TGen-led Study Discovers Genetic Cause of a Rare Type of Ovarian Cancer

TGen-led study discovers genetic cause of a rare type of ovarian cancer. Scientific breakthrough could lead to new cancer treatments; study inspired by the memory of Taryn Ritchey, a 22-year-old patient who lost her battle to the disease.

The cause of a rare type of ovarian cancer that most often strikes girls and young women has been uncovered by an international research team led by the Translational Genomics Research Institute (TGen), according to a study published online recently by the renowned scientific journal, Nature Genetics. [1] In a scientific rarity, two additional studies with similar results were also published online on the same day in Nature Genetics, producing immediate validation and reflecting a scientific consensus that usually takes months or even years to accomplish. [2-3]

By applying its groundbreaking work in genomics, TGen led a study that included: Scottsdale Healthcare, Mayo Clinic, Johns Hopkins University, St. Joseph’s Hospital and Medical Center; Evergreen Hematology and Oncology, Children’s Hospital of Alabama, the Autonomous University of Barcelona, British Columbia Cancer Agency, University of British Columbia, and the University Health Network-Toronto.

The findings revealed a “genetic superhighway” mutation in a gene found in the overwhelming majority of patients with small cell carcinoma of the ovary, hypercalcemic type, also known as “SCCOHT.” This rare type of ovarian cancer is usually not diagnosed until it is in its advanced stages. It does not respond to standard chemotherapy, and 65 percent of patients with the disease die within 2 years. SCCOHT can affect girls as young as 14 months, and women as old as 58 years – with a mean age of only 24 years old. In this study, the youngest patient was 9 years old.

The three separate groups of international researchers reported strikingly similar scientific findings related to SCCOHT, as provided below.

  • Identification of germline (i.e., inherited) and somatic (lifetime acquired) inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases, in addition to SMARCA4 protein loss in 82% (14/17) of the SCCOHT tumors. Notably, only 0.4% (2/485) of the other primary ovarian tumors tested possessed similar genomic characteristics. [Ref. 1]
  • Identification of recurrent inactivating mutations in the SMARCA4 gene in 12 of 12 SCCOHT tumor samples. [Ref. 2]
  • Indentification of germline inactivating mutations in familial cases of SCCOHT. Through additional analysis of non-familial tumors, the researchers determined that nearly 100% of tumors carry SMARCA4 mutations, and 38 of 40 lack protein expression.[Ref. 3]

Collectively, these findings implicate inactivating mutations in the SMARCA4 gene as a major cause of SCCOHT, and may lead researchers to improvements in genetic counseling, as well as the development of new targeted therapy treatment approaches.

Dr. Jeffrey Trent, President and Research Director of TGen, is the study's senior author.

Dr. Jeffrey Trent, President and Research Director of TGen, is the study’s senior author.

“This is a thoroughly remarkable study. Many genetic anomalies can be like a one-lane road to cancer; difficult to negotiate. But these findings indicate a genetic superhighway that leads right to this highly aggressive disease,” said Dr. Jeffrey Trent, President and Research Director of TGen, and the study’s senior author. “The correlation between mutations in SMARCA4 and the development of SCCOHT is simply unmistakable.”

Dr. Trent added that while the breakthrough is for a relatively rare cancer, discovering the origins of this type of ovarian cancer could have implications for more common diseases.

Much of the work in this study was inspired by the memory of Taryn Ritchey, a 22-year-old TGen patient who in 2007 lost her battle with ovarian cancer, the 5th leading cause of cancer death among American women.

“Taryn would be incredibly excited about this amazing new study, and she would be glad and thankful that other young women like her might now be helped because of TGen’s ongoing research,” said Taryn’s mother Judy Jost of Cave Creek, Arizona. “My daughter never gave up, and neither has TGen.”

The SMARCA4 gene – previously associated with lung, brain and pancreatic cancer – was the only recurrently mutated gene in the study’s samples. The implications of this discovery, therefore, may be widespread.

“The findings in this study represent a landmark in the field. The work identifies SMARCA4 mutations as the culprit, and most future research on this disease will be based on this remarkable discovery,” said Dr. Bert Vogelstein, Director of the Ludwig Center at Johns Hopkins University, Investigator at the Howard Hughes Medical Institute, and pioneer in the field of cancer genomics. He did not participate in the study but is familiar with its findings.

“The past decade of research has taught us that cancer is a vastly complex disease. Profound patient-to-patient variability has made treatment and diagnosis for many tumor types at times very difficult. In this case, however, we have found a single genetic event driving SCCOHT in nearly every patient,” said Dr. William Hendricks, a TGen Staff Scientist and another author of the study.

“We have shown that loss of SMARCA4 protein expression is extremely specific to SCCOHT and can facilitate the diagnosis of SCCOHT,” said Dr. Anthony N. Karnezis, a fellow at the British Columbia Cancer Agency located in Vancouver, Canada, and one of the study’s authors.

Pilar Ramos, a TGen Research Associate, is the study's lead author.

Pilar Ramos, a TGen Research Associate, is the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“We set out to uncover any small sliver of hope for women afflicted with this rare cancer. What we found instead are the nearly universal underpinnings of SCCOHT,” said Pilar Ramos, a TGen Research Associate, and the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

The TGen-led study was supported by grants from: the Marsha Rivkin Center for Ovarian Cancer Research, the Anne Rita Monahan Foundation, the Ovarian Cancer Alliance of Arizona, the Small Cell Ovarian Cancer Foundation, and philanthropic support to the TGen Foundation. Further support was provided by the Terry Fox Research Initiative’s New Frontiers Program in Cancer, and the Canadian Institutes of Health Research.

For more information about TGen’s research into small cell carcinoma of the ovary (SCCO), or to participate in a future study, visit: www.tgen.org/scco.

About TGen

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting cutting-edge genomic research to accelerate breakthroughs in healthcare. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

References:

1./ Ramos P, et al.  Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2928.

