A National Cancer Institute-designated Comprehensive Cancer Center

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CCG Research Program

CCG Research Program
Clinical cancer genetics research at City of Hope investigates multiple approaches that utilize the latest findings in cancer genetics in order to improve the prevention, treatment, and support of those with hereditary cancers.
 
Therapeutic Prevention and Treatment Trials for High Risk Patients
 
  • Targeted Treatments for Hereditary Breast or Ovarian Cancer (including PARP inhibitors)
     
  • For information on a Phase II trial of Single Agent ABT-888 with Post-Progression Therapy of ABT-888 in Combination with Carboplatin in Patients with Stage IV BRCA-Associated Breast Cancer, please click on the following links
 
  • CTOL (keyword search: 07211)
 
 
  • Cancer Prevention Trials and Other Studies for Postmenopausal Women
 
Laboratory Research

The major focus in the Clinical Cancer Genetics laboratory is molecular oncology and the investigation of molecular genetic changes associated with hereditary cancers.
 
Clinical and Behavioral Research
  • Clinical Outcomes Research, Genetic Epidemiology
  • Community Outreach and Health Services Research
  • Ethical, Legal, and Social Implications in Society
  • Education, Community Networks, and the Hereditary Cancer Registry
 
Hereditary Cancer Registry
The Cancer Screening & Prevention Program Network (CSPPN) is a network of City of Hope-affiliated genetic cancer risk assessment programs.  The multidisciplinary clinical cancer genetics team has developed an IRB-approved confidential registry (#96144:  Molecular Genetic Studies of Cancer Patients and Their Relatives), which allows patients who attend the CSPPN to participate in cancer genetics research.
 

Laboratory Research

Research Program Overview
 
The major focus in the laboratory is molecular oncology and the investigation of molecular genetic changes associated with women's cancers, both inherited and acquired. A subset of ovarian cancer patients is considered to have a hereditary predisposition. The BRCA1 and BRCA2 genes are implicated in the hereditary breast-ovarian cancer syndrome. The primary approach has included surveys of somatic genetic alterations in tumors, and positional cloning and characterization of tumor suppressor and growth regulatory genes.
 
Current Projects
Hereditary Breast Cancer and Novel Hispanic BRCA Mutations
We are obtaining a comprehensive dataset on the prevalence and nature of BRCA mutations among Hispanics. We documented that the Jewish founder mutation, BRCA1 185delAG, is prevalent in Hispanic populations; we discovered a novel BRCA1 rearrangement, the result of an Alu repeat-mediated recombination event, that accounts for a substantial proportion of high-risk Hispanic families. We are developing and testing the clinical effectiveness of a panel of recurrent BRCA mutations on the Sequenom (mass spectroscopy) high throughput platform for prospective screening of high-risk clinic cohorts, supported in part by an NCI R03 grant (3/1/09) for the project. This will represent the largest series of Hispanics with BRCA mutation information and clinical annotation.
 
Markel Ovarian Cancer Research Program
This project has three main focuses: 1)The development of new tools and enhanced prediction models to identify women at increased risk of ovarian cancer in order to facilitate prevention and early detection; 2) Linking molecular diagnostics to molecular therapeutics to permit individualized therapy through enhanced recruitment infrastructure of clinical trials for BRCA carriers; 3) Examining outcomes of initial therapy for women with BRCA-associated ovarian cancer and looking for genotype/phenotype correlations that may shed light on mechanisms of acquired resistance to therapy.
 
Molecular Genetic Studies of Cancer Patients and Their Relatives
A key resource in the lab is our prospective hereditary cancer registry, which includes biospecimens (more than 7,000 samples to date) for investigating factors that may contribute to the development of specific cancers in cancer patients and/or their relatives. The registry includes one of the largest existing sets of BRCA1/2 carriers (>600 families) at a single institution. Data and biospecimens from the registry also enable participation in the multi-institutional consortia that are necessary to assemble enough hereditary cases for epidemiological studies. We demonstrated remarkable concordance for hormone collaborative receptor status in BRCA1/2 carriers with bilateral breast cancer (CEBP, 2005. 14: 1534-8). BRCA modifier gene studies are also being conducted.
 
