Age Of Breast Cancer Diagnosis Research Articles

Abstract P3-08-09: Clinical and Pathological Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1

Abstract Background: Neurofibromatosis type 1(NF1) is an autosomal dominant genetic disorder affecting 1 in 3,000 individuals worldwide. Risk of cancer, including breast cancer, is increased, as NF1 is a tumour suppressor gene. There is limited data on the characteristics of breast cancer in individuals with NF1. Objectives: To study the clinical and pathological characteristics of breast cancer in women with NF1. Methodology: Patients with both NF1 and breast cancer were identified retrospectively from hospital records as well as prospectively when seen at National Cancer Centre Singapore (NCCS) and Singapore General Hospital (SGH). All women had histologically proven breast cancer and fulfilled at least 2 of the 7 criteria developed by the NIH Consensus Conference for clinical diagnosis of NF1. Germline NF1 mutation sequencing is being performed on patients with blood specimens available. Details on patient demographics, tumour grade, stage, receptor status and clinical outcome were evaluated. The pathological characteristics of NF1-associated breast cancer were then compared to sporadic breast cancers in our 2001–2004 cohort, with a focus on grade and HER2 positivity rate. Results: We identified 13 women with NF1 and breast cancer seen at our institutions from 2001 to present date. Average age of breast cancer diagnosis for women testing positive was 48 years (range 30–64). All 13 patients had invasive ductal carcinoma; of which 5 were stage 3 or 4 at diagnosis. To date, 4 out of 12 patients with stage 1–3 breast cancer have relapsed. Grade, estrogen, progesterone and HER2 receptor status were fully available for 12 patients. Ten out of 12 tumours (83%) were grade 3, compared to 45% (705/1578) among our sporadic breast cancers (p = 0.007). Eight out of 12(67%) NF1-associated breast cancers were HER2 positive (IHC 3+ or FISH positive), compared to 27% (367/1367) in sporadic cancers (p = 0.002). Two other NF1-associated tumours were triple negative, and two were hormone receptor positive and HER2 negative. Six out of 12 (50%) NF1-associated cancers were estrogen receptor (ER) positive, compared to 67% (1124/1689) in sporadic cancers (p = 0.2). Conclusion: Our findings suggest that NF1-associated breast cancer tends to be more aggressive, with a higher frequency of grade 3 and HER2 positive tumours compared to sporadic breast cancer. Further genomic profiling of these tumours (in progress) may elucidate the role of NF1 in breast cancer. This may also have implications for sporadic tumours with somatic NF1 mutations in individuals without NF1. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-09.

Breast cancer in Irish families with Lynch syndrome.

1543 Background: Breast cancer is not among the recognised malignant manifestations of Lynch Syndrome which include colorectal, endometrial, gastric, ovarian and upper urinary tract tumours. In this study we report the prevalence of breast cancer in Irish Lynch Syndrome families and determine immunohistochemical (IHC) expression of mismatch repair proteins (MMR) in available breast cancer tissue. Methods: Breast cancer prevalence was determined among Lynch Syndrome kindreds from two institutions in Ireland. One kindred was omitted due to a biallelic MMR and BRCA1 mutation.The clinicopathological data that was collected on breast cancer cases included age of onset, morphology, and hormone receptor status, and a genotype phenotype correlation was investigated. Immunohistochemical staining was performed for MLH1, MSH2, MSH6, and PMS2 on all available breast cancer tissue from affected individuals. Results: The distribution of MMR mutations seen in sixteen pedigrees were as follows; MLH1 (n=5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal cancer and 14 cases of endometrial cancer were seen. Seven breast cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of ductal carcinoma in situ were reported in 7 pedigrees. This compared with 4 cases of prostate cancer. Of the 7 LS kindreds containing breast cancer, 6 MSH2 mutations and 1 MSH6 mutations were identified. Median age of breast cancer diagnosis was 49 years (range 38-57). Hormone receptor status is available on 3 breast cancer cases at time of abstract submission; all were ER positive and HER 2 negative. All cases had grade 2 or 3 tumours. 5 samples were available for IHC evaluation. 3 out of 5 cases showed loss of MMR expression, all showed loss of MSH2 and MSH6 expression. One of the two cases with normal IHC expression in breast tissue belonged to a kindred where 3 siblings with colorectal cancer and documented deleterious mutations demonstrated no IHC loss. Conclusions: Breast cancer occurred at an early age and was more common than prostate cancer in Irish Lynch Syndrome pedigrees. All identified breast cancer were in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer screening may be warranted in certain Lynch Syndrome kindreds.