2./ Jelinic P, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovaryNature Genetics (published online 23 March 2014) doi:10.1038/ng.2922.

3./ Witkowski L, et al.  Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.  Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2931

Additional Information:

 

Canadian Researchers Link DICER1 Gene Mutation to Non-Epithelial Ovarian Cancers & Other Rare Tumor Types

Canadian researchers affiliated with the Ovarian Cancer Research Program of British Columbia report that recurrent, lifetime-acquired mutations affecting the DICER1 gene occur in a range of nonepithelial ovarian tumors as well as other rare cancer tumor types, and appear common in Sertoli-Leydig ovarian tumors. The study findings were published online today in the New England Journal of Medicine.

Dr. Gregg Morin, Head of Proteomics, Michael Smith Genome Sciences Centre, BC Cancer Agency; DICER 1 Mutation Ovarian Cancer Study Co-Leader

Dr. David Huntsman, Genetic Pathologist & Director of the Ovarian Cancer Research Program of British Columbia at the BC Cancer Agency & Vancouver Coastal Health Research Institute; DICER 1 Mutation Ovarian Cancer Study Co-Leader

Scientists at the British Columbia (BC) Cancer Agency, Vancouver Coastal Health Research Institute, and the University of British Columbia (UBC) are excited over a discovery made while studying rare tumor types.

Dr. David Huntsman, genetic pathologist and director of the Ovarian Cancer Program of BC (OvCaRe) at the BC Cancer Agency and Vancouver Coastal Health Research Institute, and Dr. Gregg Morin, a lead scientist from the Michael Smith Genome Sciences Centre at the BC Cancer Agency, led a research team who discovered that mutations in rare, seemingly unrelated cancers were all linked to the same gene, known as “DICER1.” The study findings were published online today in the New England Journal of Medicine. [1]

Background: RNA Interference, MicroRNAs, and DICER.

Nucleic acids are molecules that carry genetic information and include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). The DNA segments that carry genetic information are called “genes.” Together these molecules form the building blocks of life. DNA contains the genetic code or “blueprint” used in the development and functioning of all living organisms, while “messenger RNAs” or mRNAs help to translate that genetic code into proteins by acting as a messenger between the DNA instructions located in the cell nucleus and the protein synthesis which takes place in the cell cytoplasm (i.e., outside the cell nucleus, but inside the outer cell membrane). Accordingly, DNA is first “transcribed” or copied into mRNA, which, in turn, gets “translated” or synthesized into protein.

RNA interference” (RNAi) is a mechanism through which gene expression is inhibited at the translation stage, thereby disrupting the protein production within a cell. RNAi is considered one of the most important discoveries in the field of molecular biology. Andrew Fire, Ph.D., and Craig C. Mello, Ph.D. shared the 2006 Nobel Prize in Physiology or Medicine for work that led to the discovery of the RNAi mechanism. While the mechanism itself is termed “RNA interference,” there are two major types of RNA molecules that play a key role in effectuating that interference. The first type of RNA molecules consists of “microRNAs” or miRNAs, while the second type consists of “small interfering RNAs” or siRNAs.

Current thinking suggests that RNAi evolved as a cellular defense mechanism against invaders such as RNA viruses. When they replicate, RNA viruses temporarily exist in a double-stranded form. This double-stranded intermediate would trigger RNAi and inactivate the virus’ genes, thereby preventing viral infection. RNAi may also have evolved to combat the spread of genetic elements called “transposons” within a cell’s DNA. Transposons can wreak havoc by jumping from spot to spot on a genome, sometimes causing mutations that can lead to cancer or other diseases. Like RNA viruses, transposons can take on a double-stranded RNA form that would trigger RNAi to clamp down on the potentially harmful “jumping gene” activity. Also, as noted above, RNAi is important for regulating gene expression. For example, the turning down of specific genes is critical to proper embryonic development.

Of relevance to the Canadian study findings within the context of RNAi are miRNAs. MiRNAs can bind to mRNAs and either increase or decrease their activity, for example, by preventing a mRNA from producing a protein. [2] In this context, “gene silencing” can occur through mRNA degradation or prevention of mRNA translation.  MiRNAs play an integral role in numerous biological processes, including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development. MiRNA expression or function is significantly altered in many disease states, including cancer.

Because of its involvement in miRNA processing, the DICER1 gene plays an important role in maintaining health. It carries out a “factory style” function which involves chopping up miRNAs to activate them. [Ref. 2] These miRNAs, in turn, control hundreds of other genes as noted above. Based upon a study led by investigators from the University of Texas M.D. Anderson Cancer Center, the expression levels of DICER have global effects on the biogenesis of miRNA, and reduced gene expression correlates with a poor outcome in ovarian cancer. [3] In the M.D. Anderson study, two somatic (i.e., lifetime-acquired) missense DICER mutations were discovered in two epithelial ovarian cancer tumors. The M.D. Anderson investigators concluded that the DICER mutations were not associated with the alterations in DICER expression found in mRNAs. It is important to note that the type of somatic missense DICER mutations discovered in the M.D. Anderson study were not the same as those discovered in the Canadian study as discussed below.

Recurrent DICER Mutations Are Predominant In A Rare Form of Non-Epithelial Ovarian Cancer.

At the outset of the Canadian study, the OvCaRe team sequenced ovarian, uterine, and testicular tumors, expecting to find that their genomes would be distinct with specific, differing abnormalities. Much to their amazement, the researchers discovered that the same fundamental mutation in the DICER1 gene represented a common process underlying the different cancers which they examined.

Specifically, the Canadian investigators sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors, which included two Sertoli–Leydig cell tumors, four juvenile (not adult) granulosa-cell tumors, and eight primitive germ-cell tumors of the yolk-sac type. The researchers identified closely clustered mutations in the region of DICER1 which encode the RNase IIIb domain in four samples. Based on these findings, the OvCaRe team sequenced the same region of DICER1 in additional ovarian tumors, and tested for the effect of the mutations on the enzymatic activity of DICER1.

