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.
<div>Abstract<p>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.</p><p>We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of preinvasive lesions [ductal carcinoma <i>in situ</i> (DCIS), lobular carcinoma <i>in situ</i>, and atypical lobular hyperplasia] in tissue adjacent to invasive breast cancers.</p><p>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.</p><p>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.</p></div>
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.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.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.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.
Abstract Abstract #1094 Rationale: Genetic testing for mutations in the BRCA1 and BRCA2 genes has enabled clinicians to provide contralateral breast cancer (CBC) risk estimates for women with breast cancer. Carriers of BRCA1 or BRCA2 deleterious mutations (BRCA+) have an increased risk of developing CBC compared to women without deleterious mutations (BRCA-). Guidelines for screening, including MRI and mammogram, and risk management options, such as contralateral prophylactic mastectomies (CPM), have been developed for BRCA+ women. However, many who undergo genetic testing are BRCA-. This result is often termed “uninformative negative” and can be interpreted as reassuring if the woman has little or no family history of breast and ovarian cancer or as not reassuring if the woman has a strong family history of breast and ovarian cancer. The uninformative nature of a BRCA- result makes clinicians' assessment of CBC risk for BRCA- women difficult, with less defined screening guidelines. We evaluated current CBC risk reduction strategies used by women under the age of 50 with reassuring or non-reassuring BRCA- test results.
 Methods: 634 breast cancer patients diagnosed under 50 were seen for genetic testing at MDACC between 1997-2008. 368 tested negative for BRCA mutations. Medical records were reviewed to determine age of cancer diagnosis, interpretation of the BRCA- result (i.e., reassuring vs. non-reassuring), and risk reduction choices made including CPM and prophylactic total abdominal hysterectomy-bilateral salpingo-oopherectomy (TAH/BSO). Interpretation of the BRCA- result was determined by a genetic counselor and was based on family history information provided by the patient. Fisher's exact test was used to detect differences between groups.
 Results: 34% of the women engaged in at least one preventative measure. Risk reduction choices made depended on the interpretation of the test result and the age of breast cancer diagnosis. In women diagnosed after 40, CBC risk reduction behaviors were similar regardless of having a reassuring or non-reassuring BRCA- result. In women diagnosed under 40, there was a higher uptake of prophylactic surgeries in women with non-reassuring negative results compared to reassuring negative results (CPM: 39.5% vs. 20.4%, p < 0.05; TAH/BSO: 18.4% vs. 2%, p < 0.01). Among women with reassuring negative results, CPM uptake after genetic counseling was higher in younger women compared to older women (11.2% vs. 5.6%, p < 0.05). CBC risk reduction choices were similar between younger and older women with non-reassuring negative results.
 Discussion: Although definitive screening guidelines are not provided for BRCA- women, many women with a negative result engage in risk reduction procedures. The interpretation of the negative test result and the age of breast cancer diagnosis appear to play a role in this decision making process. Because interpretation of a negative test result is used in CBC risk management decisions, this study highlights the importance of post-genetic testing counseling by professionals who can provide an accurate interpretation of genetic testing results. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1094.
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. Fisher's exact test was used to evaluate variables in univariate and binary logistic regression model for multivariate analysis. Results: A total of 170 pts were identified who received neoadjuvant CT and also underwent genetic testing. 137 pts were BRCA negative, 23 BRCA1 positive, and 10 BRCA2 positive. 121 pts received anthracycline plus taxane based CT and 36 pts anthracycline based CT only. Statistically significantly more pts with BRCA1 mutations had grade 3 and estrogen receptor (ER) negative disease compared to BRCA negative pts (p=0.01, p=0.001, respectively). The pCR rate was higher at 41 % for pts with a deleterious BRCA 1 mutation versus 21% for BRCA negative pts (p= 0.05). Other variables associated with higher pCR included having grade 3 (p=0.01), ER negative (p=0.001), and HER-2/neu positive disease (p=0.001). In multivariate analysis ER, grade, and HER-2/neu remained significant, but not BRCA status. There was no correlation between type of CT and pCR rate in patients with BRCA 1 positive breast cancer. Conclusions: Patients with BRCA1 related breast cancer have a higher pCR rate to neoadjuvant CT compared to BRCA negative breast cancer. Even though in multivariate analysis this was no longer statistically significant, the cohort is too small to rule out more modest differences. Larger studies need to evaluate whether certain types of CT would further improve pCR rates and this would translate into improved survival rates. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Pharmacia, Roche Nuvena Biosciences AstraZeneca, Dako, Monogram Biosciences, Pfizer AstraZeneca, NCI, Pfizer
B98 Background: >Mutations in the BRCA1 and BRCA2 genes result in a greatly increased risk of developing breast cancer at a young age. However, little is known about how lifestyle factors that influence breast cancer risk in premenopausal women affect women with gene mutations. Previous research in premenopausal women suggests an inverse relationship between body-mass index (BMI) and breast cancer risk. This relationship is yet to be fully determined in women with BRCA1 and BRCA2 mutations. Thus, the primary aim of this small pilot study is to examine whether BMI is associated with breast cancer in premenopausal women with mutations in the BRCA1 and BRCA2 genes. >Materials and Methods: >Clinical information and tumor pathology were examined in 251 premenopausal women seen for genetic risk assessment and testing at MD Anderson Cancer Center’s Clinical Cancer Genetics Program. Height and weight information taken within 3 months of the participants’ diagnosis of invasive breast cancer was used to calculate BMI. Women with a BMI of ≥ 30 were characterized as obese; women with a BMI Results: >Of the 251 women, 31 tested positive for a BRCA gene mutation (BRCA+) and 220 tested negative for a mutation (BRCA-). Twenty-two BRCA+ women had a mutation in the BRCA1 gene; nine BRCA+ women had a mutation in the BRCA2 gene. 32.3 % of BRCA+ women were obese at the time of their breast cancer diagnosis whereas 17.7 % of BRCA- women were obese at the time of diagnosis (p = 0.09). Obesity status did not affect age at diagnosis in BRCA+ or BRCA- women (p = 0.3 and 0.4 respectively, n.s.). BRCA+ patients were more likely to have higher nuclear grade, ER/PR/Her2Neu negative (“triple negative”) tumors compared to BRCA- patients (ps Discussion: >There was a trend for a larger proportion of BRCA+ women to be obese at diagnosis compared to BRCA- women. However, further research with a larger sample population should be conducted to determine the validity of this finding. In addition, these results provide further support for previous research which suggests that tumor pathology differs in BRCA+ and BRCA- cancers.
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