Anna Marie Mulligan

Comparison of clinical schemas and morphologic features in predicting Lynch syndrome in mutation-positive patients with endometrial cancer encountered in the context of familial gastrointestinal cancer registries.

Endometrial cancer (EC) is the most common extraintestinal malignancy in Lynch syndrome (LS) and often is the sentinel malignancy, yet there is no consensus regarding LS‐EC detection algorithms. In this study, the authors determined the efficacy of family/personal history and tumor morphology in predicting LS in a cohort of patients with EC who had mutation‐proven LS.

Food sources of plant sterols in the EPIC Norfolk population

Objective:To investigate the intake of plant sterols and identify major dietary sources of plant sterols in the British diet.Subjects:A total of 24 798 men and women recruited during 1993–1997, participating in the European Prospective Investigation into Cancer (EPIC-Norfolk).Interventions:A database of the plant sterol (campesterol, β-sitosterol, stigmasterol, campestanol and β-sitostanol) content in foods, based on gas-liquid chromatography (GLC) analyses, was linked to nutritional intake data from food frequency questionnaires in the EPIC-Norfolk population.Results:The mean (s.d.) intake of total plant sterols was 300 (108) mg/d for men and 293 (100) mg/d for women. Bread and other cereals, vegetables and added fats were the three major food sources of plant sterols representing 18.6 (8.9), 18.4 (8.5) and 17.3 (10.4)% of the total plant sterol intake respectively. Women had a higher plant sterol density than men (36.4 vs 32.8 mg/1000 kJ, P<0.001) and in relation to energy intake higher intakes of plant sterols from vegetables, bread and other cereals, added fats, fruits and mixed dishes (all P<0.001), whilst men had higher intakes of plant sterols from cakes, scones and chocolate, potatoes (all P<0.001) and other foods (P<0.01).Conclusions:The intake of plant sterols in UK, mainly from bread, cereals, fats and vegetables, is much higher than previously reported but comparable to recent European studies.

Tumoral Lymphocytic Infiltration and Expression of the Chemokine CXCL10 in Breast Cancers from the Ontario Familial Breast Cancer Registry

Purpose: Breast carcinomas, including basal and hereditary cases, often present with a prominent tumoral lymphocytic infiltrate. Chemokines could play a role in attracting these cells and contribute to tumor progression. We explored tumoral expression of CXCL10 and determined the relationship between CXCL10 and lymphocytic infiltrate in a cohort of breast cancers. Experimental Design: Using tissue microarrays of 364 breast tumors, we evaluated expression of CXCL10 and its receptor, CXCR3, in relation to histopathologic features, biomarkers, and lymphocyte markers. In addition, we overexpressed CXCL10 and CXCR3 in MCF7 breast cancer cells and monitored T-lymphocyte migration and invasion. Results: Forty-five percent of tumors expressed CXCL10, and a significant association was found with CXCR3 and lymphocytic infiltrate. Further characterization of the lymphocytic infiltrate revealed an association with CXCL10 expression for peritumoral CD4+ and CD8+ lymphocytes. CD8+ intratumoral lymphocytes, FOXP3+ regulatory T cells (Tregs), and T-BET+ TH1 cells were associated with BRCA1 and basal tumors. Conditioned media from MCF7 cells overexpressing both CXCL10 and CXCR3 increased T-lymphocyte migration and invasion. Conclusions: Our findings suggest that CXCL10 may act in a paracrine manner, affecting the tumor microenvironment, and in an autocrine manner, acting on the tumor cells themselves and may play a role in tumor invasiveness and progression. The CXCL10-CXCR3 axis can serve as a potential target in BRCA1 and basal breast cancers, which present with a prominent lymphocytic infiltrate and a poor prognosis. Clin Cancer Res; 19(2); 336–46. ©2012 AACR.

Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry

Background:Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER−PR−) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER−PR− cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention.Methods:Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status.Results:High parity (⩾3 live births) without breastfeeding was positively associated only with ER−PR− tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10–2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71–1.22). Across all race/ethnicities, associations for ER−PR− cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER−PR− cancer only (OR=1.32, 95% CI 1.04–1.67). For women who began OC use in 1975 or later there was no increased risk.Conclusions:Our findings support that there are modifiable factors for ER−PR− breast cancer and that breastfeeding in particular may mitigate the increased risk of ER−PR− cancers seen from multiparity.

Müllerian adenosarcomas with unusual growth patterns: staging issues.

