is considered to be a risk factor for the development of invasive breast carcinoma, but it may also be a non-obligate precursor to invasive lobular carcinoma (ILC). Many LCIS lesions do not progress to ILC, and the molecular changes that are necessary for progression from LCIS to ILC are poorly understood. Disruption in the E-cadherin complex is the hallmark of lobular lesions, but other signaling molecules, such as PIK3CA and c-src, are consistently altered in LCIS. This review focuses on the molecular drivers of lobular carcinoma, a more complete understanding of which may give perspective on which LCIS lesions progress, and which will not, thus having immense clinical implications.
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http://dx.doi.org/10.1186/s13058-015-0580-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453073PMC
June 2015