Breast Neoplasms: Weber B

Armstrong K, Eisen A, Weber B. · Department of Medicine, and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, USA. · N Engl J Med. · Pubmed #10684916 No free full text.

This publication has no abstract.

Marchal C, Weber B, de Lafontan B, Resbeut M, Mignotte H, du Chatelard PP, Cutuli B, Reme-Saumon M, Broussier-Leroux A, Chaplain G, Lesaunier F, Dilhuydy JM, Lagrange JL. · Centre Alexis Vautrin, Vandoeuvre-Les-Nancy, France. · Int J Radiat Oncol Biol Phys. · Pubmed #10219803 No free full text.

Abstract: OBJECTIVES: To conduct a survey of the angiosarcomas developing after breast conservation for carcinoma in the French Cancer Centers, to study the evolution of these cases in detail, and to review literature in an attempt to propose an optimal treatment scheme. MATERIAL AND METHODS: Eleven of the 20 French Cancer Centers agreed to research and retrospectively analyze all angiosarcomas discovered in patients previously treated by conservative treatment. The majority of the patients were node negative, T1N0M0. The mean age of the patients at the time of primary breast cancer treatment was 62.5 years, and 69 years at the diagnosis of the angiosarcoma. RESULTS: During the last two decades, nearly 20,000 patients have been treated conservatively in these 11 centers, and only 9 cases of angiosarcoma were found. The median latency period between the treatment of the breast carcinoma and the diagnosis of the breast angiosarcoma was approximately 74 months, with a range of 57-108 months. Mastectomy was performed as the main treatment of this angiosarcoma. All recurrences after mastectomy for the angiosarcoma appeared within 16 months after the mastectomy. A median time of recurrence was found to be 7.5 months, regardless of the treatment. The angiosarcomas appeared to be very aggressive, and chemotherapy, radiotherapy, and sometimes hyperthermia could only palliate the condition for a short time. After the diagnosis of angiosarcoma, the median survival was 15.5 months, showing a particularly poor prognosis. Only 1 patient of 9 is alive without progressive disease at 32 months after salvage mastectomy for the recurrence of the angiosarcoma. Precise data obtained from 11 centers show that, of 18115 breast carcinomas treated conservatively, only 9 breast angiosarcomas are reported, which represents a prevalence of 5 cases of angiosarcoma per 10,000, which is the same prevalence for primary breast angiosarcomas occurring in healthy breasts. CONCLUSION: Angiosarcoma developing after breast conserving therapy for carcinoma is a rare event, and induction of it by treatment is controversial. However, early diagnosis is essential and it appears that radical mastectomy gives the highest chance of cure and the best long-term survival.

Laessig D, Stemmler HJ, Vehling-Kaiser U, Fasching PA, Melchert F, Kolbl H, Stauch M, Maubach P, Scharl A, Morack G, Meerpohl H, Weber B, Kalischefski B, Heinemann V. · Department of Medicine III, Klinikum Grosshadern, University of Munich, Munich, Germany. · Oncology. · Pubmed #18515981 No free full text.

Abstract: BACKGROUND: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. PATIENTS AND METHODS: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. RESULTS: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombocytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. CONCLUSION: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2).

Tuefferd M, Couturier J, Penault-Llorca F, Vincent-Salomon A, Broët P, Guastalla JP, Allouache D, Combe M, Weber B, Pujade-Lauraine E, Camilleri-Broët S. · JE2492, Université Paris-Sud, IFR69, Villejuif, France. · PLoS One. · Pubmed #17987122 links to  free full text

Abstract: BACKGROUND: Despite a typically good response to first-line combination chemotherapy, the prognosis for patients with advanced ovarian cancer remains poor because of acquired chemoresistance. The use of targeted therapies such as trastuzumab may potentially improve outcomes for patients with ovarian cancer. HER2 overexpression/amplification has been reported in ovarian cancer, but the exact percentage of HER2-positive tumors varies widely in the literature. In this study, HER2 gene status was evaluated in a large, multicentric series of 320 patients with advanced ovarian cancer, including 243 patients enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin-based chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: The HER2 status of primary tumors and metastases was evaluated by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis of paraffin-embedded tissue on conventional slides. The prognostic impact of HER2 expression was analyzed. HER2 gene was overexpressed and amplified in 6.6% of analyzed tumors. Despite frequent intratumoral heterogeneity, no statistically significant difference was detected between primary tumors and corresponding metastases. CONCLUSIONS/SIGNIFICANCE: Our results show that the decision algorithm usually used in breast cancer (IHC as a screening test, with equivocal results confirmed by FISH) is appropriate in ovarian cancer. In contrast to previous series, HER2-positive status did not influence outcome in the present study, possibly due to the fact that patients in our study received paclitaxel/carboplatin-based chemotherapy. This raises the question of whether HER2 status and paclitaxel sensitively are linked.

Coudert BP, Largillier R, Arnould L, Chollet P, Campone M, Coeffic D, Priou F, Gligorov J, Martin X, Trillet-Lenoir V, Weber B, Bleuse JP, Vasseur B, Serin D, Namer M. · Department of Oncology, CAC G.F. Leclerc and IFR 100, Dijon, France. · J Clin Oncol. · Pubmed #17515572 No free full text.