Recurrent somatic (i.e., lifetime-acquired) DICER1 mutations in the RNase IIIb domain were identified in 30 of 102 nonepithelial ovarian tumors (29%), including 4 tumors which also possessed germline (i.e., inherited) DICER1 mutations. The highest frequency of somatic DICER1 mutations occurred in Sertoli–Leydig cell tumors (26 of 43, or 60%). Notably, the mutant DICER1 proteins identified in the samples possessed reduced RNase IIIb activity, but retained RNase IIIa activity.

The Canadian researchers also performed additional tumor testing and detected the DICER1 mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas.

The groundbreaking nature of this discovery is reflected in the fact that the DICER1 “hotspot” mutations are not present in the 1000 Genomes Project data or the public data repository of The Cancer Genome Atlas consortium. To date, no recurrent DICER1 mutations have been reported in the mutation database of the Catalogue of Somatic Mutations in Cancer (COSMIC), in which 4 of 938 reported cancers possess somatic mutations but none in the RNase IIIb domain hot spots or RNase IIIa equivalents. Moreover, the Canadian researchers note that the newly-discovered DICER1 mutations were not observed in any of the more than 1000 cancer sequencing libraries which were studied.

Based upon the foregoing , the researchers concluded that somatic missense mutations affecting the RNase IIIb domain of DICER1 occur in a range of nonepithelial ovarian tumors, and possibly other cancers. Furthermore, the DICER1 mutations appear to be common in Sertoli-Leydig ovarian tumors (which are a subtype of nonepithelial, sex cord-stromal ovarian tumors). The researchers believe that the recurrent DICER1 mutations identified implicate a novel defect in miRNA processing which does not entirely destroy DICER1 functionality, but alters it.

Accordingly, the Canadian researchers suggest that the newly-discovered DICER1 mutations may represent an oncogenic event within the specific context of nonepithelial ovarian tumors, rather than a permissive event in tumor onset (as may be expected for loss of function in a tumor suppressor gene). The researchers note that DICER1 expression in tumors possessing the hotspot DICER1 somatic mutations argues against a role for DICER1 as a classic tumor suppressor gene. They further explain that the localized and focal pattern of the identified DICER1 mutations is typical of dominantly acting oncogenes, like KRAS and BRAF.

In sum, the Canadian researchers believe that the recurrent and focal nature of the DICER1 mutations and their restriction to nonepithelial ovarian tumors suggest a common oncogenic mechanism associated with a specifically altered DICER1 function that is selected during tumor development in specific cell types.

The Canadian study was supported through funding by Canadian Institutes for Health Research, Terry Fox Foundation, BC Cancer Foundation, VGH & UBC Hospital Foundation, Michael Smith Foundation for Health Research, and Genome BC.

Expert Commentary

DICER is of great interest to cancer researchers” said Dr. Huntsman, who also holds the Dr. Chew Wei Memorial Professorship in the departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine at UBC. “There have been nearly 1,300 published studies about it in the last 10 years, but until now, it has not been known how the gene functions in relation to cancer.”

“This discovery shows researchers that these mutations change the function of DICER so that it participates directly in the initiation of cancer, but not in a typical ‘on-off’ fashion,” says Dr. Morin who is also assistant professor in the department of Medical Genetics at UBC. “DICER can be viewed as the conductor for an orchestra of functions critical for the development and behavior of normal cells. The mutations we discovered do not totally destroy the function of DICER rather they warp it—the orchestra is still there but the conductor is drunk.”

This finding is the third of a series of papers published recently in the New England Journal of Medicine (NEJM) in which the OvCaRe team used new genomic technologies to unlock the molecular basis of poorly understood types of ovarian cancer. The first finding, published in the NEJM in 2009, identified mutations in the FOXL2 (forkhead box L2) gene as the molecular basis of adult granulosa cell ovarian cancer tumors. The second finding, published in the NEJM in 2010, determined that approximately one-half of clear-cell ovarian cancers and one-third of endometrioid ovarian cancers possess ARID1A  (AT rich interactive domain 1A) gene mutations.

The DICER gene mutation breakthrough discovery is particularly pivotal because it could lead to solutions for treatment of more common cancers.

“Studying rare tumors not only is important for the patients and families who suffer from them but also provides unique opportunities to make discoveries critical to more common cancers – both in terms of personalized medicine, but also in applying what we learn from how we manage rare diseases to more common and prevalent cancers,” said Dr. Huntsman “The discovery of the DICER mutation in this varied group of rare tumors is the equivalent of finding not the needle in the haystack, but rather the same needle in many haystacks.”

Dr. Phillip A. Sharp, Professor, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Co-winner of the 1993 Nobel Prize in Physiology and Medicine

“This breakthrough will be of interest to both the clinical and the fundamental science communities,” says Dr. Phillip A. Sharp, Professor, Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, and co-winner of the 1993 Nobel Prize in Physiology or Medicine for the discovery that genes are not contiguous strings but contain introns, and that the splicing of mRNA to delete those introns can occur in different ways, thereby yielding different proteins from the same DNA sequence. “Huntsman, Morin and colleagues’ very exciting discovery of specific mutations in DICER, a factor essential for syntheses of small regulatory RNAs in ovarian and other human tumors, could lead to new approaches to treatment.”

The Canadian OvCaRe research team is now working to determine the frequency and role of DICER mutations in other types of cancers. The research team is also expanding its collaboration to discover whether mutant DICER and the pathways it controls can be modulated to treat the rare cancers in which the mutations were discovered and more common cancers.

The Michael Smith Genome Sciences Centre (Michael Smith GSC), located at the BC Cancer agency, played a key role in this discovery. By way of background, Dr. Michael Smith was a co-winner of 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 a 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.

