bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitotic Activity Index Identifies Both Over- and Undertreated Lymph Node Negative Breast Cancer Patients < 55 Year According to the Norwegian Treatment Guidelines.
Authors: Hoel Lende T. , Hoel Lende T. , Hoel Lende T. , Gudlaugsson E. , Gudlaugsson E. , Janssen E. , Voorhorst F. , Van Diest P. , Søiland H. , Baak J. , Baak J. , Baak J.
Published: December 2010

Background: It is a challenge to avoid under- and overtreatment of breast cancer patients in the adjuvant setting. Patients who have not received adjuvant systemic treatment and with a known outcome demonstrate the natural course of the disease after surgery. Such patients may be re-evaluated in specific guidelines like the Norwegian Breast Cancer Group (NBCG) based on the St. Gallen criteria. NBCG classify the patients in a low-risk group which should not receive systemic treatment, and a high-risk group which should be offered such therapy. New factors may be evaluated in these two strata, possibly discriminating groups of under- or overtreated patients. The aim of this study was to explore if the previous established marker of proliferation, the mitotic activity index (MAI), could give any additional information.Patients and methods: The study comprised 516 lymph node negative patients < 55 years from the Dutch prospective Multicenter Morphometric Mammary Carcinoma Project (MMMCP; 1987-1989)1. No adjuvant systemic treatment was given after surgery to these patients. The guidelines from NBCG-2005 were used to classify the patients in “NBCG low-risk” group (n=100) defined as pT1/Grade 1, all ages and pT1a-b/Grade 2-3, >35 years, all hormone receptor positive. The rest of the patients (n=416) was grouped as “NBCG high-risk”. Breast Cancer Specific Survival (BCSS) was estimated by the Kaplan-Meier method. MAI was analyzed after a standardized protocol in the invasive front of the tumor. The previous established thresholds of MAI with low (<3), intermediate (3-9) and high (≥10) proliferation were used in the calculations.Results: In the “NBCG low-risk” group 10 % of the patients had MAI ≥10. These had a 14-years BCSS of 50 % (HR=15.47, 95 % CI=3.61-66.30) and may be regarded as undertreated patients. Patients with MAI <3 and 3-9 had a BCSS of 95 % and 83 % respectively. In the “NBCG high-risk”group 24 % of the patients with MAI<3 had a 14-years BCSS of 92 % indicating overtreatment. Furthermore, patients with MAI 3-9 and ≥10 had a BCSS of 74 % and 63 % (p-trend <0.0001).Discussion: MAI represents the “converging mitotic drive” from all cellular signal pathways in the peripheral growing zone of the tumor, where also micro-environmental factors are known to influence proliferation of cancer cells. This may explain why MAI gives original information strong enough to identify subgroups breast cancer patients who would not get optimal adjuvant treatment. A disadvantage of this study is that the HER-2 status in this MMMCP material is not known. National prospective studies are needed to verify our results.1 Baak, JPA et al: Pathol Res Pract 185:664-70,1989.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3182.
Reduced Lung Cancer Mortality Risk among Breast Cancer Patients Treated with Anti-Estrogens.
Authors: Rapiti E. , Verkooijen H. , Verkooijen H. , Fioretta G. , Schubert H. , Vinh-Hung V. , Vinh-Hung V. , Benhamou S. , Vlastos G. , Bouchardy C.
Published: December 2010

Background: The Women Health Initiative study recently reported that women on hormone replacement therapy (HRT) were at increased risk of dying from lung cancer. If exposure to estrogens can worsen lung cancer outcome, we hypothesized that anti-estrogens may, on the contrary, improve its prognosis. We compared lung cancer incidence and mortality among breast cancer patients with and without anti-estrogen therapy.Methods: All 6715 patients recorded with a breast cancer in the population-based Geneva Cancer registry in the period 1980-2003 were included in the study. Forty-six percent of these women (3066) received anti-estrogen therapy (tamoxifen in large majority). Age, sex and year-specific population data were used to calculate standardised incidence ratios (SIRs) and standardised mortality ratios (SMRs), to compare the study population to the general female population of Geneva canton. For each woman we computed person-years at risk from the date of diagnosis of breast cancer to the date of diagnosis of invasive lung cancer cancer, date of death, date lost to follow-up, or end of the study period (December 31, 2007).Results: The cohort yielded a total of 57,100 person-years.During the study period we observed a total of 40 cases of metachronous lung cancers (diagnosed at least six months after the breast cancer). Compared with the general population, the risk of developing a lung cancer among women who received anti-estrogens was 0.63 (95% Confidence Intervals [CI]: 0.33-1.10) and among women without anti-estrogens was 1.12 (95% CI: 0.74-1.62). Lung cancer mortality rate was 31.44/100,000. The mortality rate were 9.23/100,000 for women with anti-estrogens and 44.97/100,000 for women without anti-estrogens.Compared to the general population the SMR for lung cancer was 0.13 (95% CI: 0.02-0.47) among women who took anti-estrogens (p<0.001), and 0.76 (95% CI: 0.43-1.23) among women who did not receive anti-estrogens.Discussion: Women who received anti-estrogens as breast cancer treatment have a significantly decreased risk of dying from lung cancer. This result further supports the role of estrogens in lung cancer prognosis and suggests that exposure to anti-estrogens may offer some protection against tumor mortality.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 35.
Using Ki67 To Improve and Simplify Outcome Modeling for Breast Cancer.
Authors: Yerushalmi R. , Woods R. , Ravdin P. , Speers C. , Kennecke H. , Gelmon K.
Published: December 2010

