Lobular Carcinoma in Situ: A 29-Year Longitudinal Experience Evaluating Clinicopathologic Features and Breast Cancer Risk.

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. PATIENTS AND METHODS: Patients participating in surveillance after an LCIS diagnosis are observed 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: One thousand sixty patients with LCIS without concurrent breast cancer were identified. Median age at LCIS diagnosis was 50 years (range, 27 to 83 years). Fifty-six patients (5%) underwent bilateral prophylactic mastectomy; 1,004 chose surveillance with (n = 173) or without (n = 831) chemoprevention. At a median follow-up of 81 months (range, 6 to 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% with chemoprevention; 21% with no chemoprevention; P < .001). In multivariable analysis, chemoprevention was the only clinical factor associated with breast cancer risk (hazard ratio, 0.27; 95% CI, 0.15 to 0.50). In a subgroup nested case-control analysis, volume of disease, which was defined as the ratio of slides with LCIS to total number of slides reviewed, was also associated with breast cancer development (P = .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.

Gene expression profiling of lobular carcinoma in situ reveals candidate precursor genes for invasion.

PURPOSE: Lobular carcinoma in situ (LCIS) is both a risk indicator and non-obligate precursor of invasive lobular carcinoma (ILC). We sought to characterize the transcriptomic features of LCIS and ILC, with a focus on the identification of intrinsic molecular subtypes of LCIS and the changes involved in the progression from normal breast epithelium to LCIS and ILC. METHODS: Fresh-frozen classic LCIS, classic ILC, and normal breast epithelium (N) from women undergoing prophylactic or therapeutic mastectomy were prospectively collected, laser-capture microdissected, and subjected to gene expression profiling using Affymetrix HG-U133A 2.0 microarrays. RESULTS: Unsupervised hierarchical clustering of 40 LCIS samples identified 2 clusters of LCIS distinguished by 6431 probe sets (p < 0.001). Genes identifying the clusters included proliferation genes and other genes related to cancer canonical pathways such as TGF beta signaling, p53 signaling, actin cytoskeleton, apoptosis and Wnt-Signaling pathway. A supervised analysis to identify differentially expressed genes (p < 0.001) between normal epithelium, LCIS, and ILC, using 23 patient-matched triplets of N, LCIS, and ILC, identified 169 candidate precursor genes, which likely play a role in LCIS progression, including PIK3R1, GOLM1, and GPR137B. These potential precursor genes map significantly more frequently to 1q and 16q, regions frequently targeted by gene copy number alterations in LCIS and ILC. CONCLUSION: Here we demonstrate that classic LCIS is a heterogeneous disease at the transcriptomic level and identify potential precursor genes in lobular carcinogenesis. Understanding the molecular heterogeneity of LCIS and the potential role of these potential precursor genes may help personalize the therapy of patients with LCIS.

Is there a role for routine screening MRI in women with LCIS?

Women with lobular carcinoma in situ (LCIS) have an elevated breast cancer risk, yet the benefit of MRI screening is unclear. We examined cancer detection rates with mammography alone versus mammography plus MRI in this high-risk population. From a prospectively maintained, single-institution database, we identified 776 patients diagnosed with LCIS after the adoption of screening MRI in April 1999. In addition to annual mammography and breast exam, MRI was used at the discretion of the physician and patient. Kaplan-Meier methods and landmark analyses at 1, 2, and 3 years following LCIS diagnosis were performed to compare rates of cancer detection with or without MRI. MRI screening was performed in 455 (59 %) patients (median, 3/patient). Median time from LCIS diagnosis to first MRI was 9 months (range 0.3-137 months). Patients undergoing MRI were younger (p < 0.0001), premenopausal (p < 0.0001), and more likely to have ≥1 first-degree relative with breast cancer (p = 0.009). At a median follow-up of 58 months, 98/776 (13 %) patients developed cancer. The crude cancer detection rate in both screening groups was 13 %. MRI was not associated with earlier stage, smaller size, or node negativity. Landmark analyses at 1, 2, and 3 years after LCIS diagnosis failed to demonstrate increased cancer detection rates among women having MRI (p = 0.23, 0.26, and 0.13, respectively). Although a diagnosis of LCIS remains a significant risk factor for breast cancer, the routine use of MRI does not result in increased cancer detection rates (short-term), nor does it result in earlier stage at diagnosis, illustrating the importance of defining optimal screening strategies for high-risk patients based on tumor biology rather than numerical risk.

Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions.

