Deann P. Atchley

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.

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.

BRCA1 and BRCA2 Genetic Testing in Hispanic Patients: Mutation Prevalence and Evaluation of the BRCAPRO Risk Assessment Model

PURPOSE The BRCAPRO model, used to predict a familys likelihood of carrying a BRCA1 or BRCA2 mutation, was designed using mutation frequencies of white and Ashkenazi Jewish populations, and may not be applicable to other populations. BRCAPRO was recently validated in African Americans, although has yet to be examined in Hispanics. This retrospective study reports the mutation frequency and spectrum of BRCA1 and BRCA2 mutations in a Hispanic population and evaluates the BRCAPRO model in Hispanics. PATIENTS AND METHODS A descriptive analysis of mutation frequency and spectrum was performed for Hispanic patients who underwent BRCA1 and BRCA2 genetic testing at a single institution. For comparative analysis of the BRCAPRO risk model, Hispanic patients who underwent comprehensive analysis were compared with white controls using area under the receiver operating characteristic curves (AUROC). RESULTS Fourteen Hispanic individuals who underwent comprehensive analysis were identified to carry a mutation in BRCA1 or BRCA2 (17.9%; 95% CI, 10.2% to 28.3%) and seven individuals had a variant of uncertain significance (9.0%; 95% CI, 12.0% to 30.8%). A total of eight different mutations and three variants were observed within the entire Hispanic population. When evaluating the performance of the BRCAPRO model, the AUROC for Hispanics was 0.774 (95% CI, 0.63 to 0.90), compared with the AUROC of 0.770 (95% CI, 0.65 to 0.89) for whites. CONCLUSION Deleterious BRCA1 and BRCA2 mutations occur at considerable frequency within the Hispanic population, many of which have been identified previously in other ethnic populations. The BRCAPRO model appears to perform equally well in Hispanics as in whites.

High Prevalence of Preinvasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers

Mutations in BRCA1 and BRCA2 increase a womans lifetime risk of developing breast cancer by 43% to 84%. It was originally postulated that BRCA1/2-associated breast cancers develop more rapidly than sporadic cancers and may lack preinvasive lesions. More recent studies have found preinvasive lesions in prophylactic mastectomy specimens from mutation carriers; however, there is little information on the presence of preinvasive lesions in tissue adjacent to breast cancers. Our aim is to investigate the role of preinvasive lesions in BRCA-associated breast carcinogenesis. We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of preinvasive lesions [ductal carcinoma in situ (DCIS), lobular carcinoma in situ, and atypical lobular hyperplasia] in tissue adjacent to invasive breast cancers. Pathology was reviewed for 73 BRCA1/2-associated tumors from patients with breast cancer. We selected 146 patients with mutation-negative breast cancer as age-matched controls. Among the BRCA1/2-associated breast cancers, 59% had at least one associated preinvasive lesion compared with 75% of controls. Preinvasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% versus 52%, respectively). The most common preinvasive lesion in both groups was DCIS; 56% of BRCA1/2-associated breast cancers and 71% of the sporadic breast cancers had adjacent intraductal disease, respectively. Preinvasive lesions, most notably DCIS, are common in BRCA1/2-associated breast cancers. These findings suggest that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumor spectrum.

Accuracy of the BRCAPRO Model Among Women With Bilateral Breast Cancer

The likelihood of identifying a BRCA mutation was often calculated using the BRCAPRO model. A previous study suggested that this model may overestimate the chance of detecting a BRCA mutation among women diagnosed with bilateral breast cancer. Studies also suggested that few patients with bilateral breast cancer whose age at first diagnosis is >40 years were mutation carriers. The objectives of this study were to determine the accuracy of the BRCAPRO model among women with bilateral breast cancer and to determine whether their mutation status was dependent on their age at first diagnosis.

Effectiveness of screening women at high risk for breast cancer with alternating mammography and MRI.

