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.
 

Cancer Genetics 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

LITERATURE
 
 
 
 
 
HIGHLIGHTS OF RECENT WORK
 
Founder effect and a high prevalence of BRCA1 mutations among young Mexican triple-negative breast cancer (TNBC) patients. A podium presentation at the ASCO 50th Annual Meeting 2014.
Villarreal-Garza CM, Weitzel JN, Sifuentes E, Llacuachaqui M, Herzog J, et al.  May 30 - June 3, 2014; Chicago, IL.
 
Previous studies have shown that the prevalence of BRCA mutations among young TNBC patients is elevated. Current guidelines recommend that women ≤60 years with TNBC be referred for genetic counseling. Different studies in Mexico have shown an early age of onset of BC and a high prevalence of TNBC, which suggests that BRCA mutations may account for a higher proportion of breast cancers in this population. However, there is limited information regarding BRCA mutation prevalence mainly due to lack of access to clinical BRCA gene analyses in Mexico. Methods: The purpose of this study is to analyze BRCA mutation frequency in a cohort of young Mexican TNBC patients using a panel assay of 114 recurrent BRCA mutations found in women of Hispanic ancestry (HISPANEL) on the Sequenom platform. Mexican women diagnosed with TNBC at or before age 50 were prospectively recruited from the National Cancer Institute in Mexico City. Patients were screened by HISPANEL and by PCR for the Mexican founder BRCA1 ex9-12del large rearrangement.
Results: Among 190 consecutive TNBC cases, the median age of diagnosis was 42 years old and 69% were younger than 45 years. The majority of patients presented with locally advanced disease (69%). A BRCA mutation was detected in 43/190 (23%) of patients (42-BRCA1, 1-BRCA2), and BRCA1 ex9-12del accounted for 42% of the mutations. Only 45% of the BRCA mutation carriers had a family history of breast and/or ovarian cancer. Samples were processed in a two-week period, with a total cost of $4,000 USD.
Conclusions: There is a remarkable prevalence of BRCA1 mutations among young TNBC patients in our population. The first documented Mexican founder mutation, BRCA1 ex9-12del, was the most frequent BRCA mutation and is likely responsible for a significant burden of disease in women from Southern Mexico. The HISPANEL can be completed within 72 hours from sample collection, at a modest cost of $20 USD per sample, and implementation among women of Mexican ancestry could reduce overall genotyping cost and increase access to cancer prevention among underserved women in Mexico and the U.S.
 
Phase II trial of single agent PARP inhibitor ABT-888 (veliparib [vel]) followed by post-progression therapy of vel with carboplatin (carb) in patients (pts) with stage BRCA-associated metastatic breast cancer (MBC). California cancer consortium trial PhII-96. A podium presentation at the American Society of Clinical Oncology Annual Meeting 2014.
Somlo G, Frankel P, Luu T, Ma C, Arun B, et al.  May 30 - June 3, 2014; Chicago, IL.
 
Background:  We reported on a phase I trial showing 54% confirmed partial response (PR) with carb + vel.  Here we describe single agent vel activity and, upon progression, the feasibility and efficacy of continuing administration of vel + carb.
Methods:  Pts  with MBC with BRCA1 or 2 mutations, an ECOG performance status of ≤ 2, and measurable disease were eligible. Prior PARP-inhibitor therapy (Rx) , platinum Rx for MBC, or central nervous system metastasis requiring Rx were exclusions. Vel was administered orally at 400 mg twice daily (BID).  Cohorts (BRCA1 and BRCA2) were studied independently: 2 or more PRs to vel out of 10 pts were required to proceed to accrual of 22 pts per cohort. Upon progression, carb (AUC of 5) iv every 21 days, and vel  150 mg orally BID were prescribed.
Results:  Between 10/2012 and 1/2014, 44 pts enrolled (41 treated) carrying BRCA1 (N=21) or BRCA2 (N=20)  mutations. The median age was 43-years (range; 28-68); 50% of pts had hormone receptor + BC.  Pts received 3 prior chemo-regimens (0-7). The current PR rate in pts with at least 4 cycles of follow-up  is 2/12 (17%) for BRCA1 and 3/13 (23%) for BRCA2.  Three pts withdrew from treatment during the first cycle of vel due to grade 2 seizure (1), grade 3 thrombocytopenia (PLT [1]), grade  2 PLT and neutropenia (1).   Time to failure (TTF) on vel is 2.0 months (0-10.5+), and 5.1 months (0.9-10.3+) for the two cohorts (BRCA1, BRCA2, respectively). Twenty pts are still on vel (8 BRCA1, 12 BRCA2).  Of the 10 pts to proceed to vel + carb so far, 1 PR in a BRCA1 pt was observed.
Conclusions:  Vel is active when given at 400 mg BID daily. Further trials are indicated to assess its benefit whether in combination or as a single agent in both BRCA1 and BRCA2-associated BC.
 