Ki67 is a marker of proliferation which has several advantages over histological grade. Ki67 is determined less subjectively and is a continuous rather than a categorical variable. Many studies that have looked at Ki67 have been small and underpowered. A large population based tissue microarray was used to: A) test the prognostic value of Ki67 in testing and validation sets, and B) construct an improved model including Ki67 and conventional prognostic variables to predict patient outcome. Methods: The cohort included 2,780 patients with early breast cancer diagnosed in British Columbia and a median follow up of 14.5yrs. Variables included were: tumor size (T), number of positive nodes (N), grade, lymphovascular invasion (LVI), estrogen receptors (ER), progesterone receptors (PR), Her2, Ki67, local treatment (surgery, radiation) and systemic treatment (chemotherapy, hormonal). Prognostic factors were balanced between the training and validation sets. Prognostic variables were identified in the testing set among ER positive and ER negative cohorts using Cox Regression analysis and tested in the validation set. Results: The inclusion of Ki67 in the Cox Regression analysis resulted in the elimination of grade as a predictor. For ER positive disease independent predictors were T, N, LVI, PR, HER2, Ki67, local treatment, chemotherapy and hormonal therapy. Independent predictors among ER- cases were T, N, LVI, Ki-67, and chemotherapy. Predicted 10-yr Breast Cancer Specific Survival in the validation set was 72.0% versus 72.4% [SE: 1.2] observed. As subtle prognostic differences may result in very disparate treatment recommendations for Stage I breast cancers, we specifically reviewed this group. In analysis of stage I patients, there were no statistically significant deviations between predictions and observation; agreement between the predicted and observed 10-yr BCSS was excellent (86.0% vs 87.6% (SE: 1.6) p = 0.3169). As well, elevated Ki67 was common (53%) and was a powerful prognostic variable with causing more than a doubling of the 10-yr BrCa mortality (elevated ≥ 10% vs low < 10%, 16.8% vs 6.8%) in this group (table). Conclusion: In this study the proliferation marker Ki67 replaced histologic grade as a predictor of outcome for patients with early breast cancer. Predictive models such as Adjuvant! could incorporate Ki67 as an input variable and this modification is being developed. If models that use Ki67 are validated they may be able to be used globally and be cost effective compared to more expensive genomic predictors.Table: Predicted versus observed 10yr BCSS, based on the new modelPatientsSubgroupNPredicted SurvivalObserved Survivalp-valueAll patientsOverall139772.072.40.75 ER+101277.276.40.56 ER-38558.461.20.27 HER2+19755.658.00.50 HER2-120074.874.80.99Stage IOverall45386.087.60.32 ER+35287.690.40.09 ER-10179.678.40.77 HER2+4378.882.40.55 HER2-41086.888.40.33 

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4042.
Triple Negative Breast Cancer Has a Worse Prognosis within 3 Years after Treatment Compared to Non-Triple Negative Breast Cancer.
Authors: Lee Y. , Kwon S. , Ko B. , Seo J. , Lee J. , Kim H. , Lim W. , Ahn S. , Son B.
Published: December 2010

BackgroundTriple negative breast cancers (TNBC) become known as poor prognosis generally. Our purpose was to compare the clinical features and outcomes for TNBC with other subtypes of breast cancers in Korea.MethodsWe included 2,907 patients who diagnosed breast cancer and treated at Asan Medical Center from 2003 to 2005. Clinical and pathologic parameters, disease-free survival (DFS) and overall survival (OS) were compared between patients with TNBC and non-TNBC. All features were reviewed throughout medical records retrospectively.Results622 patients (21.4%) had TNBC. TNBC patients was associated with younger age, larger size, positive nodal involvement, overweight, family history, elevation of CaAg15-3, high tumor grade, positive p53 compared non-TNBC. The patients were followed for a median of 54 months (range 1-76 months). Relapse-free survival was 86.3% and 92.6% for TNBC and non-TNBC, respectively, with significant difference (P<0.0001). Overall survival was also 88.9% and 96.1% for TNBC and non-TNBC (P<0.0001). Compared with non-TNBC patients, TNBC had an increased likelihood of recurrence and death within 3 years after diagnosis but not thereafter. In non-TNBC, the recurrence risk and death risk seemed to be relatively constant. In univariate analysis for worse prognostic factors of TNBC associated with DFS and OS revealed that statistically significant in large tumor size, nodal status, CA15-3, Lymphovascular invasion. In multivariate analysis, nodal status was a prognostic factor for DFS (P=0.06, HR=2.28; 95% CI, 0.92-3.04) and OS (P<0.0001, HR=5.22; 95% CI, 2.11-12.96) of TNBC. Lymphovascular invasion was only poor prognostic factor for DFS (P=0.026, HR=10.2, 95% CI, 1.31-76.8), not for OS.ConclusionsTNBC has a worse prognosis than non-TNBC patients, but this effect is limited within 3 years after diagnosis. The most competent prognostic factor of recurrence and death for TNBC is a nodal status. We plan that perform analysis for prognosis according to hormone receptor and HER-2 receptor status sooner.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4044.
Prognosis of Metaplastic Breast Cancer: Poorer Than the Rest of Triple-Negative Breast Cancer.
Authors: Jung S. , Kim H. , Min S. , Lee S. , Park C. , Kwon Y. , Kim E. , Ko K. , Lee K. , Park I. , Shin K. , Lee S. , Kim S. , Kang H. , Ro J.
Published: December 2010