Abstract #5015 Background MRI has been found to be more sensitive than mammography in the detection of breast cancer, with sensitivity of 71% to 100%, compared to 16 to 40% for mammography. Therefore, MRI has been introduced as an adjunct to annual screening mammography and clinical examination (CE) in women at high risk for developing breast cancer. We investigated the efficacy of alternating screening mammography with MRI every 6 months in women at high risk for developing breast cancer.
 Methods Retrospective chart review was performed on 334 consecutive women who were seen in the high risk clinic at one institution, from January 1997 to December 2007. Patients with increased risk for breast cancer and had an MRI were included in this study. Women with hereditary breast and ovarian cancer syndrome, personal breast cancer history, a biopsy of atypia or lobular carcinoma in situ (LCIS), or a 20% or higher lifetime risk of developing breast cancer by the Gail model were included. Mammography, ultrasound, and MRI findings were reviewed, along with biopsy results.
 Results 86 of 334 (26 %) patients underwent annual screening mammography and MRI, with mammography and MRI alternating every six months. The remaining 248 patients underwent prophylactic mastectomies or were treated with chemoprevention. CE was performed every six months. 47% of 86 patients completed the 1 st round of MRI surveillance, 32% completed the 2 nd round, 15% completed the 3 rd round, and 6% completed the 4 th round. Of 86 patients who underwent MRI screening, 70 had BRCA mutations, and 16 had a history of breast cancer , a biopsy of atypia or LCIS, or a 20% or higher lifetime risk of developing breast cancer. The median follow-up period was 2 years (range, 1 to 4 years).
 Nine cancers (6 invasive ductal, 1 invasive lobular, and 2 ductal carcinomas in situ) were detected in 7 of 86 (8.1%) women who underwent screening MRI; two women had bilateral cancers. Among the 9 cancers, 4 (44 %) were identified by MRI but not by mammography, 4 (44 %) were identified by both MRI and mammography, and 1 (11 %) was not identified by mammography or MRI. No cancer was seen by mammography only. Of the 9 tumors, 8 cancers were detected by MRI (sensitivity of 89%). One cancer was identified by mastectomy only (1 mm focus of DCIS). In 4 of the 8 MRI detected-cancers, the mammogram performed six months earlier was normal or demonstrated benign findings. The mean size of the cancers was 10.4 mm (range, 1 to 25 mm). At MRI, 5 cancers appeared as a mass and 3 cancers demonstrated non-mass like enhancement. Metastatic ipsilateral axillary lymphadenopathy was seen in association with 3 of the 9 cancers detected.
 Conclusions In women at high risk for developing breast cancer, alternating mammography and MRI at six month intervals demonstrated that no cancers were detected by mammography only. Future prospective studies should be performed to evaluate screening with annual mammography and MRI, alternating at six month intervals, versus annual MRI alone. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5015.

Response to neoadjuvant chemotherapy in BRCA1- and BRCA2-related breast cancers

618 Background: Germline mutations in the BRCA1 and BRCA2 genes account for the major genetic predispositions to breast cancer. BRCA 1 and BRCA2 related breast cancers have distinct pathologic and gene expression profiles. Furthermore, some of the BRCA1 and BRCA2 proteins might be involved in response to certain chemotherapeutic agents. The objective of this study was to evaluate the pathologic response (PR) to neoadjuvant chemotherapy (CT) in breast cancer patients (pts) with or without deleterious mutations in the BRCA1 or BRCA2 gene. Methods: After obtaining IRB approval, a retrospective evaluation of PR to neoadjuvant CT in pts with breast cancer who underwent genetic testing at U.T. M.D. Anderson Cancer Center was performed. Pathologic complete response (pCR) was defined as no residual invasive cancer in the breast and negative lymph nodes after neoadjuvant CT. Fishers exact test was used to evaluate variables in univariate and binary logistic regression model for multivariate analysis. Results: A t...