Breast Cancer Research Foundation
Recently, Angelina Jolie refocused attention on hereditary breast cancer risk and difficult choices available to prevent the disease, 17 years after commercial BRCA testing became available in the U.S. However, access to BRCA gene testing and genetic counseling, long a standard of care in most developed countries, is not available in the majority of Latin America and Mexico. Our preliminary studies of 746 U.S. Hispanics documented BRCA mutations in 189 (25%) women. The pattern of mutations was not random. Rather, many mutations were recurrent, seen in multiple unrelated families. Most of these mutations appear to have originated in Spain, and likely reflect Spanish Colonial influence and spread to Latin America ~500 years ago. However, one of the mutations, BRCA1 ex9-12del (a large rearrangement mutation in BRCA1 that is not detectable by conventional sequencing tests) appears to be a Mexican founder mutation, and represents 10-12% of all BRCA1 mutations in Mexican Americans in the U.S. We propose to test a novel economical genomic panel assay (HISPANEL), that has been able to detect nearly 80% of BRCA mutations in U.S. Hispanics for a very low cost (~$25/case), among high risk breast cancer patients in Latin America with a focus in Peru and Colombia. We will also train doctors and nurses there how to provide genetic counseling and genetic testing. Thus, in this international project we will try to make important observations about BRCA mutations among Latin American women, while helping the respective countries create an infrastructure of genetic counseling clinicians, and develop and test low cost genetic testing tools to apply in their home countries. Accomplishing these objectives will enable identification of women at highest risk for breast cancer, so that limited clinical resources can be focused where they are needed the most to detect and detect breast cancer earlier, and to prevent the disease.
 
Avon Foundation
Title: Epidemiology and Prevention of Hereditary Breast Cancer in Underserved Hispanics Project description: This project will create and test innovative and low-cost genomic approaches to expand access to personalized medicine among underserved Hispanics in the US and Mexico, using genomic tools that will represent a leap forward for the health care system and have a significant impact on breast cancer prevention. In addition, through this project, collaborating clinicians in the US and Mexico will be trained in Genetic Cancer Risk Assessment (GCRA) by a team of clinicians and researchers at City of Hope who have provided intensive GCRA training to over 400 clinicians from around the world to date. The outcomes of this training will be assessed. Even simple, relatively cost-effective screening measures, such as training in breast self-exam, more frequent breast exams by doctors, and mammographic screening programs targeted to high-risk women are likely to have a significant impact by facilitating diagnosis of smaller, more curable cancers. Identifying women with hereditary breast cancer will enable prevention of new primary cancers, allowing cost-effective allocation of limited healthcare resources for screening and prevention. At least 800 of 1,000 enrolled women will undergo genetic testing, leading to ~120 testing positive for a deleterious BRCA mutation. If they take the recommended actions to reduce risk, there will be 100 fewer breast or ovarian cancers within just the span of the proposed project. This is before considering the amplified impact of genetic knowledge in their families. This will be the largest group of individuals with Mexican ancestry to undergo cancer risk counseling and BRCA gene analyses.
 
Safeway Foundation
The Division of Clinical Cancer Genetics at the City of Hope has an established research registry and outreach program that includes Olive View-UCLA Medical Center (OVMC) and Los Angeles County + University of Southern California Medical Center. Our program has been providing genetic cancer risk assessment and testing women at high risk for breast and ovarian cancer who are underinsured and Hispanic. Up until now, we have not been able to cover men and women who are at high risk for colon cancer due to a strong family history of the disease. With this new funding, we can add genetic counseling and testing to address this critical gap and provide seed-funding for a pilot program to identify and test hereditary cancer syndrome gene locations in Hispanic and others who are underserved with low income and uninsured status. We have successfully demonstrated ability to efficiently test individuals with high probability of BRCA mutations and now will be able to replicate these methods with the population at high risk for MMR (colorectal cancer causing) mutations.
 

Clinical and Behavioral Research

Clinical Outcomes Research, Genetic Epidemiology
 
Hereditary Breast Cancer and Novel Hispanic BRCA Mutations
We hypothesize that: 1) Using novel high-throughput technologies, a panel that includes the majority of recurrent BRCA mutations found in women of Hispanic ancestry to pre-screen high risk patient samples will demonstrate potential clinical utility and reduce overall genotyping cost, 2) Studying BRCA mutations from a consortium of high-risk clinics serving Hispanic populations, from published literature and public databases, and from additional population-based cohorts will enable relatively comprehensive characterization of the spectrum and prevalence of BRCA mutations associated with breast cancer in Hispanics, and 3) The characterization of the ancestral background of recurrent BRCA mutations will enhance the specificity and predictive value of our Hispanic mutation panel
 
