Disparities in Ovarian Cancer Survival in the United States

MedicalResearch.com Interview with:

The Centers for Disease Control and Prevention CDC image

Site of Ovarian Cancer CDC image

Dr. Sherri Stewart, PhD
Division of Cancer Prevention and Control
CDC

MedicalResearch.com: What do women most need to know about ovarian cancer detection and treatment?

Response: There is no effective test to detect ovarian cancer at an early stage where treatment is most likely to be effective.  Many women mistakenly believe that the Pap test can detect ovarian cancer, but it does not. The Pap test is recommended only for the detection of cervical cancer.

 Recognizing early symptoms of ovarian cancer and seeking timely care may help lead to detection of the cancer at an earlier stage, where treatment is likely to be more effective.  Symptoms – such  as abdominal and back pain, feeling full quickly after eating, and frequent urination – are often present among women with ovarian cancer.  Women should talk with their doctors if they experience any of these symptoms for 2 weeks or longer and the symptoms persist or worsen.

If a woman is diagnosed with ovarian cancer, she should seek treatment from a gynecologic oncologist, a physician specially trained to treat ovarian cancer.  Ovarian cancer patients who have been treated by gynecologic oncologists have been shown to survive longer than those treated by other physicians.           Continue reading

Niraparib Increased Progression Free Survival in 2/3 Ovarian Cancer Patients

MedicalResearch.com Interview with:

Mansoor Raza Mirza, MD Medical Director: Nordic Society of Gynecologic Oncology (NSGO) Board of Directors: Gynecologic Cancer Inter-Group (GCIG) Faculty: European Society of Medical Oncology (ESMO) Faculty: International Gynecologic Cancer Society (IGCS) Chief Oncologist, Rigshospitalet Copenhagen University Hospital Copenhagen, Denmark

Dr. Mansoor Raza Mirza

Dr. Mansoor Raza Mirza, MD
Medical Director: Nordic Society of Gynecologic Oncology
Board of Directors: Gynecologic Cancer Inter-Group (GCIG)
Faculty: European Society of Medical Oncology (ESMO)
Faculty: International Gynecologic Cancer Society (IGCS)
Chief Oncologist, Rigshospitalet
Copenhagen University Hospital
Copenhagen, Denmark

MedicalResearch.com: What is the background for this study?

Response: Recurrent ovarian cancer is an area of significant unmet medical need, and there have been few therapeutic advances for these patients in the past few decades.

Niraparib was studied to provide patients with recurrent ovarian cancer an option other than “watchful waiting,” potentially redefining the standard of care for the disease. The ENGOT-OV16/NOVA trial was a Phase 3 double-blind, randomized, placebo-controlled international study of maintenance treatment with niraparib compared with placebo. Niraparib successfully achieved the primary endpoint of prolonging progression-free survival versus placebo in all three prospectively defined primary efficacy populations:
Continue reading

Variable Effects of Dairy, Calcium, Vitamin D on Ovarian Cancer Risk in African–American Women

MedicalResearch.com Interview with:

Bo (Bonnie) Qin, Ph.D. Postdoctoral Scholar Rutgers Cancer Institute of New Jersey New Brunswick, NJ 08903

Dr. Bo Qin

Bo (Bonnie) Qin, Ph.D.
Post-Doctoral Associate
Rutgers Cancer Institute of New Jersey
New Brunswick, NJ 08903

MedicalResearch.com: What is the background for this study?
Response: Ovarian cancer is the leading cause of death from gynecologic cancer in the US. African-American patients diagnosed with ovarian cancer tend to have a worse 5-year survival rate compared to their European-American patients. Therefore, identifying preventive factors in African-Americans women is particularly important.

African Americans tend to consume less calcium and vitamin D from dietary sources, due to a higher prevalence of lactose intolerance, and supplemental intake. Meanwhile, darker color of the skin reduces the synthesis of vitamin D upon sun exposure. They together place African-American women at risk for calcium and vitamin D deficiency. It remains unknown whether calcium, vitamin D, lactose and dairy products are associated with ovarian cancer risk in African-American women and our study aimed to answer this question.