Uterine adenosarcomas are uncommon mixed Müllerian neoplasms, most commonly arising in the uterine corpus. A new Federation of International Gynecologic Organization staging system for these tumors has recently been implemented. This staging system is an improvement on the earlier generic application of the 1988 Federation of International Gynecologic Organization staging system for endometrial cancer to adenosarcoma. Herein, we report 3 uterine adenosarcomas with unusual features. For 2 of these, no specific staging guidelines are provided by either the earlier or, more importantly, the new staging system. The first case is of an adenosarcoma arising in the eutopic endometrium with involvement of underlying adenomyosis without myometrial invasion; the second originated in a mural adenomyoma in the absence of eutopic endometrial involvement; and the third case encompassed synchronous endometrial and extrauterine (peritoneal) neoplasms. Such cases are rare, and there is insufficient evidence to be definitive about staging. Thus, we suggest a descriptive reporting strategy for adenosarcomas with these unusual features. We also propose a reporting nomenclature for such cases to ensure standardization such that they can be adequately recorded in synoptic reporting protocols. This will facilitate reliable data collection such that an evidence-based staging system for these scenarios may be derived.

Endometrial giant cell carcinoma: a case series and review of the spectrum of endometrial neoplasms containing giant cells.

Poorly differentiated endometrial carcinomas of specific type include the rarely reported endometrial carcinoma with a malignant giant cell component [endometrial giant cell carcinoma (GCC)]. Since the initial description in 1991, there has only been 1 subsequent case report of this entity. We report another 5 cases. The patients ranged in age from 53 to 83 years, presenting with vaginal bleeding, anemia, or a pelvic mass. Four of the 5 tumors contained areas of endometrial adenocarcinoma of usual type, with a variable giant cell component. The conventional cell types present included 1 case with clear cell carcinoma (30% of tumor volume), 2 with high-grade endometrioid carcinoma (50% and 70% of tumor volume, respectively) and 1 with serous histology (10% of tumor volume). One was composed exclusively of giant cell carcinoma. The giant cell component in all cases consisted of poorly cohesive nests of bizarre multinucleated giant cells with mononuclear tumor cells. A striking peritumoral and intratumoral inflammatory cell infiltrate composed of lymphocytes, plasma cells and focal eosinophils, and neutrophils was present and emperipolesis was noted in 4 of the 5 cases. The giant cells showed focal staining for epithelial markers (AE1/AE3 and CAM 5.2). Three of the patients presented with stage 1A disease, 1 with stage 1B disease, and 1 tumor was advanced, presenting as stage IIIC2. One patient in whom the tumor was exclusively of the giant cell type, developed lung metastasis 4 years after diagnosis and 1 patient is disease free after 14 years. The remaining 3 patients showed no evidence of disease with 15 to 32 months of follow-up. As histotype supplemented by staging information is critical in selection of treatment modalities and in prognostication in uterine malignancies, accurate classification is mandated. Here, we present a series of endometrial carcinomas containing a component of GCC and discuss the spectrum of giant cell-containing uterine neoplasms. At this time, however, the cumulative data on endometrial GCC are limited and the prognostic significance of the presence and the extent of a giant cell component in endometrial carcinoma remains uncertain.

Encapsulated Papillary Carcinoma of the Breast

Papillary lesions of the breast include a broad spectrum of entities, many of which can be diagnostically challenging for the pathologist. This article focuses on encapsulated papillary carcinoma, a recently proposed term used to describe papillary carcinoma occurring within a cystically dilated duct. Previously considered a variant of papillary ductal carcinoma in situ, the finding that these lesions typically lack myoepithelial cells at their periphery has raised questions about their true nature. This article presents a practical approach to the diagnosis of encapsulated papillary carcinoma with a review of its histologic mimics and clinical significance.

