Tag Archives: Genetics

British Columbian Researchers Make Groundbreaking Genetic Discovery In Endometriosis-Associated Ovarian Cancers

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British Columbian researchers discover that approximately one-half of clear-cell ovarian cancers and one-third of endometrioid ovarian cancers possess ARID1A gene mutations, as reported today in the New England Journal of Medicine.

British Columbian researchers discover that approximately one-half of ovarian clear-cell cancers (OCCC) and one-third of endometrioid ovarian cancers possess ARID1A (AT-rich interactive domain 1A (SWI-like)) gene mutations, as reported today in the New England Journal of Medicine (NEJM). The research paper is entitled ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas, and represents, in large part, the collaborative work of Drs. David Hunstman and Marco Marra.

Dr. David Huntsman, Co-Founder & Acting Director, Ovarian Cancer Research Program of British Columbia

Dr. Marco Marra, Director, Michael Smith Genome Sciences Centre, British Columbia Cancer Agency

David Huntsman, M.D., FRCPC, FCCMG, is a world-renowned genetic pathologist, and the Co-Founder and Acting Director of the Ovarian Cancer Research Program of British Columbia (OvCaRe). He also heads the Centre for Translational and Applied Genomics, located in the British Columbia (BC) Cancer Agency’s Vancouver Centre.  Dr. Huntsman is the Co-Director of the Genetic Pathology Evaluation Centre, Vancouver General Hospital, and the Associate Director of the Hereditary Cancer Program, BC Cancer Agency. He is involved in a broad range of translational cancer research and, as the OvCaRe team leader, has studied the genetic and molecular structure of ovarian cancer for many years. In June 2009, the NEJM published one of Dr. Huntsman’s most recent groundbreaking discoveries:  the identification of  mutations in the FOXL2 gene as the molecular basis of adult granulosa cell ovarian cancer tumors.

Marco Marra, Ph.D. is the Director of the BC Cancer Agency’s Michael Smith* Genome Sciences Centre (GSC) , one of eight BC Cancer Agency specialty laboratories. Dr. Marra is internationally recognized as a preeminent leader in the field of genetics.  His leadership has helped transform the GSC into one of the world’s most advanced and productive centers for development and application of genomics, bioinformatics and related technologies. The work of the GSC , along with collaborations involving the BC Cancer Agency and other local, national and international researchers and organizations, have led to several major scientific breakthroughs over the past decade.

*Dr. Michael Smith won the 1993 Nobel Prize in chemistry for his development of oligonucleotide-based site-directed mutagenesis, a technique which allows the DNA sequence of any gene to be altered in a designated manner. His technique created an groundbreaking method for studying complex protein functions, the basis underlying a protein’s three-dimensional structure, and a protein’s interaction with other molecules inside the cell.

Tackling Ovarian Cancer, “One Subtype At a Time”

In December 2008, the OvCaRe team announced an important discovery about the genetics of ovarian cancer – that instead of being one single disease, it is made up of a spectrum of distinct diseases. “Until now,” says OvCaRe team leader David Huntsman, “ovarian cancer has been treated as a single disease both in the cancer clinic and the research lab.” This may help explain why there have been many fewer advances in ovarian cancer research and treatment than for other cancer types.

On the heels of this important finding, Huntsman says his team decided to tackle ovarian cancers “one subtype at a time.” For its first target, the team chose granulosa cell ovarian tumors, which account for five percent of ovarian tumors and have no known drug treatments. Working with research colleagues at the GSC, Huntsman’s team used the latest genomic sequencing equipment to decipher the genetic code of this ovarian cancer subtype.

“[T]en years ago, ovarian cancer appeared to be an unsolvable problem—the liberating moment came when we established that ovarian cancer is actually a number of distinct diseases … We tailor our research approach to each subtype with the hope of developing effective treatments specific to each disease.”

— Dr. David Huntsman, Co-Founder & Acting Director, Ovarian Cancer Research Program of British Columbia.

The genomic sequencing study results were illuminating, says Huntsman, as the research team was able to identify “a single ‘spelling mistake’ in this tumor’s DNA.” Still, Huntsman is buoyed by the promise of this research and its potential to save lives. “We’ve had dozens of letters and emails from women around the world with granulosa cell tumors, who’ve written to thank us saying this discovery has given them hope they never thought they would have. Reading these letters has been both incredibly humbling and inspiring for our team.” Libby’s H*O*P*E*™ reported Dr. Huntsman’s critical ovarian cancer discovery on June 10, 2009.

The OvCaRe team’s research findings have already been used to advance the care of BC patient Barbara Johns, a fourth grade teacher whose granulosa cell tumor was surgically removed in February 2009. “This could lead to new non-surgical treatment options for patients with this type of cancer,” says Johns, who was the first patient to benefit from the new diagnostic test. “It’s definitely a step in the right direction.”

Listen to a brief audio excerpt taken from an interview with Dr. David Huntsman, in which he explains why this is an exciting time for ovarian cancer research.

The Ovarian Cancer Research Program of British Columbia

Select NEJM Article Authors (left to right): Drs. Sohrab Shah, David Huntsman, Dianne Miller, C. Blake Gilks

OvCaRe, a multi-institutional and multi-disciplinary ovarian cancer research group, was developed as a collaboration between the BC Cancer Agency, the Vancouver Coastal Health Research Institute, and the University of British Columbia.  The OvCaRe program includes clinicians and research scientists from Vancouver General Hospital (VGH) and the BC Cancer Agency, who specialize in gynecology, pathology, and medical oncology. As noted above, Dr. Huntsman leads the OvCaRe team as its Co-Founder and Acting Director.

A team approach has ensured the building of translational research platforms, accessible to all OvCaRe team members regardless of institutional affiliation or medical/scientific discipline. The OvCaRe program research platforms include a gynecologic cancer tumor bank, the Cheryl Brown Ovarian Cancer Outcomes Unit, a tissue microarray core facility for biomarker studies, a xenograft core facility for testing experimental therapeutics, and a genomics informatics core facility. OvCaRe is developing two additional core facilities to improve knowledge dissemination and clinical trials capacity.

Although OvCaRe was formed less than ten years ago, the team has been recognized for several groundbreaking medical and scientific discoveries related to the understanding and management of ovarian cancer. The significant discoveries reported within the past two years are listed below.

  • Proved that various subtypes of ovarian ovarian are distinct diseases, and reported that potential treatment advances depend on both clinically managing and researching these subtypes as separate entities (2008)( PMID: 19053170).
  • Identified mutations in the FOXL2 gene as the molecular basis of adult granulosa cell ovarian cancer tumors using next generation sequencing – the first clinically relevant discovery made with this new technology (2009)(PMID: 19516027).
  • Discovered that women with earlier stage ovarian clear-cell cancer may benefit from lower abdominal radiation therapy (2010)(PMID: 20693298).

In many cases, these contributions have already led to changes in clinical practice in British Columbia. The international reputation of Vancouver’s OvCaRe team ensures that the positive impact of these changes is felt immediately throughout British Columbia, while also being emulated in other jurisdictions worldwide.  These contributions were made possible due to the population-based cancer system in British Columbia and strong support from the BC Cancer Foundation and the Vancouver General Hospital (VGH) & University of British Columbia (UBC) Hospital Foundation.

Background:  Ovarian Clear-Cell Cancer

Ovarian cancer ranks as the 5th deadliest cancer among U.S. women.[1] There are four general subtypes of epithelial ovarian cancer — serous, clear-cell, endometrioid, and mucinous.[2] High-grade serous ovarian cancer is the most common and represent approximately 70% of all cases of epithelial ovarian cancer in North America. [3]

The OCCC subtype represents 12 percent of ovarian cancers in North America; however, it represents up to 20 percent of ovarian cancers diagnosed in Japan and other East Asian countries. [3,4] OCCC possesses unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of vascular thromboembolic complications, and hypercalcemia. [4-6] Both OCCC and endometrioid ovarian cancer are frequently associated with endometriosis. [4-6] The genetic events associated with the transformation of endometriosis into ovarian clear-cell cancer and endometrioid cancer are unknown.

Clear cell carcinoma of the ovary

OCCC does not respond well to the standard platinum and taxane-based ovarian cancer chemotherapy: response rates are 15 per cent compared to 80 per cent for the most common type of ovarian cancer, high-grade serous ovarian cancer. [4-6] However, the exact mechanisms underlying OCCC’s resistance to chemotherapy is not fully understood. Although several mechanisms involved in drug resistance exist in OCCC, including decreased drug accumulation, increased drug detoxification, increased DNA repair activity [4-6], and low proliferation activity[4]; no particular chemoresistance system has been identified. Due to the general chemoresistant nature of OCCC, it is generally stated that the prognosis for advanced-stage or recurrent OCCC is poor. [3, 7-8] The prognosis for OCCC that is diagnosed in Stage I, and treated by complete cytoreduction that results in little or no residual disease, is usually good. [8-10]

Although OCCC is the second leading cause of death from ovarian cancer, it is relatively understudied by the medical and research community. Despite this fact, there have been a few important studies involving this subtype of ovarian cancer.

Various researchers have long noted that OCCC has a distinct genetic profile, as compared to other types of epithelial ovarian cancer.[6, 11-14] Gene expression profiling can serve as a powerful tool to determine biological relationships, if any, between tumors.  In fact, National Cancer Institute (NCI) and Memorial Sloan-Kettering Cancer Center (MSKCC) researchers observed that clear-cell cancers share similarity in gene expression profiles, regardless of the human organ of origin (including kidney), and could not be statistically distinguished from one another. [13] The researchers found that the same was not true for the non-OCCC forms of epithelial ovarian cancer.  Several investigators have made similar observations. [14-16] It is important to note, however, that there are significant genetic differences between OCCC and renal clear-cell cancer (RCCC).  For example, abnormalities of the VHL (Von Hippel-Lindau)/HIF1-α (Hypoxia-inducible factor 1-alpha) pathway have been identified in the majority of RCCC cases, but not in OCCC cases. [17, 18]

The basic finding that clear-cell tumors show remarkably similar gene expression patterns regardless of their organ of origin is provocative.  This NCI/MSKCC study finding raises the question of whether therapies used to treat RCCC would be effective against OCCC.  Targeted-therapies such as VEGFR inhibitors (e.g., sunitinib (Sutent®)), PDGFR inhibitors (e.g., sorafenib (Nexavar®)), m-TOR inhibitors (e.g., temsirolimus (Torisel®) & everolimus (Afinitor®)), and anti-angiogenesis drugs (e.g., bevacizumab (Avastin®)) are used to treat RCCC. Notably, Fox Chase Cancer Center researchers performed preclinical testing of everolimus on ovarian cancer cell lines and xenografted mice and observed significant anti-tumor activity. [19, 20] The Division of Clinical Gynecologic Oncology at the Massachusetts General Hospital also observed the anti-tumor effect of sunitinib in one refractory OCCC patient that recurred after nine years and four prior treatment lines. [21] Japanese researchers have also highlighted this potential approach to fighting OCCC. [22-25]

All of the above-mentioned drugs used to treat RCCC are currently being tested in ovarian cancer and solid tumor clinical studies.  Accordingly, these drugs are generally available to advanced-stage and recurrent OCCC patients who do not respond to prior taxane/platinum therapy and other standard lines of treatment, assuming such patients satisfy all clinical study enrollment criteria. [26-30]

In a 2009 study conducted by researchers at Johns Hopkins and University of California, Los Angeles (UCLA), it was discovered that approximately one-third of OCCCs contained PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) gene mutations. [31] Testing patients with cancer for PIK3CA gene mutations may be feasible and allow targeted treatment of the PI3K-AKT–mTOR cellular signaling pathway, according to the results of a University of Texas, M.D. Anderson Cancer Center study presented at the 2009 AACR (American Association for Cancer Research)-NCI-EORTC (European Organization For Research & Treatment of Cancer) International Conference on Molecular Targets and Cancer Therapeutics. [31] The M.D. Anderson study results may carry great significance in the future because there are several PI3K signaling pathway targeting drugs in clinical development for use against ovarian cancer and solid tumors. [32]

Also in 2009, researchers affiliated with UCLA, the Mayo Clinic, and Harvard Medical School announced that they established a biological rationale to support the clinical study of the U.S. Food & Drug Administration (FDA)-approved leukemia drug dasatinib (Sprycel®), either alone or in combination with chemotherapy, in patients with ovarian cancer (including OCCC). [33]

In August 2010, Dr. Ken Swenerton, a senior OvCaRe team member and co-leader of OvCaRe’s Cheryl Brown Ovarian Cancer Outcomes Unit, reported provocative findings relating to the use of adjuvant radiotherapy to fight OCCC. [34] Dr. Swenerton is also a co-chair of the NCI Gynecologic Cancer Steering Committee (GCSC) Ovarian Cancer Task Force.  The NCI GCSC determines all phase III clinical trials for gynecologic cancers in the U.S. and other jurisdictions. The population-based, retrospective study conducted by OvCaRe reported that a 40 percent decrease in disease specific mortality was associated with adjuvant radiotherapy administered to women with stage I (other than grade 1 tumors), II, & III clear-cell, endometrioid, and mucinous ovarian cancers, who possessed no residual (macroscopic) disease following complete cytoreductive surgery. Although the study dataset was too small to discriminate effects among the clear-cell, endometrioid and mucinous ovarian cancer histologies, the overall results highlight the curative potential of adjuvant radiotherapy in select non-serous ovarian cancer patients.  Moreover, there is limited scientific and anecdotal evidence set forth in past studies that supports the select use of radiotherapy against OCCC. [35-38]

BRCA 1 (BReast CAncer gene 1) & BRCA 2 (BReast CAncer gene 2) mutations increase a woman’s lifetime risk of breast and ovarian cancer. [39] In at least one small study, BRCA2 germline (inherited) and somatic (non-inherited) gene mutations were identified in 46 percent of the OCCC samples tested. [40] This provocative study brings into question the potential use of PARP (Poly (ADP-ribose) polymerase) inhibitors against OCCC in select patients. [41] PARP inhibitors have shown effectiveness against germline BRCA gene mutated ovarian cancers, [42, 43] and may be effective against somatic BRCA gene mutated ovarian cancers. [44, 45]

International researchers continue to identify theoretical therapeutic drug targets for OCCC. These targets include:  IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3) [46], HNF-1beta (hepatocyte nuclear factor-1beta) [47], annexin A4  [48], GPC3(Glypican-3) [49], osteopontin [50], sFRP5 (secreted frizzled-related protein 5) [51], VCAN (versican) [52], transcription factor POU6F1 (POU class 6 homeobox 1) [53], and microRNA mir-100 [54].

