Constance Albarracin

Clinical and Pathologic Characteristics of Patients With BRCA-Positive and BRCA-Negative Breast Cancer

PURPOSE Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breast cancer. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations. PATIENTS AND METHODS Tumor pathologic features and clinical characteristics were examined in 491 women with breast cancer who underwent genetic testing for BRCA mutations between 1997 and 2006. A retrospective review of medical records was conducted to determine clinical characteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-term pregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status. Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor, progesterone receptor, and HER-2/neu status. RESULTS Of the 491 patients with identified breast cancers, 391 patients were BRCA negative, and 86 patients were BRCA positive. Triple-negative breast cancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) was diagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% of the BRCA-negative patients. BRCA1 mutation carriers had higher nuclear grade tumors than the other two groups (P < .001). Of the triple-negative cancer patients, BRCA2 mutation carriers were older when diagnosed than BRCA1 mutation carriers and noncarriers (P < .01). CONCLUSION These results suggest that tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negative and non-triple-negative groups. Future studies should seek to determine whether patients with BRCA1 mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patients with similar tumor pathology.

Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer

BACKGROUND We evaluated discordance in expression measurements for estrogen receptor (ER), progesterone receptor (PR), and HER2 between primary and recurrent tumors in patients with recurrent breast cancer and its effect on prognosis. METHODS A total of 789 patients with recurrent breast cancer were studied. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Repeat markers for ER, PR, and HER2 were available in 28.9%, 27.6%, and 70.0%, respectively. Primary and recurrent tumors were classified as triple receptor-negative breast cancer (TNBC) or receptor-positive breast cancer (RPBC, i.e. expressing at least one receptor). Discordance was correlated with clinical/pathological parameters. RESULTS Discordance for ER, PR, and HER2 was 18.4%, 40.3%, and 13.6%, respectively. Patients with concordant RPBC had significantly better post-recurrence survival (PRS) than discordant cases; patients with discordant receptor status had similarly unfavorable survival as patients with concordant TNBC. IHC scores for ER and PR showed weak concordance between primary and recurrent tumors. Concordance of HER2-FISH scores was higher. CONCLUSIONS Concordance of quantitative hormone receptor measurements between primary and recurrent tumors is modest consistent with suboptimal reproducibility of measurement methods, particularly for IHC. Discordant cases have poor survival probably due to inappropriate use of targeted therapies. However, biological change in clinical phenotype cannot be completely excluded.

Ductal Carcinoma in Situ: State of the Science and Roadmap to Advance the Field

PURPOSE Ductal carcinoma in situ (DCIS) is the fourth leading cancer for women in the United States. Understanding of the biology and clinical behavior of DCIS is imperfect. This article highlights the current knowledge base and the scientific roadmap needed to advance the field. METHODS This article is based on work done by and consultations obtained from leading experts in the field over a 6-month period that culminated in a full-day symposium designed to systematically review the most pertinent MEDLINE published reports and develop a roadmap to elucidate the molecular steps of carcinogenesis, reduce the extent or prevent the need for therapies, eliminate recurrences, and reduce morbidity. RESULTS Expression profiling of pure DCIS will help elucidate the molecular characteristics that distinguish high-risk lesions from clinically irrelevant lesions. The development of new methods of extracting RNA from processed tissues may provide opportunities for research. Mammography often underestimates the pathologic extent of DCIS; other imaging methods need to be investigated for detection and monitoring of disease stability or progression. Novel biologic agents are being delivered in neoadjuvant clinical trials, and alternative methods for breast irradiation are being studied. Future trials of treatment versus no treatment for biologically selected cases of DCIS should be developed. CONCLUSION There is a critical need for a concerted international effort among patients with DCIS, clinicians, and basic scientists to conduct the research necessary to improve fundamental understanding of the biology and clinical behavior of DCIS and prevent development of invasive breast cancer.

Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers.

Methylation of lysine 27 on histone H3 (H3K27) by the EZH2 complex is an epigenetic mark that mediates gene silencing. EZH2 is overexpressed in many cancers and correlates with poor prognosis in both breast and prostate cancers. However, the status of H3K27 methylation and its clinical implication in cancer patients have not been reported. We thus examined trimethylation of H3K27 (H3K27me3) by immunohistochemistry and its association with clinical variables and prognosis in breast, ovarian, and pancreatic cancers. We found that H3K27me3 expression was significantly lower in breast, ovarian and pancreatic cancers than in normal tissues (62% in breast cancer vs. 88% in normal breast tissue, P = 0.001; 38.4% in ovarian cancer vs. 83.3% in normal ovarian tissue, P < 0.05; and 26% in pancreatic cancer vs. 89% in normal pancreatic tissue, P < 0.001). H3K27me3 expression showed significant prognostic impact in breast, ovarian and pancreatic cancers in univariate survival analyses. In all three cancer types, patients with low expression of H3K27me3 had significantly shorter overall survival time when compared with those with high H3K27me3 expression. In a multivariate model, H3K27me3 expression was an independent prognostic value for overall survival in all three cancer types. These results suggest that H3K27me3 expression is a prognostic indicator for clinical outcome in patients with breast, ovarian, and pancreatic cancers.

MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers.