Continue reading

One Size Fits All Strategy No Longer Works For Treatment of Ovarian Cancer

MedicalResearch.com Interview with:

Larissa A. Meyer, MD MPH F.A.C.O.G. Assistant Professor Dept of Gynecologic Oncology and Reproductive Medicine Houston, TX 77030-1362

Dr. Larissa Meyer

Larissa A. Meyer, MD MPH F.A.C.O.G.
Assistant Professor
Dept of Gynecologic Oncology and Reproductive Medicine
Houston, TX 77030-1362

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Despite the completion of two randomized controlled trials, controversy regarding the optimal approach for the treatment of advanced ovarian cancer remains. Our observational study highlights the importance of thoughtful selection of individuals for primary cytoreductive surgery for advanced ovarian cancer. Our results suggest that primary cytoreductive surgery may improve survival for patients with stage IIIC ovarian cancer who are likely to achieve an optimal cytoreduction, while neoadjuvant chemotherapy may be the preferred option for many women with stage IV ovarian cancer.

Continue reading

Genetic Counselling Did Not Increase Anxiety in Breast and Ovarian Cancer Patients

MedicalResearch.com Interview with:
Mag. Dr. Anne Oberguggenberger PhD
Medizinische Universität Innsbruck
Department für Psychiatrie, Psychotherapie und Psychosomatik
Innsbruck Austria

MedicalResearch.com: What is the background for this study?

Response: Genetic counseling and testing is increasingly integrated in routine clinical care for breast- and ovarian cancer (BOC). Knowledge on follow-up psychosocial outcomes in all different groups of counselees is essential in order to improve follow-up care and counselees’ quality of life.

Continue reading

Douching May Be Associated With Increased Risk of Ovarian Cancer

MedicalResearch.com Interview with:

Clarice Weinberg, Ph.D. Deputy Branch Chief Biostatistics and Computational Biology Branch National Institute of Environmental Health Sciences National Institutes of Health Research Triangle Park, NC 27709

Dr. Clarice Weinberg

Clarice Weinberg, Ph.D.
Deputy Branch Chief
Biostatistics and Computational Biology Branch
National Institute of Environmental Health Sciences
National Institutes of Health
Research Triangle Park, NC 27709

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: A number of studies have reported a link between genital use of talc powders and ovarian cancer. We wondered whether the practice of douching could contribute to that risk by moving fibers and chemicals into and up the reproductive tract. We are carrying out the Sister Study, a large cohort study that enrolled more than 50,000 women who each had a sister diagnosed with breast cancer and who are consequently at increased risk of ovarian cancer. During the Sister Study enrollment interview, we asked each of them about their douching and use of talc in the previous 12 months. During approximately 6 years of follow up, 154 participants developed ovarian cancer. Our statistical analyses did not show any relationship between talc use and risk of ovarian cancer, but we estimated that women who had said they douched had almost double the risk for ovarian cancer compared to women who did not douche.

Continue reading

Women Still Getting CA-125 and CT Testing After Ovarian Cancer, Despite Lack of Clear Benefit

MedicalResearch.com Interview with:

Katharine Mckinley Esselen, M.D. Instructor in Obstetrics, Gynecology and Reproductive Biology Beth Israel Deaconess Medical Center Brigham and Womens Hospital

Dr. Katharine M. Esselen

Katharine Mckinley Esselen, M.D.
Instructor in Obstetrics, Gynecology and Reproductive Biology
Beth Israel Deaconess Medical Center
Brigham and Womens Hospital

MedicalResearch.com: What is the background for this study?

Response: There is no consensus on how to follow a patient in remission from ovarian cancer in order to detect recurrent disease. However, a 2009 randomized clinical trial demonstrated that using CA-125 blood tests for routine surveillance in ovarian cancer increases the use of chemotherapy and decreases patient’s quality of life without improving survival compared with clinical observation. Published guidelines categorize CA-125 tests as optional and discourage the use of radiographic imaging for routine surveillance. Thus, this study aims to examine the use of CA-125 tests and CT scans at 6 Cancer Centers and to estimate the economic impact of this surveillance testing for ovarian cancer.

Continue reading

Embryonic HOX Genes May Predict Response of Ovarian Cancer to Treatment

MedicalResearch.com Interview with:

Professor Richard Morgan Director, The Institute of Cancer Therapeutics University of Bradford Richmond Road Bradford UK

Prof. Richard Morgan

Professor Richard Morgan
Director, The Institute of Cancer Therapeutics
University of Bradford
Richmond Road
Bradford UK

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Ovarian cancer is the 5th most common cause of cancer-related death in woman and the most deadly gynaecological cancer. One of the reasons for this is its resistance to conventional chemotherapy. Although tumours often respond well at first, showing dramatic shrinkage in the first few months of treatment, they usually grow again and at this point they are no longer sensitive to the drugs. We studied the role of HOX genes in ovarian cancer. The HOX genes play an important role in the early development of the embryo but are usually switched off in adult cells. However, many cancers, including ovarian cancer, turn them back on. Previous work suggested that they might have an important role in promoting the rapid proliferation of cancer cells.