Abstract: PURPOSE: Trastuzumab plus chemotherapy has become the standard of care for human epidermal growth factor receptor-2 (HER-2) -positive breast cancer. Trastuzumab-based preoperative systemic therapy (PST; neoadjuvant therapy) also appears promising, warranting further investigation. PATIENTS AND METHODS: Patients with HER-2-positive, stage II/III, noninflammatory, operable breast cancer requiring a mastectomy (but who wanted to conserve the breast) received trastuzumab 4 mg/kg (day 1), followed by 2 mg/kg weekly, plus docetaxel 75 mg/m2 every 3 weeks, and carboplatin (area under curve, 6) for six cycles before surgery. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens. RESULTS: Seventy patients were enrolled. Most patients had clinical T2/T3 tumors (100%) or clinical N1/2 nodes (53%). Sixty-seven patients (96%) completed six cycles of therapy, one patient withdrew due to progressive disease, and two patients withdrew for toxicity. A complete or partial objective clinical response occurred in 95% of patients (85% and 10%, respectively). Surgery was breast conservative in 45 (64%) of 70 patients. In an intent-to-treat analysis, tumor and nodal pCR were seen in 27 (39%) of 70 patients. Centralized retrospective analysis of HER-2 status demonstrated a 43% pCR rate in the 24 of 56 confirmed HER-2-overexpressing (3+) and/or fluorescence in situ hybridization-positive tumors. Treatment was generally well tolerated. Grade 3/4 neutropenia and febrile neutropenia were uncommon (2%). Two patients withdrew prematurely due to a transient, asymptomatic decrease in left ventricular ejection fraction. No symptomatic cardiac dysfunction occurred. CONCLUSION: PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy, with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer.

Coudert BP, Arnould L, Moreau L, Chollet P, Weber B, Vanlemmens L, Moluçon C, Tubiana N, Causeret S, Misset JL, Feutray S, Mery-Mignard D, Garnier J, Fumoleau P. · Oncology, Surgery, Radiology CAC GF Leclerc, Dijon, France. · Ann Oncol. · Pubmed #16332965 links to  free full text

Abstract: BACKGROUND: Trastuzumab plus chemotherapy has become the standard of care for women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Trastuzumab-based pre-operative systemic (neo-adjuvant) therapy (PST) also appears promising, warranting further investigation. PATIENTS AND METHODS: Patients with HER2-positive, stage II/III non-inflammatory, operable breast cancer requiring a mastectomy (but who wished to conserve the breast) received weekly trastuzumab and 3-weekly docetaxel for six cycles before surgery. The primary end point was pathological complete response (pCR) rate, determined from surgical specimens. RESULTS: Thirty-three patients were enrolled. The majority (79%) had T2 tumors, with 42% being N1/2. Twenty-nine patients completed six cycles of therapy and one patient withdrew prematurely due to progressive disease. A complete or partial objective clinical response was seen in 96% (73% and 23%, respectively) of patients. Surgery was performed in 30 patients, breast conserving in 23 (77%). In an intention-to-treat analysis, tumor and nodal pCR was seen in 14 (47%) patients. Treatment was generally well tolerated. Grade 3/4 neutropenia occurred in 85% of patients while febrile neutropenia was encountered in 18%. Only three patients withdrew prematurely due to toxicity. No symptomatic cardiac dysfunction was reported. CONCLUSIONS: PST with trastuzumab plus docetaxel achieved promising efficacy, with a high pCR rate and good tolerability, in women with stage II or III HER2-positive breast cancer.

Delozier T, Spielmann M, Macé-Lesec'h J, Janvier M, Hill C, Asselain B, Julien JP, Weber B, Mauriac L, Petit JC, Kerbrat P, Malhaire JP, Vennin P, Leduc B, Namer M. · Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France. · J Clin Oncol. · Pubmed #11032592 No free full text.

Abstract: PURPOSE: In 1986, The Fédération Nationale desCentres de Lutte Contre le Cancer Breast Group initiated a multicenter randomized trial to assess the usefulness of long-term adjuvant tamoxifen treatment. Short-term adjuvant tamoxifen treatment was to be compared with life long adjuvant tamoxifen treatment. PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen treatment were eligible for the trial. From September 1986 to May 1995, 3,793 patients were randomized from France, Belgium, and Argentina. A total of 1,882 patients stopped tamoxifen (short-term group), and 1,911 patients were to continue tamoxifen for life (long-term group) at the same dose as previously prescribed. The protocol was modified in February 1997, limiting tamoxifen treatment to 10 years after randomization, thus giving a comparison between a 2- to 3-year treatment and a 12- to 13-year treatment. To date, the median duration of tamoxifen treatment is 30 months in the short-term group, and 70 months in the long-term group. RESULTS: Overall, longer tamoxifen treatment induced a 23% reduction in relapse rates, leading to a 7-year disease-free survival rate of 78%, compared with 72% in the shorter-treatment group. In contrast, overall survival did not differ between the two groups, with a 79% overall survival rate in both groups. This improvement in disease-free survival could be observed in node-positive patients (P: =.001); however, it was not found in node-negative patients. Prolonged tamoxifen treatment corresponded to a significant increase in disease-free survival in estrogen receptor-positive patients (P: =.03) as well as in estrogen receptor-negative patients (P: =.05). Furthermore, longer treatment reduced contralateral breast cancers and did not increase the number of endometrial cancers. CONCLUSION: Although no survival advantage was noted, patients did benefit from longer tamoxifen treatment over 3 years and had significantly better disease-free survival compared with patients who stopped hormonal treatment. Long-term follow-up is needed to assess these results. Most patients in the long-term group are still receiving treatment. Comparison of results as time passes will enable conclusions to be made on the value of long-term treatment over 5 years compared with 2 to 3 years.