BRCA1 and BRCA2 (BRCA) gene analyses on an economic platform: A global consortium to demonstrate the feasibility of a shared, dedicated workflow for non-optical next generation sequencing (NGS) with a custom BRCA AmpliSeq kit on the Ion Torrent PGM™. A podium presentation at the American Society of Human Genetics Annual 63rd Annual Meeting.
Weitzel J, Costa J, Mensenkamp A, Ekici A, Herzog J, et al. 2013 October 22-26; Boston, MA.
 
While the “Jolie effect ” has refocused attention on the central role of BRCA gene analyses in the diagnosis and prevention of hereditary breast and ovarian cancer, there is a global disparity in access to affordable testing. The development of bench top NGS technologies holds promise for faster, more comprehensive and cost-effective methodologies than Sanger sequencing. We describe here a global consortium developing and demonstrating the feasibility of a shared, dedicated workflow for clinical grade BRCA gene analyses using Ion AmpliSeq ™ multiplex PCR technology combined with Ion PGM ™ System. The non-overlapping primers were designed to provide 1) 100% coverage of all coding exons and exon-intron boundaries; 2) overlapping amplicons covering exons; 3) no SNPs in the last five nucleotides of primer; and 4) maximum of three non-validated SNPs per primer. The technical protocol was developed and piloted by centers in the Netherlands and Portugal, and the current phase III testing includes 5 additional centers (California, USA; D.F., Mexico; Glasgow, Scotland; Erlangen, Germany; Ontario, Canada). More than 200 different known germline BRCA mutation positive cases were selected (~30 per center), many representative of a given region, with the aim to assess the ability to detect and call the full spectrum of mutation types, with additional cases in or within close proximity to homopolymer regions. Data analyses include independent and blind evaluation and power estimation of the new methodology. All samples were studied using both Sanger sequencing and the Ion PGM ™ System. For data-analysis various software packages were evaluated, with an aim to harmonize the analyses as a custom workflow on Ion Reporter to facilitate use in widely disparate settings. The technical platform has been established in all 7 centers, with excellent performance characteristics: 100% coverage of the targeted regions; >100x coverage across all but 1 amplicon in BRCA2 (>40x), while using barcoding to analyze 8 cases simultaneously on a 316 chip. There was high sensitivity and specificity; technical challenges in the bioinformatic component and emerging copy number variation detection methods will be discussed. This work demonstrates the potential for mutational screening of BRCA1 and BRCA2 using the Ion AmpliSeq ™ technology combined with the Ion Torrent PGM, and the feasibility of deploying a common protocol to diverse geographic settings, with a close collaboration among peers.
 
Efficacy of The Combination of ABT-888 (veliparib) and Carboplatin in Patients BRCA-Associated Breast Cancer. A poster presentation at the American Society of Clinical Oncology annual meeting, 2013.
Somlo G, Frankel P, Luu T, Ma C, Arun B, et al.. 2013 May 31-June 4; Chicago, IL. .
 