Continue reading

Breast and Ovarian Cancers May Have Common Epigenetic Origin

MedicalResearch.com Interview with:

Sibaji Sarkar Ph.D Instructor of medicine Boston University School of Medicine Boston

Dr. Sibaji Sarkar

Sibaji Sarkar Ph.D
Instructor of medicine
Boston University School of Medicine
Boston

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Sarkar: Although breast and ovarian cancers have different clinical presentations, there are certain molecular events that are conserved between the two types of cancers. For example, mutation in a few genes, such as BRCA1, BRCA2, is an indicator of possible development of both breast and ovarian cancers. ARHI, a pro-apoptotic imprinted gene is epigenetically silenced in both breast and ovarian cancers. A similar pattern was observed in microRNA as well. There are also several genes which are differentially expressed in these two types of cancers but few of these striking resemblances led us to investigate whether they have a common origin. In this paper, we compared genetic and epigenetic events in both breast and ovarian cancers and we hypothesize that they may have similar origin (mechanism of formation of cancer progenitor cells), which should be regulated by epigenetic mechanism.

Continue reading

Experimental 3DNA Nanocarrier Used to Target and Treat Ovarian Tumor Cells

MedicalResearch.com Interview with:

Janet A. Sawicki, Ph.D. Deputy Director and Professor Lankenau Institute for Medical Research 100 Lancaster Ave. Wynnewood, PA 19096

Dr. Janet Sawicki

Janet A. Sawicki, Ph.D.
Deputy Director and Professor
Lankenau Institute for Medical Research
100 Lancaster Ave.
Wynnewood, PA 19096

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Sawicki: This study addresses the need for a more effective therapy for ovarian cancer. HuR is an RNA-binding protein that is present in high amounts in ovarian tumor cells compared to amounts in normal cells. HuR regulates the expression of thousands of genes that promote the survival of tumor cells. Thus, it is an ideal therapeutic target to suppress ovarian tumor growth. In this study, we used a small interfering RNA (siRNA) to investigate the impact of suppressing HuR expression on ovarian tumor growth in an ovarian cancer mouse model. We made use of the ability to conjugate a novel DNA dendrimer nanocarrier, 3DNA®, to both siHuR and a tumor-targeting moiety to suppress HuR expression specifically in tumor cells following systemic administration while avoiding toxicity in healthy cells. Systemic administration of siHuR-conjugated FA-3DNA to ovarian tumor-bearing mice suppressed tumor growth and ascites development, and significantly prolonged lifespan. Gene expression analysis identified multiple HuR-regulated genes in tumor cells as evidenced by changes in their expression upon HuR inhibition. These HuR-regulated genes function in multiple essential cellular molecular pathways, a finding that sets this therapeutic approach apart from other therapies that target a single gene.

Continue reading

Proposed Model Clarifies Ovarian Risk Assessment By Ultrasound

Dirk Timmerman, MD PhD Department of Development and Regeneration Department of Obstetrics and Gynecology University Hospitals Leuven Leuven, Belgium

Dr. Dirk Timmerman

More on Ovarian Cancer on MedicalResearch.com
MedicalResearch.com Interview with:
Dirk Timmerman, MD PhD

Department of Development and Regeneration
Department of Obstetrics and Gynecology
University Hospitals Leuven
Leuven, Belgium

Medical Research: What is the background for this study? What are the main findings?

Dr. Timmerman: Ovarian cancer is the most aggressive and lethal gynecological malignant neoplasm. The prognosis of ovarian cancer is poor, with only about 40% of patients still alive five years after being diagnosed. The preoperative characterization of an adnexal tumor is fundamental for selecting the optimal management strategy. An accurate differentiation between benign and malignant masses can lead to optimal referral of patients with malignant diseases to gynecological oncology centers for further diagnostics and treatment, which positively influences the prognosis. On the other hand, it may help in safely selecting patients with benign ovarian masses for minimally invasive or fertility sparing surgery, and in some cases maybe even conservative follow-up. The International Ovarian Tumor Analysis (IOTA) study is the largest diagnostic accuracy study of its kind. Transvaginal ultrasound is a cheap and very accessible imaging technique. Using ultrasound features, which are easy to assess by a trained examiner, we proposed a model to define the individual risk of malignancy for each patient presenting with an adnexal tumor. This could considerably impact on the morbidity and mortality associated with adnexal pathology.