A decision was made more than 10 years ago, championed by Drs. Michael Smith, Victor Ling, and others to create and locate the Michael Smith GSC within the BC Cancer Agency and in close proximity to Vancouver General Hospital (VGH). The chosen location for this critical facility provided the multidisciplinary cancer research teams in Vancouver with access to state-of-the-art technologies.

“We are one of less than five places in the world doing this type of work successfully. This discovery is one of a series of recent landmark findings from Vancouver that are reshaping our understanding of many cancers,” says Dr. Huntsman. “Since my arrival in Vancouver 20 years ago I have never before sensed such a strong feeling of communal pride and excitement within our research community. Our next task is to bring the discoveries into the clinic.”

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

OvCaRe is a multidisciplinary research program involving clinicians and research scientists in gynecology, pathology, and medical oncology at VGH and BC Cancer Agency. OvCaRe is a unique collaboration between the BC Cancer Agency, Vancouver Coastal Health Research Institute, and UBC. The OvCaRe team is considered a leader in ovarian cancer research which is breaking new ground in better identifying, understanding, and treating this disease. The OvCaRe seminal paper in PLoS (Public Library of Science), which addresses ovarian cancer as a group of distinct diseases, has been embraced by the global research community who has adopted the BC approach to ovarian cancer research. To learn more, visit www.ovcare.ca.

About the Michael Smith Genome Sciences Centre

Canada’s Michael Smith Genome Sciences Centre is an internationally recognized state-of-the-art facility applying genomics and bioinformatics tools and technologies to cancer research. Led by Dr. Marco Marra, the Michael Smith GSC is one of ten leading genomic research centres in the world and the only one of its kind in the world integrated into a cancer facility. With a primary focus on cancer genomics research, its scientists have been involved in many world-class groundbreaking discoveries over the past decade. To learn more, visit www.bcgsc.ca.

About the Vancouver Coastal Health Research Institute

Vancouver Coastal Health Research Institute is the research body of Vancouver Coastal Health Authority, which includes BC’s largest academic and teaching health sciences centres: Vancouver General Hospital, UBC Hospital, and GF Strong Rehabilitation Centre. The institute is academically affiliated with the UBC Faculty of Medicine, and is one of Canada’s top-funded research centres, with $82.4 million in research funding for 2009/2010. To learn more, visit www.vchri.ca.

About the British Columbia Cancer Agency

The BC Cancer Agency, an agency of the Provincial Health Services Authority, is committed to reducing the incidence of cancer, reducing the mortality from cancer, and improving the quality of life of those living with cancer. It provides a comprehensive cancer control program for the people of British Columbia by working with community partners to deliver a range of oncology services, including prevention, early detection, diagnosis and treatment, research, education, supportive care, rehabilitation and palliative care. To learn more, visit www.bccancer.ca.

About the University of British Columbia

The University of British Columbia is one of North America’s largest public research and teaching institutions, and one of only two Canadian institutions consistently ranked among the world’s 40 best universities. Surrounded by the beauty of the Canadian West, it is a place that inspires bold, new ways of thinking that have helped make it a national leader in areas as diverse as community service learning, sustainability, and research commercialization. UBC offers more than 55,000 students a range of innovative programs and attracts $550 million per year in research funding from government, non-profit organizations, and industry through 7,000 grants. To learn more, visit www.ubc.ca.

References

1/Morin G, Hunstman, DG et al.  Recurrent Somatic DICER1 Mutations in Nonepithelial Ovarian CancersNEJM, published online December 21, 2011 (10.1056/NEJMoa1102903).

2/The Canadian investigators describe the operation of the RNAi pathway with respect to miRNA biogenesis as follows:

“MicroRNAs (miRNAs) are a functional class of noncoding RNA molecules that regulate translation and degradation of messenger RNA. MiRNA transcripts are processed from hairpin pre-miRNA precursors into short miRNA:  miRNA* duplexes consisting of the miRNA targeting strand and the imperfectly complementary miRNA* strand (star strand, or inert carrier strand) by Dicer, an endoribonuclease with two RNase III–like domains. The RNase IIIb domain cuts the miRNA strand, whereas the RNase IIIa domain cleaves the miRNA* strand. The resultant RNA duplex is loaded into the RNA-induced silencing complex (RISC) containing an Argonaute protein. The miRNA* strand is then removed, leaving the miRNA strand, which targets messenger RNAs (mRNAs) for degradation or interacts with the translation initiation complex to inhibit and destabilize translation of the targeted messenger RNAs.” [footnote citations omitted]

3/Merritt WM, et al. Dicer, Drosha, and outcomes in patients with ovarian cancer. N Engl J Med. 2008 Dec 18;359(25):2641-50. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. PubMed PMID: 19092150; PubMed Central PMCID: PMC2710981.

Sources:

PARP Inhibitor Olaparib Has Activity in High-Grade Serous Ovarian Cancer Without Inherited BRCA1 or BRCA2 Gene Mutations

Researchers affiliated with the British Columbia Cancer Agency reported Phase 2 clinical study results indicating that advanced ovarian cancer, with and without germline (inherited) BRCA 1 or BRCA 2 gene mutations, responded to treatment with the PARP inhibitor olaparib. The Phase 2 study results were published online in the August 21 edition of The Lancet Oncology.

Karen A. Gelmon, M.D., Lead Study Author, Medical Oncologist, and Head of the Investigational Drug Program, Experimental Therapeutics, Department of Medical Oncology, British Columbia Cancer Agency

Researchers affiliated with the British Columbia Cancer Agency reported results from a Phase 2 clinical study indicating that advanced ovarian cancer, with and without germline (inherited) BRCA 1 or BRCA 2 gene mutations, responded to treatment with the PARP (poly(ADP-ribose) polymerase ) inhibitor olaparib (a/k/a AZD2281).[1] The Phase 2 study results were published online in the August 21 edition of the Lancet Oncology.