Communication, Content & Impact of Genetics in Breast Cancer
Young women with breast cancer who carry a BRCA gene mutation are also at high risk for ovarian cancer. Due to inadequate screening and early detection tools, these women are recommended to have their ovaries removed upon completion of childbearing or no later than age 35-40. The purpose of this study, under the direction of Dr. Deborah MacDonald, is to explore psychosocial well-being (PSWB) issues related to this recommendation and facing loss of fertility and early menopause (Phase 1), and to develop and test a needs-based psychoeducational intervention to enhance the lives of ethnically diverse reproductive age BRCA+ women (Phase 2). We hypothesize that: (1) reproductive age BRCA+ women have psychoeducational support needs related to fertility and menopausal issues that can be effectively addressed by the intervention, and (2) that the intervention group will have fewer unmet PSWB needs compared to the control group. We aim to enroll at least 50% Latinas (at least half primarily Spanish-speaking) in each study phase. The study’s Latina bilingual/bicultural team member will allow participation by English or Spanish-speaking Latinas. A needs-oriented, effective, evidence-based, and easily disseminated intervention to promote PSWB in BRCA+ women will help fill a critical untapped gap in cancer prevention and control research that enhances the lives of these women. Findings may ultimately be applied to other breast cancer survivors facing premature loss of fertility or early menopause.
 
Factors Influencing Communication of Cancer Risk Information to Family Members Among Asian-Americans seen for Genetic Cancer Risk Assessment
Risk communication within families is important in cancer prevention and control yet little is known about the beliefs, practices, and barriers related to this communication among Asian-Americans seen for GCRA. This project, under the direction of Dr. Deborah MacDonald, was conducted to help address this data gap. Participants were Asians referred to our cancer genetic clinics in Southern California. The 298 respondents to our mailed survey represented various Asian ethnic groups, were mostly females (94%), between age 30-60 (83%), married/cohabitating (77%), highly educated (72%), had children (70%), had been diagnosed with breast cancer (78%), and underwent genetic testing (75%; 12% positive for hereditary cancer risk). Of these 298 individuals, 89% indicated that they had a duty to inform their relatives of cancer risk and 78% considered this to be strictly a personal (vs. healthcare provider) duty. Of 123 follow-up respondents, 80% reported informing at least one close relative of cancer risk post-GCRA, primarily sisters and daughters. Barriers to risk communication, primarily concern about upsetting relatives and loss of contact, were reported by 14%. There were no significant differences identified by ethnicity or other demographics or cancer history. These findings suggest that following genetic cancer risk assessment, most Asian-Americans execute their perceived duty to inform relatives of cancer risk with few barriers to this communication.
 
Community Outreach and Health Services Research
 
Promoting Participation in Cancer Risk Counseling for Underserved Latinas
The primary purpose of this project is to test the effectiveness of a pre-GCRA (genetic cancer risk assessment) telephone intervention for underserved Latinas at high risk for hereditary breast and ovarian cancer. We seek to determine if the culturally and linguistically appropriate intervention, which incorporates adaptive motivational interviewing (AMI), will improve the uptake, preparedness for, and effectiveness of GCRA with high-risk Latinas. We hypothesize that; 1) Relative to the control group, patients randomized to the AMI pre-GCRA intervention will demonstrate greater GCRA appointment adherence, preparedness, knowledge, and satisfaction with the GCRA consultation process and experience; 2) Relative to the control group, patients randomized to the AMI pre-GCRA intervention will experience a greater reduction in anxiety and increased personal control prior to and after GCRA, and demonstrate greater cancer genetics knowledge after GCRA.
 
IRIS for BRCA Carriers – Decision Support Tools
The aims of the project are to develop an Individualized Risk Information System (IRIS), composed of a predictive model and the visual display of its output, which will provide female breast cancer patients who have a deleterious BRCA mutation with information regarding the risk of additional primary cancers and outcomes of risk reduction treatment choices and then to pilot use of the Individualized Risk Information System in breast cancer patients undergoing BRCA mutation testing.
 
Ethical, Legal, and Social Implications in Society
 
Genetic Discrimination and Access to Cancer Genetics Care
We surveyed non-genetics clinicians to explore the extent to which potential knowledge gaps and/or opinions of cancer genetics, genetic discrimination, and protective laws influences cancer genetics referrals and consequently access to risk-appropriate cancer screening and prevention. Although 96% of responders viewed genetic testing as beneficial to their patients, 75% stated genetic testing is likely to be declined by patients due to fear of genetic discrimination. The majority did not know that federal law (HIPAA) prohibits health insurance discrimination in the group market on the basis of genetic test results (61%) or that California State law prevents genetic information from being used as a criterion for health insurance coverage decisions (67%). Results indicate knowledge gaps and misperceptions as possible barriers to referral for genetic cancer risk assessment. A proposal is pending to develop an education program for clinicians regarding cancer genetics and current, as well as future, genetic discrimination laws may help to promote access to appropriate care.
 