Background: The biologic behavior of metaplastic breast cancer (MBC) has not been well elucidated due to its rarity and heterogeneity. This study was designed to assess the clinical and tumor characteristics and outcomes of MBC patients as compared with invasive ductal carcinoma (IDC) in general and the triple-negative (TN) subtype.Materials and methods: This study included 35 MBC and 2,839 IDC patients diagnosed at the National Cancer Center, Korea between 2000 and 2008. We, retrospectively, reviewed the clinicopathologic characteristics and clinical outcomes.Results: The mean age was 47.4 years for MBC group and 48.3 years for IDC group. The MBC group presented with larger tumors (≥ T2, 78.8% vs 41.0%; P<0.001), higher histologic grade (grade 3, 92.0% vs 44.6%; P<0.001), fewer ER and PgR positivity (ER+, 14.3% vs 69.0% ; P<0.001 and PgR+, 25.7% vs 66.1%; P<0.001), higher Ki-67 expression (35.5%±26.2% vs 20.6% ±19.8%; P=0.024) and more TN subtypes (48.6% vs 11.9%; P<0.001) than IDC group. Excluding de novo stage IV patients, 14 of 32 (43.7%) MBC patients and 260 of 2782 (9.4%) IDC patents developed disease recurrence with a median follow-up of 36.2 months (range, 4.9-117.8 months). MBC was a poor prognostic factor for disease recurrence in univariate and multivariate analysis (HR 5.19; 95% CI, 2.04-13.18; P=0.001). MBC patients demonstrated aggressive pathologic features and experienced more disease recurrence (HR 4.77; 95% CI, 1.99-11.44; P=0.001) even when compared with 330 patients with TN subtype.Conclusions:Patients with metaplastic breast carcinoma appeared to have inherent aggressive tumor biology with poorer clinical outcomes than those with IDC in general and TN subtype.Partly supported by NCC Grant No 0610240

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4057.
Prognostic Factors for Breast Cancer with 10 or More Lymph Nodes Metastasis.
Authors: Choi S. , Park H. , Lee J. , Park S. , Park B.
Published: December 2010

Background: Although the proportion of early breast cancer has been increased, advanced breast cancers of N3 stage still compose about 10% of all breast cancers. The purpose of this study was to investigate factors associated with prognosis of breast cancers with extensive nodal metastasis.Patients and method: Of 3912 invasive breast cancer patients who underwent surgery between April 1986 and May 2006 at Severance Hospital, patients who had 10 or more metastatic lymph nodes without distant metastasis were 304 (7.8%). With 55 months of median follow-up period, their clinicopathologic characteristics, follow-up of survival and the factors associated with disease free survival (DFS) and overall survival (OS) were analyzed.Result: Median age was 46.5 years and median number of positive lymph node was 16 with metastases to supraclavicular lymph nodes in 14 patients (4.6%). Median 5-year DFS rate were 42.4% and OS rate was 47.5%. In the Kaplan-Meier survival analysis, age less than 35 years (19.4% vs. 45.9%; p=0.001), the history of NAC (13.1% vs. 48.8%; p<0.001), T4 stage (15.8% vs. 45.8%, excluding T4d; p<0.001), 20 or more positive lymph nodes (27.0% vs. 50.2%; p<0.001), lymphovascular invasion (20.2% vs. 48.4%; p=0.003), and negative progesterone receptor (32.8% vs. 49.3%; p=0.003) were significantly associated to poor 5-year DFS. For 5-year OS, age less than 35 years (43.8% vs. 59.7%; p=0.033), the history of NAC (28.0% VS. 63.8%; p<0.001), T4 stage (21.1% vs. 61.0%, excluding T4d; p=0.001), 20 or more positive lymph nodes (48.9% vs. 63.8%; p<0.001), and negative progesterone receptor (49.0% vs. 64.2%; p=0.013) were statistically significant. On the multivariate analysis, significant factors associated with poor DFS and OS were 20 or more metastatic lymph nodes (relative risk [RR] =1.598 and p=0.024 for DFS; RR=1.956 and p<0.001 for OS), the history of neoadjuvant chemotherapy (RR=3.163 and p<0.001 for DFS; RR=2.900 and p<0.001 for OS). The contribution of lymphovascular invasion was significant only to DFS on the multivariate analysis.Conclusion: The patients with the same N3 stage show various prognosis. Clinical trial using new therapeutic agents should be applied in advanced breast cancers with high risk, which are predicted to be refractory to conventional adjuvant therapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4064.
Should Minors Be Offered BRCA1/2 Testing for Hereditary Breast Cancer? Opinions of Parents Who Have Undergone BRCA1/2 Testing.
Authors: Bradbury A. , Patrick-Miller L. , Li T. , Egleston B. , Sands C. , Schmidheiser H. , Hlubocky F. , Olopade O. , Daly M. , Daugherty C.
Published: December 2010