Preliminary findings from this study were reported at the 2011 American Society of Clinical Oncology annual meeting, which was held in Chicago earlier this year. [2]

The Phase 2 study results indicate that approximately 41% of women with BRCA1 or BRCA 2-mutated ovarian cancer had objective responses to the targeted agent, along with 24% of patients with non-BRCA gene mutated ovarian cancer. The findings suggest that the PARP inhibitor olaparib might have broad applicability in ovarian cancer.

Unfortunately, the drug olaparib failed to produce any objective responses in patients with non-BRCA gene mutated, triple negative breast cancer. Triple negative breast cancer is a difficult to treat subtype of the disease that lacks three of the cellular “receptors” known to fuel most breast cancers: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2).

Background

Olaparib is a small-molecule, potent oral PARP inhibitor. Olaparib targets PARP, an enzyme essential for repair of single-strand DNA breaks. Preclinical evidence showed that the drug olaparib had activity against tumors with homologous recombination (HR) DNA repair defects, such as those caused by BRCA 1 or BRCA 2 gene mutations.

Germline (inherited) BRCA 1 or BRCA 2 gene mutations confer a high risk of breast and ovarian cancers, and tumors arising from the mutations have aggressive tendencies, such as triple-negative breast cancer. PARP inhibition has already demonstrated activity in cancers with germline mutations. Accordingly, the goal of the Canadian researchers was to assess the safety and tolerability of this drug in patients with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer, which did not possess BRCA1 or BRCA2 mutations.

Past study reporting associated with olaparib over the past twelve months has been somewhat mixed. Data reported at the 2010 European Society of Medical Oncology annual congress showed no significant effect of olaparib on progression-free survival (PFS) in women with advanced BRCA gene-mutated ovarian cancer. [3] In contrast, data presented at the 2011 American Society of Clinical Oncology meeting showed almost a doubling of PFS with olaparib among women with relapsed, platinum-sensitive ovarian cancer. [4]

Olaparib Phase 2 Study Design

The olaparib Phase 2 study enrolled women into 4 cohorts or trial arms. The two stage trial design included:

  • BRCA 1 or BRCA 2 gene mutation negative (or unknown mutation status) patients with high-grade serous, undifferentiated, fallopian-tube, or primary peritoneal cancer (Arm A) or triple-negative breast cancer (Arm B); and
  • Two reference groups with recurrent ovarian cancer (Arm C) or breast cancer (Arm D) who possessed BRCA 1 or BRCA 2 gene mutations.

All patients had tumor biopsies taken prior to treatment, after 2 cycles of treatment, and at disease progression to assess PARP inhibitor activity, loss of heterozygosity, gene mutational changes, BRCA 1 or BRCA 2 gene expression, and other markers of response. Computed tomography (CT)/magnetic ressonance imaging (MRI) assessments were performed prior to treatment and at every 2 treatment cycles. The patients were treated with single agent olaparib (400 mg twice a day) on a continuous basis in 4 week cycles.

Researchers at six centers in Canada enrolled 91 patients in this Phase 2, open-label, nonrandomized trial (ClinicalTrials.gov ID: NCT00679783). [5] Eligible patients had advanced metastatic or recurrent breast cancer, or advanced ovarian cancer.

The study population consisted of 65 patients with ovarian cancer and 26 patients with breast cancer. All of the breast cancer patients and 64 ovarian cancer patients received at least one dose of olaparib (400 mg twice a day) and were included in the final study analysis.

The ovarian cancer cohort consisted of 17 patients with BRCA gene mutations and 47 patients without BRCA gene mutations. The breast cancer cohort consisted of 10 patients with BRCA gene mutations and 16 patients without BRCA gene mutations.

The researchers reported that 58 patients with ovarian cancer had the serous subtype (13 patients with BRCA gene mutations, 45 patients without BRCA gene mutations). In the breast cancer cohort, 21 patients had triple-negative disease, including five patients with BRCA gene mutations.

The primary endpoint of the Phase 2 study was objective response, as determined by RECIST (Response Evaluation Criteria In Solid Tumors) criteria.

Olaparib Phase 2 Study Results

None of the breast cancer patients had objective responses, and the disease control rate (proportion of patients with complete responsepartial response, or stable disease) at eight weeks was 38% (10 of 26 patients).

In the ovarian cancer cohort, seven of 17 (41%) patients with BRCA gene mutations, and 11 of 46 (24%) patients without BRCA gene mutations, experienced objective responses. The overall disease control rate was 66% (42 of 64), including benefit in 76% (11 of 17) of BRCA-negative patients and 62% (29 of 47) of the BRCA-positive subgroup.

The researchers reported: “Although responses were seen in both platinum-sensitive and platinum-resistant populations, our post hoc analysis reported activity mostly in patients with platinum-sensitive disease.” As a precaution, the researchers noted that their findings should be interpreted conservatively because of the small study sample size.

Among the ovarian cancer patients, there were thirteen premature discontinuations, without confirmed radiological disease progression. Six patients dropped out of the Phase 2 olaparib study. Of those patients, three women dropped out because of worsening disease, and three more women dropped out because of adverse events. One patient in the breast cancer group discontinued early because of an adverse event.

The most common adverse events in ovarian and breast cancer patients were fatigue (58 patients), nausea (58), vomiting (34), and decreased appetite (30).

“To our knowledge, this study is the first to show that olaparib monotherapy has activity in women with pretreated high-grade serous ovarian cancer without germline BRCA1 or BRCA2 mutations,” said Karen A. Gelmon, M.D., lead study author, medical oncologist, and head of the Investigational Drug Program, Experimental Therapeutics, within the department of medical oncology of the British Columbia Cancer Agency, along with her co-authors. Dr. Gelmon is also a professor of  medicine at the University of British Columbia.

“New treatments targeting DNA repair mechanisms seem to provide new hope for treatment of ovarian cancer,” the Canadian researchers added. “Subsequent reports of this study assessing tumor biopsies might identify which patients obtain most clinical benefit from olaparib.”