Although researchers have identified that OCCC is distinct from high-grade serous carcinoma, OCCC-specific biomarkers and treatments have not been broadly adopted. Despite the theoretical approaches and study results highlighted above, there are no definitive (i.e., clinically-proven) anti-cancer agents for OCCC, and without understanding the molecular basis of this ovarian cancer subtype in much greater detail, the development of more targeted therapies is unlikely.

NEJM ARID1A Study Methodology

The OvCaRe team research consisted of four major analyses as described below.

  • RNA Sequencing of OCCC Tumor Samples and Cell Line (Discovery Cohort)

By way of background, DNA (deoxyribonucleic acid) is the genetic material that contains the instructions used in the development and functioning of our cells. DNA is generally stored in the nucleus of our cells. The primary purpose of DNA molecules is the long-term storage of information. Often compared to a recipe or a code, DNA is a set of blueprints that contains the instructions our cells require to construct other cell components, such as proteins and RNA (ribonucleic acid) molecules. The DNA segments that carry this genetic information are called genes.

RNA is the genetic material that transcribes (i.e., copies) DNA instructions and translates them into proteins.  It is RNA’s job to transport the genetic information out of the cell’s nucleus and use it as instructions for building proteins.  The so-called “transcriptome” consists of all RNA molecules within our cells, including messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). The sequence of RNA mirrors the sequence of the DNA from which it was transcribed or copied. Consequently, by analyzing the entire collection of RNAs (i.e., the transcriptome) in a cell, researchers can determine when and where each gene is turned on or off in our cells and tissues.  Unlike DNA, the transcriptome can vary with external environmental conditions. Because it includes all mRNA transcripts in the cell, the transcriptome reflects the genes that are being actively expressed at any given time.

A gene is essentially a sentence made up of the bases A (adenine), T (thymine), G (guanine), and C (cytosine) that describes how to make a protein.  Any change in the sequence of bases — and therefore in the protein instructions — is a mutation. Just like changing a letter in a sentence can change the sentence’s meaning, a mutation can change the instruction contained in the gene.  Any changes to those instructions can alter the gene’s meaning and change the protein that is made, or how or when a cell makes that protein.

Gene mutations can (i) result in a protein that cannot carry out its normal function in the cell, (ii) prevent the protein from being made at all, or (iii) cause too much or too little of a normal protein to be made.

The first study analysis involved the RNA sequencing of 18 patient OCCC tumors and 1 OCCC cell line.  The primary purpose of this step was to discover any prevalent genetic mutations within the sample tested.  Specifically, the research team sequenced the whole transcriptomes of the OCCC tumors and the single OCCC cell line and discovered  a variety of somatic (non-inherited) mutations in the ARID1A gene.  The researchers also found mutations in CTNNB1(catenin beta-1 gene), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue gene), and PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide gene).

ARID1A encodes the BAF250a protein, a key component of the SWI-GNF chromatin remodeling complex which regulates many cellular processes, including development, differentiation, proliferation, DNA repair, and tumor suppression. [55] The BAF250a protein encoded by ARID1A is believed to confer specificity in regulation of gene expression.

To date, mutations or other aberrations in ARID1A have not been identified in ovarian cancer, but have been identified in breast and lung cancer cell lines. [56] Other researchers have suggested that ARID1A is a tumor-suppressor gene. [56]

  • DNA Sequencing of OCCC Tumor Samples and Cell Lines (Discovery Cohort + Mutation Validation Cohort)

The finding of multiple types of mutations in a single gene, ARID1A, within the discovery cohort, led researchers to perform a mutation validation analysis.  The researchers only conducted analyses with respect to ARID1A, because it was already known that mutations in CTNNB1, KRAS, and PIK3CA are recurrent in ovarian cancer. [31, 57]

This step of the research involved DNA sequencing of 210 samples of various subtypes of ovarian cancer and one OCCC cell line, along with the 18 OCCC tumor samples and one OCCC cell line used in the discovery cohort. Upon completion of the DNA sequencing, the researchers identified ARID1A mutations in 55 of 119 (46%) OCCCs, 10 of 33 (30%) endometrioid cancers, and none of the 76 high-grade serous cancers. Also, the researchers found primarly somatic (non-inherited) truncating mutations.

Based on the second study analysis, the researchers report that the presence of ARID1A mutations are strongly associated with OCCCs and endometrioid cancers.  These two subtypes of ovarian cancer, as noted above, are associated with endometriosis.

  • Testing For BAF250a Protein Expression

In the third study analysis, the researchers used immunohistochemical analysis (IHC) to measure BAF250a protein expression in 450 ovarian cancers.

The first round of IHC testing involved 182 ovarian cancers which were available from the discovery cohorts and the mutation-validation cohorts: 73 OCCCs, 33 endometrioid cancers, and 76 high-grade serous ovarian cancers.  The goal of the first IHC analysis was to compare the loss of BAF250a protein expression in OCCCs and endometrioid cancers, with and without ARID1A mutations. Upon completion, the researchers identified loss of BAF250a protein expression in 27 of 37 (73%) OCCCs, and 5 of 10 (50%) endometrioid cancers, which possessed ARID1A mutations. In contrast, loss of BAF250a protein expression was identified in only 4 of 36 (11%) OCCCs, and 2 of 23  (9%) endometrioid cancers, which did not possess ARID1A mutations. Thus, the loss of BAF250a protein expression was much greater in OCCCs and endometrioid cancers with ARID1A mutations.

The goal of the second IHC analysis was to compare loss of BAF250a protein expression among all OCCCs, endometrioid cancers, and high-grade serous cancers. The researchers identified loss of BAF250a protein expression in 31 of 73 (42%) OCCCs, and 7 of 33 (21%) endometrioid cancers, as compared to 1 of 76 (1%) high-grade serous cancers. Thus, the loss of BAF250a protein expression was much greater in the OCCCs and endometrioid cancers, as compared to high-grade serous cancers, regardless of ARID1A mutation status.

The second round of IHC testing measured loss of BAF250a protein expression within the IHC validation cohort. This analysis revealed that 55 of 132 (42%) OCCCs, 39 of 125 (31%) endometrioid cancers, and 12 of 198 (6%) high-grade serous cancers, lost BAF250a protein expression.

By the end of IHC testing, the researchers established that the loss of BAF250a protein expression was consistently more common in OCCCs and endometrioid cancers than in high-grade serous cancers, when assessed in the discovery and mutation-validation cohorts, and again in the IHC cohort.

The researchers also reported that no significant associations with loss of BAF250a protein expression were noted on the basis of age at disease presentation, disease stage, or disease-specific survival within any of the ovarian cancer subtypes.

  • Analysis of ARID1A Gene Mutations & BAF250a Protein Expression In Continguous Atypical Endometriosis

The fourth study analysis evaluated samples taken from two OCCC patients who had ARID1A mutations and contiguous atypical endometriosis. In both instances, the patient sample included the primary OCCC tumor, clones derived from contiguous atypical endometriosis, and clones derived from a distant endometriotic lesion.

In the first patient, ARID1A mutations were identified in the OCCC tumor, and 17 of 42 clones derived from contiguous atypical endometriosis, but in none of the 52 clones derived from a distant endometriotic lesion. The samples taken from this patient’s OCCC tumor and atypical endometriosis revealed loss of BAF250a protein expression; however, expression was maintained in the distant endometriotic lesion. HNF-1beta was expressed in the OCCC tumor, but not in the contiguous atypical or distant endometriosis. Estrogen receptor expression tested positive in both the contiguous atypical and distant endometriosis, but not in the OCCC tumor.

In the second patient, ARID1A mutations and a CTNNB1 mutation were identified in the OCCC tumor and contiguous atypical endometriosis, but not in a distant endometriotic lesion.

Results Summary

Based on the foregoing discussion, the major OvCaRe study findings are summarized below.

  • 46% of patients with OCCC and 30% of those with endometrioid cancers had somatic (non-inherited) truncating or missense mutation in the ARID1A gene.
  • No ARID1A mutations were identified in the 76 high-grade serous cancers analyzed.
  • Loss of BAF250a protein expression was identified in 36% of OCCCs and endometrioid cancers, but in only 1% of high-grade serous cancers.
  • Loss of BAF250a protein expression was seen in 73% and 50% of OCCCs and endometrioid cancers with an ARID1A mutation, respectively, and in only 11% and 9% of samples without ARID1A mutations, respectively.
  • The majority of cancers possessing somatic ARID1A mutations and loss of BAF250a expression appear to have a normal (also known as “wild-type”) allele present.
  • DNA and RNA sequencing data reveals that the ratio of abnormal (mutant) to normal (wild-type) alleles at both the DNA and RNA levels is consistent, thereby suggesting that epigenetic silencing is not a significant factor.
  • In two patients, ARID1A mutations and loss of BAF250a protein expression were identified in the OCCC tumor and contiguous atypical endometriosis, but not in distant endometriotic lesions.

Conclusions

The researchers note in the study that ARID1A is located at chromosome 1p36.11. Although this fact carries little meaning for a layperson, the researchers explain that this chromosomal region is commonly deleted in tumors, and that such deletions could contain tumor-suppressor genes. Based upon the totality of the data, the OvCaRe team believes that ARID1A is a tumor-suppressor gene which is frequently disrupted in OCCCs and endometrioid cancers.  Although a bit speculative due to small sample size, the researchers also believe that because ARID1A mutation and loss of BAF250a protein expression were identified in precancerous endometriotic lesions, such events represent a transformation of endometriosis into cancer.

“The finding that ARID1A is the most frequently mutated gene described thus far in endometrioid and clear cell ovarian cancers represents a major scientific breakthrough. This discovery also sheds light on how endometriosis predisposes to the development of these cancers. The novel insights provided by this work have the exciting potential to facilitate advances in early diagnosis, treatment and prevention of endometrioid and clear cell cancers, which account for over 20 per cent of ovarian cancer cases.”

—Dr. Andrew Berchuck, Director, Division of Gynecologic Oncology, Duke University Medical Center

Inaugural Ovarian Clear-Cell Carcinoma Symposium

International Clear-Cell Carcinoma of the Ovary Symposium (June 24, 2010)

On June 24, 2010, a group of preeminent clinicians and cancer research scientists from around the world gathered for the Clear Cell Carcinoma of the Ovary Symposium (the Symposium), which was held at the University of British Columbia. To my knowledge, the Symposium is the first global scientific meeting dedicated to a specific subtype of ovarian cancer, namely OCCC.

At the invitation of Dr. David Huntsman, the founder of the Symposium, I had the distinct pleasure and honor of attending this prestigious and informative meeting as an observer. Dr. Huntsman was aware that my 26-year old cousin, Libby, died from OCCC, and he thought that the Libby’s H*O*P*E*™ community would benefit from the information presented at the Symposium.

The stated goal of the Symposium was to empower the international clinical and research community interested in OCCC, and allow that community to focus on the major barriers to improving OCCC outcomes. Moreover, the Symposium speakers and attendees were charged with presenting unpublished data and providing provocative OCCC questions for group discussion. The countries represented at that Symposium included Australia, Canada, Italy, Japan, the United Kingdom, and the U.S.