Suppression of annexin A1 (ANXA1), a mediator of apoptosis and inhibitor of cell proliferation, is well documented in various cancers but the underlying mechanism remains unknown. We investigated whether decreased ANXA1 expression was mediated by microRNAs (miRNAs), which are small, non-coding RNAs that negatively regulate gene expression. Using Sanger miRBase, we identified miR-584, miR-196a and miR-196b as potential miRNAs targeting ANXA1. Only miRNA-196a showed significant inverse correlation with ANXA1 mRNA levels in 12 cancer cell lines of esophageal, breast and endometrial origin (Pearsons correlation −0.66, P=0.019), identifying this as the candidate miRNA targeting ANXA1. Inverse correlation was also observed in 10 esophageal adenocarcinomas (Pearsons correlation −0.64, P=0.047). Analysis of paired normal/tumor tissues from additional 10 patients revealed an increase in miR-196a in the cancers (P=0.003), accompanied by a decrease in ANXA1 mRNA (P=0.004). Increasing miR-196a levels in cells by miR-196a mimics resulted in decreased ANXA1 mRNA and protein. In addition, miR-196a mimics inhibited luciferase expression in luciferase plasmid reporter that included predicted miR-196a recognition sequence from ANXA1 3′-untranslated region confirming that miR-196a directly targets ANXA1. miR-196a promoted cell proliferation, anchorage-independent growth and suppressed apoptosis, suggesting its oncogenic potential. This study demonstrated a novel mechanism of post-transcriptional regulation of ANXA1 expression and identified miR-196a as a marker of esophageal cancer.

Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: Association with poor outcome

The prognosis for patients with esophageal and esophagogastric junction (EGJ) adenocarcinoma remains poor, even after surgical resection. Pathologic assessment of depth of invasion and lymph node status are the primary prognostic factors in these patients. In patients with esophageal squamous cell carcinoma, increased epidermal growth factor receptor (EGFR) expression has been associated with a worse prognosis. It is not known whether EGFR plays a similar role in esophageal and EGJ adenocarcinomas.

Survival among women with triple receptor-negative breast cancer and brain metastases

BACKGROUND The purpose of this study was to determine the incidence of and survival following brain metastases among women with triple receptor-negative breast cancer. PATIENTS AND METHODS In all, 679 patients with nonmetastatic triple receptor-negative breast cancer diagnosed from 1980 to 2006 were identified. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for development of brain metastases. Survival was computed using the Kaplan-Meier product limit method. RESULTS Median follow-up was 26.9 months. In all, 42 (6.2%) patients developed brain metastases with a cumulative incidence at 2 and 5 years of 5.6% [95% confidence interval (CI) 3.8% to 7.9%] and 9.6% (95% CI 6.8% to 13%), respectively. A total of 24 (3.5%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 2 and 5 years of 2.0% (95% CI 2.6% to 6.0%) and 4.9% (95% CI 3.2% to 7.0%), respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases. Median survival for all patients who developed brain metastases and those who developed brain metastases as the first site of recurrence was 2.9 months (95% CI 2.0-7.6 months) and 5.8 months (95% CI 1.7-11.0 months), respectively. CONCLUSION In this single-institutional study, patients with nonmetastatic triple receptor-negative breast tumors have a high early incidence of brain metastases associated with poor survival and maybe an ideal cohort to target brain metastases preventive strategies.

Response to Neoadjuvant Systemic Therapy for Breast Cancer in BRCA Mutation Carriers and Noncarriers: A Single-Institution Experience

PURPOSE To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations. PATIENTS AND METHODS A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival. RESULTS Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not. CONCLUSION BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.

Triple Receptor–Negative Breast Cancer: The Effect of Race on Response to Primary Systemic Treatment and Survival Outcomes

PURPOSE The goal of this study was to describe the effect of race on pathologic complete response (pCR) rates and survival outcomes in women with triple receptor-negative (TN) breast cancers. PATIENTS AND METHODS Four hundred seventy-one patients with TN breast cancer diagnosed between 1996 and 2005 and treated with primary systemic chemotherapy were included. pCR was defined as no residual invasive cancer in the breast and axillary lymph nodes. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier product-limit method and compared between groups using the log-rank test. Cox proportional hazards models were fitted for each survival outcome to determine the relationship of patient and tumor variables with outcome. RESULTS Median follow-up time was 24.5 months. One hundred patients (21.2%) were black, and 371 patients (78.8%) were white/other race. Seventeen percent of black patients (n = 17) and 25.1% of white/other patients (n = 93) achieved a pCR (P = .091). Three-year RFS rates were 68% (95% CI, 56% to 76%) and 62% (95% CI, 57% to 67%) for black and white/other patients, respectively, with no significant difference observed between the two groups (P = .302). Three-year OS was similar for the two racial groups. After controlling for patient and tumor characteristics, race was not significantly associated with RFS (hazard ratio [HR] = 1.08; 95% CI, 0.69 to 1.68; P = .747) or OS (HR = 1.08; 95% CI, 0.69 to 1.68; P = .735) when white/other patients were compared with black patients. CONCLUSION Race does not significantly affect pCR rates or survival outcomes in women with TN breast cancer treated in a single institution under the same treatment conditions.

Predictors of invasion in patients with core‐needle biopsy‐diagnosed ductal carcinoma in situ and recommendations for a selective approach to sentinel lymph node biopsy in ductal carcinoma in situ

Among patients with core‐needle biopsy (CNB)‐diagnosed ductal carcinoma in situ (DCIS), the guidelines for the selection of patients to undergo sentinel lymph node (SLN) biopsy are not well defined, and many patients with no invasion undergo an unnecessary SLN biopsy. The objective of this study was to identify the predictors of invasion in patients with CNB‐diagnosed DCIS and, thus, to help determine the most appropriate candidates for SLN biopsy.