Abstract 4440: From gray to pink: Helping older adults with breast cancer understand and utilize the health care system in the real world

Abstract Background: Breast cancer education programs while abundant tend to focus on young and middle age women. However, the median age of breast cancer diagnosis is 61 years of age. With increasing debate on when to begin mammography, the risk of being diagnosed at a later age also increases. As the senior breast cancer survivor and at-risk population continues to grow, their need to be educated regarding breast cancer and other health and legal-related issues of aging is key to reducing risk, finding breast cancer early, and improving the quality of life for survivors. This pilot program was designed to educate seniors about breast cancer in relation to healthy aging and nutrition, elder law, patient advocacy, and occupational and physical therapy. The intent is to improve senior confidence and knowledge pertaining to these issues in order to create a sustainable population of seniors that can help themselves and each other. Methods and Materials: Two senior centers located in Northwest Ohio agreed to host the four individual workshops of From Gray to Pink during September and October 2011, respectively. Senior breast cancer survivors (age ≤ 60), their family and friends, and women at risk were welcome to attend. The workshops covered breast cancer and issues related to diet, aging, elder law, patient advocacy and navigation, and physical therapy and occupational therapy. Participant knowledge and confidence were assessed using pre- and post-surveys and the Student's paired t-test was used to compare mean pre- and post-test knowledge and confidence scores. Results: Among the 25 total participants, there were statistically significant differences between pre- and post-test knowledge for the aging and nutrition (p = 0.01), elder law (p < 0.01), physical and occupational therapy (p = 0.03) workshops. Conclusion: Senior breast cancer survivors and those at risk scored higher in both topic knowledge and confidence on post-surveys compared to pre-surveys. This pilot study has provided sufficient data to apply for funding to bring this program to additional rural Ohio counties. While improvements in confidence were not statistically significant, most participants did have the same level of or greater confidence following each workshop. Given the aging of our population and increasing health care costs and needs, breast cancer education for seniors at risk and senior survivors is crucial. The knowledge and confidence gained by seniors can be shared among all to provide an ever-growing network of people who can educate and help each other improve their quality of life. Further implementation will help in determining if this educational methodology may be useful in other parts of the country for seniors who have or are at risk for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4440. doi:1538-7445.AM2012-4440

Breast cancer in Irish families with Lynch syndrome.

413 Background: Breast cancer is not a recognised malignant manifestation of Lynch Syndrome which includes colorectal, endometrial, gastric, ovarian and upper urinary tract tumours. In this study we report the prevalence of breast cancer in Irish Lynch Syndrome families and determine immunohistochemical expression of mismatch repair proteins (MMR) in available breast cancer tissue. Methods: Breast cancer prevalence was determined among Lynch Syndrome kindreds from two institutions in Ireland, and a genotype phenotype correlation was investigated. One kindred was omitted due to the presence of a biallelic MMR and BRCA1 mutation. The clinicopathological data that was collected on breast cancer cases included age of onset, morphology, and hormone receptor status. Immunohistochemical staining was performed for MLH1, MSH2, MSH6, and PMS2 on all available breast cancer tissue from affected individuals. Results: The distribution of MMR mutations seen in 16 pedigrees was as follows; MLH1 (n=5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal cancer and 14 cases of endometrial cancer were seen. Seven breast cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of ductal carcinoma in situ were reported in 7 pedigrees. This compared with 4 cases of prostate cancer. Six MSH2 mutations and 1 MSH6 mutation were identified in the 7 Lynch syndrome kindreds. Median age of breast cancer diagnosis was 49 years (range 38-57). Hormone receptor status is available on 3 breast cancer cases at time of abstract submission; all were ER positive and HER 2 negative. All cases had grade 2 or 3 tumours. Final results of immunohistochemistry for mismatch repair protein expression on breast cancer samples are pending and will be reported at the meeting. One breast cancer has been tested to date and demonstrated loss of MSH2 protein expression in an individual carrying an MSH2 mutation. Conclusions: Breast cancer occurred at an early age and was more common than prostate cancer in Irish Lynch Syndrome pedigrees. All reported breast cancer cases were in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer screening may be warranted in certain Lynch Syndrome kindreds.