Background: Professional societies recommend against the genetic testing of minors for hereditary cancer syndromes that present in adulthood. Yet, many adolescent specialists indicate that they would consider BRCA1/2 testing of minor children. We conducted interviews with parents who have had BRCA1/2 testing, to evaluate their opinions regarding the genetic testing of minors for BRCA1/2. Methods: 244 parents, including 67 BRCA1/2 mutation carriers (MCs), 140 parents with uninformative negative results (UN), 14 with true negative results (TN) & 23 with a variant of uncertain significance (VUS), from two cancer risk assessment programs completed semi-structured interviews. We used multiple logistic regressions to evaluate the associations among biomedical factors, demographic factors and support of testing minors. Wald tests and likelihood ratio tests were used to assess statistical significance for binary covariates and nominal covariates. Results: 38% of parents supported testing minors for BRCA1/2 in response to a dichotomous (Y/N) question. Support was greatest among parents with TN (64%) and UN (40%) results and lower among MCs (31%) and parents with a VUS (26%). In a multivariable analysis, support was greatest among parents who tested negative (p=0.02), were of minority race (p=0.06) and among fathers (<0.01). Responses to open-ended questions suggest that 27% of parents unconditionally support testing of minors, and 25% support testing only in certain situations. Psychological risks, a lack of medical necessity and the insufficient maturity of minors, were frequent concerns of those opposed. The potential to positively impact minors' health behaviors was the most reported reason for supporting testing. Conclusions: Up to 52% of parents who have undergone BRCA1/2 testing support pediatric testing for BRCA1/2. Given willingness among general and pediatric practitioners and interest among parents, further research is necessary to formally evaluate the risks and benefits of providing genetic testing to minors for adult-onset hereditary cancer syndromes in order to inform clinical practice and public policy that will ensure optimal psychosocial and medical outcomes for all members of families at risk for hereditary cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4071.
Preliminary Results of the Mutational Analysis of the TP53 Gene in Women Diagnosed with Breast Cancer before the Age of 35 Years and Negative for BRCA1 and BRCA2 Mutations.
Authors: Balmaña J. , Ferro J. , Gutierrez-Enríquez S. , Masas M. , Gadea N. , Fortuny D. , Saura C. , Díez O. , Díez O.
Published: December 2010

Background: Early onset breast cancer is part of the tumor spectrum in the Li-Fraumeni syndrome (MIM 151623), which is associated with germ-line mutations in the TP53 gene. The aim of the study is to determine the presence of inherited mutations in TP53 in women with early onset breast cancer regardless of their family history and after having obtained a negative result for the BRCA1 and BRCA2 mutations. Patients and methods: We analyzed 41 women with breast cancer (BC) diagnosed before the age of 35 years and a negative result for the BRCA1 and BRCA2 genes (analyzed by direct sequencing and MLPA). Patients were classified according their family history in three groups: A) no family history of cancer (n=11); B) family history of breast/ovarian cancer (BC/OC) (n=22); C) family history of other neoplasms (pancreas, kidney, brain, leukemia) without fulfilling the classical Li-Fraumeni criteria (n=8). The analysis of the TP53 gene was carried out by PCR amplification and direct sequencing of the exons 4 to 10. Analysis of the remaining exons, the 5' and 3' UTR regions of the gene, and the detection of large rearrangements are in progress. Results: Among the 41 women we identified two (4.8%) deleterious mutations, and both were observed in group C (2/8, 25%): c.375G>A in exon 4 (splicing mutation) and c.524G>A in exon 5 (p.R175H). Conclusions: These preliminary results suggest that, after a negative result in the analysis of the BRCA1 and BRCA2 genes, TP53 mutations may play a relevant etiological role in the genetic predisposition of early onset BC, especially in those families with presence of different neoplasms

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4072.
Prevalence Rates of Pathogenic Mutations in the BRCA1 and BRCA2 Genes in Families with Different Disease Histories: Results from the German Consortium for Hereditary Breast and Ovarian Cancer.
Authors: Kast K. , Schmutzler R. , Distler W. , Arnold N. , Bartram C. , Bick U. , Froster U. , Grimm T. , Kreienberg R. , Naestle-Kraemling C. , Schlegelberger B. , Wieacker P. , Meindl A. , Engel C.
Published: December 2010

Introduction: In the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), a large number of families with different histories of breast and ovarian cancers was screened for pathogenic mutations in the tumor-suppressor genes BRCA1/2. We here aimed to analyse the prevalence rates of pathogenic mutations for various familial disease histories.Methods: From 1997-2009 more than 6,000 families were screened for pathogenic mutations in BRCA1/2. Mutation analysis was performed by DHPLC (denaturing high-performance liquid chromatography) pre-screening, direct sequencing of suspect fragments and MLPA (multiplex ligation-dependant probe amplification) in at least one index case of these families. Complete pedigree information over three generations was used for the analysis. All lineages within a pedigree were traced and checked for the presence of several predefined disease histories.Results: Detailed mutation prevalence rates have been determined for a variety of familial risk situations. The highest mutation prevalence rate (78%, 95%CI 67-87%) was seen in families with at least two relatives affected by pre-menopausal breast cancer and at least two affected by ovarian cancer at any age. Importantly, the presence of a single woman affected by breast and ovarian cancer or bilateral breast cancer with first breast cancer under the age of 41 was associated with a BRCA1/2 mutation prevalence of 53% (95%CI 48-59%) and 34% (95%CI 23-47%) respectively. Interestingly, low mutation prevalence rates of <10% were found in families with only one case of male breast cancer (9%, 95%CI 4-19%), and in families with three or more cases of postmenopausal breast cancer (7%, 95%CI 4-14%), the former being only BRCA2 mutations. Overall, the mutation prevalence was 27% (95% CI 26-29%) in the whole cohort.Conclusion: We provide comprehensive estimates for BRCA1/2 mutation prevalence rates that are based on a large number of families with comprehensive pedigree information. Such estimates can be used to develop cost effective screening strategies for public health care providers.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4073.
Communicating Risk of Hereditary Breast/Ovarian Cancer among Underserved Women: Interim Findings from the CREdIT Study.
Authors: Braithwaite D. , Metrikin M. , Lee R. , Beattie M. , Luce J.
Published: December 2010