Caleffi M, Ribeiro RA, Duarte Filho DL, Ashton-Prolla P, Bedin AJ, Skonieski GP, Zignani JM, Giacomazzi J, Franco LR, Graudenz M, Pohlmann P, Fernandes JG, Kivitz P, Weber B. · Associação Hospitalar Moinhos de Vento, Porto Alegre, Brazil. · BMC Public Health. · Pubmed #19284670 links to  free full text

Abstract: BACKGROUND: Breast cancer (BC) is a major public health problem, with rising incidence in many regions of the globe. Although mortality has recently dropped in developed countries, death rates are still increasing in some developing countries, as seen in Brazil. Among the reasons for this phenomenon are the lack of structured screening programs, a long waiting period between diagnosis and treatment, and lack of access to health services for a large proportion of the Brazilian population. METHODS AND DESIGN: Since 2004, an intervention study in a cohort of women in Southern Brazil, denominated Porto Alegre Breast Health Intervention Cohort, is being conducted in order to test the effectiveness and cost-effectiveness of a model for BC early detection and treatment. In this study, over 4,000 women from underserved communities aged 40 to 69 years are being screened annually with mammography and clinical breast examination performed by a multidisciplinary team, which also involves nutritional counseling and genetic cancer risk assessment. Risk factors for BC development are also being evaluated. Active search of participants by lay community health workers is one of the major features of our program. The accrual of new participants was concluded in 2006 and the study will last for 10 years. The main goal of the study is to demonstrate significant downstaging of BC in an underserved population through proper screening, attaining a higher rate of early-stage BC diagnoses than usually seen in women diagnosed in the Brazilian Public Health System. Preliminary results show a very high BC incidence in this population (117 cases per 100,000 women per year), despite a low prevalence of classical risk factors. DISCUSSION: This study will allow us to test a model of BC early diagnosis and treatment and evaluate its cost-effectiveness in a developing country where the mortality associated with this disease is very high. Also, it might contribute to the evaluation of risk factors in a population with a different ethnic background from that studied in developed countries. If our model is proven effective, it may be replicated in other parts of the globe where BC is also a major public health problem.

Tchou J, Greshock J, Bergey MR, Sonnad SS, Sargen M, Weinstein S, Czerniecki BJ, Boraas M, Fraker DL, Rosato E, Fox K, Weber B, Solin LJ. · Department of Surgery, Division of Endocrine and Oncologic Surgery, University of Pennsylvania Health System, Philadelphia, PA 19104, USA. · Clin Breast Cancer. · Pubmed #18621610 No free full text.

Abstract: BACKGROUND: Recent studies have shown that breast cancer detected by screening has a more favorable prognosis than interval breast cancer. To further understand the biologic significance of this finding, we investigated the association of disease recurrence, local and distant, with the method of detection of the primary breast cancer in a cohort of 1686 women treated with breast conservation. PATIENTS AND METHODS: The charts of 1686 women with primarily stage I or II invasive breast cancer treated by breast conservation between 1977 and 2002 were reviewed. The median length of follow-up was 6 years. Univariate and multivariate analyses using binary logistic regression were performed for 2 subgroups: (1) those with local recurrence versus those without; and (2) those with distant metastasis versus those without distant metastasis. RESULTS: Our data confirmed several of the well-known risk factors for local and distant recurrence. In addition, we found that individuals with breast cancer detected on physical examination alone have a significantly higher risk for local recurrence compared with patients with cancer detected on mammogram alone, independent of tumor size (odds ratio [OR], 2.369; 95% CI, 1.235-4.547; P = .01). We also found a similar correlation for risk of distant metastasis in these 2 groups of women (OR, 2.201; 95% CI, 1.211-3.998; P = .01). CONCLUSION: Breast cancers that are palpable might represent an aggressive biologic subtype with an increased risk of local and distant recurrence. Risk stratification might need to include this clinical feature in addition to conventional prognostic factors.

Quraishi I, Rishi M, Feldman M, Wargovich MJ, Weber B. · University of Pennsylvania Philadelphia, PA , USA. · Appl Immunohistochem Mol Morphol. · Pubmed #17536306 No free full text.