Expert Commentary

Melinda Telli, M.D., Assistant Professor, Stanford School of Medicine, Stanford University

The study findings by Gelmon et al. were accompanied by a commentary which was written by Melinda L. Telli, M.D., assistant professor, Stanford School of Medicine. [6] In that commentary, Dr. Telli states:

… Their [Gelson et al.] study is noteworthy in that it shows, for the first time, activity of a PARP inhibitor as monotherapy in women with advanced high-grade serous ovarian cancer who do not have a germline BRCA1 or BRCA2 mutation. This finding not only suggests new therapeutic possibilities for women with this aggressive type of ovarian cancer, but also importantly confirms the hypothesis that subpopulations of patients with common sporadic tumors can be targeted effectively with PARP inhibitor therapy. An additional important negative finding of this study was the absence of objective responses to single-agent olaparib in women with sporadic triple-negative breast cancer, although the numbers were small and patients heavily pretreated. With new therapies come new challenges, and the clinical development of PARP inhibitors has certainly encountered many obstacles. Thus, to see the potential of these drugs realized is particularly satisfying. This important finding of activity in high-grade serous ovarian cancer marks a new beginning to what will hopefully be a long and fruitful future for PARP inhibitors as they make their move beyond BRCA.

Another expert expressed excitement about the future potential of olaparib. Stephanie V. Blank, M.D., an assistant professor in clinical gynecologic oncology at NYU School of Medicine, said:

It is extremely exciting that an agent as promising as olaparib can be effective in a broader group of women than had been expected. The next challenge will lie in getting our hands on the drug, which at present is only available for patients on clinical trials.

Study Relationship Disclosures

The study was supported by AstraZeneca. Gelmon and several co-authors disclosed relationships with AstraZeneca. The co-authors included AstraZeneca employees. Dr. Telli reported no relevant disclosures.

Libby’s H*O*P*E* Commentary

We would like to extend our congratulations to Dr. Gelmon, as well as her co-investigators, many of whom are critical team members of  the Ovarian Cancer Research Program of British Columbia (OvCaRe). On September 8, 2010, we reported on the OvCaRe team finding of prevalent ARID1A gene mutations in endometriosis-associated, epithelial ovarian cancers (i.e., clear cell and endometrioid). [7]

The findings reported by Gelmon et al. will take on critical importance if it is eventually proven that PARP inhibitors could benefit up to 50% of high-grade serous ovarian cancer patients who possess germline (inherited) or somatic (lifetime acquired) mutations in the BRCA 1 or BRCA 2 gene, or other alternations in the HR DNA repair pathway, as suggested by past preclinical study findings, [8] including those recently reported by The Cancer Genome Atlas. [9]

References

1/ Gelmon KA, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase II, multicenter, open-label, nonrandomized study. Lancet Oncol 2011; 12: 852-861. [Abstract]

2/Gelmon KA, et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. J Clin Oncol 28:15s, 2010 (suppl; abstr 3002) [2011 American Society of Clinical Oncology Annual Meeting, Abstract 3002]

3/Kaye S, et al Phase II study of the oral PARP inhibitor olaparib (AZD2281) versus liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or BRCA2 mutations. Annals of Oncology 2010 21(8)8): viii304–viii313, 2010 doi:10.1093/annonc/mdq526 [2010 European Society of Medical Oncology Annual Meeting, Abstract 9710, Adobe Reader PDF Document].

4/Ledermann JA, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). J Clin Oncol 29: 2011 (suppl; abstr 5003) [2011 American Society of Clinical Oncology Annual Meeting, Abstract 5003]

5/Phase II, Open Label, Non-Randomized Study of AZD2281 in the Treatment of Patients With Known BRCA or Recurrent High Grade Serous/ Undifferentiated Tubo-Ovarian Carcinoma and in Known BRCA or Triple Negative Breast Cancer to Determine Response Rate and Correlative Markers of Response, ClinicalTrials.gov ID: NCT00679783.

6/Telli ML. PARP inhibitors in cancer: Moving beyond BRCA. Lancet Oncol 2011; 12: 827-828. [Full Text]

7/British Columbian Researchers Make Groundbreaking Genetic Discovery In Endometriosis-Associated Ovarian Cancers, by Paul Cacciatore, Libby’s H*O*P*E*™, September 8, 2010.

8/New Assay Test Predicts That 50% of Ovarian Cancers Will Respond To In Vitro PARP Inhibition, by Paul Cacciatore, Libby’s H*O*P*E*™, November 11, 2010.

9/In-Depth Review: The Cancer Genome Atlas Reports On Landmark Analysis of High-Grade Serous Ovarian Cancer, by Paul Cacciatore, Libby’s H*O*P*E*™, August 5, 2011.

Additional Sources:

PARP Inhibitor Clinical Trial Information

Related Libby’s H*O*P*E* Posts

  • Inherited Mutations in RAD51D Gene Confer Susceptibility to Ovarian Cancer, August 7, 2011.
  • In-Depth Review: The Cancer Genome Atlas Reports On Landmark Analysis of High-Grade Serous Ovarian Cancer, August 5, 2011.
  • ASCO 2011: Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer, May 19, 2011.
  • PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study, November 17, 2010.
  • New Assay Test Predicts That 50% of Ovarian Cancers Will Respond To In Vitro PARP Inhibition, November 11, 2010.
  • PARP Inhibitor Olaparib Benefits Women With Inherited Ovarian Cancer Based Upon Platinum Drug Sensitivity, April 23, 2010.

Related WORD of HOPE Ovarian Cancer Podcast

  • 10 Exciting Ovarian Cancer Research Topics from 2010 — PARP Inhibitors & BRCA Gene-Mutated Ovarian Cancer (Topic #2 of 10), Episode #2, WORD of HOPE Ovarian Cancer Podcast, April 11, 2011.

“Smile, Open Your Eyes, Love and Go On.”

