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.

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.

The biological and clinical characteristics of breast carcinoma with mixed ductal and lobular morphology.

UNLABELLED: Although invasive ductal (IDC) and lobular (ILC) breast carcinomas are well characterised in the literature, the biological and clinical significance of mixed tumours with both ductal and lobular components has not been investigated. In the current study, we have examined a well-characterised series of breast carcinoma with a long term follow-up that comprised 140 mixed tumours, 2170 IDC and 380 pure ILC. RESULTS: Mixed tumours constituted 3.6% of all cases. The majority (59%) of the mixed tumours were grade 2 compared to 33% in IDC and 88% in ILC. Positive lymph nodes (LN) were found in 41% and definite vascular invasion (VI) in 26% of the cases. DCIS was detected in 123 (89%) and LCIS in 43 (31%) (both DCIS and LCIS were found in 39 cases). The majority of tumours were predominantly (>50 of tumour area) of ductal type (57%). When compared to pure IDC, mixed tumours showed an association with lower grade, ER positivity and lower frequency of development of distant metastases. When compared to pure ILC, mixed tumours showed an association with higher grade, positive LN metastasis, VI and development of regional metastasis. After adjustment for grade most of these differences were no longer apparent. There was an association between histologic type of carcinoma in LN metastasis and the predominant histologic type of the primary tumour. Mixed tumours showed metastatic patterns similar to that of ILC with frequent metastasis to bone. No clinically meaningful differences in survival were found between these mixed carcinomas and pure IDC or ILC of the breast or between mixed tumours with predominantly ductal or lobular phenotype.

Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes.

UNLABELLED: Invasive lobular carcinoma (ILC) comprises approximately 5-15% of breast cancers and appears to have a distinct biology. It is less common than invasive ductal carcinoma (IDC) and few large studies have addressed its biologic characteristics and behaviour with respect to long-term clinical outcome and response to adjuvant therapy. METHODS: This study is based on a large and well-characterised consecutive series of invasive breast carcinomas with a long-term follow-up (up to 25 years). This series included 415 (8%) patients with pure ILC and 2901 (55.7%) with IDC (not otherwise specified) identified from a consecutive cohort of 5680 breast tumours presented to our Breast Unit that were treated in a similar conventional manner. Clinicopathological, therapy and outcome information as well as data on a large panel of biomarkers were available. RESULTS: Compared to IDC, patients with ILC tended to be older and present with tumours which are more frequently lower grade (typically, grade 2 [84%]), hormone-receptor positive (86% compared to 61% in IDC), of larger size, and with the absence of vascular invasion. A higher frequency of ILC was placed in the good Nottingham Prognostic Index group (40% compared to 21% in IDC). ILC showed indolent but progressive behavioural characteristics with nearly linear survival curves which crossed those of IDC after approximately 10years of follow-up, thus eventually exhibiting a worse long-term outcome. Importantly, ILC showed a better response to adjuvant hormonal therapy (HT) with improvement in survival in patients who received HT compared with matched patients with IDC. CONCLUSION: ILC is a distinct entity of breast cancer that responds well to adjuvant HT. These data add important clinical information for assessing the long-term benefits of adjuvant HT use in ILC.

Screen-detected breast lesions with malignant needle core biopsy diagnoses and no malignancy identified in subsequent surgical excision specimens (potential false-positive diagnosis).