Abstract: The results of previous studies done in our laboratory on breast cancer gene expression profile, using DNA microarrays, led to the discovery of several genes associated with breast cancer progression. Further evaluation of these genes and their involvement at various stages of cancer progression required performance of immunohistochemistry on thousands of different tissue blocks. Tissue microarray (TMA) technology facilitates rapid translation of DNA microarrays results to clinical specimens by using immunohistochemical analysis of protein expression. DNA microarray analysis done in our laboratory showed a significantly higher expression of prostatic-specific antigen (PSA) in invasive ductal carcinomas as compared to ductal carcinoma in situ, a finding contrary to the previously published data for PSA immunoreactivity in breast carcinomas. To find out whether TMA strategy could be used to explore the expression of the candidate genes involved in the breast cancer progression, we constructed a breast cancer progression TMA. It consisted of 2 normal ductal epithelium, 8 ductal carcinoma in situ, 19 invasive ductal carcinomas, and 3 metastatic ductal carcinomas of breast in triplets. Two prostatic adenocarcinomas and 2 normal colons were used as positive and negative controls, respectively. We first used well-documented and well-tested markers, such as antibodies to estrogen receptor, progesterone receptor, and p53. Results of these 3 antibodies were according to the previously published data. To validate our result, we then used antibody to PSA and looked for the expression of this protein on breast cancer progression TMA. Except for the 2 positive controls all 98 cores were found to be negative for PSA expression highlighting the importance of validation studies for DNA microarray results.

Reis-Filho JS, Simpson PT, Turner NC, Lambros MB, Jones C, Mackay A, Grigoriadis A, Sarrio D, Savage K, Dexter T, Iravani M, Fenwick K, Weber B, Hardisson D, Schmitt FC, Palacios J, Lakhani SR, Ashworth A. · The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom. · Clin Cancer Res. · Pubmed #17121884 links to  free full text

Abstract: PURPOSE: Classic lobular carcinomas (CLC) account for 10% to 15% of all breast cancers. At the genetic level, CLCs show recurrent physical loss of chromosome16q coupled with the lack of E-cadherin (CDH1 gene) expression. However, little is known about the putative therapeutic targets for these tumors. The aim of this study was to characterize CLCs at the molecular genetic level and identify putative therapeutic targets. EXPERIMENTAL DESIGN: We subjected 13 cases of CLC to a comprehensive molecular analysis including immunohistochemistry for E-cadherin, estrogen and progesterone receptors, HER2/neu and p53; high-resolution comparative genomic hybridization (HR-CGH); microarray-based CGH (aCGH); and fluorescent and chromogenic in situ hybridization for CCND1 and FGFR1. RESULTS: All cases lacked the expression of E-cadherin, p53, and HER2, and all but one case was positive for estrogen receptors. HR-CGH revealed recurrent gains on 1q and losses on 16q (both, 85%). aCGH showed a good agreement with but higher resolution and sensitivity than HR-CGH. Recurrent, high level gains at 11q13 (CCND1) and 8p12-p11.2 were identified in seven and six cases, respectively, and were validated with in situ hybridization. Examination of aCGH and the gene expression profile data of the cell lines, MDA-MB-134 and ZR-75-1, which harbor distinct gains of 8p12-p11.2, identified FGFR1 as a putative amplicon driver of 8p12-p11.2 amplification in MDA-MB-134. Inhibition of FGFR1 expression using small interfering RNA or a small-molecule chemical inhibitor showed that FGFR1 signaling contributes to the survival of MDA-MB-134 cells. CONCLUSIONS: Our findings suggest that receptor FGFR1 inhibitors may be useful as therapeutics in a subset of CLCs.

Friedman E, Kotsopoulos J, Lubinski J, Lynch HT, Ghadirian P, Neuhausen SL, Isaacs C, Weber B, Foulkes WD, Moller P, Rosen B, Kim-Sing C, Gershoni-Baruch R, Ainsworth P, Daly M, Tung N, Eisen A, Olopade OI, Karlan B, Saal HM, Garber JE, Rennert G, Gilchrist D, Eng C, Offit K, Osborne M, Sun P, Narod SA, Anonymous00308. · The Suzanne Levy Gertner Oncogenetics Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. · Breast Cancer Res. · Pubmed #16563180 links to  free full text

Abstract: INTRODUCTION: BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date. METHODS: In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer. RESULTS: There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16-0.83; p = 0.02). CONCLUSION: Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers.

Armstrong K, Weber B, Ubel PA, Peters N, Holmes J, Schwartz JS. · Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · J Clin Oncol. · Pubmed #16361631 No free full text.