Today marks the 2nd anniversary of Libby’s death from ovarian cancer at the age of 26. Although the family healing process continues, we celebrate Libby’s life formally on this day to honor her memory, and remind ourselves that life is precious and should not be taken for granted.

Today marks the 2nd anniversary of Libby’s death from ovarian cancer at the age of 26. Although the family healing process continues, we celebrate Libby’s life formally on this day to honor her memory, and remind ourselves that life is precious and should not be taken for granted.  This day also reminds us that there is a considerable amount of work yet to be done in raising ovarian cancer awareness and finding a reliable screening test, and ultimately a cure, for this unforgiving disease.

As reported by the American Cancer Society earlier this month, the estimated number of newly diagnosed ovarian cancer cases and related deaths in the U.S. during 2010 will be 21,880 and 13,850, respectively.  Simply stated, a U.S. woman will die every 38 minutes from ovarian cancer in 2010. Cancer Research U.K. also reported this month that the 10-year ovarian cancer survival rate nearly doubled since the 1970s. Unfortunately, this much heralded statistical “doubling” represents an increase of the long-term ovarian cancer survival rate from 18% to only 35%. Ovarian cancer still remains the most lethal gynecologic cancer in women. I know that if Libby were alive today, she would say, “we must do better.”

Although the vast majority of visitors to this website never knew Libby, it is because of her that Libby’s H*O*P*E*™ was created and shared with the general public. What began as a family website used to exchange ovarian cancer and cancer-related information within the family during Libby’s illness, has rapidly become a global information resource for ovarian cancer survivors and their families after her death. It is my greatest hope that Libby would be proud of the following accomplishments achieved over the past two years, which are dedicated to her memory:

  • Created Libby’s H*O*P*E*™ mission statement to be carried out by a future nonprofit, tax-exempt organization.
  • Generated approximately 145,000 website visitors, from 60 countries around the world.
  • Generated 5% to 10% of daily website visitors from major U.S. and international cancer centers and elite academic institutions actively engaged in cancer research.
  • Established a website library containing over 500 videos relating to ovarian cancer and cancer-related topics.
  • Responded to approximately 700 ovarian cancer survivor (and family) general informational inquiries, which were answered within 96 hours of website posting or email receipt.
  • Created Vox Populi website article features which provide the general public with a better understanding of how ovarian cancer impacts the daily life of a woman diagnosed with the disease and her family. These stories have been well-received by our readers as a source of inspiration and hope.
  • Highlighted in the Eyes on Advocacy section of the 2010 University of Washington Tumor Vaccine Group (UWTVG) quarterly (Winter) newsletter entitled, TVG Focus. The UWTVG is headed by Mary L. (Nora) Disis, M.D., a Professor of Medicine and Adjunct Professor of Pathology and Obstetrics & Gynecology at the University of Washington, and a Member of the Fred Hutchinson Cancer Research Center. Dr. Disis is a world-renowned cancer immunologist.
  • Established a new working relationship with Women’s Oncology Research & Dialogue (WORD), a non-profit, tax-exempt organization dedicated to raising gynecological cancer awareness.  To promote this new relationship, WORD recently shot a video of Paul Cacciatore, the Libby’s H*O*P*E* founder.  In the video, Paul addresses the genesis of the website, the Libby’s H*O*P*E* mission statement, and why it is important for all women to educate themselves about the early warning signs of ovarian cancer.  WORD will be launching a new website before the end of 2010, and it is anticipated that this video will appear on both the WORD and Libby’s H*O*P*E* websites at that time.

“Remember Me”

Based upon instructions from Her Majesty Queen Elizabeth II (“Her Majesty”), a poem entitled, She Is Gone, was recited at the Queen Mother’s funeral, which was held in Westminster Abbey on April 9, 2002. The poem recitation sparked a glut of media interest because of its simple, upbeat nature – and mystery author, who was credited in the service program as “Anon” [i.e., Anonymous].  Apparently, Her Majesty found the poem while leafing through old memorial service books and she chose it to be read at her mother’s funeral, where it struck a chord with millions of mourners.

After the conclusion of the Queen Mother’s funeral, the BBC, The Times, and other U.K. media outlets took great effort to identify the author, with attributions going to, among others, Immanuel Kant and Joyce Grenfell. Eventually, it was discovered that the true author was Mr. David Harkins, who wrote the poem in 1981 while working at a bakery.  Mr. Harkins, who now works as an artist selling paintings over the Internet, said he “couldn’t believe his eyes” when he saw his poetry published in several newspapers after the funeral.

Quite shocked by all of the media attention, David Harkins sent the original manuscript of the poem to Prince Charles (of Wales), and St. James’s Palace replied thanking Mr. Harkins for explaining its origin. As it turned out, the poem was originally written by David Harkins in homage to an unrequited love. Mr. Harkins recalled: “I was 23 when I first met Anne Lloyd, my inspiration for the poem I called Remember Me.”  The reply received by David Harkins from the Prince of Wales’s office stated: “I have no doubt that it [Remember Me] will be reproduced on many occasions over the years to come. The Prince of Wales has asked me to send you his very best wishes.”

I chose to include Remember Me as part of our tribute to Libby for two reasons.  First, the poem is instructive as to how Libby would want all of us to continue on with our lives, energized by our loving memories of her.  Second, Libby would no doubt find great joy and humor in the fact that a talented baker from a small U.K. town became famous worldwide for his literary prowess rather than his pastries. The full text of Remember Me is provided below.

Remember Me

You can shed tears that she is gone

Or you can smile because she has lived

You can close your eyes and pray that she will come back

Or you can open your eyes and see all that she has left

Your heart can be empty because you can’t see her

Or you can be full of the love that you shared

You can turn your back on tomorrow and live yesterday

Or you can be happy for tomorrow because of yesterday

You can remember her and only that she is gone

Or you can cherish her memory and let it live on

You can cry and close your mind, be empty and turn your back

Or you can do what she would want: smile, open your eyes, love and go on.