Purpose: With the support of the Avon Foundation, genetic counseling is available to underserved populations at the San Francisco General Hospital. One of the major challenges in providing genetic counseling for hereditary breast and ovarian cancer among these women is the lack of culturally appropriate educational tools.The purpose of this study is to evaluate the use of a Cancer Risk Educational Intervention (CREdIT), a novel audio-visual PowerPoint-based tool as an adjunct to genetic counseling. Methods: CREdIT took on average 15 minutes to view and was available in English and Spanish. It employed non-scientific images and language specifically designed for use by our target population. Participant questionnaires evaluating patient satisfaction, risk perception, knowledge of cancer genetics, and anxiety were administered before and after the intervention and at 1 year follow-up. For each of the continuous outcomes, differences from pre- to post-intervention were assessed with analyses of variance, while chi-squared tests were used to examine the differences among categorical variables. Results: A total of 52 women of diverse backgrounds who were on average 47 years old (range 27-69) took part in the study. Of these, 15% reported previous history of cancer, 58% were non-white and 59% had a below college education. Twenty-one percent viewed the presentation in Spanish. Following the presentation of CREdIT, we found an increase in the knowledge of BRCA inheritance and associated risk of malignancy, and options for risk reduction (all p < .05). However, participants' perceived risk perception did not change from baseline to post-CREdIT (p=.73). Virtually all participants (98%) reported that CREdIT helped them learn more about cancer risk. Although patient anxiety decreased post-CREdIT (p=.02), 29% patients reported that CREdIT made them worry more about cancer. Among 32 participants who were interviewed at the long-term follow-up, we found that, compared to post-CREdIT, knowledge changed for only two of the seven questions (p< .05). There were also no changes in anxiety or cancer worry compared to baseline (both p< .05). Conclusions: These interim findings suggest that our intervention was successful at increasing knowledge regarding breast cancer genetics without increasing anxiety or cancer worry. Our long-term goal is to perform a large-scale evaluation among underserved women at risk of hereditary cancer across the Avon Foundation-supported clinics nationwide.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4074.
Prevalence of BRCA1/2 Mutations and Variants in a Southwest Hispanic Population.
Authors: Ballinger L. , Wallace A. , Dayao Z. , Royce M.
Published: December 2010

Background: There have been a limited number of studies of BRCA mutations in U.S. Hispanics. Of those previously published, two common mutations have been identified, and estimates of their prevalence vary, depending on the population studied. North American Hispanics are a heterogeneous population, consisting of Mexican, Caribbean, Central and South American descent. Furthermore, each of these groups has a significant admixture of other racial and ethnic groups. A limitation of most published studies is that they do not differentiate between these ethnically and genetically diverse Hispanics. In New Mexico, there is a large but relatively homogeneous Hispanic population. Since the University of New Mexico Cancer Center (UNMCC), sees a socially and economically diverse group of patients, the demographics of its Hispanic patients are similar to those of the whole state. Herein, we describe the prevalence of specific mutations and variants in Hispanics from a clinic-based population.Materials and Methods: A chart review of all patients evaluated for hereditary breast cancer risk from 1/1/2005 through 5/30/2009 was conducted. Data collected included patient age, self-reported ethnicity (including, if known, area of ancestral origin), cancer status, family history, BRCA testing status, including method (comprehensive analysis, Ashkenazi panel, single site, and/or comprehensive rearrangement testing), and what, if any, BRCA mutations or variants were found.Results: BRCA testing was performed on 312 patients, 70 of whom identified as NM Hispanic. Another 24 patients were of other Hispanic origins, mainly Mexican. Approximately 30% of those identified as NM Hispanic tested positive for mutations, and most mutations were found in BRCA1. All variants of uncertain significance in this group were found in BRCA2. Approximately 20% of other Hispanics tested positive for mutations, but variants of uncertain significance comprised a higher percentage of the results. In New Mexican Hispanics, 47% tested positive for BRCA1 187delAG, and another 19% tested positive for BRCA1 deletion of exons 9-12, both of which are previously described in the Hispanic populations from southern California and Colorado.Discussion: Although we found a large proportion of previously described mutations in our Hispanic population, 34% had other mutations. In this group, no mutation was seen more than once, indicating the need to offer these patients comprehensive BRCA testing or a combination of founder mutations testing followed by comprehensive sequencing. As most of our patients, even those identified as “Other Hispanic” have Colonial Spanish origins (via Mexico), this data is likely not applicable to Hispanics with other admixtures or historic arrival in the New World, such as Hispanics from the Caribbean.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4077.
A New Safer and More Effective Triphenylethylene Antiestrogen (SS1020) for the Treatment and Prevention of Breast Cancer.
Authors: Shibutani S. , Okamoto Y. , Suzuki N. , Liu X. , Kim H. , Laxmi Y.
Published: December 2010

Background: Tamoxifen (TAM) is widely used as a first-line endocrine therapy for breast cancer patients and as a prophylactic agent for women at high risk of developing this disease. Besides the significant benefit, long-term administration of TAM has serious side effects, including endometrial cancer. These side-effects are due to the DNA damaging and/or estrogenic action of the drug. Raloxifene (RAL) approved as a chemopreventive agent for postmenopausal women at high risk for invasive breast cancer retains an estrogenic action. RAL has a poor bioavailability. This makes it difficult to achieve adequate bioavailability by oral administration in humans. High doses are required to obtain an efficacy quivalent to that achieved with TAM. Several other antiestrogens were dropped out from the clinical trials due to their undesirable effects on the uterus. Therefore, development of new antiestrogen alternatives, but free of genotoxic and estrogenic potential, having significant antitumor potential beyond TAM and RAL is urgently required for breast cancer therapy and prevention.Results: SS1020 was developed as a new triphenylethylene antiestrogen in our laboratory. Although TAM is a hepatic carcinogen and produces a high level of DNA damage in rats, SS1020 did not produce such DNA damage. Unlike TAM and RAL, SS1020 had no detectable uterotrophic activity in OVX-rats even treated with a high dose (10 mg/kg). These indicate that SS1020 is free of genotoxic and estrogenic activities. The antitumor potential of SS1020 against 7,12-dimethyl-benz(a)anthracene (DMBA)-induced mammary carcinoma in rats and human MCF-7 breast cancer xenograft in athymic nude mice was superior to that of TAM and RAL. In addition, the development of estrogen-induced mammary tumor in rats was completed inhibited by dietary intake of SS1020, indicating that this compound has preventive potential. The bioavailability of SS1020 was approximately 35 times higher than that of RAL. The maximum blood concentration (493 ng/ml serum) of SS1020 was observed at 2 hour after the oral treatment while that of RAL (15.6 ng/ml) was at 6 hours, indicating that SS1020 is absorbed rapidly into the body. SS1020 has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL.Conclusion: Taken together, SS1020 lacking genotoxic and estrogenic actions has anti-breast cancer activity superior to that of TAM and RAL and has a preventive potential. SS1020 is a safer and more effective antiestrogen candidate for breast cancer therapy and prevention.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4085.
Cost-Effectiveness of Adding Zoledronic Acid to Endocrine Therapy in Premenopausal Women with Hormone-Responsive Early Breast Cancer in Sweden, Norway, Denmark, and Finland, Based on the ABCSG-12 Study.
Authors: Taneja C. , Lindman H. , Paija O. , Kamby C. , Kaura S. , Jnosson L. , Delea T.
Published: December 2010