Abstract: PURPOSE: Women with BRCA1/2 mutations are faced with complex decisions about breast and ovarian cancer risk management. This study was conducted to determine the effect of a tailored decision support system (DSS) that provides individualized survival and cancer incidence curves specific to expected outcomes of alternative management strategies. PATIENTS AND METHODS: This was a double-blind, randomized controlled trial of 32 women with BRCA1/2 mutations. Primary outcome measures were decision satisfaction, cancer anxiety, perceptions of cancer risk given alternative management strategies, and management decisions. RESULTS: Twenty-seven women completed a 6-week follow-up. Women in the intervention arm (n = 13) reported significantly higher decision satisfaction at follow-up than women in the control arm (n = 14; adjusted mean difference, 9.7; P < .0005). The effect of the DSS was greater among women with low cancer anxiety at baseline than women with high cancer anxiety at baseline (P = .01 for interaction). However, the DSS did not significantly alter cancer anxiety at follow-up, perceptions of cancer risk given alternative management strategies, or management decisions. CONCLUSION: The presentation of individualized survival and incidence curves for alternative management options improves satisfaction about cancer risk management decisions among women with BRCA1/2 mutations without increasing anxiety or changing management decisions. The benefit of the DSS is greatest among women with relatively low cancer-related anxiety at baseline.

Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, Weber B, Rebbeck T, Neuhausen SL, Ghadirian P, Foulkes WD, Gershoni-Baruch R, Friedman E, Rennert G, Wagner T, Isaacs C, Kim-Sing C, Ainsworth P, Sun P, Narod SA. · Toronto-Sunnybrook Regional Cancer Center, Toronto, ON, Canada. · J Clin Oncol. · Pubmed #16234515 No free full text.

Abstract: PURPOSE: The purpose of this study was to estimate the extent of protection offered against breast cancer by prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations and to determine to what extent risk reduction varies with age at oophorectomy, age at diagnosis, and time elapsed since surgery. PATIENTS AND METHODS: We analyzed 1,439 patients with breast cancer and 1,866 matched controls derived from a registry of BRCA1 and BRCA2 carriers. We estimated odds ratios (ORs) of breast cancer for having had a bilateral oophorectomy, using conditional logistic regression, matched for parity and for oral contraceptive use. RESULTS: A previous history of oophorectomy was associated with a significant reduction in breast cancer risk of 56% for BRCA1 carriers (OR = 0.44; 95% CI, 0.29 to 0.66) and of 46% for BRCA2 carriers (OR = 0.57; 95% CI, 0.28 to 1.15). The risk reduction was greater if the oophorectomy was performed before age 40 (OR = 0.36; 95% CI, 0.20 to 0.64 for BRCA1 carriers) than after age 40 (OR = 0.53; 95% CI, 0.30 to 0.91). The protective effect was evident for 15 years post-oophorectomy (OR = 0.39; 95% CI, 0.26 to 0.57). CONCLUSION: Oophorectomy is an effective means of reducing the risk of breast cancer in carriers of BRCA1 mutations. The data suggest oophorectomy is protective in BRCA2 carriers as well, but needs to be confirmed in other studies.

Kotsopoulos J, Olopado OI, Ghadirian P, Lubinski J, Lynch HT, Isaacs C, Weber B, Kim-Sing C, Ainsworth P, Foulkes WD, Eisen A, Sun P, Narod SA. · Centre for Research in Women's Health, Women's College Hospital, University of Toronto, Toronto, ON, Canada. · Breast Cancer Res. · Pubmed #16168130 links to  free full text

Abstract: BACKGROUND: Several anthropometric measures have been found to be associated with the risk of breast cancer. Current weight, body mass index, and adult weight gain appear to be predictors of postmenopausal breast cancer. These factors have been associated with a reduced risk of premenopausal breast cancer. We asked whether there is an association between changes in body weight and the risk of breast cancer in women who carry a mutation in either breast cancer susceptibility gene, BRCA1 or BRCA2. METHODS: A matched case-control study was conducted in 1,073 pairs of women carrying a deleterious mutation in either BRCA1 (n = 797 pairs) or BRCA2 (n = 276 pairs). Women diagnosed with breast cancer were matched to control subjects by year of birth, mutation, country of residence, and history of ovarian cancer. Information about weight was derived from a questionnaire routinely administered to women who were carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between weight gain or loss and the risk of breast cancer, stratified by age at diagnosis or menopausal status. RESULTS: A loss of at least 10 pounds in the period from age 18 to 30 years was associated with a decreased risk of breast cancer between age 30 and 49 (odds ratio (OR) = 0.47; 95% confidence interval (CI) 0.28-0.79); weight gain during the same interval did not influence the overall risk. Among the subgroup of BRCA1 mutation carriers who had at least two children, weight gain of more than 10 pounds between age 18 and 30 was associated with an increased risk of breast cancer diagnosed between age 30 and 40 (OR = 1.44, 95% CI 1.01-2.04). Change in body weight later in life (at age 30 to 40) did not influence the risk of either premenopausal or postmenopausal breast cancer. CONCLUSION: The results from this study suggest that weight loss in early adult life (age 18 to 30) protects against early-onset BRCA-associated breast cancers. Weight gain should also be avoided, particularly among BRCA1 mutation carriers who elect to have at least two pregnancies.

