BACKGROUND Multiple studies have suggested that resection of the primary tumor improves survival in patients with stage IV breast cancer, yet in the era of targeted therapy, the relation between surgery and tumor molecular subtype is unknown. The objective of the current study was to identify subsets of patients who may benefit from primary tumor treatment and assess the frequency of local disease progression. METHODS Patients presenting with stage IV breast cancer and intact primary tumors (n = 186) were identified from a prospectively maintained clinical database (2000-2004) and clinical data were abstracted (grading determined according to the American Joint Committee on Cancer staging system). RESULTS Surgery was performed in 69 (37%) patients: 34 (49%) patients with unknown metastatic disease at the time of surgery, 15 (22%) patients for local control, 14 (20%) patients for palliation, and in 6 (9%) patients to obtain tissue. Surgical patients were more likely to be HER-2/neu negative for HER-2/neu (P = .001), and to have smaller tumors (P = .05) and solitary metastasis (P <.001). Local therapy included axillary lymph node clearance in 33 (48%) patients and postoperative radiotherapy in 9 (13%) patients. The median survival was 35 months. Cox regression analysis identified estrogen receptor (ER) positivity (hazard ratio [HR], 0.47; 95% confidence interval [95% CI], 0.29-0.76), progesterone receptor positivity (HR, 0.57; 95% CI, 0.36-0.90), and HER-2/neu amplification (HR, 0.51; 95% CI, 0.34-0.77) as being predictive of improved survival. There was a trend toward improved survival with surgery (HR, 0.71; 95% CI, 0.47-1.06). On exploratory analyses, surgery was found to be associated with improved survival in patients with ER/PR positive or HER-2/neu-amplified disease (P = .004). No survival benefit was observed in patients with triple-negative disease. CONCLUSIONS Although a trend toward improved survival with surgery was observed, it was noted most strongly in patients with ER/PR positive and/or HER-2/neu-amplified disease. This suggests that the impact of local control is greatest in the presence of effective targeted therapy, and supports the need for further study to define patient subsets that will benefit most.
An underlying malignancy was identified in 30/306 (10%) patients with ND and negative standard evaluation. Ductography is a poor predictor of underlying pathology and cannot exclude malignancy. MRI's higher predictive values may allow for improved patient selection and treatment planning; however, MRI should not replace MDE as the gold standard to exclude malignancy in patients with ND and negative standard evaluation.
Purpose The increased breast cancer risk conferred by a diagnosis of lobular carcinoma in situ (LCIS) is poorly understood. Here we review our 29-year longitudinal experience with LCIS to evaluate factors associated with breast cancer risk. Methods Patients participating in surveillance following an LCIS diagnosis are followed in a prospectively maintained database. Comparisons were made among women choosing surveillance, with or without chemoprevention, and those undergoing bilateral prophylactic mastectomies between 1980 and 2009. Results 1060 patients with LCIS without concurrent breast cancer were identified. Median age at LCIS diagnosis was 50 years (range, 27–83). 56 (5%) underwent bilateral prophylactic mastectomy; 1004 chose surveillance with (n=173) or without (n=831) chemoprevention. At a median follow-up of 81 months (6–368 months), 150 patients developed 168 breast cancers (63% ipsilateral, 25% contralateral, 12% bilateral), with no dominant histology (ductal carcinoma in situ 35%, infiltrating ductal carcinoma 29%, infiltrating lobular carcinoma 27%, other 9%). Breast cancer incidence was significantly reduced in women taking chemoprevention (10-year cumulative risk: 7% chemoprevention; 21% no chemoprevention, p<.0001). In multivariate analysis, chemoprevention was the only clinical factor associated with breast cancer risk (hazard ratio 0.27, 95% confidence interval 0.15–0.50). In a subgroup nested case-control analysis, volume of disease defined as the ratio of slides with LCIS to total number of slides reviewed was also associated with breast cancer development (p=0.008). Conclusion We observed a 2% annual incidence of breast cancer among women with LCIS. Common clinical factors used for risk prediction including age and family history were not associated with breast cancer risk. The lower breast cancer incidence in women opting for chemoprevention highlights the potential for risk reduction in this population.
Background E-cadherin (E-CD) inactivation with loss of E-CD-mediated cell adhesion is the hallmark of lesions of the lobular phenotype. E-CD is typically absent by immunohistochemistry in both lobular carcinoma in situ (LCIS) and invasive lobular lesions, suggesting it occurs early in the neoplastic process. In laboratory models, downstream post-transcriptional modifiers such as TWIST and SNAIL contribute to the dissociation of the intracellular component of the cadherin-catenin complex (CCC), resulting in tumor progression and invasion. We hypothesized that complete CCC dissociation may play a role in lobular neoplasia progression. Here we explore the relationship between loss of E-CD and dissociation of the CCC in pure LCIS and LCIS associated with invasive cancer. Methods Fresh-frozen tissues were obtained from 36 patients undergoing mastectomy for pure LCIS (n=11), LCIS with ILC (n=18) or LCIS with IDC (n=7). Individual lesions were subject to laser-capture microdissection and gene-expression analysis (Affymetrix HG-U133A 2.0). Immunohistochemistry for ER,PR,HER2, E-CD,N-CD,α-,β-, and phosphoβ-catenin, TWIST, and SNAIL were evaluated in normal, in situ, and invasive components from matched formalin-fixed paraffin-embedded samples(n=36). CCC-dissociation was defined as negative membranous E-CD, α- and β-catenin expression. Results E-CD was negative in all LCIS and ILC lesions, and positive in all normal and IDC lesions. Membranous α and β-catenin expression decreased with the transition from LCIS to ILC (pure LCIS 82%;LCIS w/ILC 28%;ILC 0%), while TWIST expression increased (pure LCIS low;LCIS w/ILC moderate;ILC high). Gene expression paralleled IHC staining patterns with a stepwise downregulation of E-CD, α and β-catenin from normal to LCIS to invasive lesions, and increasing expression of TWIST from normal to LCIS to ILC. Conclusions Loss of E-CD expression is an early event in lobular neoplasia. Decreasing membranous catenin expression in tandem with increasing levels of TWIST across the spectrum of lobular lesions suggests CCC dissociation is a progressive process.
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