Shirin Muhsen

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

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.

Pleomorphic lobular carcinoma in situ: A distinct entity of controversial significance.

177 Background: Pleomorphic lobular carcinoma in situ (PLCIS) is an increasingly diagnosed variant of lobular carcinoma in situ. Histologically, it resembles ductal carcinoma in situ (DCIS), leading to controversy over proper management. Yet, the natural history of PLCIS is unknown. Here we describe our experience with PLCIS. METHODS Review of pathology reports (1995-2012) identified 233 cases of LCIS variants. Patients with synchronous ipsilateral DCIS or invasive cancer (IC) were excluded leaving 25 cases for review. Consensus review by 3 pathologists further excluded 7; leaving 18 cases, 12 of which were classified as PLCIS and 6 as LCIS with pleomorphic features (LCIS-PF). (Table) PLCIS was defined by cellular dyshesion, nuclear pleomorphism with a 2-3 fold size variation, conspicuous nucleoli, mitoses and abundant cytoplasm; lesions not meeting all parameters were classified as LCIS-PF. Loss of e-cadherin was confirmed; clinical data were obtained from medical records. RESULTS Mean patient age at diagnosis of PLCIS/LCIS-PF was 57 yrs (42-67 yrs). All cases presented with imaging abnormalities. A previous history of breast cancer was present in 7/18 (39%) pts (3/7, ipsilateral; 4/7, contralateral). Following PLCIS/LCIS-PF diagnosis, 6/18 (33%) pts underwent mastectomy and 12/18 had excision alone, with (n=3) or without chemoprevention (n=9). Margin status was negative in 4/12 pts; close in 3/12 pts and positive in 5/12 pts undergoing excision. At a median follow-up of 27 mos (2-148 mos), 2/12 pts treated with excision developed ipsilateral breast cancer (1 DCIS; 1 IC). Both had close margins at initial excision; median time to cancer, 54 mos. CONCLUSIONS Pure PLCIS is an uncommon lesion. Synchronous malignancy or prior history of breast cancer are often present in patients with PLCIS, contributing to the difficulty in determining the actual risk conferred by this lesion and appropriate management. Efforts to systematically characterize LCIS variants and prospective documentation of outcomes are needed to clarify the significance of these lesions. [Table: see text].

Abstract PD04-05: Molecular predictors for type of recurrence following conservative treatment for DCIS

Background: The identification of molecular predictors of type of recurrence (non-invasive vs invasive) after local therapy for ductal carcinoma in situ (DCIS) remains a challenge. We hypothesized that gene expression profiling using a panel of 32 breast cancer-related genes could identify a signature predictive of type of recurrence. Methods: From a prospectively maintained database of 1873 pts treated with conservative surgery +/− radiation for DCIS (1991–2006), we identified 190 (10%) patients who recurred. Original DCIS archival blocks were available for 108 (57%) of these cases. Freshly cut sections were obtained for microdissection of pure DCIS lesions, RNA was extraction and mRNA transcript quantification was performed with the Nanostring™ nCounter® system. Data were normalized using the nCounter® digital analyzer software for analysis. Results: Among the 108 studied cases, 66 (61%) recurred as DCIS and 42 (39%) recurred as invasive cancer. Median time to recurrence was 40 months (range 7–156 mo) and did not differ by type of recurrence. Similarly, patient age, grade of DCIS, ER status, use of radiation or tamoxifen therapy did not differ. Unsupervised hierarchical clustering using all 32 genes demonstrated two predominant groups, one enriched for recurrent-as-invasive (RI) tumors, and the other enriched for recurrent-as-DCIS (RD) tumors. Refined analysis by selection of 14 genes with significant differential expression between the RI and the RD tumors identified four main groups. The first cluster was dominated by ERBB2 over-expression and is equally composed of RI and RD tumors. The second cluster was composed almost exclusively of RI tumors and showed high level of COX2 and CCND1 and low level of CDKN2A (p16). The clusters 3 and 4 were enriched for RD tumors, with the fourth cluster completely devoid of RI cases. This RD-only group showed the lowest level of CCND1, but highest level of AKT3, EGFR, CDKN2A, and MKI67, thus displaying molecular traits typical of basal-like tumors. Conclusion: In this cohort of patients who recurred following conservative treatment for DCIS, HER2 expression was not predictive, however gene expression analysis demonstrated that high COX2 and CCND1 and low CDKN2a (p16) levels were strongly associated with invasive recurrences (RI), whereas increased AKT3 and MKI67 were associated with non-invasive recurrences (RD). Although the optimal combination of predictive markers requires validation, these data suggest that molecular alterations associated with RI differ from those associated with RD and warrant further investigation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD04-05.

Abstract P4-06-07: PI3K Mutations Are More Common in Low Grade DCIS

Background: DCIS is a non-obligate precursor to invasive breast cancer yet it remains difficult to predict which lesions will progress or over what time interval. Factors associated with a higher risk of progression include high histologic grade and HER2 amplification. HER2 signaling via the PI3K pathway is associated with accelerated invasiveness in laboratory models and mutations in the helical domain of PI3K have been associated with a worse prognosis in invasive cancer. We hypothesized that PI3K pathway mutations are associated with higher risk of progression in DCIS and therefore would be more common in high grade DCIS. Methods: 195 cases of pure DCIS were identified from the MSKCC breast service database (1999-2003). All cases were reviewed by a single pathologist to assign histologic grade. Sections were obtained from archived formalin-fixed paraffin embedded (FFPE) blocks for manual microdissection to isolate pure DCIS lesions for DNA extraction. Multiplex array (Sequenom®) genotyping for PIK3CA was performed on prePCR amplified DNA. Comparisons were made between high and low grade DCIS using Fisher9s exact test. Results: Among 195 pure DCIS cases, 89 were classified as high grade and 106 as low grade. Sequenom® analysis was informative in all cases. PIK3CA mutations were identified in 4/89 (4%) cases of high grade DCIS and in 24/106 (23%) cases of low grade DCIS (p=0.000). All 4 mutations in high grade DCIS were located in the kinase domain, whereas in low grade DCIS, 9/24 (37%) mutations were in the kinase domain (H1047R) and 15/24 (67%) mutations were in the helical domain (E542K, E545K, N345K). Conclusion: PI3K mutations were relatively uncommon in pure high grade DCIS as compared to low grade DCIS. PI3K mutations in low grade DCIS were observed in both the kinase and helical domain. These findings support the hypothesis that breast tumorigenesis differs by grade and PI3K mutations may be more prominent in low grade carcinogenesis. The significance of helical domain mutations in low grade lesions requires further investigation. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-07.