Inherited Mutations in RAD51D Gene Confer Susceptibility to Ovarian Cancer

Cancer Research UK-funded scientists have discovered that women who carry a faulty copy of a gene called RAD51D have almost a 1-in-11 chance of developing ovarian cancer. The finding that inherited mutations in the RAD51D gene confer susceptibility to ovarian cancer was reported in a study published online in Nature Genetics on August 7, 2011.

Cancer Research UK-funded scientists have discovered that women who carry a faulty copy of the RAD51D gene have nearly a 1-in-11 chance of developing ovarian cancer. The finding that inherited mutations in the RAD51D gene confer susceptibility to ovarian cancer was reported in a study published online in Nature Genetics on August 7, 2011.

(Photo: Cancer Research UK)

Although hereditary faults in RAD51D are thought to account for less than one in every hundred ovarian cancer cases – fewer than 60 women every year in the UK – this discovery could prove very important in the future in connection with the prevention and treatment of the disease in women who carry the faulty gene.

The team at The Institute of Cancer Research (ICR) examined DNA from women from 911 families with ovarian and breast cancer and compared differences in DNA with a control group of 1,060 people from the general population.

The team discovered eight germline (inherited) gene faults in the RAD51D gene in women with cancer, compared with one in the control group.

Ovarian cancer is the fifth most common cancer in women with approximately 6,500 cases diagnosed annually in the UK. The researchers estimate that RAD51D gene faults are present in almost one percent of women with ovarian cancer; that is, around 50 UK women each year.

Around one woman in 70 in the general population is at risk of developing ovarian cancer, but for those with a RAD51D gene fault this risk is increased to 1-in-11 – making these women six times more likely to develop the disease. The RAD51D gene fault also caused a slight increase in the risk of breast cancer.

The RAD51D gene is important for repairing damaged DNA. When the RAD51D gene is faulty, a key DNA repair pathway known as “homologous recombination” (HR) fails. This means DNA damage is not fixed and DNA faults build up in cells which make them more likely to turn into cancer.

The UK team also showed that cells with faulty RAD51D can be selectively destroyed by a relatively new class of cancer drugs called “PARP (poly (ADP-ribose) polymerase) inhibitors.” When the researchers tested the drugs on cells with the faulty RAD51D gene, they observed a dramatic effect – nearly 90 percent of the cells died, compared with just 10 percent of cells with fully functional RAD51D. These drugs are showing great promise in clinical trials for the treatment of breast and ovarian cancers with faults in the BRCA1 and BRCA2 genes, which are also important for repairing damaged DNA.

Professor Nazneen Rahman

Cancer Research UK-funded scientist and study author Professor Nazneen Rahman, head of the Division of Genetics and Epidemiology at The Institute of Cancer Research and The Royal Marsden cancer center, said:

“Women with a fault in the RAD51D gene have a 1-in-11 chance of developing ovarian cancer. At this level of risk, women may wish to consider having their ovaries removed after having children, to prevent ovarian cancer from occurring. There is also real hope on the horizon that drugs specifically targeted to the gene will be available.”

Professor Nic Jones

Professor Nic Jones, Cancer Research UK’s chief scientist, said:

“It’s incredibly exciting to discover this high risk gene for ovarian cancer. It’s further evidence that a range of different high risk genes are causing the development of breast and ovarian cancer and we hope there are more waiting to be discovered in different cancers. We believe the results of this research will help inform personalized treatment approaches and give doctors better information about risks of cancer to tell patients.”

Harpal S. Kumar, CEO, Cancer Research UK

Harpal Kumar, Cancer Research UK’s chief executive, said:

“Survival from ovarian cancer has almost doubled in the last 30 years. This landmark discovery is another piece of the jigsaw deepening our understanding of the disease. We hope this will have a significant impact in providing more personalised treatments for patients based on their genetic make-up, saving more lives from ovarian cancer. All of our research is generously funded by the public. This support has allowed us to invest heavily in the identification of DNA changes which paint a picture of which parts of a person’s gene set are linked to cancer. This life-changing discovery exemplifies the importance of this research and the importance of ongoing public support.”