Wang C, Fan S, Li Z, Fu M, Rao M, Ma Y, Lisanti MP, Albanese C, Katzenellenbogen BS, Kushner PJ, Weber B, Rosen EM, Pestell RG. · Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia 20007, USA. · Cancer Res. · Pubmed #16061635 links to  free full text

Abstract: The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor alpha (ERalpha)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERalpha binding. Cyclin D1 and BRCA1 were both capable of binding ERalpha in a common region of the ERalpha hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERalpha and for rescue of BRCA1-mediated ERalpha transcriptional repression. In chromatin immunoprecipitation assays, 17beta-estradiol (E2) enhanced ERalpha and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERalpha recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERalpha recruitment at 12 hours. Cyclin D1 expression antagonized BRCA1 inhibition of ERalpha recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERalpha repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.

Kotsopoulos J, Lubinski J, Lynch HT, Neuhausen SL, Ghadirian P, Isaacs C, Weber B, Kim-Sing C, Foulkes WD, Gershoni-Baruch R, Ainsworth P, Friedman E, Daly M, Garber JE, Karlan B, Olopade OI, Tung N, Saal HM, Eisen A, Osborne M, Olsson H, Gilchrist D, Sun P, Narod SA. · Centre for Research in Women's Health, University of Toronto, Women's College Hospital, 790 Bay Street, 7th Floor, Totonto, Ontario M5G 1N8, Canada. · Cancer Causes Control. · Pubmed #16049805 No free full text.

Abstract: Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman's age at menarche. A matched case-control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was < or =11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30-0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation.

Nkondjock A, Ghadirian P, Kotsopoulos J, Lubinski J, Lynch H, Kim-Sing C, Horsman D, Rosen B, Isaacs C, Weber B, Foulkes W, Ainsworth P, Tung N, Eisen A, Friedman E, Eng C, Sun P, Narod SA. · Epidemiology Research Unit, Research Centre, Centre Hospitalier de 'Universitaire de Montréal, CHUM Hôtel-Dieu, Montréal, Canada. · Int J Cancer. · Pubmed #16032702 No free full text.

Abstract: Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the association between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1-3, 4-5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72-1.12), 0.75 (95% CI 0.47-1.19) and 0.31 (95% CI 0.13-0.71; p-trend = 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee consumption is unlikely to be harmful and that high levels of consumption may in fact be related to reduced breast cancer risk.

Cullinane CA, Lubinski J, Neuhausen SL, Ghadirian P, Lynch HT, Isaacs C, Weber B, Moller P, Offit K, Kim-Sing C, Friedman E, Randall S, Pasini B, Ainsworth P, Gershoni-Baruch R, Foulkes WD, Klijn J, Tung N, Rennert G, Olopade O, Couch F, Wagner T, Olsson H, Sun P, Weitzel JN, Narod SA. · City of Hope National Medical Center, Duarte, CA, USA. · Int J Cancer. · Pubmed #15986445 No free full text.

Abstract: Early age at first birth and multiparity have been associated with a decrease in the risk of breast cancer in women in the general population. We examined whether this relationship is also present in women at high risk of breast cancer due to the presence of a mutation in either of the 2 breast cancer susceptibility genes, BRCA1 or BRCA2. We performed a matched case-control study of 1,260 pairs of women with known BRCA1 or BRCA2 mutations, recruited from North America, Europe and Israel. Women who had been diagnosed with breast cancer were matched with unaffected control subjects for year of birth, country of residence, and mutation (BRCA1 or BRCA2). Study subjects completed a questionnaire detailing their reproductive histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. Among BRCA1 carriers, parity per se was not associated with the risk of breast cancer (OR for parous vs. nulliparous = 0.94; 95% CI = 0.75-1.19; p = 0.62). However, women with a BRCA1 mutation and 4 or more children had a 38% decrease in breast cancer risk compared to nulliparous women (OR = 0.62; 95% CI = 0.41-0.94). In contrast, among BRCA2 carriers, increasing parity was associated with an increased risk of breast cancer; women with 2 or more children were at approximately 1.5 times the risk of breast cancer as nulliparous women (OR = 1.53; 95% CI = 1.01-2.32; p = 0.05). Among women with BRCA2 mutations and who were younger than age 50, the (adjusted) risk of breast cancer increased by 17% with each additional birth (OR = 1.17; 95% CI = 1.01-1.36; p = 0.03). There was no significant increase in the risk of breast cancer among BRCA2 carriers older than 50 (OR for each additional birth = 0.97; 95% CI = 0.58-1.53; p = 0.92). In the 2-year period following a birth, the risk of breast cancer in a BRCA2 carrier was increased by 70% compared to nulliparous controls (OR = 1.70; 95% CI = 0.97-3.0). There was a much smaller increase in breast cancer risk among BRCA2 carriers whose last birth was 5 or more years in the past (OR = 1.24; 95% CI = 0.79-1.95). A modest reduction in risk of breast cancer was observed among BRCA1 carriers with 4 or more births. Among BRCA2 carriers, increasing parity was associated with a significant increase in the risk of breast cancer before age 50 and this increase was greatest in the 2-year period following a pregnancy.