P1-08-17: Pregnancy-Associated Breast Cancer Does Not Have a Worse Outcome in the 4912 Women with Breast Cancer of the AMAZONA Project.

Abstract Introduction: Pregnancy traditionally is considered a protective factor for breast cancer. Recent data suggests that pregnancy-associated breast cancer (PABC), a distinct biologic variant possibly related to breast involution, can occur up to 10 years post-partum and may carry a worse prognosis than that of age matched sporadic or nulliparous breast cancer. The Amazona project is a retrospective cohort of 4,912 Brazilian women with breast cancer that has previously reported on worse outcomes of patients according to type of institution where treatment was received (San Antonio 2009 abstr. 3082). We have assessed the outcomes of PABC in the Amazona cohort. Objectives: 1- To identify whether women who were diagnosed with breast cancer up to 10 years after their first pregnancy had worse disease free survival (DFS) and overall survival (OS) than nulliparous women (NW); 2- to assess if age at first pregnancy is related to age of breast cancer diagnosis and worse DFS or OS; 3- to assess whether number of pregnancies is associated with worse DFS or OS; 4- to assess whether time from first pregnancy to diagnosis or age of first pregnancy are associated with histological grade, clinical stage or tumor expression of ER, PR, and HER2. Methods: We analyzed 4836 women for whom parous history was available, in respect to DFS, OS, tumor clinical stage, histological grade, expression of ER, PR and HER2, according to age of first pregnancy, diagnosis up to 5 and 10 years after first pregnancy, and number of pregnancies, using NW as controls. Analysis of DFS and OS was done by Cox regression modeling adjusted for institution type, stage, ER, PR, HER2 and grade. Results: Our cohort had 1996 nulliparous women and 2840 parous women. The median follow up was 28 months and there were 318 deaths and 735 recurrences. We did not find any correlation between PABC with DFS (5 year interval HR 1.15, 95%CI 0.43−3.07; 10 year interval HR 1.01, 95%CI 0.57−1.81) or OS (5 year interval HR 1.88, 95%CI 0.6−5.94; 10 year interval HR 0.5, 95%CI 0.73−3.09), nor was there a correlation between age at first pregnancy with age of breast cancer diagnosis. We also did not see any difference between age of first pregnancy and DFS or OS. Women with 3 or more pregnancies had worse OS (HR 0.71, 95%CI 0.54−0.93) but not worse DFS (HR 0.93, 95%CI 0.76−1.13).Tumors diagnosed within 5 or 10 years from first pregnancy did not differ by grade, ER, PR, HER2, and clinical stage from those of NW. Women who had their first pregnancy after age 20 tended to have more ER positive (OR 1.99, 95%CI 1.49−2.65), PR positive (OR 1.40, 95%CI 1.06−1.87), and HER2 positive (OR 1.85, 95%CI 1.22−2.79) tumors than NW. Conclusions: In this large cohort of breast cancer patients from the diverse geographic and socioeconomic spectrum of Brazil we did not find any association between PABC or age of first pregnancy to DFS or OS. The association with worse OS but not DFS for women with 3 or more pregnancies might be due to confounding factors. PABC was not associated with worse clinical prognostic factors. Women who had their first pregnancy after age 20 were more likely to have ER+, PR+ and HER2 + tumors than nulliparous patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-17.

ES6-3: Breast Cancer in the Older Adult.