Although breast needle core biopsy (NCB) is now a standard diagnostic procedure in the triple assessment of screen-detected breast lesions, data on the false-positive diagnoses of malignancy (malignant NCB 'B5' with normal/benign surgery) are lacking. In this study, we have studied a large series of NCBs (101,440) to assess the causes and pitfalls resulting in false-positive NCB diagnoses and to evaluate their impact on patients' management in the screening service. Our results showed that of 40,395 malignant NCBs reported during the period of this study, 174 NCBs are considered as false-positives (0.43%; (95% confidence interval [CI]=0.37-0.49%)). However, on review, 165 cases (95%) were found to be the result of true removal of the whole lesion in the core with subsequent negative excision biopsy samples (true-positive NCBs). This may reflect sampling of small screen detected lesions and the use of larger core biopsies at assessment. The remaining 9 cases were considered as true false-positive cores, giving a false-positive rate of 0.02% (95% CI=0.01-0.04%). Analysis of these 9 cases showed that 8 cases, originally diagnosed as DCIS, were classified as borderline lesions or lesions of uncertain malignant potential after surgical excision. The classification and management of such borderline lesions remains controversial and diagnostic surgical excision is usually the optimum management. One case was the result of pathological misinterpretation of fat necrosis as invasive carcinoma. This was the only case that resulted in a significant over-management of the patient. In conclusion, our results showed that the true false-positive rate of NCB is extremely rare. Significant over-management of screen-detected breast lesions as a result of false-positive NCB may be considered almost nil.

Audit of performance of needle core biopsy diagnoses of screen detected breast lesions.

Breast needle core biopsy (NCB) is now a standard diagnostic procedure in the triple assessment of screen detected breast lesions. Therefore, it is important to provide robust and up-to-date data on the performance of NCB in the screening setting. However, previous studies of NCB have suffered from either limitation in the number of assessed cases or included a mix of symptomatic and screen detected breast lesions. In this study, we have evaluated the performance of a large series of uniformly assessed NCBs of screen detected lesions (20001 cases) over a period of 10 years (1997-2007). Our results showed a gradual increase in the number of NCBs and an improvement of their performance over the period of the study; absolute sensitivity increased from 84.9% to 96.4% and complete sensitivity increased from 90.9% to 99.7%. There was also a gradual reduction in the number of surgical interventions after benign (B2) and negative (B1) NCB diagnoses. Our study provides data showing variance from the suggested thresholds for the measures of performance of NCB in the United Kingdom which could be used to provide updated evidence-based thresholds for assessment of performance of NCB diagnosis use in the assessment of breast cancer screen detected lesions in the UK and elsewhere.

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

UNLABELLED: 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.

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.

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.

Prognostic markers in triple-negative breast cancer.

BACKGROUND: 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. METHODS: In this study, the authors examined a large and well characterized series of invasive breast carcinoma (n = 1944) with a long-term clinical follow-up (median, 56 months) by using tissue microarray. The series were also stained with concurrent immunohistochemical prognostic panels (estrogen receptor, progesterone receptor, HER-2, androgen receptor, epidermal growth factor receptor (EGFR), P-cadherin, E-cadherin, and basal (CK5/6, CK14), and p53), to characterize this specific subgroup of breast cancer and to identify prognostic markers that can identify tumors with more aggressive behavior. RESULTS: Of informative cases, 16.3% were of the triple-negative phenotype. The majority of these tumors were grade 3, ductal/no-specific-type carcinomas. There were positive associations with larger size, pushing margins, poorer Nottingham Prognostic Index, development of recurrence and distant metastasis, and poorer outcome. In addition, associations were found with loss of expression of androgen receptor and E-cadherin, and positive expression of basal cytokeratins (basal phenotype), P-cadherin, p53, and EGFR. In all tumors, tumor size, lymph node stage, and androgen receptor were the most useful prognostic markers. In the lymph node-positive subgroup, both size and androgen receptor retained their prognostic significance. However, in the lymph node-negative tumors, basal phenotype was the sole prognostic marker identified in this subgroup. Other parameters including age, histological grade, tumor size, vascular invasion or other biomarkers included in the current study were not significant. CONCLUSIONS: The authors concluded that assessment of androgen receptor and basal phenotype, in addition to the established pathologic variables, mainly lymph node status and tumor size, can be used to select high-risk and low-risk patients at the time of primary surgery and can provide valuable information on treatment options in these triple-negative tumors.

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.