INTRODUCTION: Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the ductal and lobular phenotype. METHODS: Patients with prior LCIS undergoing mastectomy were identified preoperatively from 2003 to 2008. Specimens were widely sampled, and frozen blocks were screened for LCIS and co-existing malignant lesions, and were subject to microdissection. Samples from 65 patients were hybridized to the Affymetrix SNP 6.0 array platform. Cases with both an LCIS sample and an associated ductal carcinoma in situ (DCIS) or invasive tumor sample were evaluated for patterns of somatic copy number changes to assess evidence of clonal relatedness. RESULTS: LCIS was identified in 44 of the cases, and among these a DCIS and/or invasive lesion was also identified in 21 cases. A total of 17 tumor pairs had adequate DNA/array data for analysis, including nine pairs of LCIS/invasive lobular cancer, four pairs of LCIS/DCIS, and four pairs of LCIS/invasive ductal cancer. Overall, seven pairs (41%) were judged to be clonally related; in five (29%) evidence suggested clonality but was equivocal, and five (29%) were considered independent. Clonal pairs were observed with all matched lesion types and low and high histological grades. We also show anecdotal evidence of clonality between a patient-matched triplet of LCIS, DCIS, and invasive ductal cancer. CONCLUSION: Our results support the role of LCIS as a precursor in the development of both high-grade and low-grade ductal and lobular cancers.

Cadherin-catenin complex dissociation in lobular neoplasia of the breast.

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. 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-,ß-, and phosphoß-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 ß-catenin expression. E-CD was negative in all LCIS and ILC lesions, and positive in all normal and IDC lesions. Membranous α and ß-catenin expressions 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 ß-catenins from normal to LCIS to invasive lesions, and increasing expression of TWIST from normal to LCIS to ILC. 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 that CCC dissociation is a progressive process.

Differentially expressed genes in window trials are influenced by the wound-healing process: lessons learned from a pilot study with anastrozole.

BACKGROUND: Perioperative window trials provide an opportunity to obtain intact tumor samples at two different time-points for evaluation of potential surrogate biomarkers. We report results of a pilot trial designed to determine if treatment-mediated changes in gene expression can be detected in formalin-fixed paraffin-embedded (FFPE) samples after 10-d exposure to anastrozole in estrogen receptor (ER)-positive breast cancer compared with untreated controls. METHODS: Paired tumor samples (biopsy, surgical) were obtained from 26 postmenopausal women with ER-positive breast cancer. Patients were assigned anastrozole (1 mg/d) for 10 d immediately prior to surgery (13 cases) or no treatment (13 controls). Five hundred two cancer-related genes were examined by the Illumina cDNA-mediated annealing, selection, extension, and ligation, FFPE cDNA array (moderated t-test, P ≤ 0.005). Surrogate biomarkers reflecting changes in gene expression were examined by immunohistochemistry (Wilcoxon rank-based test, P < 0.05). RESULTS: Sufficient RNA was available from 19 paired samples (8 controls, 11 cases). Frozen tissue and FFPE showed good correlation (r = 0.82). Within each group, 18 genes, reflecting roles in proliferation, angiogenesis, and apoptosis, showed differential expression from biopsy to surgery (P < 0.005). Estrogen-related genes were dysregulated in the treated group only. A reduction in Ki-67 was observed in 7 (54%) treated cases and in 1 (7.7%) control patient. CONCLUSIONS: 10-d exposure to anastrozole resulted in dysregulation of 18/502 cancer-related genes, and Ki-67 was reduced in 54% of cases. FFPE samples demonstrated good correlation with frozen samples. However, changes in gene expression and increased Ki-67 in the control group suggest local effects of wound healing may represent a confounding factor in the interpretation of perioperative window trials.

A prospective evaluation of the durability of palliative interventions for patients with metastatic breast cancer.

BACKGROUND: Although systemic therapy for metastatic breast cancer (MBC) continues to evolve, there are scant data to guide physicians and patients when symptoms develop. In this article, the authors report the frequency and durability of palliative procedures performed in the setting of MBC. METHODS: From July 2002 to June 2003, 91 patients with MBC underwent 109 palliative procedures (operative, n=76; IR n=39, endoscopic n=3). At study entry, patients had received a mean of 6 prior systemic therapies for metastatic disease. System-specific symptoms included neurologic (33%), thoracic (23%), musculoskeletal (22%) and GI (14%). The most common procedures were thoracostomy with or without pleurodesis (27%), craniotomy with resection (19%) and orthopedic open reduction/internal fixation (19%). RESULTS: Symptom improvement at 30 days and 100 days was reported by 91% and 81% of patients, respectively, and 70% reported continued benefit for duration of life. At a median interval of 75 days from intervention (range, 8-918 days), 23 patients (25%) underwent 61 additional procedures for recurrent symptoms. The durability of palliation varied with system-specific symptoms. Patients with neurologic or musculoskeletal symptoms were least likely to require additional maintenance procedures (P<.0002). The 30-day complication rate was 18% and there were no procedure-related deaths. At a median survival of 37.4 mos from MBC diagnosis (range, 1.6-164 months) and 8.4 months after intervention (range, 0.2-73 months), 7 of 91 patients remained alive. CONCLUSIONS: Palliative interventions for symptoms of MBC are safe and provide symptom control for the duration of life in 70% of patients. Definitive surgical treatment of neurologic or musculoskeletal symptoms provided the most durable palliation; interventions for other symptoms frequently require subsequent procedures. The longer median survival for patients with MBC highlights the need to optimize symptom control to maintain quality of life.