Abstract Breast cancer is a disease associated with aging. In the US, the median age of breast cancer diagnosis and death is 61 years and 68 years, respectively. The number of older adults in the US is rising, and the number of individuals age 65 and older is expected to double by the year 2030. This demographic shift will lead to an increase in the number of individuals diagnosed with breast cancer. It is estimated that from 2010 to 2030 there will be a 57% growth in the number of new cases of breast cancer in patients age 65 and older.1 A challenge in caring for older adults with breast cancer is that they have been historically underrepresented in clinical trials that set the standard for breast cancer care.2 However, a growing body of evidence-based literature can be utilized to inform and optimize the care of the older adults with breast cancer. This presentation will focus on the treatment of early stage breast cancer in older adults, including the risks and benefits of local and systemic therapies, as well as survivorship issues. Recently reported phase III studies have led to advances in the treatment of older adults with breast cancer. A phase III randomized study evaluated the role of radiation therapy following lumpectomy in patients age 70 and older with stage I hormone receptor (HR) positive breast cancer who received treatment with tamoxifen. Receipt of radiation therapy was associated with a decrease in the risk of locoregional recurrence; however, there was no difference in overall survival. The study results underscore the importance of competing comorbidity as a cause of death in older adults with early stage breast cancer.3 The role of axillary lymph node dissection was evaluated in a randomized study of women over age 60 with node-negative, HR positive breast cancer who received treatment with tamoxifen. Patients were randomized to breast surgery and axillary dissection, or breast surgery alone. There was no difference between disease-free and overall survival in the 2 study arms.4 A phase III randomized study evaluated the efficacy of standard adjuvant IV chemotherapy (doxorubicin and cyclophosphamide [AC] or cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) versus oral chemotherapy (capecitabine) in patients age 65 and older with stage I-III breast cancer. Those patients who received standard chemotherapy showed improvement in progression-free and overall survival compared with patients who received capecitabine. This study demonstrates that IV polychemotherapy regimens remain the standard of care for older adults who are prescribed adjuvant chemotherapy.5 These phase III studies advance our understanding in the care of older adults with breast cancer. Furthermore, they demonstrate the feasibility and importance of accruing older adults to phase III trials, which will improve our evidence-based care of this growing population.

P4-11-22: Familial History of Cancer among Breast Cancer Women under 36 yr. in Rio De Janeiro, Brazil.

Abstract Background. Antecedents of familial history of cancer (FHC) have been reported as an important feature observed among young women with breast cancer (BC). Objective. To explore the distribution of FHC in a sample of young women with BC in Brazil. Methods. Antecedents of FHC were obtained by a face to face interview carried out with 224 BC cases 20–35 yr., and 246 age-frequency matched controls, enrolled in a hospital-based case control study carried out along 1996–2006 in Rio de Janeiro, Brazil. Unconditional logistic regression was performed and BC odds ratios adjusted for age and education (adj. OR) were obtained according to FHC characteristics (parenthood degree, age of diagnosis and amount of relatives with cancer). Results. BC antecedents among 1 st degree relatives was 5.4% among BC cases and 1.2% of controls (p=0.01). The adj. OR for BC among 1st degree relatives was 4.3, 95% CI 1.2−15.8. Comparatively to families without BC antecedents, an adj. OR =2.4, 95% CI 1.4−4.1 was observed for those with 1 reported BC case, and an adj. OR = 3.7, 95% CI 1.0–14.0 for those with 2 or more BC cases (p trend =0.0002). A similar trend was verified according to all other cancer sites (p-trend < 0.0001). The reported median age of BC diagnosis in the 1st generation (proband grand-mothers) was 76 yr., being 45 yr. at the 2nd generation (proband mothers), and 38,4 yr. at the 3rd (proband sisters). A similar trend along generations was also verified for other cancer sites among case relatives, respectively, 69 yr., 58 yr. ***, and 45 yr. The mean age of diagnosis among the cases offspring was 6.7 yr. (standard deviation, SD = 0.6) and 12.0 yr. (SD = 1.4) among the controls descents (p< 0.01). Brain cancer reported among case relatives was 6.0 fold higher than among control relatives (3.7 fold higher for ovarian cancer, and 3.2 higher for skin cancer). Discussion. The observed results reveal that cancer risks among relatives of young women with BC are either higher for BC or other selected cancer sites. The observed decline along successive generations on the age at diagnosis of BC and other tumors is suggestive of recent genetic-environmental interaction in the studied sample of young women with BC in Brazil. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-22.