Background: The ABCSG-12 trial demonstrated that adding zoledronic acid 4 mg IV q 6 months (ZOL) to endocrine therapy with goserelin 3.6 mg sc q 28 days plus tamoxifen 20 mg oral qd or anastrozole 1mg oral qd (ET) in premenopausal women with hormone receptor positive (HR+) early breast cancer (EBC) improves disease free survival versus ET alone. The objective of this study was to estimate the cost-effectiveness of ZOL in this setting from the perspectives of the healthcare systems in Sweden, Norway, Denmark, and Finland.Material and Methods: A Markov model was used to project lifetime outcomes and costs of breast cancer care for premenopausal women with HR+ EBC receiving 3 yrs of ET or 3 yrs of ET plus ZOL. Cost-effectiveness was measured as the incremental cost per quality adjusted life year (QALY) gained. Probabilities of breast cancer recurrence were based on ABCSG-12 (median [maximum] follow-up 48 [84] months). Probabilities and costs were from the published literature. Results were generated under 2 scenarios: (1) benefits of ZOL persist to the maximum follow-up in ABCSG-12 (trial benefits); (2) benefits persist until recurrence or death (lifetime benefits). Local currencies were converted to Euros to facilitate cross-country comparisons.Results: Expected costs of 3 yrs of ZOL q6m (medication and administration) were €1,869 for Sweden, €1,947 for Norway, €2,647 for Finland, and €2,824 for Denmark. Under the trial benefits scenario, these costs were partially offset by savings in the expected lifetime costs of treatment of breast cancer recurrence of €1,105 for Sweden, €1,422 for Norway, €1,400 for Finland, and €1,585 for Denmark. ZOL was therefore projected to increase total costs by €800 for Sweden, €559 for Norway, €1,247 for Finland, and €1,293 for Denmark. QALYs gained with ZOL were 0.37 in all settings. Cost per QALY gained was therefore €2,162 for Sweden, €1,510 for Norway, €3,369 for Finland, and €3,494 for Denmark. Assuming lifetime benefits, savings from preventing breast cancer exceeded additional costs of ZOL for all four countries, with net savings of €3,364 for Sweden, €4,736 for Norway, €3,753 for Finland, and €4,644 for Denmark. QALYs gained with ZOL were similar across countries, ranging from 1.22 to 1.24. ZOL was therefore a “dominant” strategy (more effective and less costly) in all settings under this assumption.Conclusion: Adding ZOL to ET in premenopausal women with HR+ EBC may be highly cost-effective (<€50,000 per QALY gained) from the healthcare system perspectives of Sweden, Norway, Finland, and Denmark even under conservative assumptions of the duration of ZOL benefit. Adding ZOL to ET leads to cost savings in all four Nordic countries if benefits observed in ABCSG-12 are assumed to persist until disease progression or death.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4088.
A Phase II Study (FINDER 2) Comparing Three Dosing Regimens of Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive Advanced Breast Cancer.
Authors: Pritchard K. , Rolski J. , Pápai Z. , Mauriac L. , Cardoso F. , Fukase K. , Lindemann J. , Macpherson M. , Neven P.
Published: December 2010