The 1-day event was presented through three major sessions.  The first session addressed issues that challenge the clinical dogma relating to OCCC, and covered topic areas such as epidemiology, surgery, pathology, systemic oncology, and radiation oncology. The second session addressed OCCC molecular pathology and genomics.  The third session addressed global OCCC translational research and covered topic areas including OCCC outcomes from conventional clinical trials, current OCCC clinical trials, and novel approaches to OCCC treatment and the testing of new agents.

The international Symposium presenters, included the following individuals:

  • David Bowtell, Group Leader, Cancer Genetics & Genomics Research Laboratory, Peter MacCallum Cancer Centre; Program Head, Cancer Genetics & Genomics, Peter MacCallum Cancer Centre, Melbourne (Australia).
  • Michael A. Quinn, MB ChB Glas. MGO Melb. MRCP FRCOG FRANZCOG CGO, Director of Oncology/Dysplasia, Royal Women’s Hospital, Melbourne, Australia; Professor, Department of Obstetrics and Gynecology, University of Melbourne; Chair, National Cancer Control Initiative; Chair, Education Committee, International Gynecological Cancer Society; Chair, Ovarian Cancer Research Group, Cancer Council; Member, National Expert Advisory Group on Ovarian Cancer. (Australia)
  • C. Blake Gilks, M.D., FRCPC,  Co-Founder, Ovarian Cancer Research Program of BC; Professor & Acting Head, Department of Pathology and Laboratory Medicine, University of British Columbia; Head of Anatomic Pathology, Vancouver General Hospital; Member, Vancouver Coastal Health Research Institute; Co-Founder & Co-Director, Genetic Pathology Evaluation Centre, Vancouver General Hospital. (Canada)
  • Paul Hoskins, MA, M.B. B. CHIR, MRCP., FRCPC, Clinical Professor, University of British Columbia. (Canada)
  • David Huntsman, M.D., FRCPC, FCCMG, Co-Founder & Acting Director, Ovarian Cancer Research Program of British Columbia; Director, Centre for Translational and Applied Genomics, BC Cancer Agency; Co-Director, Genetic Pathology Evaluation Centre, Vancouver General Hospital; Associate Director, Hereditary Cancer Program, BC Cancer Agency. (Canada)
  • Helen MacKay, M.D., Staff Physician, Division of Medical Oncology and Hematology, Princess Margaret Hospital; Assistant Professor, University of Toronto; Member: (i) ICON 7 Translational Committee (representing NCIC CTG),  (ii) Study Committee of the TFRI Ovarian Cancer Biomarker Program, (iii) Gynecologic Cancer Steering Committee Cervical Cancer Task Force: Intergroup/NCI/National Institutes of Health, (iv) Cervix Working Group (NCIC CTG), (v) Gynecologic Disease Site Group (Cancer Care Ontario), and (vi) the GOC CPD Committee. (Canada)
  • Amit M. Oza, Bsc, MBBS, M.D., FRCPC, FRCP, Senior Staff Physician & Professor of Medicine, Princess Margaret Hospital, University of Toronto; Clinical Studies Resource Centre Member, Ontario Cancer Institute. (Canada)
  • Ken Swenerton, M.D., Co-Leader, Cheryl Brown Ovarian Cancer Outcomes Unit, Ovarian Cancer Research Program of BC; Clinical Professor, Medical Oncology, University of British Columbia; Department of Pathology, Vancouver Coastal Health Research Institute;  Genetic Pathology Evaluation Centre,Vancouver General Hospital; Co-Chair, NCI Gynecologic Cancer Steering Committee Ovarian Cancer Task Force. (Canada).
  • Anna Tinker, M.D., FRCPC, Clinical Assistant Professor, University of British Columbia, Department of Medicine; Medical Oncologist, Oncology, British Columbia Cancer Agency (Canada).
  • Gillian Thomas, M.D., FRCPC, Professor, Department of Radiation Oncology & Obstetrics and Gynecology, University of Toronto; Radiation Oncologist, Odette Cancer Centre; Co-Chair, NCI Gynecologic Cancer Steering Committee; Member, ACRIN Gynecologic Committee; Member, Cervix Committee and Executive Committee, Gynecologic Cancer Intergroup (GCIG); Member, Cervix Committee – Gynecologic Oncology Group (GOG); Associate Editor, International Journal of Gynecologic Cancer. (Canada)
  • Aikou Okamoto, M.D., Department of Obstetrics & Gynecology, Jikei University School of Medicine, Tokyo (Japan).
  • Ian McNeish, MA, Ph.D., MRCP, MRC, Senior Clinical Fellow, Professor of Gynecological Oncology & Honorary Consultant in Medical Oncology, Deputy Director of the Barts Experimental Cancer Medicine Centre, Institute of Cancer, Barts and the London School of Medicine. (United Kingdom) (See Libby’s H*O*P*E*™, April 7, 2009)
  • Michael J. Birrer, M.D., Ph.D., Director of GYN/Medical Oncology at the Massachusetts General Hospital Cancer Center; Professor, Department of Medicine, Harvard Medical School; Co-Chair, NCI Gynecologic Cancer Steering Committee; formerly, Chief of the Molecular Mechanisms Section, Cell and Cancer Biology Branch, NCI Center for Cancer Research; formerly official representative from NCI Center for Cancer Research to the Gynecological Cancer Steering Committee. (United States)(See Libby’s H*O*P*E*™, December 8, 2009)

OvCaRe Ovarian Clear-Cell Carcinoma Research Initiative

As noted above, OCCC has been identified as distinct subtype of ovarian cancer.  OCCC-specific biomarkers or treatments have not been broadly adopted. Moreover, there are currently no clinically proven anti-cancer agents for OCCCs. For this reason, the OvCaRe team and other BC Cancer Agency scientists, have initiated a pioneering OCCC research initiative that consists of six separate, but interrelated projects.

The project will begin with the most fundamental research, the large scale sequencing of RNA and DNA derived from OCCC tumors. In the second, concurrent project, the vast quantities of genome sequence data will be transformed into usable knowledge that will be evaluated for clinical relevance by local and international experts. Identifying and validating novel biomarkers from the data obtained will be the focus of the third project, and the fourth project will permit scientists to specifically target those cellular biochemical signaling pathways that are considered to be useful tools for future drug development. The development and testing of the therapeutic targets and new drugs or new combinations of drugs in animal and human testing will complete this initiative.

The OvCaRe and the BC Cancer Agency scientists have a unique opportunity to completely reshape the scientific and medical understanding of OCCC and impact the way patients with this rare form of cancer are treated. The strength of their research initiative is based on linking the clinical research resources developed through OvCaRe with the genomic sequencing capacity of the BC Cancer Agency’s Genome Sciences Centre, and the drug development capacity of the Centre for Drug Research and Development and the NanoMedicine Research Group.

“This pioneering discovery by Dr. Huntsman and his dedicated ovarian cancer research team will allow the international research community to take the genomic ‘high ground’ in the battle against these formidable subtypes of epithelial ovarian cancer. The Ovarian Cancer Research Program of BC’s reported findings represent a critical first step towards development of one or more personalized targeted therapies to combat these lethal forms of ovarian cancer.”

—Paul Cacciatore, Founder, Libby’s H*O*P*E*™

The impact of this research may not be experienced by women diagnosed with OCCC today, but this foundational research must begin immediately so as to impact outcomes in the years to come. Ably led by Dr. David Huntsman, this team of dedicated individuals represents a depth and breadth of medical and scientific expertise not often found in a single geographic location.

The hope is that through the identification of therapeutic targets for OCCC, this team will yield a powerful “superstar” drug such as Herceptin (used successfully for HER-2 positive breast cancer) or Gleevec (used successfully for chronic myelogenous leukemia (CML)). These drugs are examples of therapeutics that were created based on a direct match of an identified genetic target to the therapeutic solution.

This project is of utmost importance as it will define the unique aspects of OCCC and lead to the development of more effective therapies for women diagnosed with this rare subtype of ovarian cancer.

Special Acknowledgments

First and foremost, I want to thank Dr. Huntsman for his intelligence, creative vision and compassion, which he utilizes to great effect each day, in conducting scientific research designed to ultimately benefit all women with OCCC. I also want to thank Dr. Huntsman for the generous invitation to attend the OCCC Symposium in June. It was a privilege and honor to attend and listen to international OCCC experts discuss and debate the merits of various approaches to beating this subtype of epithelial ovarian cancer. In sum, Dr. Huntsman has been extremely generous to me with respect to his time and expertise during my recent trip to Vancouver and throughout my preparation of this article.

Prior to today’s ARID1A gene mutation discovery announcement, women with OCCC did not have a “voice” in the cancer research scientific community. Dr. Huntsman has not only given these women a voice, he has given them hope for the future.  As the late Christopher Reeve said: “Once you choose hope, anything is possible.”

I also want to thank the OvCaRe team members and BC Cancer Agency scientists that I met in Vancouver during my June trip, including Ken Swenerton, M.D., Sohrab Shah, Ph.D., Dianne Miller, M.D., Sam Aparicio, Ph.D., and Blake Gilks, M.D., for taking the time to answer all of my novice questions with a great understanding and passion.

Simply stated, this article would not have been possible without the substantial assistance provided to me by Sharon Kennedy, a Senior Director of Development with the BC Cancer Foundation. Sharon exemplifies the “heart and soul” behind the BC Cancer Foundation’s philanthropic activities.

Last, but certainly not least, I want to thank Mr. Douglas Gray, a highly successful entrepreneur and attorney, for introducing me to the BC scientific cancer research community. Doug is a tireless supporter of all women with OCCC, through his compassion, caring, and philanthropic generosity.

The Talmud says: “And whoever saves a life, it is considered as if he saved an entire world.” Doug Gray is in the business of saving women’s lives.

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References:

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2/Cellular Classification of Ovarian Epithelial Cancer, Ovarian Epithelial Cancer Treatment (PDQ®)(Health Professional Version), National Cancer Institute, July 9, 2010.

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6/Sugiyama T & Fujiwara K.  Clear Cell Tumors of the Ovary – Rare Subtype of Ovarian Cancer, Gynecologic Cancer, ASCO Educational Book, 2007 ASCO Annual Meeting, June 2, 2007 (Microsoft Powerpoint presentation).

7/Chan JK, Teoh D, Hu JM, Shin JY, Osann K, Kapp DS. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol. 2008 Jun;109(3):370-6. [Epub 2008 Apr 18].

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9/Takano M, Sasaki N, Kita T, Kudoh K, Fujii K, Yoshikawa T et. al. Survival analysis of ovarian clear cell carcinoma confined to the ovary with or without comprehensive surgical staging; Oncol Rep. 2008 May;19(5):1259-64.

10/Takano M, Kikuchi Y, Yaegashi N, Kuzuya K, Ueki M, Tsuda H et. al.  Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging. Br J Cancer. 2006 May 22;94(10):1369-74.

11/Sugiyama T, Kumagai S, & Hatayama S. Treatments of epithelial ovarian cancer by histologic subtype. Gan To Kagaku Ryoho. 2009 Feb;36(2):187-92.

12/Pectasides D, Pectasides E, Psyrri A, Economopoulos T. Treatment Issues in Clear Cell Carcinoma of the Ovary: A Different Entity?. Oncologist. 2006 Nov-Dec;11(10):1089-94.

13/Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ et. al.  Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer; Clin Cancer Res. 2005 Sep 15;11(18):6422-30.

14/Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, et. al. Gene Expression Patterns in Ovarian Carcinomas; Mol. Bio. Cell 2003 Dec.; 14(11):4376-4386.

15/Tan DS, Kaye S.  Ovarian clear cell adenocarcinoma: a continuing enigma.  J Clin Pathol. 2007 Apr;60(4):355-60. Epub 2006 Oct 3.

16/ Dent J, Hall GD, Wilkinson N, Perren TJ, Richmond I, Markham AF, et. al. Cytogenetic alterations in ovarian clear cell carcinoma detected by comparative genomic hybridisation. Br J Cancer. 2003 May 19;88(10):1578-83.

17/Costa LJ, Drabkin HA. Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies. Oncologist 2007;12:1404-1415.

18/Köbel M, Xu H, Bourne PA, Spaulding BO, Shih IM; Mao TL et. al. IGF2BP3 (IMP3) Expression Is a Marker of Unfavorable Prognosis in Ovarian Carcinoma of Clear Cell Subtype. Modern Pathology. 2009;22(3):469-475. [Epub 2009 Jan 9].

19/Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, et. al. RAD001[everolimus] inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model.  Clin. Cancer. Res. 2007 Jul; 13, 4261-4270.

20/Mabuchi S, Altomare DA, Connolly DC, Klein-Szanto A, Litwin S, Hoelzle MK, et. al. RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer.  Cancer Res. 2007 Mar 15;67(6):2408-13.

21/Rauh-Hain JA, Penson RT. Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma. Int J Gynecol Cancer. 2008 Sep-Oct;18(5):934-6. Epub 2007 Dec 13.

22/Yoshida S, Furukawa N, Haruta S, et. al. Theoretical model of treatment strategies for clear cell carcinoma of the ovary: focus on perspectives. Cancer Treat Rev. 2009 Nov;35(7):608-15. Epub 2009 Aug 8. Review.

