Treatment with 8-OH-DPAT attenuates the weight loss associated with activity-based anorexia in female rats.

Serotonin (5-HT) plays an important role in controlling food intake and regulating body weight. In addition, clinical studies suggest a possible role for 5-HT in the etiology of anorexia nervosa. Recently, we have examined the effects of pharmacological manipulation of the 5-HT system in female rats exposed to conditions that promote activity-based anorexia (ABA). In this animal model of anorexia nervosa, rats are food restricted (2 h access/day) while given the opportunity to exercise in running wheels. These conditions promote symptoms of anorexia nervosa including hypophagia, hyperactivity, progressive weight loss, and disruptions of the ovarian reproductive cycle. Previously, we demonstrated that increased 5-HT activity increased the weight loss associated with ABA in female rats. Here, we investigated whether decreased 5-HT activity would attenuate symptoms of ABA. Food-restricted female rats received injections of 8-OH-DPAT, a drug that reduces serotonergic neurotransmission, or saline vehicle 40 min prior to food access. During this restricted-feeding phase, food intake was similar between groups; however, 8-OH-DPAT prevented the hyperactivity observed in saline-treated rats. This resulted in less weight loss in 8-OH-DPAT-treated rats, suggesting that decreased activation of the 5-HT system attenuates the development of ABA.

Taste responses to dilute sucrose solutions are modulated by stage of the estrous cycle and fenfluramine treatment in female rats.

Meal size is decreased during the estrous stage of the rat's ovarian reproductive cycle. This is mediated, in part, by estradiol's ability to increase the strength by which negative-feedback signals function to inhibit meal size. For example, we recently reported that the anorectic effect of fenfluramine, a serotonin agonist, is enhanced during estrus. Here, we investigated whether a decrease in the strength of positive-feedback signals, like those related to the taste of food, contributes to the decrease in meal size observed either in estrous rats or following fenfluramine treatment. Rats were given brief access to six sucrose solutions (0.0, 0.025, 0.05, 0.1, 0.2, and 0.4 M) and the mean number of licks to these solutions was monitored in diestrous and estrous rats treated with 1 mg/kg fenfluramine or saline vehicle. Following saline treatment, estrous rats displayed fewer licks than diestrous rats to the 0.025 M sucrose solution. Following fenfluramine treatment, a decrease in the number of licks to 3 of the 5 sucrose solutions was observed in diestrous rats only. This decrease in sucrose palatability was limited to brief access tests, as overnight preference for the 0.025 M sucrose solution was not decreased by fenfluramine in either diestrous or estrous rats. Our findings suggest that estrous rats experience a decrease in the strength of positive-feedback signals elicited by a dilute sucrose solution and that the anorectic effect of fenfluramine is associated with a decline in positive-feedback signaling in the diestrous rat.

Fenfluramine treatment in female rats accelerates the weight loss associated with activity-based anorexia.

Serotonin plays an important role in controlling food intake and regulating body weight. Thus, altered serotonergic function may be involved in the etiology of anorexia nervosa. To investigate this hypothesis, we examined whether activation of the serotonin system increases the severity of activity-based anorexia, an animal model of anorexia nervosa in which food-restricted rats are housed with access to running wheels. This paradigm promotes symptoms of anorexia nervosa, including hypophagia, hyperactivity, and weight loss. Food-restricted rats received injections of a serotonin agonist, fenfluramine, or saline 1.5 h prior to their daily 2-h period of food access. A third saline-injected group was pair-fed to the fenfluramine group. Drug treatment and food restriction were terminated following a 25% weight loss. During food restriction, each group developed symptoms of activity-based anorexia. Although similar reductions in food intake were observed in fenfluramine-treated and pair-fed rats, only fenfluramine-treated rats displayed an accelerated rate of weight loss, relative to saline-treated rats. Thus, some other nonanorexic aspect of fenfluramine, perhaps its influence on metabolism, must underlie the accelerated rate of weight loss in this group. Our results suggest that increased activation of the serotonin system exacerbates the weight loss associated with activity-based anorexia.

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.

Accuracy of the BRCAPRO model among women with bilateral breast cancer.