Again, it is important to stress that faults in the RAD51D gene are rare, probably causing fewer than one in every 100 ovarian cancers. Yet for the small proportion of women who carry a faulty RAD51D gene, there is a chance of developing ovarian cancer, thereby making it a significant new finding.

Cancer Research UK is the largest single funder of ovarian cancer research in the UK – last year it spent more than £12 million of public donations on tackling the disease.

The RAD51D gene mutation study findings in relation to ovarian cancer susceptibility add to past evidence which links the gene to the disease. On April 21, 2010, Libby’s H*O*P*E*™ reported that a team of German researchers determined that RAD51C also increases a woman’s risk of breast and ovarian cancer.  Specifically, the identified risk for breast cancer in women with the RAD51C mutation was reported to be 60 percent to 80 percent, while the identified risk for ovarian cancer was 20 percent to 40 percent.

On November 11, 2010, we also reported that a separate group of U.K. researchers concluded that (i) HR-deficient status can be determined in primary ovarian cancer through a “RAD51 assay,” and (ii) such status correlates with in vitro response to PARP inhibition. Accordingly, the researchers concluded that potentially 50 percent to 60 percent of ovarian cancers patients could benefit from PARP inhibitors, but they noted that use of the RAD51 assay as a biomarker requires additional clinical trial testing. Although the RAD51 assay test that was used by these U.K. researchers to examine tumor samples in the laboratory is not yet suitable for routine clinical practice, the U.K. research team hopes to refine it for use in patients.

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About Cancer Research UK

  • Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research.
  • The charity’s groundbreaking work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. This work is funded entirely by the public.
  • Cancer Research UK has been at the heart of the progress that has already seen survival rates double in the last forty years.
  • Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses.
  • Together with its partners and supporters, Cancer Research UK’s vision is to beat cancer.

For further information about Cancer Research UK’s work or to find out how to support the charity, please call 020-7121-6699 or visit www.cancerresearchuk.org

About The Institute of Cancer Research (ICR)

  • The ICR is Europe’s leading cancer research center.
  • The ICR has been ranked the UK’s top academic research center, based on the results of the Higher Education Funding Council’s Research Assessment Exercise.
  • The ICR works closely with partner The Royal Marsden NHS Foundation Trust to ensure patients immediately benefit from new research. Together the two organisations form the largest comprehensive cancer centre in Europe.
  • The ICR has charitable status and relies on voluntary income.
  • As a college of the University of London, the ICR also provides postgraduate higher education of international distinction.

Over its 100-year history, the ICR’s achievements include identifying the potential link between smoking and lung cancer which was subsequently confirmed, discovering that DNA damage is the basic cause of cancer and isolating more cancer-related genes than any other organization in the world.

For more information visit www.icr.ac.uk

About The Royal Marsden

  • The Royal Marsden is a world-leading cancer centre specializing in cancer diagnosis, treatment, research and education.
  • The Royal Marsden is also partners with The Institute of Cancer Research. Through this partnership, it undertakes groundbreaking research into new cancer drug therapies and treatments. The partnership makes The Royal Marsden the biggest and most comprehensive cancer center in Europe, with a combined staff of 3,500.

ASCO 2011: Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer

A randomized phase II clinical trial showed that the oral PARP inhibitor drug olaparib (AZD2281), given after chemotherapy, improved progression-free survival in women with the most common type of recurrent ovarian cancer.

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving maintenance therapy with the PARP (poly (ADP-ribose) polymerase) inhibitor olaparib were highlighted today in the ASCO press briefing, as summarized below.