Education, Community Networks, and the Hereditary Cancer Registry
 
Community Cancer Genetics and Research Training
The goal of our project is to provide intensive professional training programs in clinical cancer genetics and research collaboration for community-based clinicians. Interest and active participation in the course by clinicians from distinct disciplines, as well as outcomes to date, indicate that the course is a practical, cost-effective and efficacious way to deliver interdisciplinary cancer genetics training and post-course clinical and research support to clinicians practicing cancer genetic in the community setting, where there is defined need for cancer risk assessment services. Web-conference and web board interfaces being refined through the project are being utilized by many of the clinicians trained. On a practical level, numerous course participants joined the City of Hope Hereditary Cancer Registry, creating a broad based high risk clinic research network as a community laboratory for genetic epidemiology and clinical outcomes research.
 
Clinical Cancer Genetics Community Research Network (CCGCRN)
The Hereditary Cancer Research Registry (Molecular Genetic Studies in Cancer Patients and their Relatives; IRB #96144) is a prospective research registry protocol that was initiated at City of Hope in 1996 as a biospecimen repository with associated personal and family medical history, psycho-social and clinical follow-up data (e.g., screening and risk reduction behavior, risk communication) collection. The CCGCRN is a network of City of Hope-affiliated sites and allows patients with a personal or family history of cancer to participate in cancer genetics research. To date, the study has accrued over 10,000 participants with 4-generation family histories and banked biospecimens (including DNA, cryopreserved lymphocytes and/or lymphoblastoid cell lines, and more recently collections of plasma for proteomic studies; a subset have snap-frozen tumor tissue).
 

Highlights of Recent Work and Literature

Impact of Web-based Case Conferencing on Cancer Genetics Training Outcomes for Community-based Clinicians.
Blazer, K. R., Christie, C., Uman, G., & Weitzel, J. N. (2012 ePub ahead of print). Journal of Cancer Education
 
Introduction: Technology and market forces are driving the demand for cancer risk assessment services in the community setting, where few clinicians are trained to order and interpret predictive genetic tests. City of Hope conducts a three-phase course in genetic cancer risk assessment (GCRA) for community-based clinicians, comprised of distance didactics, face-to-face workshops and 12 months of professional development. As designed, the course cannot meet increasing demands for GCRA training. Action research identified face-to-face workshops as a barrier to increasing course capacity. This study compared the learning effectiveness of Web-based case conferencing to face-to-face training. Methods: A quasi-experimental design compared pre-post knowledge, skills and professional self-efficacy outcomes from 2009-2010 course cohorts (n=96). The intervention group (n=52) engaged in Web-based case conferences during distance learning; the comparison group (n=44) participated in the course as originally designed. Results: Both groups and all practice disciplines demonstrated significant pre-to-post increases on all measures. Knowledge increases were higher for the intervention group (p < .015); skills and self-efficacy increases were comparable between groups (p < .33 and p < .30, respectively). Discussion: Findings support the learning utility of Web-based case conferencing. Further studies may inform the development of tools to assess the impact of Webbased case conferencing on practice change and patient outcomes, in alignment with the highest standards of continuing professional development.
 
Closing the Loop: Action research in a multimodal hereditary cancer patient conference is an effective tool to assess and address patient needs.
Espenschied, C. R., MacDonald, D. J., Culver, J. O., Sand, S., Hurley, K., Banks, K. C., Weitzel, J. N., Blazer, K. R.. (2012 In press). Journal of Cancer Education
 
This paper describes the use of action research in a patient conference to provide updated hereditary cancer information, explore patient and family member needs and experiences related to genetic cancer risk assessment (GCRA), elicit feedback on how to improve the GCRA process, and inform future research efforts. Invitees completed GCRA at City of Hope or collaborating facilities and had a BRCA mutation or a strong personal or family history of breast cancer. Action research activities were facilitated by surveys, roundtable discussions, and Reflection Time to engage participants, faculty, and researchers in multiple cycles of reciprocal feedback. The multimodal action research design effectively engaged conference participants to share their experiences, needs, and ideas for improvements to the GCRA process. Participants indicated that they highly valued the information and resources provided and desired similar future conferences. The use of action research in a patient conference is an innovative and effective approach to provide health education, elicit experiences, and needs of high-risk patients and their family members, and generate research hypotheses. Insights gained yielded valuable feedback to inform clinical care, future health services research, and Continuing Medical Education.
 