23/Mabuchi S, Kawase C, Altomare DA, et. al.  mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary. Clin Cancer Res. 2009 Sep 1;15(17):5404-13. Epub 2009 Aug 18.

24/Miyazawa M, Yasuda M, Fujita M, et. al. Therapeutic strategy targeting the mTOR-HIF-1alpha-VEGF pathway in ovarian clear cell adenocarcinoma. Pathol Int. 2009 Jan;59(1):19-27.

25/Mabuchi S, Kawase C, Altomare DA, et. al.  Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol Cancer Ther. 2010 Aug;9(8):2411-22. Epub 2010 Jul 27.

26/For open ovarian cancer clinical trials using sunitinib, CLICK HERE; For open solid tumor clinical trials using sunitinib, CLICK HERE.

27/For open ovarian cancer clinical trials using sorafenib CLICK HERE; For open solid tumor clinical trials using sorafenib, CLICK HERE.

28/For open ovarian cancer clinical trials using temsirolimus, CLICK HERE; For open solid tumor clinical trials using temsirolimus, CLICK HERE.

29/For open ovarian cancer clinical trials using everolimus, CLICK HERE; For open solid tumor clinical trials using everolimus, CLICK HERE.

30/For open ovarian cancer clinical trials using bevacizumab, CLICK HERE; For open solid tumor clinical trials using bevacizumab, CLICK HERE.

31/PI3K Pathway: A Potential Ovarian Cancer Therapeutic Target?, by Paul Cacciatore, Libby’s H*O*P*E*™, November 30, 2009.

32/For open ovarian cancer clinical trials using a phosphoinositide 3′-kinase (PI3K)-targeted therapy; CLICK HERE; For open solid tumor clinical trials using a phosphoinositide 3′-kinase (PI3K)-targeted therapy, CLICK HERE.

33/UCLA Researchers Significantly Inhibit Growth of Ovarian Cancer Cell Lines With FDA-Approved Leukemia Drug Dasatinib (Sprycel®),by Paul Cacciatore, Libby’s H*O*P*E*™, November 30, 2009.

34/Swenerton KD, Santos JL, Gilks CB, et. al. Histotype predicts the curative potential of radiotherapy: the example of ovarian cancers. Ann Oncol. 2010 Aug 6. [Epub ahead of print]

35/Nagai Y, Inamine M, Hirakawa M, et. al. Postoperative whole abdominal radiotherapy in clear cell adenocarcinoma of the ovary. Gynecol Oncol. 2007 Dec;107(3):469-73. Epub 2007 Aug 31.

36/Skirnisdottir I, Nordqvist S, Sorbe B. Is adjuvant radiotherapy in early stages (FIGO I-II) of epithelial ovarian cancer a treatment of the past? Oncol Rep. 2005 Aug;14(2):521-9. PubMed PMID: 16012740.

37/Takai N, Utsunomiya H, Kawano Y, et. al. Complete response to radiation therapy in a patient with chemotherapy-resistant ovarian clear cell adenocarcinoma. Arch Gynecol Obstet. 2002 Dec;267(2):98-100.

38/Suzuki M, Saga Y, Tsukagoshi S, et. al. Recurrent ovarian clear cell carcinoma: complete remission after radiation in combination with hyperthermia; a case study and in vitro study. Cancer Biother Radiopharm. 2000 Dec;15(6):625-8.

39/BRCA1 and BRCA2: Cancer Risk and Genetic Testing, National Cancer Institute Fact Sheet, Cancer Topic, National Cancer Institute, May 29, 2009.

40/Goodheart MJ, Rose SL, Hattermann-Zogg M, et. al. BRCA2 alteration is important in clear cell carcinoma of the ovary. Clin Genet. 2009 Aug;76(2):161-7. Epub 2009 Jul 28.

41/For open ovarian cancer clinical trials using PARP inhibitors, CLICK HERE; For open solid tumor clinical trials using PARP inhibitors, CLICK HERE.

42/Audeh MW, Carmichael J, Penson RT, et. al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010 Jul 24;376(9737):245-51. Epub 2010 Jul 6.

43/PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity, by Paul Cacciatore, Libby’s H*O*P*E*™, April 23, 2010.

44/Konstantinopoulos PA, Spentzos D, Karlan BY, et. al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010 Aug 1;28(22):3555-61. Epub 2010 Jun 14.

45/Bast RC Jr, Mills GB. Personalizing therapy for ovarian cancer: BRCAness and beyond. J Clin Oncol. 2010 Aug 1;28(22):3545-8. Epub 2010 Jun 14.

46/Köbel M, Xu H, Bourne PA, et. al. IGF2BP3 (IMP3) expression is a marker of unfavorable prognosis in ovarian carcinoma of clear cell subtype. Mod Pathol. 2009 Mar;22(3):469-75. Epub 2009 Jan 9.

47/Köbel M, Kalloger SE, Carrick J, Huntsman D, et. al. A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol. 2009 Jan;33(1):14-21.

48/Kim A, Serada S, Enomoto T, Naka T. Targeting annexin A4 to counteract chemoresistance in clear cell carcinoma of the ovary. Expert Opin Ther Targets. 2010 Sep;14(9):963-71.

49/Maeda D, Ota S, Takazawa Y, et. al. Glypican-3 expression in clear cell adenocarcinoma of the ovary. Mod Pathol. 2009 Jun;22(6):824-32. Epub 2009 Mar 27.

50/Matsuura M, Suzuki T, Saito T. Osteopontin is a new target molecule for ovarian clear cell carcinoma therapy. Cancer Sci. 2010 Aug;101(8):1828-33. Epub 2010 May 12.

51/Ho CM, Lai HC, Huang SH, et. al. Promoter methylation of sFRP5 in patients with ovarian clear cell adenocarcinoma. Eur J Clin Invest. 2010 Apr;40(4):310-8.

52/Yamaguchi K, Mandai M, Oura T, et. al. Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes.  Oncogene. 2010 Mar 25;29(12):1741-52. Epub 2010 Jan 11.

53/Yoshioka N, Suzuki N, Uekawa A, et. al. POU6F1 is the transcription factor that might be involved in cell proliferation of clear cell adenocarcinoma of the ovary. Hum Cell. 2009 Nov;22(4):94-100.

54/Nagaraja AK, Creighton CJ, Yu Z, et. al. A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. Mol Endocrinol. 2010 Feb;24(2):447-63. Epub 2010 Jan 15.

55/Reisman D, Glaros S, Thompson EA. The SWI/SNF complex and cancer. Oncogene 2009;28:1653-68.

56/Huang J, Zhao YL, Li Y, et. al.  Genomic and functional evidence for an ARID1A tumor suppressor role.  Genes Chromosomes Cancer 2007;46:745-50.

57/Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results, by Paul Cacciatore, Libby’s H*O*P*E*™, August 3, 2010.

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Sources:

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Genetics 101

The information hyperlinked above was obtained from GeneticHealth & the BC Cancer Agency’s Michael Smith Genome Sciences Centre.

About David Huntsman, M.D., FRCPC, FCCMG

David Huntsman, M.D., FRCPC, FCCMG, is a world-renowned genetic pathologist, and the Co-Founder and Director of the Ovarian Cancer Research Program of British Columbia(OvCaRe). He also heads the Centre for Translational and Applied Genomics, located in the British Columbia (BC) Cancer Agency’s Vancouver Centre.  Dr. Huntsman is also the Co-Director of the Genetic Pathology Evaluation Centre, Vancouver General Hospital, and the Associate Director of the Hereditary Cancer Program, BC Cancer Agency. He is involved in a broad range of translational cancer research and, as the OvCaRe team leader, has studied the genetic and molecular structure of ovarian cancer for many years.

His recent retrospective assessment of 21 candidate tissue-based biomarkers implicated that ovarian cancer subtypes are different diseases, contributing to the view that contemplation of disease subtype is crucial to the study of ovarian cancer. To ultimately beat ovarian cancer, Huntsman and his dedicated OvCaRe team believe that ovarian cancer must be genetically tackled “one subtype at a time.”  In June 2009, the NEJM published one of Dr. Huntsman’s most recent groundbreaking discoveries:  the identification of  mutations in the FOXL2 gene as the molecular basis of adult granulosa cell ovarian cancer tumors.  As of today, Dr. Huntsman and his OvCaRe team can add to their groundbreaking discoveries, the identification of frequent ARID1A gene mutations in endometriosis-associated ovarian cancers (i.e., the clear-cell and endometrioid ovarian cancer subtypes).

About Marco Marra, Ph.D.

Marco Marra, Ph.D. is the Director of the BC Cancer Agency’s Michael Smith Genome Sciences Centre (GSC), one of eight BC Cancer Agency specialty laboratories. Dr. Marra is internationally recognized as a preeminent leader in the field of genetics.  His leadership has helped transform the GSC into one of the world’s most advanced and productive centers for development and application of genomics, bioinformatics and related technologies.

The work of the GSC , along with collaborations involving the BC Cancer Agency and other local, national and international researchers and organizations, have led to several major scientific breakthroughs over the past decade.  These breakthroughs include the rapid genome sequencing of the SARS Coronavirus, and the sequencing and genome analysis of the avian flu (H7N3).

About the Ovarian Cancer Research Program of British Columbia (OvCaRe)

The Ovarian Cancer Research Program of BC was formed in late 2000 when a group of Vancouver-based physicians and scientists joined with the common vision of enhancing ovarian cancer research in British Columbia and the explicit goal of improving outcomes for ovarian cancer patients. OvCaRe was developed as a collaboration between the BC Cancer Agency, the Vancouver Coastal Health Research Institute, and the University of British Columbia.  The OvCaRe program includes clinicians and research scientists from the Vancouver General Hospital (VGH) and the British Columbia (BC) Cancer Agency, who specialize in gynecology, pathology, and medical oncology.

OvCaRe is currently focused on three major goals.

1. To improve ovarian cancer survival through early detection of disease. OvCaRe researchers are working to identify proteins that are produced in the early stages of ovarian cancer. Detection of these proteins can then be developed into diagnostic tests to allow for earlier diagnosis of ovarian cancer.

2. To develop new therapies for ovarian cancer treatment. This is being achieved through research aimed at identifying the cause of ovarian cancer at the cellular level and then directly and specifically targeting that defect. OvCaRe is using a similar strategy to develop treatments to prevent ovarian cancer recurrence.

3. To develop individualized ovarian cancer treatments. Ovarian cancer can be subdivided into several groups based on their pathological appearance, however these groups are currently all treated in the same manner, though their responses are quite variable. OvCaRe is working to determine what is responsible for division between ovarian cancers subtypes and developing subtype specific treatments.

OvCaRe is funded through generous donations to the VGH & UBC Hospital Foundation and BC Cancer Foundation. The OvCaRe team is considered a leader in ovarian cancer research, breaking new ground to improve the identification, understanding, and treatment of this disease.

About the British Columbia (BC) Cancer Agency

The BC Cancer Agency provides a comprehensive province-wide, population-based cancer control program for the people of British Columbia, Canada, including prevention, screening and early detection programs, translational research and education, and care and treatment.

The BC Cancer Agency’s mandate covers the spectrum of cancer care, from prevention and screening, to diagnosis, treatment, and rehabilitation. The BC Cancer Agency’s mandate is driven by a three-fold mission: (1) reduce the incidence of cancer, (2)  reduce the mortality rate of people with cancer, and (3) improve the quality of life of people living with cancer. This mission includes providing screening, diagnosis and care, setting treatment standards, and conducting research into causes of, and cures for, cancer.

The BC Cancer Agency operates five regional cancer centres, providing assessment and diagnostic services, chemotherapy, radiation therapy, and supportive care.  Each of the BC Cancer Agency’s centres delivers cancer treatment based on provincial standards and guidelines established by the Agency.

Research is an essential part of the BC Cancer Agency’s mission to not only find the causes of cancer, but to find better treatments for prolonged life and better quality of life. With direct links between the BC Cancer Agency’s physicians and researchers at its five centres (including the Deeley Research Centre (located in Victoria) and the BC Cancer Agency’s Research Centre (located in Vancouver)), the BC Cancer Agency can quickly translate new discoveries into clinical applications. The BC Cancer Agency’s Research Centre includes eight specialty laboratories including the Michael Smith Genome Sciences Centre, and the Terry Fox Laboratory.

The BC Cancer Agency includes the following among its many accomplishments:

  • Canada’s largest fully integrated cancer and research treatment organization;
  • the best cancer incidence and survival rates in Canada as a result of the unique and longstanding population-based cancer control system;
  • leadership in cancer control with world-renowned programs in lymphoid, lung, breast, ovarian and oral cancer research and care; and
  • a unique set of research platforms that form the basis of research and care, including one of the world’s top four genome sciences centres.

About the Vancouver General Hospital (VGH)

The Vancouver General Hospital (VGH) is a 955 bed hospital that offers specialized services to residents in Vancouver and across the province.  VGH is also a teaching hospital, affiliated with the University of British Columbia and home to one of the largest research institutes in Canada.

