Mary Morrogh

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

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.

The Predictive Value of Ductography and Magnetic Resonance Imaging in the Management of Nipple Discharge

BackgroundStandard 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.MethodsUsing ICD-9 codes, we retrospectively identified 376 patients who presented with suspicious nipple discharge (ND) (1995–2005); 306 patients (68%) had negative standard evaluation.ResultsAmong 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).ConclusionsAn 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.

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.

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.

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.

Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions

IntroductionLobular 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.MethodsPatients 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.ResultsLCIS 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.ConclusionOur results support the role of LCIS as a precursor in the development of both high-grade and low-grade ductal and lobular cancers.

The Significance of Nipple Discharge of the Male Breast

Abstract:  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.

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

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.

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

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.

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.