Reflex Immunohistochemistry and Microsatellite Instability Testing of Colorectal Tumors for Lynch Syndrome among US Cancer Programs and Follow-up of Abnormal Results.
Beamer, L., Grant, M., Huizenga, C., Blazer, K.R., Hampel, H., Weitzel, J.N., MacDonald, D.J. (2012 ePub ahead of print). Journal of Clinical Oncology.
 
Background: Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 protein expression and microsatellite instability (MSI) are well-established tools to screen for Lynch Syndrome (LS). While many cancer centers have adopted these tools as reflex LS-screening following a colorectal cancer diagnosis, to date the standard of care has not been established and no formal studies have described this practice in the U.S.
Purpose: To describe the prevalent practices regarding IHC/MSI reflex testing for LS in the U.S. and subsequent follow-up of abnormal results.
Methods: A 12-item survey was developed following interdisciplinary expert input. A letter of invitation, survey, and online-survey option was sent to a contact at each cancer program. A modified Dillman’s strategy was used to maximize response rate. The sample included 39 NCI-designated Comprehensive Cancer Centers (NCI-CCC), 50 randomly-selected ACS-accredited Community Hospital Comprehensive Cancer Programs (COMPs) and 50 Community Hospital Cancer Programs (CHCPs).
Results: The overall response rate was 50%. Seventy-one percent of NCI-CCCs, 36% of COMPs, and 15% of CHCPs were conducting reflex IHC/MSI for LS; 48% used IHC, 14% used MSI and 38% used both. One program used a pre-surgical information packet, four offered an opt-out option, and none required written consent.
Conclusion: While most NCI-CCCs use reflex IHC/MSI to screen for LS, this practice is not well-adopted by community hospitals. These findings may indicate an emerging standard of care and diffusion from NCI-CCC to community cancer programs. Our findings also describe an important trend away from requiring written patient consent for screening.
 
Genetics, Genomics and Cancer Risk Assessment: State of the art and future directions in the era of personalized medicine.
Weitzel, J. N., Blazer, K. R., MacDonald, D. J., Culver, J. O., & Offit, K. (2011). CA-Cancer J Clin, 61(5), 327-359
 
Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently-discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease-risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine.
 
Personalized cancer genetics training for personalized medicine: Improving community-based healthcare through a genetically literate workforce.
Blazer, K. R., MacDonald, D. J., Culver, J. O., Huizenga, C. R., Morgan, R. J., Uman, G. C., Weitzel, J. N. (2011) Genet Med, 13(9), 832-840.
 
Purpose: To assess the impact of a multimodal interdisciplinary course on genetic cancer risk assessment and research collaboration for community-based clinicians. Clinicians are increasingly requested to conduct genetic cancer risk assessment, but many are inadequately prepared to provide these services. Methods: A prospective analysis of 131 participants (48 physicians, 41 advanced-practice nurses, and 42 genetic counselors) from community settings across the United States. The course was delivered in three phases: distance didactic learning, face-to-face training, and 12 months of web-based professional development activities to support integration of skills into practice. Cancer genetics knowledge, skills, professional self-efficacy, and practice changes were measured at baseline, immediate, and 14 months post-course.
Results: Knowledge, skills, and self-efficacy scores were significantly different between practice disciplines; however, post-scores increased significantly overall and for each discipline (P < 0.001). Fourteen-month practice outcomes reflect significant increases in provision of genetic cancer risk assessment services (P = 0.018), dissemination of cancer prevention information (P = 0.005) and high-risk screening recommendations (P = 0.004) to patients, patient enrollment in research (P = 0.013), and educational outreach about genetic cancer risk assessment (P = 0.003).
Conclusions: Results support the efficacy of the multimodal course as a tool to develop a genetically literate workforce. Sustained alumni participation in web-based professional development activities has evolved into a distance-mediated community of practice in clinical cancer genetics, modeling the lifelong learning goals envisioned by leading continuing medical education stakeholders.
 
Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
Domchek, S. M., Friebel, T. M., Singer, C. F., Evans, D. G., Lynch, H. T., Isaacs, C., Garber, J. E., Neuhausen, S. L., Matloff, E., Eeles, R., Pichert, G., Van t'veer, L., Tung, N., Weitzel, J. N., Couch, F. J., Rubinstein, W. S., Ganz, P. A., Daly, M. B., Olopade, O. I., Tomlinson, G., Schildkraut, J., Blum, J. L., & Rebbeck, T. R. (2010). JAMA, 304(9), 967-975.
 