Abstract P3-12-01: Increased Rate of HER2-Positive Breast Cancers among Women with Germline TP53 Mutations

Abstract Background: Germline TP53 mutations are the primary cause of Li Fraumeni syndrome (LFS), which is a cancer predisposition syndrome primarily associated with breast cancer, sarcomas, brain tumors, and adrenocortical carcinoma. The risk of cancer is higher for women than men and is mostly the result of the increased frequency of breast cancer among women with LFS. Published data on the specific clinical and pathological characteristics among women with breast cancer and germline TP53 mutations is limited. Methods: To better describe the genotype-phenotype characteristics of women with breast cancer and LFS, we performed a retrospective chart review of all women with a known history of breast cancer that have undergone genetic testing for suspected germline TP53 mutations at M. D. Anderson Cancer Center between 2001 to present date. All women had documented breast pathology and most met the NCCN consortium guidelines for TP53 mutational analysis testing based on their personal and/or family history of cancer. The pathological characteristics of the women testing positive for TP53 mutation were then compared to the women testing negative, with a focus on specific histological features, Estrogen Receptor (ER) and HER2 status (as assessed by FISH ratio > 2.2 or IHC 3). Results: We identified 45 women with breast cancer who underwent testing for germline TP53 mutations because of a personal and family history suggestive of LFS. A total of 15 out of 45 women tested positive as identified by TP53 mutational analysis. Average age of breast cancer diagnosis for women testing positive was 30 years (range 20-45) and for women testing negative 32 years (range 21-58). Of the 15 women with LFS, 2 had DCIS, one had a spindle cell cancer of the breast, and one had incomplete pathologic assessment (HER2 unknown). These were excluded from the analysis. Of the 30 women testing negative for LFS, only 25 had complete pathological assessment available and were includedfor the comparison. The remainder of the patients all had Invasive Ductal Carcinoma of the breast. Among the LFS patients who had documented pathological grade, all had high grade. 73% of the LFS patients tested positive for ER expression as compared to 60% in the non-LFS group (p=0.71). 63% of the LFS patient had evidence of Her-2/neu amplification and/or overexpression compared to 24% in the non-LFS group (p=0.03). Conclusion: These data suggest an association between early onset HER2 positive breast cancer and LFS. If confirmed in a larger cohort of patients, these results could guide genetic testing strategies or open the door for future chemoprevention trials incorporating HER2 targeted therapies and vaccine trials in women with LFS. This association could also shed some light on the potential interaction between TP53 and Her2-neu both major molecular markers in breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-01.

Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation‐positive families?

Women who carry BRCA mutations are advised to begin breast cancer screening based on the age-specific risks of breast cancer development. It is not clear to what extent the family history of breast cancer influences age of onset. We evaluated the use of family history to predict the age of breast cancer onset in BRCA mutation carriers. Pedigrees from an Ontario-based registry were reviewed to identify the index case of breast cancer (most recent diagnosis) and other family cases of breast cancer. The youngest age of breast cancer diagnosis and mean age at breast cancer diagnosis in the other family cases were compared to the age of onset in the index case. The 260 BRCA1 and 213 BRCA2 pedigrees were reviewed. In BRCA2 families, the index case was diagnosed on average at 44.4 years when the youngest reported family case was less than or equal to 35 years, compared to 51.9 years when the earliest cases were diagnosed after age 50 (p = 0.04). A modest trend was seen for BRCA1 carriers, but this was not statistically significant. To a small extent, the onset of breast cancer in a BRCA2 mutation carrier can be predicted from her family history of cancer, however, the trend is modest and should not alter clinical recommendations regarding initiation of screening.

Other malignancies in patients with breast cancer: a single institute experience

To The Editor, Patients with breast cancer survive longer after advances in treatment options [1]. During their follow-up, they may develop secondary malignancies or became patients with breast cancer secondary to previously diagnosed malignancies. The aim of our study was to evaluate the other malignancies among patients with breast cancer. Between years 2004 and 2009, 987 consecutive patients with breast cancer presenting at Hacettepe University Institute of Oncology were evaluated retrospectively. Median follow-up of all patients was 3.6 years (range 0.3–28). Of all the study population, 19 (1.9%) had other malignancies. Among all patients with breast cancer, 14 and 5 patients developed secondary malignancies before and after the diagnosis of breast cancer, respectively. The most frequently observed ones were ovarian cancer. The frequency of other malignancies was shown in Table 1. Median age of breast cancer diagnosis was 49, while median age of previous malignancies was 45 years old. Patients with breast cancer can survive longer after the advances in treatments. This can cause enough time to develop secondary malignancies. Secondary malignancies may develop sporadically, or due to environmental factors, genetic susceptibility and treatment complications [2]. Ewertz et al. reported the risk of second primary cancer in approximately 55,000 patients with breast cancer. They found that risk of a developing second malignancy was 13% [3]. In our study, frequency of other malignancies was 1.9%. This is most probably due to the short follow-up period. In our series, nearly 50% malignancies diagnosed were gynecological tumors. Therefore, close follow-up of patients who had gynecological tumors is very important due to risk of developing secondary cancer, especially breast cancer.