About the British Columbia (BC) Cancer Foundation

The BC Cancer Foundation is an independent charitable organization that raises funds to support breakthrough cancer research and care at the BC Cancer Agency.

Over 70 years ago, the BC Cancer Foundation, led by a group of prominent BC citizens, created what is today the BC Cancer Agency. The Foundation has offices in all five of the BC Cancer’s Agency’s treatment centres – Abbotsford, Fraser Valley, Southern Interior, Vancouver Island and Vancouver.

About the Vancouver General Hospital (VGH) & University of British Columbia (UBC) Hospital Foundation

The VGH & UBC Hospital Foundation is a registered charity that raises funding for the latest, most sophisticated medical equipment, world-class research and improvements to patient care for VGH, UBC Hospital, GF Strong Rehab Centre and Vancouver Coastal Health Research Institute. For more than 25 years, the Foundation and its donors have been a bridge between the essential health care governments provide and the most advanced health care possible.


Hollywood Celebs Raise Awareness Regarding Hereditary Breast and Ovarian Cancer

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Christina Applegate – Samantha Who?

ABC

Christina Applegate as Samantha in the ABC sitcom Samantha Who? Photo Credit: American Broadcasting Company

Recently diagnosed in July 2008 with breast cancer, Christina Applegate appeared on ABC’s Good Morning America program in August. The talented, Emmy award winning actress is currently the star of the ABC sitcom “Samantha Who?” Applegate came into the Hollywood limelight when she appeared in popular Fox sitcom “Married With Children,” in the role of “Kelly Bundy.”

With a great deal of courage, Christina revealed in the Good Morning America interview that she had a double mastecomy three weeks earlier to remove a tumor in one breast and prevent future breast cancer in the other. Christina made the decision to have a prophylatic double mastecomy because she tested positive previously for the BRCA 1 (breast cancer 1) gene mutation.

“I just wanted to kind of be rid of it,” explained Christina Applegate. “So this was the choice I made and it was a tough one.” Applegate is 36 years old, but because her mother is a two time survivor of breast cancer, Christina was carefully screened for breast cancer since she was 30 years old. “After looking at all the treatment plans, the one that was going to work for me was to have a bilateral mastectomy,” she said during the interview with ABC’s Robin Roberts, also a breast cancer survivor.

“I didn’t want to go back to the doctors every four months for testing. … I’m clear,” she declared. “Absolutely 100 percent clear and clean. It did not spread. They got everything out, so I’m definitely not going to die from breast cancer.”

To view Christina Applegate’s August 19, 2008 interview on ABC’s Good Morning America, CLICK HERE.

Jessica Queller – Pretty is What Changes

Jessica Queller, author of "Pretty is What Changes"

Jessica Queller, author of "Pretty Is What Changes"

Jessica Queller is a famous Hollywood writer/producer who worked on several hit television programs like Felicity, One Tree Hill, and most recently, the Gilmore Girls, which is an Emmy Award-winning, Golden Globe-nominated, American comedy-drama series. Eleven months after her mother succumbed to cancer, Jessica Queller had herself tested for the breast cancer (BRCA) gene mutation. Queller was 34 years old when she took the BRCA gene mutation blood test, and she tested positive, like Applegate, for the BRCA 1 (breast cancer) gene mutation.

Jessica’s mother had suffered from both diseases and ultimately died of ovarian cancer. In 2005, shortly after testing positive, Jessica wrote an Op-Ed piece for the New York Times entitled Cancer and the Maiden about the burden of knowledge that comes with testing positive for the breast cancer gene. This article was the launching point for her first book, a memoir, called Pretty Is What Changes: Impossible Choices, The Breast Cancer Gene and How I Defied My Destiny. Ultimately, Queller, like Applegate, decided to have both breasts removed to stave off cancer, and she wants to have her ovaries removed before she is 40 in the hope of preventing ovarian cancer in the future.

Jessica Queller is the recipient of the 2008 LIFE Hero award from the Val Skinner Foundation

To view Jessica Queller’s April 2, 2008 interview with Good Morning America’s Robbin Roberts, CLICK HERE.

What is Hereditary Breast and Ovarian Cancer?

Hereditary breast and ovarian cancer (HBOC) is identified generally by one or more of the following characteristics found in a family:

  • early age onset of breast cancer (often before age 50);
  • family history of both breast and ovarian cancer;
  • bilateral cancers (cancer that develop in both breasts, or both ovaries, independently) or an individual with both breast and ovarian cancer;
  • an autosomal dominant pattern of inheritance (vertical transmission through either the mother or father’s side of the family); and
  • an increased incidence of tumors of other specific organs, such as the prostate.

Other factors that increase the chance that hereditary breast and ovarian cancer exists within a family include:

What Are BRCA 1 & BRCA 2 Genes?

In 1990, DNA linkage analysis studies on large families with the characteristics described above, identified the first gene associated with breast cancer. Scientists named this gene “breast cancer 1″ or “BRCA1.” BRCA1 mutations are transmitted in an autosomal dominant pattern within a family. Since it was clear that not all breast cancer families were linked to BRCA1, studies continued and in 1994, scientists discovered another gene similar to BRCA1, and named it “breast cancer 2″ or “BRCA2.” BRCA2 gene mutations are also transmitted in an autosomal dominant pattern within a family. If a disease is autosomal dominant, it means that an individual only needs to get the abnormal gene from one parent to inherit the disease. One of the parents may often have the disease.

BRCA1 and BRCA2 are tumor suppressor genes, which means that they are responsible for controlling cell growth and cell death. Each individual possesses two BRCA1and two BRCA2 genes. When an individual possesses one altered or mutated copy of the BRCA1 or BRCA2 gene, the risk for various types of cancer increases:

  • BRCA1 Mutation Risks

— 36 percent to 85 percent lifetime risk for breast cancer

— 40 percent to 60 percent lifetime risk for second breast cancer (not reappearance of first tumor)

— 20 percent to 60 percent lifetime risk for ovarian cancer

— increased risk for other cancer types, such as prostate cancer

  • BRCA2 Mutation Risks

— 36 percent to 85 percent lifetime risk for breast cancer in females

— 6 percent lifetime risk for breast cancer in males

— up to 27 percent lifetime risk for ovarian cancer

— increased risk for other cancer types, such as pancreatic, prostate, laryngeal, stomach cancer, and melanoma

It is important to note that both copies of a tumor suppressor gene must be altered or mutated before a person will develop cancer. In HBOC, the first mutation is inherited from the mother or father and is therefore present in all cells of the body. This is called a “germline mutation.” Whether an individual with a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. For example, assuming the second mutation is in the ovary, then ovarian cancer could develop. Assuming the second mutation is in the breast, breast cancer could develop. The development of a tumor ultimately requires mutations in multiple growth control genes. Loss of both copies of BRCA1 or BRCA2 is just the first step in the process. What causes these additional mutations to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures, or cell replication errors.

An individual who possesses an inherited germline BRCA1 or BRCA2 mutation may not develop cancer in the future due to the non-occurrence of a second gene mutation which is necessary to knock out the function of the gene and start the process of tumor formation. The lack of a second gene mutation can make the cancer appear to skip generations in a family, when, in reality, one gene mutation is present. Regardless of whether cancer ultimately develops, an individual with a mutation possesses a 50/50 chance of passing the mutation on to the next generation, which could include male and/or female children. It is also important to note that the BRCA1 and BRCA2 genes are not located on the sex chromosomes, and therefore, BRCA gene mutations can be inherited from the mother’s or father’s side of the family.

What is a founder’s effect?

The majority of BRCA1 or BRCA2 gene mutations within a single family are unique. There are, however, a few exceptions. For example, specific recurring mutations have been found in individuals of Ashkenazi (Eastern Europe) Jewish descent, and persons from the Netherlands, Iceland, and Sweden. Mutations recur in these groups because of a so-called “founder’s effect.” “Founders” consist of a small group of people that interbred due to geographic or religious isolation. The “founder’s effect” occurs when that small group of people interbreeds over generations, thereby causing specific rare gene mutations to recur and become more common in the population.

The present day Ashkenazi Jewish population arose from a small group of founders. One or more of those founders probably carried specific gene mutations in BRCA1 or BRCA2. Notably, there are three mutations (two in BRCA1 and one in BRCA2) that account for the majority of the BRCA gene mutations possessed by Ashkenazi Jews. Accordingly, the existence of the founder’s effect is important to Ashkenazi Jewish individuals because it results in an increased occurrence of BRCA gene mutations in this population. This information hold practical importance within the context of gene testing, because some testing laboratories offer “ethnic-specific” gene mutation panels. Thus, laboratories can first investigate for specific gene mutations based upon the ethnic background of the indivdual, rather than search through the entire gene each time that person is tested.

In the general population, it is estimated that 1 in 500 individuals has a mutation in BRCA1 or BRCA2. In contrast, 1 in 40 Ashkenazi Jews possess recurring BRCA mutations. This increased occurrence places added emphasis on the assessment of family history for breast and ovarian cancer in Ashkenazi versus non-Ashkenazi persons.

NCI Population Estimates — Likelihood of a BRCA1 or BRCA2 Gene Mutation

The National Cancer Institute (NCI) statistics regarding the percentage of women found to possess BRCA gene mutations, as compared to samples of women and men with a variety of personal cancer histories regardless of family history, are provided below. The estimates are general in nature and cannot replace a personalized risk assessment by a certified genetic counselor, which may indicate a higher or lower mutation likelihood based upon specific family history characteristics.

Among non-Ashkenazi Jewish individuals (likelihood of having any BRCA mutation):

  • General non-Ashkenazi Jewish population: 1 in 500 (.2%).
  • Women with breast cancer (all ages): 1 in 50 (2%).
  • Women with breast cancer (younger than 40 years): 1 in 11 (9%).
  • Men with breast cancer (regardless of age): 1 in 20 (5%).
  • Women with ovarian cancer (all ages): 1 in 10 (10%).

Among Ashkenazi Jewish individuals (likelihood of having one of three founder mutations):

  • General Ashkenazi Jewish population: 1 in 40 (2.5%).
  • Women with breast cancer (all ages): 1 in 10 (10%).
  • Women with breast cancer (younger than 40 years): 1 in 3 (30%-35%).
  • Men with breast cancer (regardless of age): 1 in 5 (19%).
  • Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%-41%).

Sources:

Comment: The vast majority of cancers are not due to inherited mutations. The decision to obtain genetic testing, and the action to take if you test positive for a gene mutation(s), are intensely personal decisions. It is generally recommended that you speak with a certified genetic counselor or similarly trained healthcare professional prior to engaging in genetic testing.

Additional Resources:

2008 Genetic Information Nondiscrimination Act Signed Into Law By President Bush

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“For Immediate Release
Office of the Press Secretary
May 21, 2008

President Bush Signs H.R. 493, the Genetic Information Nondiscrimination Act of 2008

Oval Office

2:05 P.M. EDT

THE PRESIDENT: I want to thank the members of Congress who’ve joined us as I sign the Genetic Information Nondiscrimination Act, a piece of legislation which prohibits health insurers and employers from discriminating on the basis of genetic information. In other words, it protects our citizens from having genetic information misused, and this bill does so without undermining the basic premise of the insurance industry.I also want to pay homage today to — and not only to members of the Congress who are behind me, but also to Senator Ted Kennedy, who has worked for over a decade to get this piece of legislation to a President’s desk. All of us are so pleased that Senator Kennedy has gone home, and our thoughts and prayers are with him and his family.

Now it’s my honor to sign the Genetic Information Nondiscrimination Act.

(The Act was signed.)

Thank you. (Applause.)

END 2:06 P.M. EDT”

[Quoted Source: “President Bush Signs H.R. 493, the Genetic Information Nondiscrimination Act of 2008,” White House Press Release, May 21, 2008.]

Comment: The enactment of the Genetic Information Nondiscrimination Act (GINA) of 2008 is momentous. Yesterday marks the start of the genetic medicine era – an era made possible by the Federal privacy protection extended to each individual under GINA. For additional GINA background, see Federal Enactment of the 2008 Genetic Information Nondiscrimination Act (GINA) As Law Appears Imminent, by Paul Cacciatore, H*O*P*E*™ Weblog posting dated April 30, 2008.

How Genomic Medicine Is Changing the Management of Breast & Ovarian Cancer — Live Webcast on May 21st

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“Helix Health, the first U.S. stand-alone genomic medicine practice, is hosting a 90-minute webcast this Wednesday, May 21, 2008 from 1:00-2:30 PM EDT examining: How Genomic Medicine Is Changing the Management of Breast & Ovarian Cancer.

Every hour, 150 people in the United States are diagnosed with cancer. There is a growing number of people who are not willing to wait for that diagnosis. They are undergoing genetic testing to discover, and to know what they must do to manage these risks… personalized medicine for effective heath care management.

Topics:

What should a doctor and patient do when a patient tests positive?

What is the risk in taking a “wait and see” approach?

