Maysa E. El-Sayed

Prognostic markers in triple-negative breast cancer.

Triple‐negative breast cancer (estrogen receptor‐negative, progesterone receptor‐negative, and HER2‐negative) is a high risk breast cancer that lacks the benefit of specific therapy that targets these proteins.

Triple-Negative Breast Cancer: Distinguishing between Basal and Nonbasal Subtypes

Purpose: Triple-negative (TN; estrogen receptor, progesterone receptor, and HER-2 negative) cancer and basal-like breast cancer (BLBC) are associated with poor outcome and lack the benefit of targeted therapy. It is widely perceived that BLBC and TN tumors are synonymous and BLBC can be defined using a TN definition without the need for the expression of basal markers. Experimental Design: We have used two well-defined cohorts of breast cancers with a large panel of biomarkers, BRCA1 mutation status, and follow-up data to compare the clinicopathologic and immunohistochemical features of TN tumors expressing one or more of the specific basal markers (CK5/6, CK17, CK14, and epidermal growth factor receptor; BLBC) with those TN tumors that express none of these markers (TN3BKE−). Results: Here, we show that although the morphologic features of BLBC are not significantly different from that of TN3BKE- tumors, BLBC showed distinct clinical and immunophenotypic differences. BLBC showed a statistically significant association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, and other markers of poor prognosis such as p53. A difference in the expression of cell cycle-associated proteins and biomarkers involved in the immunologic portrait of tumors was seen. Compared with TN3BKE- tumors, BLBC was positively associated with BRCA1 mutation status and showed a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival. Conclusion: TN breast cancers encompass a remarkably heterogeneous group of tumors. Expression of basal markers identifies a biologically and clinically distinct subgroup of TN tumors, justifying the use of basal markers (in TN tumors) to define BLBC.

Prognostic Significance of Nottingham Histologic Grade in Invasive Breast Carcinoma

PURPOSE The three strongest prognostic determinants in operable breast cancer used in routine clinical practice are lymph node (LN) stage, primary tumor size, and histologic grade. However, grade is not included in the recent revision of the TNM staging system of breast cancer as its value is questioned in certain settings. MATERIALS AND METHODS This study is based on a large and well-characterized consecutive series of operable breast cancer (2,219 cases), treated according to standard protocols in a single institution, with a long-term follow-up (median, 111 months) to assess the prognostic value of routine assessment of histologic grade using Nottingham histologic grading system. RESULTS Histologic grade is strongly associated with both breast cancer-specific survival (BCSS) and disease-free survival (DFS) in the whole series as well as in different subgroups based on tumor size (pT1a, pT1b, pT1c, and pT2) and LN stages (pN0 and pN1 and pN2). Differences in survival were also noted between different individual grades (1, 2, and 3). Multivariate analyses showed that histologic grade is an independent predictor of both BCSS and DFS in operable breast cancer as a whole as well as in all studied subgroups. CONCLUSION Histologic grade, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive breast cancer and should be incorporated in breast cancer staging systems.

Biologic and Clinical Characteristics of Breast Cancer With Single Hormone Receptor–Positive Phenotype

PURPOSE Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PgR) status. It is usually easier to decide treatment strategies in cases of double-positive/-negative phenotypes than in single-positive tumors. PATIENTS AND METHODS We have examined a large and well-characterized series of primary invasive breast carcinoma (1,944 cases) with long-term clinical follow-up and hormone therapy data. Patients were stratified according to ER and PgR expression and the study was focused on the single-positive groups (ER-/PgR+ and ER+/PgR-), to assess their main features and evaluate any prognostic and predictive difference between them and compare them with the double-positive/-negative tumors. RESULTS ER+/PgR-tumors were found more frequently in elderly, postmenopausal women. The majority were grade 2 ductal/no specific type carcinomas. There was no difference between the two groups with regard to lymph node stage. Survival analyses showed no difference between the two groups in terms of disease-free interval and overall survival. However, when compared with the double-negative phenotype, ER+/PgR-showed an association with better outcome but no such survival advantage was detected in case of ER-/PgR+ tumors. In the group of patients with ER+ tumors who received adjuvant hormonal therapy, absence of PgR (ER+/PgR-) was an independent predictor of development of recurrence and shorter survival and, hence, poorer response to hormonal therapy. CONCLUSION ER+/PgR-and ER-/PgR+ tumors are biologically and clinically distinct groups of breast cancer that may require different treatment strategies with ER-/PgR+ exhibiting more aggressive behavioral characteristics.

Breast carcinoma with basal differentiation: a proposal for pathology definition based on basal cytokeratin expression.

Aim:  To assess the expression and coexpression of a range of different biomarkers that have been used to define breast carcinomas with a basal phenotype (BP) and their relationship with prognosis in an attempt to refine the definition of BP and to evaluate the reliability of using a single biomarker to identify these tumours.