Randomized Study Shows that Maintenance Therapy With PARP Inhibitors Could Play Important Role in Treatment of Recurrent Ovarian Cancer

A phase II randomized trial showed that maintenance treatment with the oral PARP inhibitor drug olaparib (AZD2281) improved progression-free survival by about four months in women with the most common type of relapsed ovarian cancer. This is the first randomized trial to demonstrate a benefit for maintenance therapy for recurrent ovarian cancer, and the first randomized trial in ovarian cancer of a PARP inhibitor– a novel class of molecularly targeted drugs.

The results of this study, if confirmed in larger trials, could lead to a new treatment approach for recurrent ovarian cancer in which drugs like olaparib are given over a long period of time to prevent recurrences or prolong remissions. This somewhat novel approach, called maintenance therapy, has already proven useful in lung cancer. Standard treatment for ovarian cancer includes platinum-based chemotherapy. After this regimen, patients are observed until recurrence, and then treated with another course of chemotherapy. While some tumors respond well to chemotherapy, the regimens are too toxic for patients to take continuously, and clinical trials have not shown any benefit for extended courses of chemotherapy.

Jonathan A. Ledermann, M.D., Lead Author & Principal Investigator of PARP Maintenance Study; Professor, Medical Oncology, UCL Cancer Institute, University College London

“A well-tolerated antitumor agent that could be used for months or perhaps years as maintenance therapy after standard chemotherapy could be a big step forward and ultimately extend survival,” said lead author Jonathan A. Ledermann, M.D., principal investigator of the study and Professor of Medical Oncology at UCL Cancer Institute, University College London. “This study demonstrates proof of principle for the concept of maintenance therapy in ovarian cancer using a PARP inhibitor. Our progression-free survival difference was very impressive and better than we anticipated.”

The multicenter, international study randomized 265 women with high-grade serous ovarian cancer to either olaparib or placebo. Patients were enrolled in the trial within 8 weeks of having achieved either a complete or partial response to platinum-based treatment. PARP inhibitors have been shown to work better in patients whose tumors have responded to platinum.

In the study, the progression-free survival (PFS) – the amount of time during and after treatment in which the cancer does not return – was significantly longer in the group receiving olaparib than the placebo group, with a median of 8.4 months versus 4.8 months. At the time of data analysis, half the patients randomized to olaparib (68 patients) had not relapsed and were still receiving the drug, while only 16 percent (21 patients) remained on placebo – so overall survival data were not yet available for analysis.

Adverse events were more commonly reported in the group receiving olaparib than placebo, including nausea, fatigue, vomiting, and anemia, but the majority of these were not severe. Dose reductions to manage side effects were allowed in the study and were more prevalent in the olaparib group (23 percent) compared to the placebo group (7 percent).

Olaparib inhibits the enzyme poly (ADP-ribose) polymerase — abbreviated “PARP” — which is involved in DNA (deoxyribonucleic acid) repair. Up to half of women with high-grade serous ovarian cancer – the most common type of ovarian cancer – may have a DNA repair deficiency that makes them more susceptible to treatment with PARP inhibitors.

A number of PARP inhibitors are being studied in phase II and phase III clinical trials, as single agents and in combination with standard chemotherapies and radiation, in some types of breast and ovarian cancers believed to have DNA repair defects.

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PARP Clinical Trials:
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Related Libby’s H*O*P*E*™ Postings:
Related Libby’s H*O*P*E*™ Videos Re PARP Inhibitors


PARP Inhibitor MK-4827 Shows Anti-Tumor Activity in First Human Clinical Study

MK-4827, a new drug that targets proteins responsible for helping cancer cells repair their damaged DNA, has shown promising anti-tumor activity in its first human clinical trial.

MK-4827, a new drug that targets proteins responsible for helping cancer cells repair their damaged DNA, has shown promising anti-tumour activity in its first human clinical trial. Some patients with a range of solid tumors, many of whom had been treated unsuccessfully for their cancer with other therapies, have seen their tumors shrink or stabilize for periods of between 46 days to more than a year. The research will be presented today (Thursday) at the 22nd EORTCNCIAACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is being held in Berlin, Germany.