BACKGROUND: 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. METHODS: A retrospective chart review was performed. Women who were diagnosed with bilateral or unilateral breast cancer and who had undergone comprehensive BRCA1 and BRCA2 genetic testing at M. D. Anderson Cancer Center between 1997 and 2006 were included in the study. RESULTS: For individuals with pre-test carrier probabilities >31%, the proportion of positive tests was significantly lower than predicted by the BRCAPRO model (P < .05). In addition, the carrier rate of BRCA mutations was significantly higher (P = .002, Fisher exact test) in women with bilateral breast cancer whose age at first diagnosis was 40 years. CONCLUSIONS: The BRCAPRO model was overestimating the relative contribution bilateral breast cancer had on the likelihood of detecting a BRCA1 or BRCA2 mutation. Bilateral breast cancer did not appear to be a good indicator of mutation status, particularly for women whose age at first diagnosis is >40 years.

High prevalence of preinvasive lesions adjacent to BRCA1/2-associated breast cancers.

Mutations in BRCA1 and BRCA2 increase a woman's 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.

Mammographic features of triple receptor-negative primary breast cancers in young premenopausal women.

BACKGROUND: The mammographic features of triple receptor-negative [TRN] breast cancers, a distinct cancer subtype with a poor prognosis have not been reported to our knowledge. The aim of this study was to compare the mammographic breast density, visibility, and tumor features of different breast cancer immunophenotypes. PATIENTS AND METHODS: We identified all premenopausal women aged 45 years or less who had been diagnosed with primary breast cancer between January 1999 and November 2005 at a single institution and who had undergone mammography at initial diagnosis. Patient characteristics including clinical, histologic, and mammographic features of breast cancers were tabulated by immunophenotype and compared with the chi-square test or the Kruskal-Wallis test. The P values less than 0.05 were considered statistically significant. RESULTS: We identified 198 premenopausal women who had been diagnosed with breast cancer. Thirty-eight (19%) women had TRN cancer, 67 (34%) had HER2+ cancer, and 93 (47%) had ER+ cancer. Mammographic density and cancer visibility were similar between all immunophenotypes of cancers. TRN cancers were more frequently associated with a mass (33/33 [100%]) than were HER2+ (35/64 [55%]) and ER+ cancers (42/87 [48%]) (P < 0.0001), and were less frequently associated with calcifications (5/33 [15%]) than were HER2+ (43/64 [67%]) and ER+ (53/87 [61%]) cancers (P < 0.0001). Associated ductal carcinoma in situ was reported in 18% (7/38), 57% (38/67), and 48% (52/93) of TRN, HER2+, and ER+ patients, respectively (P = 0.0003). CONCLUSION: The mammographic features of TRN breast cancer suggest more rapid carcinogenesis leading directly to invasive cancer, that may require adjunct imaging tools for early diagnosis.

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.

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 family's 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.

The anorectic effect of fenfluramine is influenced by sex and stage of the estrous cycle in rats.

The controls of food intake differ in male and female rats. Daily food intake is typically greater in male rats, relative to female rats, and a decrease in food intake, coincident with the estrous stage of the ovarian reproductive cycle, is well documented in female rats. This estrous-related decrease in food intake has been attributed to a transient increase in the female rat's sensitivity to satiety signals generated during feeding bouts. Here, we investigated whether sex or stage of the estrous cycle modulate the satiety signal generated by fenfluramine, a potent serotonin (5-HT) releasing agent. To examine this hypothesis, food intake was monitored in male, diestrous female, and estrous female rats after intraperitoneal injections of 0, 0.25, and 1.0 mg/kg D-fenfluramine. The lower dose of fenfluramine decreased food intake only in diestrous and estrous females, suggesting that the minimally effective anorectic dose of fenfluramine is lower in female rats, relative to male rats. Although the larger dose of fenfluramine decreased food intake in both sexes, the duration of anorexia was greater in diestrous and estrous female rats, relative to male rats. Moreover, the magnitude of the anorectic effect of the larger dose of fenfluramine was greatest in estrous rats, intermediate in diestrous rats, and least in male rats. Thus our findings indicate that the anorectic effect of fenfluramine is modulated by gonadal hormone status.