Protocol for PTEN expression by immunohistochemistry in formalin-fixed paraffin-embedded human breast carcinoma.

The PI3K/PTEN pathway plays a major role in carcinogenesis. Dysregulation of this pathway occurs frequently in breast cancer, and loss of PTEN expression is emerging as a potentially important mechanism of resistance to the widely used anti-HER2 therapy, trastuzumab. However, assays for loss of PTEN expression have suffered from lack of consistency. Here, we describe an automated and reliable protocol for PTEN protein expression by immunohistochemistry in formalin-fixed paraffin-embedded tissue that can be easily incorporated into clinical trials.

Lessons learned from 416 cases of nipple discharge of the breast.

BACKGROUND: For patients with nipple discharge (ND), surgical duct excision is often required to exclude underlying malignancy. Our objective was to define clinical predictors of malignancy and examine the utility of common preoperative studies. STUDY DESIGN: We retrospectively identified 475 patients presenting with a chief complaint of ND from 1995 to 2005; 416 (88%) were eligible for review. RESULTS: Following standard evaluation (clinical breast examination/mammogram/ultrasound), 129 of 416 (31%) were considered to have physiological ND and were managed expectantly, whereas 287 of 416 (69%) underwent further evaluation (cytology/ductography/magnetic resonance imaging) followed by biopsy +/- surgery. Clinical features associated with pathological ND included bloody ND (adjusted odds ratio 3.7) and spontaneous ND (adjusted OR 3.2). Biopsy/surgery identified a causative lesion in 259 of 287 (90%), of which 37% were either malignant (n = 65) or high-risk (n = 30) lesions. The sole clinical predictor of malignant/high-risk lesion was a palpable mass (adjusted odds ratio 4.3). Preoperative evaluation identified 76 of 95 (80%) malignant/high-risk lesions, whereas 19 of 95 (20%) were identified by duct excision alone. CONCLUSIONS: Although clinical stratification alone reliably identified patients with pathological ND, neither the clinical characteristics nor preoperative studies can reliably distinguish between benign and malignant pathology. Surgical duct excision remains the gold standard to exclude underlying malignancy.

Stage IV breast cancer in the era of targeted therapy: does surgery of the primary tumor matter?

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 (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 (PR) 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.

The significance of nipple discharge of the male breast.

Although male breast cancer typically presents as a palpable mass, failure to recognize the significance of other symptoms may lead to a delay in diagnosis. Here we present our experience with male patients presenting with a chief complaint of nipple discharge (ND). Using the ICD-9 code for "breast symptoms," we identified 2,319 patients without a current cancer diagnosis who presented to Memorial Sloan-Kettering Cancer Center for evaluation; 24 (1%) patients were male (1995-2005). Data were collected by retrospective review. Among 24 male patients presenting for evaluation, 14 (58%) presented with a chief complaint of ND, while the remaining 10 (42%) presented for evaluation of a palpable mass in the absence of ND. Among 14 patients presenting with ND, subsequent clinical breast examination identified a breast mass +/- nipple changes in 7 of 14 patients. In total, 8 of 14 (57%) patients had an underlying malignancy; two of seven patients with ND alone had DCIS (median interval from onset of ND to presentation 3 weeks, range 2-4 weeks), and six of seven patients with ND and a palpable mass had invasive disease (median interval between onset of ND and presentation 16 weeks, range 2-52). The remaining 10/24 patients presented with a painless palpable mass of whom 8 (80%) were found to have underlying invasive disease (median interval between onset of mass, and presentation was 4 weeks, range 2-20 weeks). All patients with invasive disease were node-positive. At 23.7 months median follow-up (range, 7.7-88.3 months), 14 of 16 cancer patients remain free of disease and two have died as a direct result of metastatic disease. The incidence of cancer among males presenting with ND was 57%. In the absence of additional clinical findings, ND may be a herald for early, non-invasive disease. Increased awareness of subtle features of malignancy may represent a window of opportunity for early diagnosis and improved outcomes for male breast cancer patients.

Changing indications for surgery in patients with stage IV breast cancer: a current perspective.