Abstract 3038: Characterization of ZHX1 in node-negative breast cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Women with breast cancer but without local metastasis to the axillary lymph nodes (ANN) have a good prognosis. However, 20 to 30% of patients with ANN breast cancer will still experience recurrence and distant metastases. Lymphatic invasion (LVI) is an important prognostic factor for ANN breast cancer. Therefore, LVI status was incorporated to provide a unique approach to identify novel genes related to outcome in ANN breast cancer. Gene expression microarrays were used to discriminate between tumors 1) with or without LVI (LVI+ or LVI-, respectively) and 2) from patients who experienced early recurrence (within 4 years) and those who were disease-free (for at least 10 years). Biostatistical analyses were performed to compile a list of statistically significant genes common to both comparisons. Zinc fingers and homeoboxes 1 (ZHX1) was identified as a candidate gene involved in LVI and associated with early recurrence of ANN breast cancer. Real-time RT-PCR (qPCR) was performed to quantify ZHX1 expression in a subset of cell lines and tumor samples. ZHX1 is expressed at different levels, mostly at an intermediate level in the tumors. A more network-based approach was used to examine biological pathways that may be associated with this poor prognosis. We discovered that ZHX1 may be involved in transcription, signaling, metabolism, and development, which is consistent with previous findings. ZHX1 binds to the other two members of the ZHX family, ZHX2 and ZHX3. All three members bind to the activation domain of the alpha subunit of nuclear transcription factor γ (NF-γ). NF-γ activates transcription of several genes, including the cell cycle progression gene, cell division cycle 25 homolog C (CDC25C). However, ZHX2 represses promoter activity of CDC25C, which would prevent cells from progressing into mitosis. Since ZHX1 binds to ZHX2 and NF-γ, this suggests that ZHX1 may be involved in the cell cycle. ZHX1 is significantly over-expressed in LVI+ tumors and in those from patients who experienced early recurrence of ANN breast cancer. The potential role of ZHX1 in the cell cycle may be associated with this poor prognosis. Gene and protein expression of ZHX1 and its candidate interactors are being quantified in cell lines via qPCR and Western blotting, respectively, and potential correlations examined. Immunohistochemistry is being performed on tissue microarrays to observe ZHX1 protein levels and localization and correlate with gene expression. Cell lines are being transfected via vector- or siRNA- based methods to over-express or knock down ZHX1, respectively. Alterations in tumorigenicity are being investigated via MTT proliferation and migration and/or invasion assays. Findings may aid in determining which ANN breast cancer patients may benefit from systemic therapy and identifying novel targets for cancer therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3038. doi:10.1158/1538-7445.AM2011-3038

Assessing the Differential Expression of Molecular Biomarkers in Breast Cancer.

Background : Molecular profiling of breast cancer has identified multiple biomarkers with potential to better predict clinical outcomes and response to treatment than existing clinicopathological indices. We focused on 8 biomarkers of particular relevance as suggested by the literature: CD44, methyl guanine methyltransferase (MGMT), epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX2), cytokeratin-5 (CK5), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This study aims to clarify the prognostic value of these breast cancer biomarkers as well as to define their relationships with each other. Methods : Formalin fixed paraffin embedded (FFPE) breast tumor samples from 140 patients diagnosed with breast cancer from Jan 2001 to Dec 2005 at St. Michael9s Hospital in Toronto, Canada were examined retrospectively using tissue microarray analysis. Samples were stained for CD44, COX2, MGMT, EGFR, CK5, ER, PR, and HER2 by immunohistochemistry. Biomarkers including histological features and staining patterns were then evaluated. A manual chart review documenting relevant clinical and pathological features was also conducted. Subsequent statistical analysis utilized Kaplan-Meier survival curves to identify biomarker-survival associations and simple linear regression analysis to determine biomarker cluster groups. Results : Median patient age was 56 (range 31-86). Median follow-up time was 62 months (range 5-102). Tumors were of various pathological types and stages (I – IV). No significant associations between biomarkers and disease-free survival (DFS) were found. DFS (median = 53.5 months) did correlate with tumor stage, nuclear grade, and lymphovascular invasion (LVI) as expected. However, only LVI was found to correlate with DFS in triple negative patients (n=24). Regression analysis yielded two cluster groups of biomarkers; Cluster group 1 includes ER, PR, Cox2, CD44; and Cluster group 2 includes HER2, EGFR, CK5. Expression of biomarkers within one cluster group relate directly with those in the same group, but inversely with biomarkers from the other cluster group. In addition, biomarkers in Cluster group 1 relate inversely to the mitotic count, tumor size, and nuclear grade, while biomarkers from Cluster group 2 relate directly with these indices. For example, CK5 positive tumors with HER2 and EGFR overexpression tend to have a high mitotic count, large tumor size, and high nuclear grade. MGMT did not show association with any histological feature or DFS. Conclusions : This retrospective observational study of 140 breast cancer patients focused on the prognostic implications and relationships of 8 biomarkers: CD44, COX2, MGMT, EGFR, CK5, ER, PR, and HER2. Two cluster groups of biomarkers have been identified. Cluster group 1 (ER, PR, COX2, CD44) correlates with a less aggressive tumor morphology, while Cluster group 2 (HER2, EGFR, CK5) correlates with a more aggressive one. No associations have yet been found between biomarkers and DFS. This study has been extended to include 373 patients with further analysis underway. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6041.