Context: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. OBJECTIVE: To estimate risk and mortality reduction stratified by mutation and prior cancer status.
Design, Setting, And Participants: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.
Main Outcomes Measures: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.
Results: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]).
Conclusions: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.
 
Extending comprehensive cancer center expertise in clinical cancer genetics and genomics to diverse communities: The power of partnership.
MacDonald, D. J., Blazer, K. R., & Weitzel, J. N. (2010). Journal of the National Comprehensive Cancer Network, 8(5), 615-624.
 
Rapidly evolving genetic and genomic technologies for genetic cancer risk assessment (GCRA) are revolutionizing the approach to targeted therapy and cancer screening and prevention, heralding the era of personalized medicine. Although many academic medical centers provide GCRA services, most people receive their medical care in the community setting. However, few community clinicians have the knowledge or time needed to adequately select, apply, and interpret genetic/genomic tests. This article describes alternative approaches to the delivery of GCRA services, profiling the City of Hope Cancer Screening & Prevention Program Network (CSPPN) academic and community-based health center partnership as a model for the delivery of the highest-quality evidence-based GCRA services while promoting research participation in the community setting. Growth of the CSPPN was enabled by information technology, with videoconferencing for telemedicine and Web conferencing for remote participation in interdisciplinary genetics tumor boards. Grant support facilitated the establishment of an underserved minority outreach clinic in the regional County hospital. Innovative clinician education, technology, and collaboration are powerful tools to extend GCRA expertise from a National Cancer Institute-designated Comprehensive Cancer Center, enabling diffusion of evidenced-base genetic/genomic information and best practice into the community setting.
 
Oral poly (adp-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial.
Tutt, A., Robson, M., Garber, J. E., Domchek, S., Audeh, M. W., Weitzel, J.N., Friedlander, M., Arun, B., Loman, N., Schmutzler, R., Wardley, A., Mitchell, G., Earl, H., Wickens, M., & Carmichael, J. (2010). The Lancet, 376(9737), 211-213.
 
Background: Olaparib, a novel, orally active poly (ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer.
Methods: Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov , number NCT00494234.
Findings: Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]).
Interpretation: The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.
 
Oral poly (adp-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial.
Audeh, M. W., Carmichael, J., Penson, R. T., Friedlander, M., Powell, B., Bell-McGuinn, K. M., Scott, C., Weitzel, J. N., Oaknin, A., Loman, N., Lu, K., Matulonis, U., Wickens, M., & Tutt, A. (2010). The Lancet, 376(9737), 211-213.
 
Background: Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations.
Methods: In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >or=18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442.
Findings: Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4).
Interpretation: Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.

Occult ovarian cancers identified at risk-reducing salpingo-oophorectomy in a prospective cohort of BRCA1/2 mutation carriers.
Domchek, S. M., Friebel, T. M., Garber, J. E., Isaacs, C., Matloff, E., Eeles, R., Evans, D. G., Rubinstein, W., Singer, C. F., Rubin, S., Lynch, H. T., Daly, M. B., Weitzel, J.N., Ganz, P. A., Pichert, G., Olopade, O. I., Tomlinson, G., Tung, N., Blum, J. L., Couch, F., & Rebbeck, T. R. (2010)Breast Cancer Res Treat, 124(1), 195-203.
 
Risk-reducing salpingo-oophorectomy (RRSO) is widely used for cancer risk reduction in BRCA1 or BRCA2 (BRCA1/2) mutation carriers. Occult ovarian/fallopian tube cancers (OOC) detected at the time of RRSO have been reported in several studies with wide variability in reported prevalence. We estimated the prevalence of OOC in a prospective cohort of 647 BRCA1/2 mutation carriers from 18 centers (PROSE consortium) who underwent RRSO between 2001 and 2008. OOC was detected in 16 of 647 women (2.5%). The mean age at RRSO was 51.7 in those with OOC versus 46.6 in those without OOC (P = 0.017). Twelve of the 16 OOCs (75%) were diagnosed in women with BRCA1 mutations. Thirty-eight percent of women with OOC had stage 1 cancer versus none of the women in the PROSE database diagnosed with ovarian cancer outside of screening. Among 385 women (60%) in whom pathology reports were available for central review, 246 (64%) RRSOs were performed at participating PROSE centers while 139 (36%) were performed at local sites. Ovarian and fallopian tube tissues removed at major genetics referral centers were significantly more likely to have been examined in toto compared to specimens obtained at non-referral centers (75% vs. 30%, P < 0.001). Our results confirm that OOC may be found at the time of RRSO in BRCA1/2 mutation carriers and suggest that OOC are of a more favorable stage than cancers found outside RRSO. An unacceptably high proportion of pathologic examinations did not adequately examine ovaries and fallopian tubes obtained at RRSO.
 