Evaluation of SNPs inmiR-146a,miR196a2andmiR-499as low-penetrance alleles in German and Italian familial breast cancer cases

Recently, the SNPs rs11614913 in hsa-mir-196a2 and rs3746444 in hsa-mir-499 were reported to be associated with increased breast cancer risk, and the SNP rs2910164 in hsa-mir-146a was shown to have an effect on age of breast cancer diagnosis. In order to further investigate the effect of these SNPs, we genotyped a total of 1894 breast cancer cases negative for disease-causing mutations or unclassified variants in BRCA1 and BRCA2, and 2760 controls from Germany and Italy. We compared the genotype and allele frequencies of rs2910164, rs11614913 and rs3746444 in cases versus controls of the German and Italian series, and of the two series combined; we also investigated the effect of the three SNPs on age at breast cancer diagnosis. None of the performed analyses showed statistically significant results. In conclusion, our data suggested lack of association between SNPs rs2910164, rs11614913 and rs3746444 and breast cancer risk, or age at breast cancer onset.

Childhood Cancer Survivors: Many Miss Mammograms Later in Life

Despite recommendations and being at an increased risk of breast cancer, most young women who were treated with chest radiation for a childhood cancer do not undergo appropriate mammography screening, according to a study in the January 28 issue of JAMA . Women treated with chest radiation for a pediatric malignancy face a significantly increased risk of breast cancer at a young age. “The risk of breast cancer begins to increase as early as eight years after radiation and the median [midpoint] age of breast cancer diagnosis ranges from 32 to 35 years,” the authors write. By age 45 years, it's estimated that from 12 percent to 20 percent of women treated with moderate- to high-dose chest radiation will be diagnosed with breast cancer. Experts recommend annual screening mammography for women exposed to moderate- to high-dose chest radiation, starting at 25 years of age or eight years after radiation, whichever occurs last. It's estimated that in the United States there are approximately 20,000 to 25,000 women who are 25 years or older and were treated for a pediatric malignancy with moderate- to high-dose chest radiation. There is limited published information regarding the breast cancer screening practices of women who were treated with chest radiation for a childhood malignancy, according to background information in the article.

Contralateral breast cancer risk reduction choices in BRCA negative women with breast cancer under age 50.

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.

MDM2 SNP309 is associated with high grade node positive breast tumours and is in linkage disequilibrium with a novel MDM2 intron 1 polymorphism

IntroductionA functional polymorphism within MDM2, SNP309 T>G, has been linked to early onset cancer. This study examined clinical associations of breast cancer with SNP309 in a Scottish Caucasian population and investigated additional MDM2 intron 1 polymorphisms.MethodsIntron 1 of MDM2 was PCR amplified and directly sequenced from 299 breast cancer patients and 275 cancer free controls and compared with clinical and pathological parameters.ResultsSNP309 was observed, for the control and breast cancer cohorts respectively, at frequencies of: T/T = 44.7% and 39.5%; G/T = 42.2% and 47.2%; G/G = 13.1% and 13.4%, indicating that SNP309 is not a predisposing factor for breast cancer. The 309G/G genotype was associated with high grade tumours (OR = 1.64, 95%CI = 1.06–2.53, p = 0.025) and greater nodal involvement (OR = 2.51, 95%CI = 1.26–4.98, p = 0.009). SNP309 was not associated with an earlier age of cancer diagnosis. No association was observed between genotype and age of breast cancer diagnosis when patients were stratified by menopausal status and estrogen receptor status. Three additional low frequency SNPs were identified: 344T>A, 285G>C and 443G>T, the latter two novel. SNP285 was in complete linkage disequilibrium with SNP309 (D' = 1.0) with the minor alleles being in phase with each other. Moreover, the 285C/C, 309G/G double homozygous genotype was only observed in the breast cancer cohort.ConclusionSNP309G/G is associated with poor prognostic breast cancer features in the Scottish population. Additionally, a novel SNP, SNP285, that is in linkage disequilibrium with SNP309, may also have a role in breast tumorigenesis.