Expression of BRCA1 protein in breast cancer and its prognostic significance

BRCA1 is a tumor suppressor gene which, when mutated, is associated with the development of hereditary breast cancers. In sporadic tumors, although inherent gene mutations are rare, loss of BRCA1, resulting from reduced expression or incorrect subcellular localization, is postulated to be important. The purpose of the current study was to examine the expression and localization of BRCA1 protein and to assess its prognostic value, in a well-characterized series of unselected breast carcinomas. We have examined BRCA1 in a series of invasive breast carcinoma (1940 cases) using tissue microarray and immunohistochemistry, to evaluate its expression pattern and to correlate this with clinicopathologic variables and patient outcome. In breast cancer, complete loss of nuclear expression was observed in 223 cases (15%) and cytoplasmic expression was found in 541 breast cancers (36.6%). Absent or reduced nuclear BRCA1 expression was observed more frequently in ductal carcinoma of no special type and medullary-like carcinoma and less frequently in lobular and tubular mixed carcinomas. It was also associated with high-grade, advanced lymph node stage, larger size, vascular invasion, negative estrogen receptor, progesterone receptor and androgen receptor expression, and positive p53 and P-cadherin expression, and with the basal-like class of breast cancer. Altered BRCA1 was associated with shorter disease-free interval. Cytoplasmic expression was also associated with development of recurrence and positive EGFR and HER2 expression. It showed an inverse association with survival particularly in low-grade, small-size, and estrogen receptor-positive subgroups. In the grade 1 subgroup, multivariate analysis with adjustment for other prognostic factors showed that cytoplasmic expression of BRCA1 was an independent predictor of disease-free interval. BRCA1 alteration may play a significant role in the development and progression of breast cancer. Immunohistochemical assessment of BRCA1 expression could provide additional clinically relevant information in routine classification of breast cancer.

Histologic grading is an independent prognostic factor in invasive lobular carcinoma of the breast

Invasive lobular carcinoma (ILC) comprises approximately 5–15% of breast cancers and appears to have a distinct biology. As it is less common than invasive ductal carcinoma, few studies of large size have addressed the value of assessment of histologic grade in ILC. Methods: This study is based on a large and well-characterised consecutive series of breast cancer (4,987 cases), from a single institution, with a long-term follow-up to assess the prognostic value of routine assessment of histologic grade in ILC. Histologic grade and other clinicopathological data were available in 517 pure ILC cases. A panel of biomarkers was also available for 215 cases. Results: The majority of ILC was of classical and mixed lobular variants (89%). Most ILC cases were moderately differentiated (grade 2) tumours (76%), while a small proportion of tumours were either grade 1 or 3 tumours (12% each). There were positive associations between histologic grade and other clinicopathological variables of poor prognosis such as larger size, positive lymph node, vascular invasion, oestrogen receptor and androgen receptor negativity and p53 positivity. Multivariate analyses showed that histologic grade is an independent predictor of shorter breast cancer specific survival and disease free interval. Conclusion: Histologic grade of ILC, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive lobular carcinoma of the breast and should be provided routinely in pathology reports.

The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast

UNLABELLED The new gene expression molecular taxonomy of breast cancer places medullary carcinoma in the basal group. The basal group is considered to have a poor prognosis, but medullary carcinoma is considered to have a better prognosis than other grade 3 carcinomas. The prognostic significance of tumour associated inflammation, an important feature of medullary carcinomas, remains controversial. The aim of this study was to assess the prognostic importance of medullary histological type and inflammation in breast cancer. One thousand five hundred and ninety-seven patients who received no systemic adjuvant treatment and who had a median follow up of 9.5 years were studied. RESULTS Prominent inflammation was associated with high histological grade and with better survival [relative risk (RR) 0.57, 95% confidence intervals (CI) 0.44-0.74] on multivariate analysis. Typical and atypical medullary carcinomas (n=132) did not have significantly different survival and were grouped together. Medullary carcinoma did not have significantly different prognosis than grade 3 ductal carcinoma with prominent inflammation, but both had a better prognosis than grade 3 ductal carcinoma without prominent inflammation (P<0.0001 and P=0.03). These differences were independent of other prognostic factors. These results question the current separation of typical and atypical medullary carcinoma. Prominent inflammation is associated with a better prognosis, and may explain the better prognosis in medullary carcinoma compared with grade 3 ductal carcinoma without prominent inflammation. The good prognosis of medullary carcinoma emphasises the heterogeneity of basal-like breast carcinomas. Further studies are needed to investigate the difference in survival between medullary carcinoma and other forms of basal carcinomas and the role of inflammation in any such differences in behaviour.

Patho-biological aspects of basal-like breast cancer

Breast cancer comprises a remarkably diverse group of diseases in terms of presentation, morphology, molecular profile and response to therapy. Recent gene expression profiling of breast cancer has identified specific molecular subtypes of clinical significance. Basal-like cancers (BLC) comprise a group of tumours that are characterised by an expression signature similar to that of the basal/myoepithelial cells of the breast and cluster together with BRCA1 associated tumours. Although BLC has fascinated oncologists and scientists alike due to its enigmatic clinical and pathological parameters, there is no consensus about the definition and method of identification in routine practice of this rather heterogeneous group of cancers. Furthermore, the prognostic significance of BLCs and response to specific chemotherapy regimens are still a matter debate. In this review, we discuss the molecular and morphological features, prognostic significance of BLC, and explore its impact on the concept of the breast cancer stem cell.

Expression profiling technology: its contribution to our understanding of breast cancer

Breast cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations. Routine clinical management of breast cancer relies on clinical and pathological factors, however. These seem insufficient to reflect the whole clinical heterogeneity of tumours and are less than perfectly adapted to each patient. Recent advances in human genome research and high‐throughput molecular technologies have made it possible to tackle the molecular complexity of breast cancer and have contributed to the realization that the biological heterogeneity of breast cancer has implications for treatment. Gene expression profiling of breast cancer has been performed using several approaches. This review will describe the details of gene expression profiling of breast cancer, the different approaches and the impact on clinical management.