Women's perceptions of the personal and family impact of genetic cancer risk assessment: Focus group findings
MacDonald, D. J., Sarna, L., Weitzel, J. N., & Ferrell, B. (2009). Journal of Genetic Counseling, 19(2), 148-160.
 
Women with a personal or family history of breast or ovarian cancer are increasingly presenting for genetic cancer risk assessment (GCRA). To explore the personal and family impact of GCRA, four focus groups were conducted of women seen for risk assessment. Participants were 22 primarily non-Latina White women with a personal or family history of breast or ovarian cancer. Analysis of the data identified new themes related to balancing time to assimilate risk information with the need to make timely healthcare decisions, physicians’ lack of sufficient genetic knowledge, and concern for daughters regardless of the daughters’ age. Other themes related to protecting others, knowledge as empowerment, reassessing personal attribution of cancer risk, managing uncertainty, reappraising body image, and experiencing divergent family responses to communication of cancer risk and healthcare decisions. Understanding the personal and family impact of GCRA may enable genetics professionals to tailor their counseling efforts to better meet the needs of these women. Additional research is needed to extend these findings and identify interventions to support positive outcomes of GCRA.
 
Social cognitive aspects of underserved Latinas preparing to undergo genetic risk assessment for hereditary breast and ovarian cancer.
Lagos, V.I., Perez, M.A., Ricker, C.N., Blazer, K.R., Santiago, N.M., Feldman, N., Viveros, L., & Weitzel, J.N. (2008). Psycho-Oncology, 17(8), 774-782.
 
Objectives: As Latinos are a growing ethnic group in the United States, it is important to understand the socio-cultural factors that may be associated with cancer screening and prevention in this population. The socio-cultural factors that may affect preparedness to undergo genetic cancer risk assessment (GCRA) deserve particular attention. The pre-GCRA period can provide insight into variables that may influence how medically underserved Latinas, with limited health resources and access, understand hereditary cancer information and subsequently implement cancer risk management recommendations. This study explores social, cognitive and cultural variables in Latinas prior to undergoing GCRA.
Methods: The study sample consisted of low-income, underserved Latinas referred for GCRA because of a personal and/or family history of breast or ovarian cancer. Acculturation, cancer-specific fatalism, self-efficacy and social support were assessed prior to GCRA.
Results: Fifty Latinas (mean age=40.1+/-7.7) completed instruments; 86% had invasive cancer, 78% spoke primarily Spanish and 61% were of Mexican ancestry. Low levels of acculturation (n=50, mean=9.0+/-5.8) and cancer-specific fatalism (n=43, mean=5.6+/-3.2), but relatively high self-efficacy (n=49, mean=40.9+/-7.8) and social support (n=49, mean=37.3+/-8.7) were reported. Cancer-specific fatalism and self-efficacy were inversely correlated (r=-0.47, p=0.002). Those over age 38 at the time of cancer diagnosis reported higher acculturation (mean=11.4+/-7.2, p=0.02) and social support (mean=40.5+/-1.2, p=0.05).Conclusions: These findings suggest that medically underserved Latinas may already possess some of the necessary skills to successfully approach the GCRA process, but that special attention should be given to cultural factors.
 

Therapeutic Prevention and Treatment Trials

Targeted Treatments for Hereditary Breast or Ovarian Cancer (including PARP Inhibitors)
 
Novel Targeted Therapies for BRCA-associated Cancer
BRCA deficiency in tumor cells is associated with genomic instability due in part to impaired homologous recombination repair (HRR). Inhibitors of poly (ADP-ribose) polymerase (PARP), a therapeutic target that functions in base excision repair that is complementary to HRR, have shown promising results in pre-clinical models and early phase clinical trials. Recently completed Phase II multi-center studies to assess the efficacy and safety of KU-0059436 given orally to patients with advanced BRCA1- or BRCA2-associated breast or ovarian cancer showed promising results. We demonstrated pre-clinical activity of a novel PARP inhibitor (ABT-888) obtained from NCI/CTEP in BRCA-deficient breast cancer cell lines, and a multi-center randomized phase II trial (ABT-888 +/- carboplatinum) in advanced BRCA-associated breast cancer is now open to accrual. An NCI R21 grant is enabling prospective study of molecular mechanisms of resistance. Drs. Weitzel and O’Connor are developing a translational therapeutics program targeted to hereditary cancers, to bring other DNA repair targeted agents from the bench to the bedside. These clinical trials constitute a paradigm shift and proof of principle that complementary DNA repair pathways can be inhibited by the study drug, resulting in specific tumor killing and a very mild toxicity profile.
 