Platinum and PARP inhibitors have both shown single agent activity in BRCA-associated breast cancer patients  (Silver et al. J Clin Oncol 2010; Tutt et al. Lancet 2010). However, data on combining these two classes of agents are limited, and the optimal dose, frequency, and duration have not been defined. 
In line with the concept of synthetic lethality (Rehman et al. Nat Rev 2010),  we designed a trial to treat women with BRCA-associated stage IV breast cancer. We planned to compare carboplatin and ABT-888 vs. single agent ABT-888. Precinical data suggest synergism between platinum agents and ABT-888 (Clark CC et al. Mol Cancer Ther. 2012).
Since neither the dose-limiting toxicity (DLT) nor the maximum tolerated dose(MTD)  of daily ABT-888 has been firmly established, we conducted a phase I trial of carboplatin  and escalating doses of ABT-888.
We report on the MTD and observed DLTs of this combination, and early efficacy data in 28 patients accrued as part of a California Cancer Consortium-lead trial with participation from multiple NO-1-supported consortia.
 
Hispanic MMR Mutations: A Multi-Institutional Report from Southwestern United States and Puerto Rico. A poster presentation at the 17th Annual Meeting Collaborative Group of the Americas on Inherited Colorectal Cancer.
Sunga A, Ricker C, Espenschied C, Herzog J, Bannon S, et al.; 2013 October 7-8; Anaheim, CA.
 
Background:  Knowledge of founder mutations can enable efficient and cost-effective strategies for genetic testing, a potential benefit for populations with limited access to services.  We have shown several BRCA mutations, most of Spanish origin, to be founder mutations in Hispanic populations.  We hypothesized that the same population factors may be operative in Lynch syndrome.  There is limited literature on the spectrum of mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) in Hispanic populations.  The goal of this study was to identify recurrent MMR mutations in Hispanic patients and explore potential ancestral origins of identified mutations. 
Methods:  Subjects included Hispanic patients seen for genetic cancer risk assessment at City of Hope Clinical Cancer Genetics Community Research Network collaborating institutions, MD Anderson Cancer Center, USC Norris Comprehensive Cancer Center and the University of Puerto Rico Comprehensive Cancer Center.  A total of 120 patients underwent genotyping for mutations in one or more of the four MMR genes due to abnormal MSI, loss of MMR protein(s) on IHC, and/or strong family history.  A comprehensive review of the literature and of multiple MMR variant databases was conducted for all identified mutations. 
Results:  Sixty unrelated Hispanic families were found to have at least one MMR gene mutation and among these, 49 different mutations were identified (33-MLH1, 19-MSH2, 6-MSH6, and 2-PMS2).  Nine mutations were observed two or more times: MLH1 350C>T, 1790del2ins9, 2041G>A, 1852del3, 1024del16, and IVS7+5G>A; and MSH2 1216C>T, 425C>G, and 1705delGA. Most (6/9) recurrent mutations were detected in separate institutions.  MSH2 1216C>T, MSH2 1705delGA, and MLH1 1852del3 were each seen three times and have been reported multiple times in various European populations. MLH1 350C>T, 2041G>A, 332C>T, and 676C>T and MSH2 1216C>T, deletion of exons 4-8, and deletion of exon 8 have all been reported previously in Spain.  The MSH2 deletion of exons 4-8 was seen in one Mexican family in our series and has been reported as a Spanish founder mutation.  Though seen twice at one center in our series, to our knowledge, MLH1 1790del2ins9 has not been previously reported in the literature or MMR mutation databases, nor have 18 other mutations identified in our cohort. 
Conclusion:  Our finding, that three of the nine recurrent mutations and the MSH2 deletion of exon 8 identified in our cohort were previously reported in Spain, supports the hypothesis of the likely influence of Spanish ancestral heritage on MMR gene mutations in Hispanic populations.  While this is the largest reported cohort of Hispanic patients with MMR mutations in North America, a larger sample and haplotype analyses are needed to  better define the spectrum and origin of MMR mutations in Hispanic populations.
 