Are there alternatives to radical surgery?

What are potential tort issues in predictive genetic testing and medical
uses of genetic tests?
Panel:

Steven A.R. Murphy, MD – Clinical Genetics Fellow at Yale School of Medicine, and Helix Health’s Managing Partner will moderate the panel.

Barbara A. Ward, MD – Director, The Breast Center of Greenwich Hospital; principal investigator of the STAR Trial; surgical oncologist affiliated with Yale-New Haven Health System.

Jessica Queller – author of Pretty Is What Changes; television writer for Felicity, The Gilmore Girls and One Tree Hill. Writer/producer on Gossip Girl.

Jennifer Ibrahim, MD – clinical geneticist specializing in preconception genetics as well as familial cancer syndromes.

David Ewing Duncan – bestselling author of Masterminds: Genius, DNA and the Quest to Rewrite Life; Director, Center for Life Sciences Policy, UC Berkeley; Chief Correspondent and co-host of National Public Radio’s “Biotech Nation“.

Gary E. Marchant, Ph.D. J.D., Lincoln Professor of Emerging Technologies, Law & Ethics, Sandra Day O’Connor College of Law; Executive Director, Center for Law, Science & Technology, Professor, School of Life Sciences Arizona State University.

Registration is limited, so please register soon. If you are unable to attend, a podcast of the session will soon be available on the Helix Health website.

About Helix Health, PLLC/LLC – a medical practice that is bringing genomic medicine to health care. With offices in Greenwich, CT and New York, NY, Helix Health offers patients and their physicians expertise in genomic medicine and provides the tools required to take full advantage of genetic testing.

Contact info@helixhealth.org for more information, or visit http://www.helixhealth.org/”

Click Here To Register For the Helix Health Live Webcast

[Quoted Source: “Join NPR’s David Ewing Duncan, Author Jessica Queller and a Panel of Medical and Legal Experts in a 90-Minute Webcast on Genetic Testing, Genomic Medicine and Breast & Ovarian Cancer,” The Earth Times Press Release dated May 19, 2008.]

Global Consortium Formed To Hunt For Cancer Genes

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“The International Cancer Genome Consortium is one of most ambitious biomedical research efforts since the Human Genome Project. The consortium will help to coordinate current and future large-scale projects to understand the genomic changes involved in cancer. This genomic information will accelerate efforts to develop better ways of diagnosing, treating and preventing many types of cancer.”

“Toronto, April 29, 2008 –Research organizations around the world announced today that they are launching the International Cancer Genome Consortium (ICGC), a collaboration designed to generate high-quality genomic data on up to 50 types of cancer through efforts projected to require up to a decade. The ICGC, which is extending an invitation to all nations to participate, will make its data rapidly and freely available to the global research community.

Each ICGC member intends to conduct a comprehensive, high-resolution analysis of the full range of genomic changes in at least one specific type or subtype of cancer, with studies built around common standards of data collection and analysis. Each project is expected to involve specimens from approximately 500 patients and have an estimated cost of $20 million (U.S.).

As part of its coordination efforts, the ICGC will generate a list of approximately 50 cancer types and subtypes that are of clinical significance around the globe. ICGC members plan to assume responsibility for specific cancers, and one of the ICGC’s roles will be to facilitate the exchange of information so participants’ efforts do not duplicate each other.

Current ICGC members include:

* Australia: National Health and Medical Research Council (Observer Status)
* Canada: Genome Canada (Observer Status); Ontario Institute for Cancer Research
* China: Chinese Cancer Genome Consortium
* Europe: European Commission (Observer Status)
* France: Institut National du Cancer
* India: Department of Biotechnology, Ministry of Science & Technology
* Japan: RIKEN; National Cancer Center
* Singapore: Genome Institute of Singapore
* United Kingdom: The Wellcome Trust; Wellcome Trust Sanger Institute
* United States: National Institutes of Health

‘Clearly, there is an urgent need to reduce cancer’s terrible toll. To help meet that need, the Consortium will use new genome analysis technologies to produce comprehensive catalogs of the genetic mutations involved in the world’s major types of cancer,’ said Thomas Hudson, MD, of the ICGC Secretariat, which is based at the Ontario Institute for Cancer Research in Toronto. ‘Such catalogs will be valuable resources for all researchers working to develop new and better ways of diagnosing, treating and preventing cancer.’

Worldwide, more than 7.5 million people died of cancer and more than 12 million new cases of cancer were diagnosed in 2007. Unless progress is made in understanding and controlling cancer, those numbers are expected to rise to 17.5 million deaths and 27 million new cases in 2050.

Once thought of as a single disease, cancer is now understood to consist of a large number of different conditions. In almost all forms, however, cancer changes the genetic blueprint, or genomes, of cells, and causes disruptions within normal biological pathways, leading to uncontrolled cell growth. Because genomic changes are often specific to a particular type or stage of cancer, systematically mapping the changes that occur in each cancer could provide the foundation for research to identify new therapies, diagnostics and preventive strategies.

The ICGC’s main criteria for prioritizing cancer types will be: impact, including incidence and mortality rates, availability of therapies and age of onset; scientific interest; and feasibility, which includes the ability to obtain enough high-quality samples to conduct a large-scale project.

To facilitate comparisons among different types of cancer, the ICGC guidelines list key factors for its members to consider in the production of genomic catalogs. Those factors include comprehensiveness, which involves detecting all cancer genes mutated in at least 3 per cent of tumor samples; resolution, which involves generating data at the level of individual DNA bases; quality, which involves monitoring based on common standards for pathology and technology; and controls, which involves comparisons of data from matched, non-tumor tissue.

ICGC member nations plan to agree to common standards for informed consent and ethical oversight. While the informed consent process will necessarily differ according to each member country’s requirements, the consortium’s policies state that cancer patients enrolled in an ICGC-related study should be informed that their participation is voluntary, that their clinical care will not be affected by their participation and that data obtained from analyses using their samples will be made available to the international research community. ICGC members will ensure that all samples will be coded and stored in ways that protect the identities of the participants in the study.

To maximize the public benefit from ICGC member research, data will be made rapidly available to qualified investigators. In addition, all consortium participants will agree not to file any patent applications or make other intellectual property claims on primary data from ICGC projects.

The ICGC is open to all entities that agree to its policies and guidelines. A white paper detailing those policies and guidelines is available on the consortium’s Web site at www.icgc.org.

The International Cancer Genome Consortium is one of most ambitious biomedical research efforts since the Human Genome Project. The consortium will help to coordinate current and future large-scale projects to understand the genomic changes involved in cancer. This genomic information will accelerate efforts to develop better ways of diagnosing, treating and preventing many types of cancer.

For more information and updates about ICGC activities, go to www.icgc.org”

[Source: “Scientists Form International Cancer Genome Consortium,” International Cancer Genome Consortium, PressRelease dated April 29, 2008.]

Testing and Management for Hereditary Breast and Ovarian Cancer

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The term “hereditary cancer syndrome” describes an inherited gene mutation that increases the chance to develop one or more types of cancer. For instance, the main hereditary breast cancer syndromes-caused by mutations in the BRCA1 or BRCA2 genes-are also associated with an increased risk for ovarian cancer. Testing is available to identify hereditary breast and ovarian cancer (HBOC) syndrome. Signs of hereditary breast & ovarian cancer syndrome may include, but are not limited to:

  • Breast cancer at age 45 or younger
  • Breast cancer in both breasts in a woman at any age
  • Both breast and ovarian cancer in the same woman
  • Two or more family members with ovarian cancer and/or breast cancer, especially if the breast cancer was diagnosed at or before age 50
  • At least one family member with breast cancer and one with ovarian cancer
  • Breast cancer in men
  • A number of relatives on the same side of the family with breast or ovarian cancer and one of these cancers:

o Prostate cancer
o Pancreatic cancer
o Melanoma

Identifying HBOC is important because there are effective medical options that can reduce the high risk of breast and/or ovarian cancer associated with this syndrome.

The video Making Informed Decisions: Testing & Management for Hereditary Breast and Ovarian Cancer, created by Myriad Genetic Laboratories, Inc., is designed to answer common questions about HBOC syndrome testing and medical management options. In the video, you will meet several women who share their experiences with genetic testing and the use of genetic test results to make decisions regarding their healthcare, including genetic risk management.

Please note that the video is not a substitute for consultation with your doctor. With the information from this video, you should consult with your doctor so as to make the most informed decision possible regarding testing and management of HBOC syndrome.

You can view the 22 minute video by clicking on the hyperlink below. The video viewing screen is located under the “Ovarian Cancer Video Archive” posting dated May 6, 2008.

Making Informed Decisions: Testing & Management for Hereditary Breast and Ovarian Cancer Video

Comment/Additional Resources: For more information regarding HBOC syndrome, genetic testing, genetic counseling & counselors, and genetic risk management, please click the “Genetics” caption tab located at the top of the H*O*P*E* homepage. The BRCA mutation chart above was provided by Myriad Genetics Laboratories, Inc.

Federal Enactment of the 2008 Genetic Information Nondiscrimination Act (GINA) As Law Appears Imminent

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“Although nearly 40 states have had individual forms of the legislation in place, with the federal passage of GINA, the message would be unambiguous: the misuse of genetic information resulting in discrimination in employment or health insurance is against the law in all U.S. states.”

“After installing compromises and ‘minor’ changes, including a ‘firewall’ separating the potential liabilities insurers and employers could face, the US Senate last week unanimously passed the Genetic Information Nondiscrimination Act [‘GINA’].

The bill, which seeks to protect individuals’ genetic information from being misused by insurers and employers, now moves to the House, where it is also expected to pass, and then to the White House, where President Bush is expected to sign it into law.

According to American Society of Human Genetics Executive VP Joann Boughman, the Senate version of the bill adopts language appearing in the House bill (HR 493) designed to ‘limit, but not completely prevent,’ employees from suing their employer for being denied insurance based on genetic information obtained by a payor.

The bill exempts employers from liabilities if the employer ‘inadvertently’ garners genetic information through a company-sponsored wellness program, or must request such information in order to monitor biological effects of toxic substances in the workplace. The bill’s language also specifies that ‘an employer, employment agency, labor organization, or joint labor-management committee shall not be considered to be in violation … [for the] use, acquisition, or disclosure of medical information that is not genetic information about a manifested disease, disorder, or pathological condition of an employee or member, including a manifested disease, disorder, or pathological condition that has or may have a genetic basis.’

Industry observers have long said that the lack of legal protections for people’s genetic information deters them from participating in clinical trials for gene-based therapies and tests, which in turn hampers advances in the genetics field.

In an NIH-funded study of families newly -diagnosed with a hereditary cancer syndrome named hereditary non-polyposis colorectal cancer, researchers found that participants consistently asked how their involvement in the study would impact their and their families’ insurance. During the study, ‘it was clear that there was an overwhelming concern, and in some cases, a palpable anxiety about the impact of genetic testing on health insurance,’ Donald Hadley, an associate investigator and a genetic counselor with the National Human Genome Research Institute, said in a 2004 testimony to the HHS Secretary’s Advisory Committee on Genetics, Health, and Society.

‘These concerns dominate our informed consent process and recur session after session with an intensity that opened our eyes to the level of concern that the public feels about genetic discrimination,’ Hadley said in his testimony.

With the expected passage of GINA, academic genetic researchers, diagnostics firms, and pharmacogenomics companies can better assure clinical trial participants that their genetic data will not be used to make insurance or employment decisions, and that they have recourse under the law if their genetic information is abused in such a manner.

GINA is expected to go back to the House of Representatives where it will be aligned with the Senate version of the bill and voted on again. Because GINA has already passed in the House twice with ‘considerable support,’ it is not expected to encounter any problems when the lower chamber votes on it, which can happen as early as this week.

Once it clears the House, GINA is expected to be signed into law ‘in short order,’ Kurt Bardella, press secretary for GINA sponsor Sen. Snowe, told Pharmacogenomics Reporter sister publication GenomeWeb Daily News last week.

In a recent address to the National Institutes of Health, President George Bush said he is willing to sign the bill into law if it passes Congress.

GINA’s Long Haul

Since last summer, after GINA cleared the House the first time by a vote of 420 to 3, the bill has had many detractors. The bill’s main opponent was Senator Coburn, who placed a hold on GINA, citing concern that the bill could potentially increase lawsuits against employers.

Mainly, Coburn wanted the bill to include a ‘firewall’ that would prohibit employees from being able to sue their employers if an insurer denied coverage based on genetic information.

Then in March, in a surprising move, the House passed GINA by a vote of 264 – 148 as part of the Paul Wellstone Mental Health and Addiction Equity Act of 2007 (H.R. 1424), which would require health insurers to cover mental health and substance abuse-related disorders under group health plans.

Attaching GINA to that bill appeared to invite more detractors to the expanded legislation. When the Wellstone bill passed in the House, 11 senators, including Coburn, sent a letter to Democratic leaders in Congress raising concerns about GINA’s ability to ‘maintain current law distinctions between employee benefit disputes … and disputes about civil rights in the employment context.’