Background: The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive (ER+) advanced breast cancer (FINDER) 2 study investigated the efficacy, safety, and pharmacokinetic (PK) profile of 3 fulvestrant dosing regimens in postmenopausal women with ER+ advanced breast cancer, recurring/progressing after prior endocrine therapy.Objectives: Primary: to evaluate the objective response rate (ORR). Secondary included assessment of: time to progression (TTP), clinical benefit rate (CBR), duration of response (DOR), tolerability, and PK parameters.Methods: This randomized, double-blind, parallel-group, multicenter, Phase II study, evaluated patients (pts) randomized 1:1:1 to different doses of fulvestrant: 250 mg (approved dose [AD]; given on Days 0, 28 and every 28 days thereafter), 250 mg plus loading dose (LD; 500 mg on Day 0, then 250 mg on Days 14, 28 and every 28 days thereafter), and 500 mg (high dose [HD]; Days 0, 14 and 28 and every 28 days thereafter). Treatment continued until disease progression, or until any other criterion for discontinuation was met.Results: In total, 144 pts were randomized from 34 centers in 8 countries and 143 received treatment: fulvestrant AD (n=47); LD (n=50); HD (n=46). ORRs were: 8.5% (95% confidence interval [CI] 2.4-20.4%), 5.9% (1.2-16.2%), and 15.2% (6.3-28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI 19.1-47.1%), 47.1% (32.9-61.5%), and 47.8% (32.9-63.1%) for the AD, LD, and HD arms, respectively. Median TTP was numerically longer for the HD (6.0 months) and LD (6.1 months) arms vs the AD arm (3.1 months). The low number of responders in all treatment arms prevented DOR assessment. The incidence of adverse events (AEs) was similar in all groups (76.6% AD, 72.0% LD, 69.6% HD); few pts experienced serious AEs (4 pts AD, 9 LD, 4 HD) with no clustering of event type. AEs with an incidence of ≥10% (in any arm) were back pain, arthralgia, fatigue, injection-site pain, nausea, dyspnea, cough, and hot flash. Concentrations in the AD arm approached steady state in the 3rd month of dosing and within the 1st month for LD and HD. Exposure (AUC, Cmin and Cmax) appeared to be linear across the dose range studied and, for the 250mg arms, similar to that previously reported in Western populations (Studies 9238IL/0020 & 0021).Conclusion: No statistically significant differences in efficacy could be proven between AD, LD and HD given the widely overlapping CIs for median TTP. The tolerability profile was similar across the three dosing regimens. Steady-state concentrations were achieved earlier with LD and HD. A parallel study in Japanese pts will be used for comparisons of fulvestrant efficacy and tolerability in Japanese and non-Japanese pts.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4095.
N0539 Phase II Trial of Fulvstrant and Bevacizumab in Patients with Metastatic Breast Cancer Previously Treated with an Aromatase Inhibitor: A North Central Cancer Treatment Group Trial.
Authors: Tan W. , Dueck A. , Flynn P. , Steen P. , Anderson D. , Rowland K. , Nothfeldt D. , Lingle W. , Copland J. , Perez E.
Published: December 2010

Background: Treatment of aromatase refractory metastatic breast cancer (MBC) is difficult and challenging. Estrogen receptor (ER) resistance causes enhanced expression of the vascular endothelial growth factor (VEGF).Several studies have shown that the ER interacts with the VEGF pathway and is an important mechanism of resistance. Therefore we embarked on a phase II study of fulvestrant, a complete ER suppressor and bevacizumab, a well studied VEGF monoclonal antibody in aromatase refractory MBC patients. Methods: A single stage phase II study with an interim analysis of fulvestrant and bevacizumab was conducted with these objectives: 6 month progression-free survival rate (PFS), tumor response, toxicity, and overall survival. Regimen: fulvestrant 250 mg day1 and 15 (cycle 1) then day 1 (cycle 2 and beyond) and bevacizumab 10mg/kg days 1 and 15 of each 4 weeks is a cycle. Results: At the time of interim analysis, 11/20 evaluable patients achieved 3-month progression-free survival status while remaining on treatment for at least 3 months, not meeting the protocol specified efficacy requirements and thus halting accrual. 36 patients were enrolled from September 2007-December 2008; 33 patients were evaluable. Number of prior metastatic chemotherapy regimens: 0 in 26 patients and 1 in 7 patients. 22 (67%) patients received prior hormonal therapy in the metastatic setting. 18 (55%) had measurable disease. A median of 6 cycles (range 1-19) were administered. 12/33 evaluable patients (95% CI:20-55%) achieved 6-month progression-free survival status while remaining on treatment for a least 6 months. Among 18 patients with measurable disease, 2 (11%) patients CI:1.4-35%) had a confirmed tumor reponse (both PR). Additionally, 2 patients had stable disease for greater than 6 months, for a clinical benefit rate of 22%. Median follow up was 8.5 months (range 1.7-17.5 months). Median progression-free survival was 6.2 months (95% CI:5.4-10.1 months). The 6 -month overall survival rate was 84.8% (95% CI 73.5-98%). The median dose level administered was 250 mg for fulvestrant and 10 mg/kg for bevacizumab for cycles 1-19. The most common grade 3/4 adverse events (AEs) were hypertension 2 (6%), headache pain 2 (6%), and confusion 2 (6%). There was 1 grade 5 central nervous system hemorrhage. 13 (39%) patients experienced a grade 3 non-hematologic AE and 4 (12%) experience a grade 4+ non-hematologic AE. Conclusion: Fulvestrant/bevacizumab is safe and tolerable. Although this regimen did not meet its statistical endpoint, 22% of evaluable patients with aromatase refractory diesease achieved clinical benefit with minimal toxicity.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4096.
Pentoxifylline and Vitamin E Treatment for Prevention of Radiation Induced Side Effects in Women with Breast Cancer: A Phase Two, Double Blind, Placebo Controlled Randomised Clinical Trial (Ptx-5).
Authors: Malmström P.
Published: December 2010