PARP is a key signaling enzyme involved in triggering the repair of single-strand DNA damage. PARP inhibition has been demonstrated to selectively kill tumor cells lacking components of the homologous recombination (HR) DNA repair pathway while sparing normal cells. Known defects in HR repair include the well-characterized hereditary BRCA1 and BRCA2 mutations in breast and ovarian cancer, as well as nonhereditary BRCA mutations. (Photo Credit: AstraZeneca Oncology)

Laboratory studies of the drug, MK-4827, have shown that it inhibits proteins called PARP1 and PARP2 (poly(ADP)-ribose polymerase). PARP is involved in a number of cellular processes and one of its important functions is to assist in the repair of single-strand breaks in DNA. Notably, if one single-strand DNA break is replicated (replication occurs before cell division), then it results in a double-strand break.  By inhibiting the action of PARP, double-strand breaks occur, which in turn, lead to cell death. Tumors that are caused by a mutation in the BRCA1 or BRCA2 genes are susceptible to cell death through PARP inhibition because correctly functioning BRCA genes assist in repairing double-strand DNA breaks via a process called homologous-recombination-dependent DNA repair, whereas mutated versions are unable to perform this role. Normal cells do not replicate as often as cancer cells and they still have homologous repair operating; this enables them to survive the inhibition of PARP and makes PARP a good target for anti-cancer therapy.

In a Phase I trial [2] conducted at the H. Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumors such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers. Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.

Robert M. Wenham, M.D., MS, FACOG, Clinical Director, Gynecologic Oncology, Department of Women's Oncology, H. Lee Moffitt Cancer Center

The drug was given in pill form once a day, and the researchers found that the maximum tolerated dose was 300 mg per day. Dr. Robert Wenham, Clinical Director for Gynecologic Oncology in the Department of Women’s Oncology at the Moffitt Cancer Center, who is presenting data on behalf of the participating investigators, said: “MK-4827 is generally well tolerated, with the main dose-limiting toxicity being thrombocytopenia – an abnormal decrease in the number of platelets in the circulatory blood. The most common side effects are mild nausea, vomiting, anorexia and fatigue.”

The researchers saw anti-tumor responses in both sporadic (non-inherited) and BRCA1/2 mutation-associated cancers [emphasis added]. Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment. Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.

Dr. Wenham said: “Most patients in the trial had exhausted standard therapies and those who responded to this drug have benefited. Several patients have been receiving treatment for more than a year. The responses mean that MK-4827 is working as hoped and justify additional studies. Just how well MK-4827 works compared to other treatments is the goal of the next set of studies.”

He gave a possible explanation as to why patients with cancers that were not caused by BRCA1 or BRCA 2 gene mutations also responded to the PARP inhibition. “BRCA is a tumor suppressor gene that assists in repairing double stranded DNA breaks. In BRCA-mutation related cancers, loss of both copies of the gene results in a non-functional protein and thus BRCA deficiency. Because BRCA works with other proteins, BRCA-pathway related deficiency can be seen in the absence of two mutated copies of the BRCA genes. This may explain why responses have been reported for this class of drugs in non-BRCA mutant cancers.”

Dr. Wenham and his colleagues are recruiting more patients for additional studies and an expansion of the existing trial. “We want to understand what types of cancers will respond best to treatment with MK-4827,” he said. “Cohorts are currently open for patients with ovarian cancer, patients without germ-line BRCA mutations, and prostate cancer patients. Cohorts will open soon for patients with T-cell prolymphocytic leukemia, endometrial cancer, breast cancer and colorectal cancer. MK-4827 is also being studied in combination with conventional chemotherapy drugs.”

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References:

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] This study was funded by Merck & Co., Inc. MK-4827 is owned by Merck & Co., Inc.