Some of GINA’s other detractors, including the US Chamber of Commerce, the National Association of Manufacturers, and the National Retail Federation, shared the Senators’ concerns. These groups, which formed the Genetic Information Non-Discrimination in Employment Coalition, remained optimistic that the group may be appeased with ‘minor technical fixes’ to GINA, according to Michael Eastman, executive director of labor policy at the US Chamber of Commerce.

With GINA’s passage in the Senate, it seems those ‘minor fixes’ are now in place.

Senator Coburn’s office did not return requests for comment on GINA’s passage prior to deadline.

Employer Exemptions

Although the bill would make it unlawful for an employer to obtain genetic information from an employee or a family member in order to make employment decisions, the employer is not held liable for a number of scenarios.

For example, an employer would not be breaking the law if he “inadvertently requests or requires family medical history of the employee or family member of the employee” through a employee-provided wellness program; if the employee provides prior, knowing, voluntary, and written authorization; if the employee and the doctor receive individually identifiable information concerning the results of such services; and if the employer receives genetic information regarding these services in ‘aggregate terms that do not disclose the identity of specific employees.’

The employer is also exempt if genetic information is requested to comply with medical leave laws; if an employer purchases documents that are commercially and publicly available that include family medical history; or where the information involved is to be used for genetic monitoring of the biological effects of toxic substances in the workplace. In the last instance, the employer is required to provide written notice of the genetic monitoring on an employee.

Genetic Alliance President Sharon Terry described the compromise as a product of a “great conversation” between all parties involved and the engagement of the genetics community. She also suggested that the sudden advancement in consumer genetic testing businesses over the past year, and greater discussion in the media about the uses and ethics of such tests, could have helped push the bipartisan effort to pass GINA.

Grassroots Instruction

Expecting GINA to be signed into law, its supporters are now focused on educating physicians and patients regarding their rights.

‘Our challenge now is to make sure that doctors and patients are aware of these new protections so that fear of discrimination never again stands in the way of a decision to take a genetic test that could save a life,’ Kathy Hudson, director of the Genetics and Public Policy Center at Johns Hopkins University.

The pending passage of the bill also was lauded by the Personalized Medicine Coalition, a collection of industry, academic, payor, and other partners. The PMC lauded two of its members, IBM and Eli Lilly, for adding genetic nondiscrimination to their employment policies in advance of GINA’s passage.

‘GINA closes important gaps in the current patchwork of federal and state protections against the misuse of genetic information,’ the PMC said in a statement. ‘Current federal statutes for protecting medical information, including the Health Insurance Portability and Accountability Act, do not prohibit insurers from requiring genetic testing or from denying coverage based on genetic information; and while the Americans with Disabilities Act protects individuals with symptomatic genetic disabilities, it is not clear if it explicitly covers discrimination based on unexpressed genetic susceptibility to disease.’

In the ASHG‘s view, the promulgation of a national genetic anti-discrimination law will help clear up the confusing patchwork of state laws that have emerged.

‘Although nearly 40 states have had individual forms of the legislation in place, with the federal passage of GINA the message would be unambiguous: the misuse of genetic information resulting in discrimination in employment or health insurance is against the law in all US states,’ the ASHG said in a statement.”

[Quoted Source: “Senate Unanimously Passes GINA, Though With‘Compromises’; Now Faces Sympathetic House,” by Turna Ray, Pharmacogenomics Reporter, April 30, 2008.]

Comment: For additional GINA and genetic discrimination information, please refer to the following: (i) “Genetic Information Nondiscrimination Act: 2007-2008,” National Human Genome Research Institute, National Institutes of Health, April 24, 2008; (ii) “Senate Gives GINA Critical Boost Toward Becoming Law,” National Human Genome Research Institute, National Institutes of Health, April 24, 2008; (iii) “Genetic Discrimination” Overview, National Human Genome Research Institute, National Institutes of Health, April 28, 2008; and (iv) “State Genetic Privacy Laws,” National Conference of State Legislatures, January 2008.

Updates:

Jewish Women Change Their Destinies by Testing for Genetic Mutation

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“One in 40 Ashkenazi Jews – compared to one in 500 in the general population – carries a mutation that gives women a 50 percent to 85 percent chance of getting breast cancer by the time they are 80. The genetic mutation, discovered in 1994, also increases the likelihood of melanoma and ovarian, prostate or pancreatic cancer. While within the general population about 5 percent of cancers can be attributed to a hereditary syndrome, in the Jewish community, that number is closer to 30 percent. ”

“Erika Taylor didn’t want to know whether she had the breast cancer gene.

‘My thinking was I would never get a prophylactic mastectomy,’ Taylor, 44, said of the idea of removing her breasts as a preventive measure. ‘I just thought it was horrible thing to do to myself, and if I was unwilling to do that, why bother finding out?’

Her grandmother died of breast cancer at 56, and her mother battled and beat the disease in her 30s. Taylor, who is single and the mother of a 14-year-old boy, always suspected cancer was in her future, but taking steps to confirm that was not something she wanted to do. Until she got her own diagnosis.

A routine mammogram last November revealed early stage noninvasive cancer cells in Taylor’s milk ducts, making information about her genetic status vital for determining her treatment.

All of a sudden, the idea of ‘I would never do such a thing’ goes out the window,’ she said. ‘It’s astonishing how quickly you go, ‘OK, OK, what do I need to do? I’ll do it.” Taylor’s mother tested first, and when she was identified as a carrier of the BRCA 2 genetic mutation common in Ashkenazi Jews, Taylor tested next. In January, she found out she, too, carries the gene that makes it likely that even if she were to rid herself of her diagnosed cancer, it would probably recur.

Like a growing number of women, Taylor faced both the gift and the terror of knowledge.

One in 40 Ashkenazi Jews – compared to one in 500 in the general population – carries a mutation that gives women a 50 percent to 85 percent chance of getting breast cancer by the time they are 80. The genetic mutation, discovered in 1994, also increases the likelihood of melanoma and ovarian, prostate or pancreatic cancer. While within the general population about 5 percent of cancers can be attributed to a hereditary syndrome, in the Jewish community, that number is closer to 30 percent.

The good news is that knowledge about how the mutation causes cancer is opening scientific doors to more effective, targeted treatment for those already diagnosed. And people who have the genetic mutation can take preventative measures to drastically reduce their breast and ovarian cancer risk.

Surgery – removal of the breasts and ovaries – reduces the risk of breast cancer by 90 percent, to well below the 13 percent odds of getting breast cancer in the general population. But less-drastic measures, such as drug therapy, removal of just the ovaries and careful screening to catch and cure the cancer at an early stage, can also save lives. Genetic information also helps women feel empowered to take control of other factors that raise risk, such as smoking, alcohol consumption and obesity.

‘The use of genetic information to understand a person’s risk for diseases like cancer is clearly reaping huge benefits,’ said Dr. William Audeh, a medical oncologist with an emphasis on hereditary risk at Cedars-Sinai Medical Center‘s Samuel Oschin Comprehensive Cancer Institute. ‘It’s gone from being a somewhat frightening piece of information that gave people concerns to a hugely important piece of information that empowers people to either take preventative steps that can save their lives or to accurately target therapy if one develops cancer. There is a general understanding that genetic information for cancer is going to be critical for taking the best care of people.’

Knowing she had the genetic mutation sent Taylor, editor of the trade publication, Pool and Spa magazine, into a tailspin of research and soul-searching. Treatment for DCIS (ductal carcinoma in situ) usually consists of removal of the tumor and perhaps radiation. But Taylor’s genetic status put her in a different risk category, and after hearing from four different doctors that her cancer, even if cured, would return, she opted for a double mastectomy and reconstruction. Her surgery is scheduled for May.

Taking the test

While Taylor confirmed her genetic status after a cancer diagnosis, experts encourage people to test before cancer strikes. For Ashkenazi Jews, having just one relative who has had premenopausal breast cancer warrants getting tested, according to geneticists. (For non-Jews, testing is indicated if there are two relatives.) Any history of male breast cancer or any ovarian cancer in the family also raises a red flag, as do multiple cases of melanoma or pancreatic cancer. And women who themselves have early onset breast cancer should be tested, so they can tailor their treatment and inform other family members.

In the last five years, the number of people testing for the BRCA mutation has increased by 50 percent every year, according to Myriad Genetics, which patented the blood test for BRCA about 12 years ago. About 70,000 people tested last year. Myriad recently launched an East Coast direct-marketing campaign for the test.

Of the estimated 600,000 people who carry the gene in the United States, only about 20,000 have been identified. Of those 600,000 carriers, about 150,000 are Jewish, mostly Ashkenazi. Other ethnic groups, such as French Canadians and Filipinas, also have a genetic predisposition, as do some Latina subpopulations – some of which have been traced back to having Jewish genes.

Only about 15 percent of people who test come out with positive results, though the percentage is somewhat higher among Jews. But even a negative result is not entirely reassuring, since it indicates only that the specific mutations were not found. Other as-yet-undiscovered mutations, or other genes, could also cause a heavy incidence of cancer in a family, according to Dr. Ora Gordon, director of the GenRISK adult genetics program at Cedars.

Gordon encourages anyone being tested to see a genetic counselor to get the results properly interpreted and to understand their options if they find out they are carriers.

‘When learning about this for the first time, very frequently people say to themselves, If I’m not going to have surgery, I shouldn’t get this test.” Gordon said. ‘But that would be a tremendous loss in terms of potential reassurance for people who are not carriers and for identifying people who might have a whole variety of other options that might provide very substantial risk reduction.’

Prophylactic bilateral mastectomy – or having both breasts removed before any sign of cancer – seems to be growing in popularity as an option in the United States, though hard statistics are just now being compiled.

One recent study of women with the BRCA mutation and a cancer diagnosis put the rate of mastectomy at 50 percent in the United States, the highest by far of anywhere in the world. In Israel, that number is 2 percent, Gordon said.

In Los Angeles in particular, the numbers seem to be especially high.

Gordon estimates that 65 percent to 70 percent of BRCA-positive women in Cedars’ cancer programs opt for the surgery, some immediately, some after a few years of surveillance. ‘The quantity and quality of medical options makes the surgery more attractive in big cities, and Los Angeles has a high tolerance for breast surgery,’ Gordon said. She is spearheading a study about decision-making among BRCA-positive women at Cedars’ Gilda Radner early detection program, which screens genetically high-risk women for ovarian cancer.

Gordon understands that a woman’s decision about treatment is intertwined with her relationship status, her self-image and how many family members she saw battle or succumb to cancer.

Surgery or surveillance?

‘The decision to take off your breasts is really hard. It’s a part of your body that is associated with your outward appearance, and it’s a part of who you are. It’s a part of your sex life,’ said Joi Morris, who was 41 when she learned she carried the same genetic mutation that gave her mother and grandmother breast cancer at a young age.

Morris remembers a day, not long after she found out, when she really confronted the issue as her sons, then 7 and 10, played at the beach.

‘My kids were in the water and jumping and playing and having a fabulous time, and I looked down at my breasts in my swimming suit and thought, “Oh my God, what would it be like to not have these?'” ‘It’s a seesaw of emotions,’ she said, because at the same time, ‘you wake up every morning, and you know you are at risk, and you wonder if there is something in there you can’t find.’

Morris initially opted for close surveillance – a regimen of regular mammograms, manual exams, ultrasounds and breast MRIs – the most sensitive, noninvasive screening available, used only for high-risk patients. Her first MRI revealed a lump close to her chest wall.

‘I panicked. There is no other way to put it. That lump turned out to be benign, but the whole process was so stressful for me and hard on my family. I just decided if this lump is not cancer, the next one could be,’ Morris said.

She had a prophylactic bilateral mastectomy, with immediate reconstruction. As it turned out, her surgery wasn’t prophylactic at all – pathology revealed pre-cancerous cells scattered throughout both breasts.

Early in the process, Morris turned for support and information to FORCE: Facing Our Risk for Cancer Empowered, an organization that advocates for people at high genetic risk for breast and ovarian cancer.

Today, she is an outreach coordinator for FORCE, helping link women through face-to-face groups and one-on-one pairings as they face life-altering decisions.

‘It was very hard getting those results,’ said Lisa Stein, a 43-year-old mother of two, who found out she has the gene last year. ‘I was trying to prepare for being positive, but I don’t think you ever can. After I got the results, I really struggled. I was feeling raw for a while, crying easily knowing that it was going to be life-changing.’

Stein’s mother died of breast cancer at 57, and her grandmother died of ovarian cancer, but she didn’t test until her older sister, Lauren Rothman, tested positive.

Rothman opted for a mastectomy, but Stein chose to keep her breasts.

‘I think I knew instinctively that I was not going to have a double mastectomy. That felt too radical to me,’ Stein said. ‘I didn’t feel psychologically prepared or that it was necessary. I don’t feel like cancer is imminent; I feel like I have a few years to take it in and think about it and prepare, so I’ve put that decision on hold.’