Background: A previous study has shown that pentoxifylline in combination with vitamin E can reverse radiation induced fibrosis. Our aim in the present study was to investigate if the same drugs could prevent radiation induced side effects in women with breast cancer.Patients and Methods: A randomised, placebo-controlled, double blind, parallel group trial was performed. Women with breast cancer were treated for 12 months with pentoxifylline 400 mg t.i.d. or placebo, in combination with vitamin E 100 mg t.i.d. starting 1-3 months after the completion of radiotherapy. The primary endpoint was passive abduction of the shoulder, and the secondary endpoint was difference in arm volumes. The trial is registered on the ISRCTN.org website, number ISRCTN39143623.Results: 83 patients were included in the study; 42 in the pentoxifylline + vitamine E group and 41 in the placebo + vitamine E group. Both treatments were generally well tolerated. Seven patients were withdrawn from treatment due to disease progression; four in the pentoxifylline group and three in the placebo group. At inclusion patients had impaired passive abduction of the shoulder. During treatment both groups improved significantly. With one year of follow-up median improvement from baseline was 3.7° (p=0.0035) in the pentoxifylline group and 9.4° (p= 0.0041) in the placebo group, but no difference between the groups was detected (p=0.20). Arm volumes increased over time in the placebo group (1.04%), but not in the pentoxifylline group (0.50%). This difference between the groups was statistically significantl(p=0.0172).Conclusions: The combination of pentoxifylline and vitamin E was safe and may be used for prevention of some radiation induced side effects. We found that pentoxifylline in combination with vitamin E diminished development of lymphoedema.(Accepted for publication in European Journal of Cancer)Updated results with longer follow-up will be presented.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4100.
Feasibility of Preoperative Single Fraction Partial Breast Radiotherapy for Early Stage Breast Cancer.
Authors: Palta M. , Yoo S. , Horton J.
Published: December 2010

Introduction: Preliminary data supports the efficacy of partial breast irradiation (PBI) in carefully selected patients. However, in 2008, several series evaluating external beam PBI reported negative toxicity outcomes, possibly related to large volumes of normal tissue receiving near-prescription doses.We hypothesized that delivery of external beam PBI in a single fraction to the preoperative tumor volume, as defined by magnetic resonance imaging (MRI), would be dosimetrically feasible and result in decreased dose to the ipsilateral breast as compared to institutional historical controls.Methods: Ten patients with unifocal T1 breast cancer who had undergone a preoperative MRI were identified. Contrast-enhanced subtraction MR images were loaded into Eclipse treatment planning software and used to define the gross tumor volume (GTV). A 1.5cm uniform expansion (minus first 5mm of skin) was used to generate the clinical target volume (CTV) for dose-volume analysis. An additional 2-3 mm margin was included for penumbra.The first 3mm of skin/subcutaneous tissue was defined as an avoidance structure. Bilateral lungs and heart were segmented. A prospective “virtual plan” was created using four photon beams in a non-coplanar beam arrangement and optimized to deliver 15Gray (Gy) to the CTV.Specific dosimetric data was extracted including dose conformity (breast volume receiving 100% of the dose/CTV) and dose to the ipsilateral breast, ipsilateral lung, and heart.Results: The median breast volume was 1713cc's (range 1014 – 2140cc's) and the median target volume only 41cc's (26-62cc's). In all cases, 95% of the prescription dose covered 100% of the CTV volume. Median dose conformity was 1.2 (range 1.1-1.6). Maximum dose for all plans was not greater than 110%. Doses to the heart and lung were negligible.Median maximum skin dose was 9.3Gy or 62% of the prescription dose. Median maximum dose to 1cc of skin was reduced to 7.0Gy and at 10cc's skin volume, the median maximum was only 4.9Gy.Median percent of the ipsilateral breast volume receiving 100% of the dose (V100) was only 3.5% (range 2.4-4.7%). The median percent volume receiving 50% of the dose (V50) was 13% (range 7.5-20.8%), substantially less than institutional experience with post-operative PBI. Pre-operative PBIPost-operative PBI n=10n=27 Median (range)Median (range)V1003.5% (2.4-4.7)20% (3-42)V5013% (7.5-20.8)43% (24-65) Conclusion: Pre-operative radiotherapy is dosimetrically feasible in women with small breast tumors. Excellent target coverage with negligible dose to normal tissue can be achieved. Skin dose appears reasonable given the small volumes.Median V100 and V50 compare favorably to institutional experience with post-operative PBI. A prospective Phase I trial evaluating this technique is undergoing institutional review.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4105.
Guideline Compliant Irradiation Following Breast Conserving Surgery or Mastectomy Improves Recurrence Free Survival.
Authors: Kurzeder C. , Wolters R. , Wischnewsky M. , Woeckel A. , Atassi Z. , Wiegel T. , Kreienberg R.
Published: December 2010

Purpose: Two pivotal studies by Veronesi and Fisher have established the concept of breast conserving surgery for small breast cancers stage T1 or with size less than 4 cm respectively. The aim of this retrospective study was to validate the current practice of BCS in an unselected cohort of patients within the network of 16 regional breast cancer centres in germany and to quantify the detrimental effect of guideline non-compliant locoregional therapy on recurrence free survival.Methods: 4507 patients who received primary therapy between 1992 and 2005 were recorded. Data on surgery, axillary dissection and postoperative irradiation were used to categorize patients according to adherence to guidelines. The effect of guideline compliant locoregional therapy on recurrence free survival was calculated.Results: Out of 3579 patients (79.4%) who were treated by BCS 3036 (84.8%) received postoperative irradiation as mandated by the guideline. A total of 928 (20.6%) patients underwent mastectomy, out of these a fraction of 344 patients received postoperative irradiation as required by the guideline. No significant difference in recurrence free survival was found between patients who underwent BCS plus postoperative irradiation and those patients who underwent mastectomy (T1: HR=1.08 (95%-CI: 0.70-1.67), p=0.281; T2: HR=1.21 (95%-CI: 0.61 - 2.39), p=0.577). Guideline compliant locoregional therapy resulted in a significant improvement in RFS as shown for patients receiving guideline compliant BCS plus irradiation or guideline compliant mastectomy without irradiation versus patients with any type of non-compliant locoregional therapy (HR=3.53, 95%-CI: 2.97-4.18, p<0.001).Conclusion: Our findings support current clinical practice of BCS in small tumors as initially indicated and also in tumors of stage T2. Violations of guidelines for locoregional therapy were clearly associated with a poorer prognosis.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4106.