BACKGROUND: Evolving concepts of cancer biology and emerging evidence of a potential survival benefit from local surgery have raised the question of an expanded role for surgery in select patients with metastatic breast cancer (MBC). To determine whether such developments have influenced clinical practice, the authors evaluated surgical practice patterns in the study institution over the last 15 years. METHODS: Two institutional databases were screened to identify patients with MBC who underwent breast surgery (1990-2005). Retrospective review was conducted to assess trends over time and to evaluate the role of surgery in the more modern era (1995-2005). RESULTS: The overall frequency of mastectomy remained stable over time (1.7%); however, between early (1990-1995) and late (2000-2005) periods the rate of 'symptom control' mastectomy decreased (41% to 25%), whereas the rate of 'local control' mastectomy increased (34% to 66%). Conversely, the overall frequency of wide-local excision (WLE) increased over time (1995-2001), from 1% to 9% (P< .001) with no differences noted between rates of symptom control or local control procedures. In the modern era (1995-2005), 256 of 12,529 patients (2%) with MBC underwent breast surgery (33% mastectomy, 52% WLE); most frequently to 'optimize local control' (50%) and primarily in the setting of limited/stable distant disease. Surgery was performed for palliation in only 19% of patients. At a median follow-up of 33.9 months (range, 0-198.7 months), 136 of 256 patients (53%) in this cohort remained alive; 88% were free of local disease. CONCLUSIONS: Although surgery in MBC has historically been reserved for palliation, the authors observed a decreasing rate of traditional 'toilet mastectomy' and a broadened surgical approach to the asymptomatic patient. When viewed in parallel with evolving concepts in cancer biology, these data reflect a change in the traditional approach to patients with MBC and warrant further investigation.

MRI identifies otherwise occult disease in select patients with Paget disease of the nipple.

INTRODUCTION: For patients with Paget disease (PD) of the nipple, preoperative imaging to detect and evaluate the extent of an underlying malignancy can facilitate appropriate treatment planning. The purpose of this study was to evaluate the role of breast MRI in this setting. STUDY DESIGN: Using ICD-9 codes for "breast symptoms," we identified 2,294 patients without a current cancer diagnosis seen at our institution (1995 to 2006). Sixty-nine patients (3%) had nipple changes suspicious for PD as the only physical finding. Skin/nipple biopsy confirmed PD in 39 of 69 (57%) patients. Thirty-four patients were eligible for review. RESULTS: Surgical pathology identified cancer in 32 of 34 (94%) patients (7 invasive ductal carcinoma, 25 ductal carcinoma in situ). Nineteen (59%) cancers were confined to the central quadrant of the breast (unifocal). Preoperative imaging (mammography 34 of 34, MRI 13 of 34) detected 15 of 32 (49%) cancers. Mammography detected 11 cancers, accurately demonstrating extent of disease in 9 of 11 patients. MRI detected seven cancers, accurately demonstrating extent of disease in six of seven patients. After positive mammography (n = 11), MRI (n = 5) did not change management. After negative mammography (n = 23), MRI (n = 8) detected otherwise occult disease in 4 of 8 patients, accurately demonstrating extent of disease in 4 of 4 patients and ruling out an underlying cancer in 1 of 1 patient. CONCLUSIONS: Ninety-four percent of patients with biopsy-proved PD as the only physical finding had an underlying cancer and 59% had unifocal disease. Negative preoperative imaging did not reliably exclude an underlying cancer, but the increased sensitivity of MRI detected otherwise occult disease. In the setting of negative mammography, MRI can facilitate treatment planning for patients with PD.

The predictive value of ductography and magnetic resonance imaging in the management of nipple discharge.

BACKGROUND: Standard evaluation (physical examination, mammography, sonography) often fails to identify an underlying lesion in patients with suspicious nipple discharge. The aim of this study was to determine the predictive value of ductography (DG) and magnetic resonance imaging (MRI) in this setting. METHODS: Using ICD-9 codes, we retrospectively identified 376 patients who presented with suspicious nipple discharge (ND) (1995-2005); 306 patients (68%) had negative standard evaluation. RESULTS: Among 306 patients, 186 (61%) underwent further evaluation with DG (n = 163) and/or MRI (n = 52), 35 (11%) underwent major duct excision alone (MDE), and 85 (28%) were followed clinically. Ultimately, 182/306 (59%) patients underwent surgery and/or biopsy. Overall incidence of malignant or high-risk pathology was 15% (46/306). DG was completed in 139/163 (85%) studies and detected 12 cancers and seven high-risk lesions (HRL), but failed to identify four cancers and 2 HRL (PPV 19%, NPV 63%). MRI detected seven cancers and three HRL, but failed to identify one cancer and one HRL (PPV 56%, NPV 87%). MDE alone (n = 35) detected five cancers and three HRL. Of all patients not having surgery, (142/306, 41%), one (0.01%) presented with an invasive cancer at 102 months (median follow-up, 6.3 months; range, 0-124 months). CONCLUSIONS: 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.