— written by David Harkins, Silloth, Cumbria, U.K. (1981)

Did You Ever Hear An Angel Sing?

The inspirational story of Rhema Marvanne provides further proof that it is possible to “smile, open your eyes, love and go on,” after the death of a family member from ovarian cancer. It is difficult to believe that the life lesson highlighted by this touching story is provided to us through the example of a 7-year old child, albeit it a very talented one.

Rhema Marvanne was born on September 15, 2002.  Rhema lives with her father Teton Voraritskul, and a family pet dog named, “Mojo.” According to her father, Rhema began singing at the same time she began talking.

Rhema’s mother, Wendi Marvanne Voraritskul, loved Rhema with all of her heart. Wendi was diagnosed with ovarian cancer when Rhema was just 3 years old. Succumbing to the disease three years later, Wendi Marvanne died at the age of 36 on November 8, 2008.  According to Teton Voraritskul, most of Rhema’s memories with her mom were pleasant ones, but revolved around surgery, multiple chemotherapy treatments, sickness and struggle. Wendi was a strong believer in God and never complained about or questioned God during her illness. Teton explains that Wendi always encouraged those around her, even in the midst of her cancer battle. During Wendi’s final months, Rhema and Teton took care of her. Rhema spent almost every hour with her mother. When asked what her greatest accomplishment was prior to her death, Wendi simply replied, “Rhema.” A YouTube video featuring Wendi and her original songs is provided below. You can learn more about Wendi Marvanne’s life and music at www.jchouseofmercy.org.

It was less than a year ago that Rhema recorded her first song, Amazing Grace, and quickly became an Internet singing sensation. She obtains great inspiration from her mother, Wendi.  It is Rhema’s greatest hope to make her mother proud, both as a singer and as a “servant of God,” which is why she also performs for church congregations, non-profit organizations, charities, hospitals and special events.

Already a supremely talented singer, recording artist, and actor, Rhema counts the following among her recent accomplishments:

  • Acted in 1st featured film entitled Machine Gun Preacher, a Lionsgate production set to release in Fall 2011. The movie Machine Gun Preacher is based upon the true story of Sam Childers (portrayed by well-known actor Gerard Butler), a drug-dealing biker who finds religion and dedicates his life to helping Sudanese children escape the Lord’s Resistance Army (LRA) in Africa. Childers founded the Angels of East Africa, a children’s village located in southern Sudan, for the children he saves from the LRA.

During her free time Rhema enjoys playing with her friends and dolls, and loves to watch movies. The best description of Rhema is provided by her father:

…The best way to describe Rhema is that she has a beautiful heart and soul. She is sweet, kind, caring and most importantly pure in heart. Most people who have dealt with or are currently dealing with cancer, disease, challenges, etc…..see hope and inspiration in Rhema. The little girl who should have been scared or harmed by seeing her mother suffer and gone, is strong and perfect. I see Rhema as a cancer survivor. She gives me hope for goodness in mankind. God gave her a beautiful heart and the voice of an angel. Most people that hear her sing can not deny that God does speak through a child. Her voice touches people’s hearts.

Whenever we remember Libby, or any woman who lost her battle to ovarian cancer, we should follow Rhema’s example and heed the call to action set forth in the last line of the poem Remember Me, ” … smile, open your eyes, love and go on.”

Libby, we will always love you and keep your memory alive in our hearts and minds.

How Can You Help?

To support Libby’s H*O*P*E*™, you can make a donation ($10 minimum) through our Facebook Cause page.  All donations made to the Libby’s H*O*P*E*™ Facebook cause are designated for the benefit of the Ovarian Cancer Research Fund (OCRF). OCRF is one of the largest U.S. private, non-profit organizations dedicated to finding an early detection test, and ultimately a cure, for ovarian cancer.

If you are not a Facebook member, you can still make a donation through the Libby’s H*O*P*E*™ Facebook donation page (no membership or registration required).

If you are unable to donate, you can nevertheless support OCRF without any out-of-pocket cost by clicking on our “SocialVibe” widget that appears on the website homepage right sidebar, or by using our designated SocialVibe website. For each reader that clicks on the SocialVibe widget (or goes to our designated SocialVibe website), and watches the video presented and/or answers the question(s) listed, our current SocialVibe sponsor will donate money to OCRF on your behalf for ovarian cancer research. It’s fast & it’s free!

Special Thanks:

We would like to extend special thanks to Teton Voraritskul for allowing us to feature Rhema’s story and music videos, as well as the video of Wendi’s life.  To learn more about Rhema Marvanne and her music, go to www.RhemaMarvanne.com. Rhema’s songs are sold on iTunes®, Amazon.com, and RhemaMarvanne.com.

Sources:

  • Jemal A., Siegel R., Xu J. et. al. Cancer Statistics, 2010.  CA Cancer J Clin. 2010 Jul 7. [Epub ahead of print] [PMID: 20610543].
  • Remember Me, written by David Harkins, Silloth, Cumbria, U.K., PoeticExpressions.co.uk.

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*“Vox Populi,” a Latin phrase that means “voice of the people,” is a term often used in broadcast journalism to describe an interview of the “man on the street.”

In the spirit of Vox Populi, Libby’s H*O*P*E*™ searches online for original writings and visual media created by ovarian cancer survivors, survivors’ family members, cancer advocates, journalists, and health care professionals, which address one or more aspects of ovarian cancer within the context of daily life. The written and visual media features that we discover run the gamut; sometimes poignant, sometimes educational, sometimes touching, sometimes comedic, but always honest. The Vox Populi feature may take the form of an essay, editorial, poem, letter, story, song or video picture montage.

It is our hope that the Vox Populi feature will allow our readers to obtain, in some small way, a better understanding of how ovarian cancer impacts the life of a woman diagnosed with the disease and her family. We invite all readers to submit, or bring to our attention, original writings and visual media suitable for publication as Vox Populi features.