Kasper G, Vogel A, Klaman I, Gröne J, Petersen I, Weber B, Castaños-Vélez E, Staub E, Mennerich D. · metaGen Pharmaceuticals GmbH i.L., Oudenarderstr. 16, 13347 Berlin, Germany. · Cancer Lett. · Pubmed #15911104 No free full text.

Abstract: LAPTM4b (lysosome associated protein transmembrane 4 beta) was recently identified as a gene overexpressed in human hepatocellular carcinoma and belongs to the mammalian LAPTM family. By analysing genome-wide expression profiles of microdissected solid tumour samples by the means of Affymetrix GenChip hybridisation, we found LAPTM4b to be upregulated in 88% (23/26) of lung and in 67% (18/27) of colon carcinoma patients. Northern blots revealed additionally an overexpression of LAPTM4b in the majority of carcinomas of the uterus (30/44), breast (27/53) and ovary (11/16). Other members of the LAPTM family were not overexpressed in the investigated tumour samples according to GeneChip hybridisation data. Northen blot and quantitative RT-PCR on different normal tissues, detected highest levels of LAPTM4b mRNA in uterus, heart and skeletal muscle. Due to sequence analysis of bilaterian LAPTM proteins we suggests the presence of four transmembrane helices per protein, which are probably packed together by hydrophobic forces that are excerted by several evolutionary conserved aromatic residues within the alpha-helices. We discuss an active role for LAPTM4b during disease progression of malignant cells and conclude that its putative dual functional involvement in tumour cell proliferation as well as in multidrug-resistance may represent LAPTM4b as a target suitable for development of novel therapeutic agents.

Metcalfe KA, Lynch HT, Ghadirian P, Tung N, Olivotto IA, Foulkes WD, Warner E, Olopade O, Eisen A, Weber B, McLennan J, Sun P, Narod SA. · Faculty of Nursing, University of Toronto, 50 St. George Street, Toronto, ON, Canada, M5S 3H4. · Gynecol Oncol. · Pubmed #15589605 No free full text.

Abstract: OBJECTIVE: To estimate the risk of ovarian cancer after a primary diagnosis of breast cancer among women with a BRCA1 or BRCA2 mutation and to identify host and treatment-related factors that might modify the risk. PATIENTS AND METHODS: Patients were 491 women with stage I or stage II breast cancer, diagnosed from 1975 to 2000 and for whom a BRCA1 or BRCA2 mutation had been identified. Patients were followed from the initial diagnosis of breast cancer until either ovarian cancer, prophylactic oophorectomy, death, or 2002. The medical treatment records and pathology documents were reviewed. Information that was abstracted from the medical charts included date of breast cancer diagnosis, stage of disease, use of chemotherapy, use of radiation therapy, usage of tamoxifen, oophorectomy, recurrence, second malignancy, and vital status. RESULTS: The 10-year actuarial risk of ovarian cancer after breast cancer was 12.7% for BRCA1 carriers and 6.8% for BRCA2 carriers (P = 0.03). The use of tamoxifen (OR = 1.79; P = 0.16) and chemotherapy (OR = 0.59; P = 0.15) did not significantly impact on the risk of subsequent ovarian cancer. Twenty-five percent of the deaths in women with stage I breast cancer were due to a subsequent ovarian cancer. CONCLUSIONS: The high incidence of ovarian cancer suggests that oophorectomy should be recommended in female BRCA1 and BRCA2 mutation carriers with a diagnosis of breast cancer, especially those with stage I disease. Breast cancer systemic therapy did not significantly alter the risk of ovarian cancer.

Klopocki E, Kristiansen G, Wild PJ, Klaman I, Castanos-Velez E, Singer G, Stöhr R, Simon R, Sauter G, Leibiger H, Essers L, Weber B, Hermann K, Rosenthal A, Hartmann A, Dahl E. · Freie Universität Berlin, Berlin, Germany. · Int J Oncol. · Pubmed #15289865 No free full text.

Abstract: Aberrant activation of the Wnt signaling pathway plays an important role in the development of solid tumors such as breast and colon cancer. Secreted Frizzled-related protein 1 (SFRP1) is a negative regulator of the Wnt pathway. It has been described that SFRP1 mRNA is strongly down-regulated in breast cancer and a putative tumor suppressor function has been postulated. We have generated and characterized an SFRP1 specific antibody to analyze its expression on protein level and to investigate the association of SFRP1 expression with clinicopathological parameters and patient survival. Analysis of >2000 invasive breast tumors and 56 carcinoma in situ revealed similar frequencies of SFRP1 loss in these tumors (46% and 43% respectively). Therefore, we propose that loss of SFRP1 expression is an early event in breast tumorigenesis. SFRP1 expression was inversely correlated with tumor stage (p<0.001) but not with tumor grade (p=0.14) or lymph node status (p=0.84). Performing a multivariate analysis we could confirm the association between tumor stage and SFRP1 expression (p=0.029). In particular, loss of SFRP1 expression in early stage breast tumors (pT1) was associated with poor prognosis (p=0.04). In conclusion, expression of SFRP1 is commonly lost in breast cancer. SFRP1 expression might be useful as a novel prognostic marker in early stage breast cancer.

Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, Olopade OI, Eisen A, Weber B, McLennan J, Sun P, Foulkes WD, Narod SA. · Centre for Research on Women' s Health, Women's College Hospital, Toronto, Ontario, Canada. · J Clin Oncol. · Pubmed #15197194 No free full text.

Abstract: PURPOSE: To estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers after diagnosis and to determine which factors are predictive of the risk of a second primary breast cancer. PATIENTS AND METHODS: Patients included 491 women with stage I or stage II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up. RESULTS: The actuarial risk of contralateral breast cancer was 29.5% at 10 years. Factors that were predictive of a reduced risk were the presence of a BRCA2 mutation (v BRCA1 mutation; hazard ratio [HR], 0.73; 95% CI, 0.47 to 1.15); age 50 years or older at first diagnosis (v <or= 49 years; HR, 0.63; 95% CI, 0.36 to 1.10); use of tamoxifen (HR, 0.59; 95% CI, 0.35 to 1.01); and history of oophorectomy (HR, 0.44; 95% CI, 0.21 to 0.91). The effect of oophorectomy was particularly strong in women first diagnosed prior to age 49 years (HR, 0.24; 95% CI, 0.07 to 0.77). For women who did not have an oophorectomy or take tamoxifen, the 10-year risk of contralateral cancer was 43.4% for BRCA1 carriers and 34.6% for BRCA2 carriers. CONCLUSION: The risk of contralateral breast cancer in women with a BRCA mutation is approximately 40% at 10 years, and is reduced in women who take tamoxifen or who undergo an oophorectomy.

Lubinski J, Phelan CM, Ghadirian P, Lynch HT, Garber J, Weber B, Tung N, Horsman D, Isaacs C, Monteiro AN, Sun P, Narod SA. · Hereditary Cancer Center-Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin, Poland. · Fam Cancer. · Pubmed #15131399 No free full text.

Abstract: Inherited mutations of the BRCA2 gene give rise to a multi-site cancer phenotype which includes breast cancer (in female and males), ovarian, pancreatic and prostate cancer, ocular and other melanomas, laryngeal, colon and stomach cancers. Interpretation of test results and risk assessment is therefore complex. It has been proposed that families with mutations in the ovarian cancer cluster region (OCCR) of exon 11 (nucleotides 3035-6629) express a higher ratio of ovarian to breast cancer, than families with mutations elsewhere in the BRCA2 gene. In this study we have investigated the presence of 7 types of cancer (ovary, male breast, pancreas, prostate, colon, stomach and melanoma) in first- and second-degree relatives of mutation-positive individuals in 440 families with a BRCA2 mutation. We reviewed histories of cancer in relatives among families with mutations distributed throughout the gene. Families with ovarian cancer were more likely to harbour mutations in the OCCR (nucleotides 3035-6629) than elsewhere in the gene (OR = 2.21; P = 0.0002). We also compared cancer risks according to ethnic group. Ashkenazi Jewish families with the 6174delT founder mutation were more likely to have a family member with ovarian cancer (OR = 1.58; P = 0.002) and less likely to have a family member with prostate cancer (OR = 0.62; P = 0.04) than were non-Jewish families. In contrast, a reduced presence of ovarian cancer was found in families of French-Canadian ancestry, compared to other ancestries (OR = 0.37; P = 0.0026). A high risk of male breast cancer was observed with the 6503delTT mutation (OR = 15.7; P = 0.023). Families of Polish ancestry had a reduced frequency of pancreatic cancer (OR = 0.0; P = 0.03) compared to families of other ethnic origins. In conclusion, both the position of mutation and the ethnic background of the family appear to contribute to the phenotypic variation observed in families with BRCA2 mutations.

Ghadirian P, Lubinski J, Lynch H, Neuhausen SL, Weber B, Isaacs C, Baruch RG, Randall S, Ainsworth P, Friedman E, Freidman E, Horsman D, Tonin P, Foulkes WD, Tung N, Sun P, Narod SA. · Epidemiology Research Unit, Centre Hospitalier del'Universite de Montreal Hotel-Dieu, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada. · Int J Cancer. · Pubmed #15095307 No free full text.

Abstract: The effect of cigarette smoking on the risk of breast cancer is controversial, although most studies show little or no effect. It has been suggested that smoking may reduce the risk of developing hereditary breast cancer. We completed a case-control study on 1,097 women with breast cancer who were BRCA1 or BRCA2 mutation carriers and 1,097 age-matched controls with a mutation in the same gene but without breast cancer. There were no statistically significant differences between the cases and controls in terms of the number of current and ex-smokers (41.2% and 40.4%, respectively) or the age at smoking commencement (18.2 years and 18.5 years, respectively). There were no statistically significant differences between cases and controls regarding beginning smoking within 5 years of menarche (OR = 1.03; 95% CI 0.83 to l.28) or before the first pregnancy (OR = 1.09; 95% CI = 0.90 to 1.33). In conclusion, contrary to our previous report, smoking does not appear to be a risk factor for breast cancer among carriers of BRCA mutations.