Angiosarcomas of the Breast

Angiosarcoma arising in the irradiated breast after breast-conserving therapy is being reported with increasing frequency. As more women undergo breast-conserving therapy, the incidence can be expected to increase. The objective of this study was to review breast angiosarcomas diagnosed from 1981 to 2000 from our state cancer registry. A comprehensive review of a population-based registry, Florida Cancer Data System, identified 70 cases of breast angiosarcomas from 1981 to 2000. Descriptive statistical and chi analyses were performed. Of the 70 cases at presentation, 39 were primary breast angiosarcomas (PBAs) and 31 were secondary breast angiosarcomas (SBAs). The mean ages were 59 and 72.9 for the PBA and SBA groups, respectively. In the SBA group the mean age of breast cancer diagnosis was 67.6. The mean time to diagnosis of the angiosarcoma was 5.2 years after breast cancer irradiation. At presentation 82% (n = 32) and 48% (n = 15), in the PBA and SBA groups, respectively had local disease (P = 0.003). The primary treatment was mastectomy in each group. There was no difference in mortality between the 2 groups (PSA; n = 18, SBA; n = 17). Angiosarcoma of the breast is rare and this study reports a review of 70 cases from 1980 to 2000. Angiosarcoma after breast-conserving therapy is increasingly diagnosed in a small but significant portion of breast carcinoma survivors. SBA patients present with more advance disease. Surgical resection is the primary therapy. The aggressive nature of this disease demands further investigation of adjuvant therapy to prevent recurrence of disease after surgery.

Changes in the age of breast cancer diagnosis along the last century in Argentina

875 Background: The age of breast cancer (BC) onset seems to have decreased during the last century in Buenos Aires.To validate this trend we tripled the number of patients(pts),including other Argentine oncology centers. Methods: We performed a multicenter,retrospective,observational study.The clinical records of 6063 pst with BC diagnosis,born between 1900 and 1980 were reviewed.The population was divided in to three groups(G). Born between 1900 and 1930 (GA),1931 and 1960(GB) and after GC.The following variables were evaluated: birth decade,age at initial disease diagnosis,number of pts ≤ 40 years in the three groups. The T-Student Test was used for independent variables for age analysis., the square Chi Test to determine the rate of pts ≤ 40 years and the Estadistica 6.0 Program for data analysis. Results: The average age of populations was 57 (± 13 years). GA included 2371 pts with a mean age of 69 (± 9 years), GB 3439 pts with a mean age of 53 (± 9 years) and GC 253 pts with a mean age of 35 (± 4 years).(GA vs. GB p< 0.001). The pts who were≤ 40 years represented 9% of total population (543 pts) and were distributed in the following manner:GA 21 pts (0,9%),GB 286 pts (8%) and GC 236 pts (93%). GA vs GB p< 0.01. Conclusions: 1-A 16-year decrease in the age of BC diagnosis was confirmed among pts born between 1931 and 1960 with the respect to those born before, 2-in GB the number of pts who were ≤ 40 years old increased almost ten times with respect to GA. 3-We believe tha early diagnosis, a better access to health services, environmental changes and life style have had a significant impact on results. No significant financial relationships to disclose.

Is family history related to preventive health behaviors and medical management in breast cancer patients?

Women diagnosed with breast cancer who also have a family history of the disease are at increased risk of developing additional primary breast or ovarian cancers. We investigated whether a relationship exists between family history and health behaviors in a cross-sectional study of breast cancer survivors. Participants in the Women's Healthy Eating and Living (WHEL) Study (a randomized trial designed to test the effect of a plant-based diet on breast cancer recurrence) completed baseline questionnaires about their family history and health behaviors. Medical records and self-reports provided treatment data. Participants were defined as having a family history (FH+) if they met specific family history criteria (n=195), and were compared with women having no family history (FH-) of breast cancer (n=1736). The mean age of breast cancer diagnosis was 51.2 years for both groups, but FH+ women were more likely to be diagnosed before age 40. FH+ and FH- women had similar dietary patterns, alcohol intake, exercise patterns, body mass index and smoking histories. However, FH+ women were more likely to have undergone prophylactic contralateral mastectomy (OR=3.6, 95% CI=2.2 - 6.2) and bilateral oophorectomy (OR=1.6; 95% CI=1.0 - 2.3) following diagnosis, adjusted for age and time since diagnosis. The FH+ and FH- groups had similar patterns of use of anti-estrogen medications and frequency of medical follow-up. Breast cancer survivors with a strong family history of breast cancer are more likely to undergo surgical preventive measures to reduce their risk of additional cancer, but do not report undertaking more preventive lifestyle behaviors compared to breast cancer survivors without a family history.

BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer risk evaluation clinic.

To determine the prevalence of BRCA1 and BRCA2 mutations in families identified in a breast cancer risk evaluation clinic. One hundred sixty-four families seeking breast cancer risk evaluation were screened for coding region mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis and DNA sequencing. Mutations were identified in 37 families (22.6%); 28 (17.1%) had BRCA1 mutations and nine (5.5%) had BRCA2 mutations. The Ashkenazi Jewish founder mutations 185delAG and 5382insC (BRCA1) were found in 10 families (6.1%). However, 6174delT (BRCA2) was found in only one family (0.6%) despite estimates of equal frequency in the Ashkenazi population. In contrast to other series, the average age of breast cancer diagnosis was earlier in BRCA2 mutation carriers (32.1 years) than in women with BRCA1 mutations (37.6 years, P =.028). BRCA1 mutations were detected in 20 (45.5%) of 44 families with ovarian cancer and 12 (75%) of 16 families with both breast and ovarian cancer in a single individual. Significantly fewer BRCA2 mutations (two [4.5%] of 44) were detected in families with ovarian cancer (P =.01). Eight families had male breast cancer; one had a BRCA1 mutation and three had BRCA2 mutations. BRCA1 mutations were three times more prevalent than BRCA2 mutations. Breast cancer diagnosis before 50 years of age, ovarian cancer, breast and ovarian cancer in a single individual, and male breast cancer were all significantly more common in families with BRCA1 and BRCA2 mutations, but none of these factors distinguished between BRCA1 and BRCA2 mutations. Evidence for reduced breast cancer penetrance associated with the BRCA2 mutation 6174delT was noted.

BRCA1 Sequence Analysis in Women at High Risk for Susceptibility Mutations

<h3>Octext.</h3> —A mutation in the<i>BRCA1</i>gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete. <h3>Objectives.</h3> —To identify<i>BRCA1</i>mutations and to determine factors that best predict presence of a deleterious<i>BRCA1</i>mutation in patients with breast and/or ovarian cancer. <h3>Design.</h3> —A complete sequence analysis of the<i>BRCA1</i>coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland. <h3>Participanta.</h3> —Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of<i>BRCA1</i>mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the<i>BRCA1</i>locus. <h3>Major Outcome Measures.</h3> —Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for<i>BRCA1</i>mutations. <h3>Results.</h3> —In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious<i>BRCA1</i>mutation. <h3>Conclusions.</h3> —Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious<i>BRCA1</i>mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.

Breast cancer, genetics, and age at first pregnancy.

Hereditary breast cancer shows a distinctive natural history characterised by an earlier age of onset, excess bilaterality, vertical transmission, heterogeneous tumour associations, and improved survival when compared to its sporadic counterpart. To date, very little attention has been given to interrelationships between breast cancer risk factors and genetics. In the general population, early age of first term pregnancy has been generally accepted as protective against breast cancer. In addition, recent findings suggest that an early age of first pregnancy may be associated with an earlier age of breast cancer diagnosis. We studied the age at first pregnancy and age at onset of breast cancer among 162 females at 50% genetic risk, 72 of whom had already developed the disease. We then compared them to 154 consecutively ascertained breast cancer patients from the Creighton Cancer Center. In the hereditary subset (1) early first term pregnancy did not alter the frequency of breast cancer; (2) early age at first term pregnancy was not associated with an earlier age at cancer diagnosis; and (3) age of breast cancer onset in nulliparous females was not significantly lower than that in females having at least one term pregnancy. We speculate, therefore, that in our hereditary population, pregnancy does not influence the natural history of breast cancer in the same way that it does in the population at large.