Searching for Recurrent MMR Mutations in Hispanic Patients. A poster presentation at the NSGC 32nd Annual Education Conference.
Espenschied C, Sunga A, Herzog J, Bannon S, Lynch P, et al. ; 2013 October 9-12; Anaheim, CA.
 
Knowledge of founder mutations can enable efficient and cost-effective strategies for genetic testing, a potential benefit for populations with otherwise limited access to services.  We have shown several BRCA mutations, most of Spanish origin, to be founder mutations in Hispanic populations.  We hypothesized that the same population factors may be operative in Lynch syndrome.  There is limited literature on the spectrum of mismatch repair (MMR) gene mutations (MLH1, MSH2, MSH6, and PMS2) in Hispanic populations.  This study aims to identify recurrent MMR mutations in Hispanic patients and explore potential ancestral origins of mutations identified.  Subjects included Hispanic patients seen for genetic cancer risk assessment at City of Hope Clinical Cancer Genetics Community Research Network collaborating institutions and at MD Anderson Cancer Center.  Literature review was performed for all mutations identified.  Among 30 unrelated Hispanic families, 26 different MMR mutations were identified.  MLH1 350C>T and MLH1 1790del2ins9 were each seen in two families and MSH2 1216C>T was seen in three families in our cohort.  Literature review revealed that MLH1 350C>T and MSH2 1216C>T have been reported in the Spanish and other European populations.  We found no previous reports of MLH11790del2ins9.  A deletion of exons 4-8 in MSH2 was seen in one Mexican family and has been reported as a Spanish founder mutation.  Given that two of three recurrent mutations in our cohort were previously reported in the Spanish population, and an additional large deletion has been reported as a Spanish founder mutation, this provides evidence of population factors similar to those previously described among BRCA carriers.  To our knowledge, this is the largest reported cohort of Hispanic patients with MMR mutations in North America; however, the sample is small and further studies are needed to expand and better define the spectrum and origin of MMR mutations in Hispanic populations.
 
Next-generation Sequencing for Genetic Cancer Risk Assessment. A poster presentation at the ASCO annual meeting.
Blazer KR, Espenschied C, Weissman S, Sand S, Weitzel JN. ; 2013 May 31-June 4; Chicago, Illinois.
 
Background: Current standard-of-care practice for genetic cancer risk assessment (GCRA) focuses on single-gene testing for specific hereditary cancer syndromes. Next-generation sequencing (NGS) technologies recently became available for clinical applications. This study explored the perspectives and experiences of community-based clinicians regarding NGS testing for personalized GCRA.
Methods: A 27-item survey was developed and administered online to 325 members of an interdisciplinary nationwide clinical cancer genetics community of practice. Results: Of 94 (29%) respondents, 25 (27%) have ordered at least one multi-gene panel and only 2 (2.1%) have ordered a whole exome or genome test from a commercial vendor for GCRA. Concerns about clinical utility, the challenge of interpreting and communicating results, lack of knowledge about and potential costs were most often cited as reasons for not pursuing NGS testing. Respondents were significantly more confident about their ability to interpret and counsel about single gene test results compared with multi-gene panels or whole exome/genome sequencing; and about multi-gene panels over whole exome/genome sequencing (p<.0001 for all comparisons).
Conclusions: Findings suggest that while NGS tests are entering the realm of GCRA, multidisciplinary genomics education and clinical support resources are needed to address barriers to utilization and promote successful integration of NGS testing into community-based GCRA practice settings.
 
Prevalence and type of BRCA mutations in Hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the Clinical Cancer Genetics Community Research Network.
Weitzel JN, Clague J, Martir-Negron A, Ogaz R, Herzog J, et al. (2013) Journal of Clinical Oncology 31: 210-216.
 
Purpose: To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA).
Patients and Methods: Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board–approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement.
Results: Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States.
Conclusion: BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.
 
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) Journal of Cancer Education; 27: 217-225.
 
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 Web-based 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) Journal of Cancer Education; 27: 467-477.
 
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) Journal of Clinical Oncology; 30: 1058-1063.
 
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.
 

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 on this study, 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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