Protocol #07211 Principal Investigator: Jeffrey Weitzel, M.D.
Title: PHII-96 NCI #8264: Phase II Trial of Single Agent ABT-888 with Post-Progression Therapy of ABT-888 in Combination with Carboplatin in Patients with Stage IV BRCA-associated Breast Cancer
 
The purpose of this study is to find the most effective and well-tolerated dose-level of ABT-888 when used with carboplatin and to evaluate the effectiveness of ABT-888 alone and in combination with carboplatin in treating BRCA1- or BRCA2-associated advanced breast cancer.
 
Cells contain a type of molecule called deoxyribonucleic acid (DNA). DNA carries the genetic information for the development of cells. If DNA becomes damaged, chemicals inside the cell try to repair it. One such chemical is the protein PARP-1. ABT-888 is an inhibitor of PARP-1. This means ABT-888 stops PARP-1 from repairing DNA. Functioning BRCA genes in normal cells can repair DNA damage even if PARP-1 is inhibited. However, cells with abnormal BRCA, such as BRCA1 and BRCA2 cancer cells, cannot. ABT-888 is in an early phase of development so there is limited information about the use of ABT-888 in human subjects. In previous studies, ABT-888 has been well-tolerated and has caused less side effects than conventional chemotherapies. ABT-888 has not yet been approved for use by the Food and Drug Administration (FDA) except in research studies.
 
In laboratory and animal experiments, ABT-888 was found to enhance the anti-tumor activity of carboplatin. This study will evaluate whether ABT-888 and/or ABT-888 with carboplatin can prevent the survival of BCRA1- and BCRA2-associated breast cancer cells.
 
Protocol #09158 Principal Investigator: Mihaela Cristea, M.D.
Title: A Phase 1 Study of ABT-888 in Combination with Carboplatin and Gemcitabine in Subjects with Advanced Solid Tumors
 
Protocol #08240 Principal Investigator: Robert Morgan, M.D.
Title: PHI-63 NCI #8282: A Phase I Study of Chronically-Dosed, Single Agent ABT-888 in patients with Either BRCA 1/2-Mutated Cancer: Platinum Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer; or Basal Like Breast Cancer
 
Protocol #07242 Principal Investigator: Karen Reckamp, M.D.
Title: PHI-61 NCI#7967: A Phase I Study of ABT-888 in Combination with Carboplatin and Paclitaxel in Advanced Solid Malignancies
 
For more detailed information on each of the above studies, please call 1-877-482-HOPE(4673) or visit http://clinicaltrials.coh.org. Please note, that clinical trials are occasionally on hold, so if you are unable to find a particular trial, please check back later. In all cases, patients must be under the care of a City of Hope physician in order to be eligible.
 
For information on clinical trials in other locations, please visit www.clinicaltrials.gov.
 
Cancer Prevention Trials and Other Studies for Postmenopausal Women
 
03178 - Grape seed as an aromatase inhibitor for breast cancer risk reduction– The goal of this project is to determine whether grape seed extract (GSE) significantly suppresses serum estrogens in normal postmenopausal women and to determine if there is a dose effect between GSE and suppression of estrogen biosynthesis.
 
Principal Investigator: Melanie Palomares, M.D., M.S.
 
For more detailed information onthisstudy, please call 1-877-482-HOPE(4673) or visit http://clinicaltrials.coh.org. Please note, that clinical trials are occasionally on hold, so if you are unable to find a particular trial, please check back later. In all cases, patients must be under the care of a City of Hope physician in order to be eligible.
 
For information on clinical trials in other locations, please visit www.clinicaltrials.gov.
 
Overview
Beckman Research Institute of City of Hope is responsible for fundamentally expanding the world’s understanding of how biology affects diseases such as cancer, HIV/AIDS and diabetes.
 
 
Research Departments/Divisions

City of Hope is a leader in translational research - integrating basic science, clinical research and patient care.
 

Research Shared Services

City of Hope embodies the spirit of scientific collaboration by sharing services and core facilities with colleagues here and around the world.
 

Our Scientists

Our research laboratories are led by the best and brightest minds in scientific research.
 

City of Hope’s Irell & Manella Graduate School of Biological Sciences equips students with the skills and strategies to transform the future of modern medicine.
Develop new therapies, diagnostics and preventions in the fight against cancer and other life-threatening diseases.
 
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