She goes in for screening every few months, and she said the anxiety of waiting for those results has been manageable.

Both Rothman and Stein had their ovaries removed, however, which doctors are now recommending for women who test positive and who are finished having children or who are over age 35. Removing ovaries not only reduces the risk of ovarian cancer – which is notoriously hard to catch early and thus has a high mortality rate – but it reduces the risk of breast cancer by 50 percent. Stein also went on Tamoxifen, a drug taken by breast cancer survivors to reduce the risk of recurrence and which reduces risk by 50 percent in BRCA-positive women. The birth control pill, which stops the ovaries from cycling, can also reduce the risk of ovarian cancer but requires more vigilant screening for breast cancer.

Both ovary removal and Tamoxifen push women into menopause, with all its emotional, sexual and physiological ramifications.

‘I think of myself as a healthy person but not like I used to – it’s kind of tainted,’ Stein said. ‘It’s an identity issue. I still think of myself as youthful, but suddenly, I’m dealing with instant menopause, and that doesn’t sit well with me. But I’m dealing with it.’

Stein and Rothman provide support for each other, despite the different routes they’ve taken.

‘I came to reality very quickly – and the reality was I wanted to see my children grow up, and I didn’t want cancer, and I didn’t want chemotherapy. I wanted the rest of my life,’ Rothman said. Her daughters were 3 and 5 years old when she had surgery.

Rothman, a program director for Hadassah of Southern California, traveled to New Orleans for her breast procedure – two surgeries and tatoooing – at a small clinic that specializes in natural-tissue reconstruction, where a solid flap of fat is removed from the belly and inserted into the shell of the breast after tissue has been removed. The surgery offers a more natural result than silicone implants, though it is longer and more involved.

‘This procedure has provided me with a new outlook on life. It has taken a huge weight off my shoulder,’ Rothman said. ‘I no longer go into mammograms thinking, “Is this the year I’m going to get cancer like mom?'”

And she loves her new body – she got not only a breast lift but a bonus tummy tuck, too.

Advances in reconstructive techniques mean that women have several options for maintaining a body they can feel proud of.

Decades ago, radical mastectomies removed all the tissue and muscle of the chest wall. Today, the muscle is not removed, and reconstructive surgery, usually at the time of mastectomy, can leave intact the women’s natural skin, but in most cases the nipples and areola are removed. A silicone implant, or, as in Rothman’s case, fat from the abdomen, fills the pocket from which breast tissue was removed. Nipples and areola are tattooed on, or some surgeons use a new technique that leaves a woman’s own nipple and areola intact. Doctors try to bury scars in the fold beneath the breast, though that is not always possible.

But even the most beautifully done reconstructions leave a woman with scars and no sensation in her breasts.

‘When women come to see me, my approach is to listen to them and find out where they are in life and how they relate to their own breasts,’ said Dr. Kristi Funk, a breast surgeon and director of patient education at Cedars’ Brandman Breast Center. ‘Women have different feelings about sexuality and what roles breasts play, and that makes a big difference.’

Funk also finds out about the woman’s relationship status, and how she has been affected by a family history of cancer.

More information, better treatment

Family histories can be deceptive, however. Some families don’t know their medical histories, because they were lost due to the Holocaust or immigration.

The gene also can hide out in male members of a family.

A BRCA 1 gene mutation raises the risk of male breast cancer to 6 percent, and there is no increased risk for other cancers. BRCA 2 mutation also increases the risk for melanoma, prostate and pancreatic cancer. Still, men who carry the gene are likely never to get any cancer, although they have a 50 percent chance of passing the gene to children. Families with few females may never discern any cancer history.

Dora Cohen (not her real name) suspects it was her father who passed the BRCA 1 gene mutation to her. Last year, she was diagnosed with DCIS, a noninvasive cancer, which was treated with a lumpectomy and radiation. Of the many oncologists she saw, only one recommended that as an Ashkenazi woman in her 40s, she probably should have genetic testing.

In the last six months, Dora has had her ovaries, uterus and breasts removed.

Her daughter, Diane (not her real name), who is 27 and has been married for two years, doesn’t want to get tested yet.

‘I see what my mom is going through,’ Diane said. ‘I want to have kids, and I’m not in a place where I would take those measures [mastectomy and removal of the ovaries]. Knowing I’m positive and having that pressure on me would be something very difficult to live with.’

She and her husband of two years have pushed up their plans for children, and she worries that a positive test could jeopardize her medical insurance, especially because she is self-employed.

Federal and California law provide fairly good protection against genetic discrimination from insurers, stipulating that a genetic predisposition cannot be considered a pre-existing condition. But individual policies are not as well protected as group policies.

Still, genetics experts say much of the fear is overblown. They point out that there has been little litigation involving genetic discrimination, and that the insurance industry is open to the reality that genetic testing can lead to better and more cost-effective treatment. Most insurers cover genetic testing, and some genetic counseling – a rapidly growing field.

‘The genetics community has been struggling to help people understand the importance of talking to someone who knows the nuances of genetic testing,’ said Heather Shappell, a genetic counselor and founder of Informed Medical Decisions, which offers over-the-phone genetic counseling.

‘Genetic tests do not always yield a yes-or-no answer,’ Shappell said, ‘and often doctors aren’t sure how to read the results and guide patients through their decisions.’

In August, Aetna extended full coverage for Shappell’s phone-counseling services to its 14 million policyholders.

What geneticists are looking for is an error in the sequencing of the BRCA gene.

All people carry two genes, BRCA 1 and BRCA 2, which prevent cancer by repairing damaged cells. A mutation damages the genes’ repair function, which leads to uncontrolled growth and causes cells to become cancerous.

About 95 percent of Ashkenazi Jews who have the mutation have one of three errors, which means the mutation is easier to find and the test costs much less – about $400, as compared to $3,000 for a test that analyzes the entire gene.

As researchers learn more about how BRCA mutations cause cancer, they are developing targeted treatments.

A clinical trial with sites at Cedars and City of Hope uses a drug called a PARP-inhibitor to shut down the cell’s backup repair function. Normal cells are not affected, because the primary repair pathway is still functioning. But cancerous cells are left with no functioning repair system, so those cells die. Because normal cells are not affected, there are few major side effects.

‘We have a promising situation where you have a treatment which is completely targeted to cancer and leaves the normal cells alone. And that is very different from treatments like chemotherapy, where there is toxicity to every cell,’ said Audeh of Cedars.

Another study in Israel has found that women with ovarian cancer who are BRCA positive respond better to chemotherapy and have a higher survival rate than women who are not carriers, according to Jeff Weitzel at City of Hope. Weitzel, an investigator in the PARP-inhibitor trial, is also working on a study that manipulates hormones to reduce breast density, which makes surveillance through mammography and ultrasound more effective.

In February, the Jerusalem Post reported that doctors for an Orthodox woman undergoing in-vitro fertilization at Hadassah Hospital were able to identify and screen out embryos that had inherited her BRCA mutation. [Jerusalem Post Feb. 2008 article abstract]

A gift of life?

But while such progressive procedures have been generally well received in Israel, there is still social reluctance to test for the gene, especially in traditional circles, where families fear a genetic flaw could hurt the marriageability of their kids.

Debra Nussbaum Stepen, a Los Angeles therapist who now lives in Israel, is trying to break those perceptions. She works as a therapist at a clinic for hereditary breast and ovarian cancer, and she volunteers for Bracha, a Hebrew-language Web site for BRCA carriers.

The name of the site – bracha means blessing and is a play on BRCA – connotes that knowing one’s genetic makeup is a blessing that can save one’s life.

It is a lesson Stepen learned personally.

Her father had several kinds of cancer, including breast cancer, and before he died at 77, Debra urged him to get genetic testing. She was 51 and had never had cancer when she found out she carried the gene.

‘My doctor told me my breasts were ticking time bombs, and I couldn’t go to bed at night knowing that and thinking today am I going to get cancer?’ said Stepen, who has three stepchildren and a new stepgranddaughter.

She observed her father’s first yahrzeit in New Orleans, where she was undergoing the third and last part of a double mastectomy and reconstruction.

‘I said to my husband, in my father’s death he gave me the gift of life,’ Stepen said.

It takes time to reach this comfort level. As Erika Taylor prepares for her surgery in a few weeks, she worries about the ‘gift’ she may give to her son. She and her mom have talked about how irrational that guilt is.

‘I can say to my mom, “You didn’t know. It’s OK. It’s not your fault,’” she said. ‘But when it comes to me and my son, I think how could I have done this to my son. I am in abject horror that I might have passed this on to him. I know it’s irrational, but the whole idea fills me with grief.’

At the same time, she has hope.

‘My grandmother died from breast cancer at 56. My mother almost died of this disease. And I’m not going to even come close to dying,’ Taylor said. ‘My hope for my son, if he has this, is that he may not have to have any medical intervention at all. Maybe they can repair this mutation. The idea that there is trajectory moving in the right direction gives me some comfort and hope.’”

[Quoted Source: “Jewish women change their destinies by testing for genetic mutation,” by Julie Gruenbaum Fax (Jewish Journal of Greater Los Angeles), Texas Jewish Post, April 24, 2008 (emphasis added)]

Comment: For additional information relating to hereditary breast and ovarian cancer with respect to all women (Jewish and Non-Jewish), refer to the following: (i) FORCE: Facing Our Risk of Cancer Empowered; (ii) National Breast and Ovarian Cancer Coalition; (iii) “Clinical Considerations,” Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility Recommendation Statement, U.S. Preventive Services Task Force (USPSTF), Agency for Healthcare Research & Quality (AHRQ), U.S. Department of Health & Human Services, September 2005; (iv) “Genetics” hyperlinked materials, H*O*P*E* Blog homepage.

Advanced-stage Ovarian Cancer Patients With BRCA Live Longer, May Respond Better To Standard Treatment

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“Two abstracts underscoring the importance of testing for BRCA1/2 mutations in women with ovarian cancer were presented at this week’s Society of Gynecologic Oncologists 39th Annual Meeting on Women’s Cancers, by researchers from The University of Texas M. D. Anderson Cancer Center.

In the first study, a multicenter research team led by M. D. Anderson found advanced- stage ovarian cancer patients with non-Ashkenazi Jewish BRCA (non-AJ BRCA) mutations experience longer progression-free and overall survival rates compared to those with sporadic ovarian cancer. The data confirms previous research which reported that among ovarian cancer patients of Ashkenazi-Jewish heritage, BRCA1/2 mutations (AJ BRCA) are associated improved long-term survival.

For this study, researchers examined 85 advanced-stage ovarian cancer patients with non-AJ BRCA mutations and 116 patients who did not express any type of BRCA mutation. Compared to patients without BRCA mutations, non-AJ BRCA carriers had longer progression-free survival of 19.0 vs. 27.8 months and improved overall survival of 65.6 vs. 101.4 months. Non-AJ BRCA patients had a 2.15 times greater odds of complete response to initial chemotherapy response over sporadic, non-carrier patients.

Karen Lu, M.D., associate professor in the Department of Gynecologic Oncology at M. D. Anderson and senior author on the study said the difference in survival rates indicate that individuals with BRCA mutations might respond better to standard chemotherapy for ovarian cancer. ‘Thus, it becomes increasingly valuable to know a patient’s BRCA status to guide and personalize treatment decisions,’ Lu said.

Majority of Patients Unaware BRCA Testing Available
A second study conducted at M. D. Anderson concluded that, despite being available for more than 10 years, a majority of women with ovarian cancer were unaware genetic counseling and testing for BRCA1/2 mutations was an option. Of the 225 ovarian cancer patients surveyed, 56 percent had not heard of BRCA testing. This lack of awareness was more profound in minorities – 69 percent of Hispanic and 88 percent of African American respondents were unaware of BRCA testing compared to 52 percent of white women.

Patients typically associate genetic testing with benefiting family members and offspring,’ Lu said. ‘Both of these studies illustrate that it is equally important for the cancer patient to get information from their doctors about genetic testing because it not only has implications for their family, but their own treatment and prognosis.’

She said that more than 85 percent of ovarian cancer patients surveyed would be willing to undergo BRCA testing if it would affect their care, but the cost of testing may be a barrier. ‘Currently, oncologists are inconsistent in their testing for BRCA mutations. Based on the treatment implications of our findings and the surprisingly low knowledge that such testing is available, we recommend developing ways to systematically evaluate every ovarian cancer patient for BRCA,’ Lu said.

A family history of breast and/or ovarian cancer is reported in approximately five percent to 15 percent of ovarian cancer cases, with BRCA1/2 mutations expressed in a significant proportion of these cases. …”

Quoted Source: [“Advanced-stage Ovarian Cancer Patients With BRCA Live Longer, May Respond Better To Standard Treatment,” M.D. Anderson News Release, dated March 10, 2008.] See also Survival in advanced-stage ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: Abstract #5514.

Comment: Both studies illustrate the importance of obtaining genetic testing information from your doctor. This information is important for your family and relatives and your own treatment and prognosis.