Continue reading

Nivolumab Has Potential Activity Against Platinum Resistant Ovarian Cancer

Junzo Hamanishi M.D., Ph.D. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine Assistant Professor Kyoto Japan

Dr. Hamanishi

MedicalResearch.com Interview with:
Junzo Hamanishi  M.D., Ph.D.
Department of Gynecology and Obstetrics,
Kyoto University Graduate School of Medicine
Assistant Professor
Kyoto Japan

Medical Research: What is the background for this study?

Dr. Hamanishi: More than 70% of patients with advanced ovarian cancer who achieve remission ultimately relapse and there are few effective treatments for these patients. Because the development of new treatment strategies for these patients is urgently required, we have focused on and studied the potential of cancer cells to escape from host immunity with PD-1/PD-L1 immunosuppressive signal in the tumor microenvironment to find new treatment strategies to overcome this phenomenon, collaborating with Professor Honjo who discovered PD-1 since 2006. Therefore, we conducted a phase II clinical trial in 20 platinum-resistant, recurrent ovarian cancer patients to evaluate the safety and anti-tumor efficacy of anti-PD-1 antibody (nivolumab) with 2 cohort at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts).

Medical Research: What are the main findings?

Dr. Hamanishi: This study is the first investigator-initiated phase II clinical trial testing the safety and efficacy of nivolumab against platinum-resistant ovarian cancer. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, including two patients with a durable complete response (3mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival was 3.5 months, with a median overall survival of 20.0 months. Especially in the 3 mg/kg cohort, two patients achieved a complete response, and disease stabilized in another two patients. The objective response rate in 3mg/kg cohort cohort was 20% and disease was controlled in 40% of the higher-dose group. In the four patients who demonstrated an antitumor response, responses were durable and evident. Grade 3 or 4 treatment-related adverse events (AE) occurred in eight out of 20 patients or 40% overall. However, the frequency of AEs were not different in 2 cohorts.

Continue reading

Advanced Metabolite Detection May Allow Earlier Ovarian Cancer Detection

Professor John McDonald PhD Director of its Integrated Cancer Research Center School of Biology at the Georgia Institute of Technology

Dr. McDonald

MedicalResearch.com Interview with:
Professor John McDonald PhD
Director of its Integrated Cancer Research Center
School of Biology at the Georgia Institute of Technology

Medical Research: What is the background for this study? What are the main findings?

Response: Ovarian cancer is a deadly disease because it cannot be diagnosed at early stages when it can be most effectively effectively treated.

It has long been recognized that there is a great need for an accurate diagnostic test for early stage ovarian cancer.

Until now, efforts to develop a highly accurate way to detect early stage ovarian cancer have been unsuccessful.

We have used a novel approach that integrates advanced methods in analytical chemistry with advanced machine learning algorithms to identify 16 metabolites that collectively can detect ovarian cancer with extremely high accuracy (100% in the samples tested in our study)

Continue reading

Health Diet May Reduce Ovarian Cancer Risk in African American Women

Bo (Bonnie) Qin, PhD Postdoctoral associate at Rutgers Cancer Institute of New Jersey

Dr. Qin

MedicalResearch.com Interview with:
Bo (Bonnie) Qin, PhD

Postdoctoral associate at Rutgers Cancer Institute of New Jersey

Medical Research: What is the background for this study? What are the main findings?

Response:  Ovarian cancer is among the top five causes of cancer death among women in the US. Compared to white women, African-American women tend to have a worse 5-year survival rate of ovarian cancer. It highlights a critical need for identifying preventive factors in African Americans, particularly through dietary modification, which is relatively low cost and low risk compared to medical treatments.

We found that adherence to an overall healthy dietary pattern i.e. Alternate Healthy Eating Index (AHEI)-2010 may reduce ovarian cancer risk in African-American women, and particularly among postmenopausal women. Adherence to the current Dietary Guidelines for Americans i.e. Healthy Eating Index-2010, were also strongly associated with reduced risk of ovarian cancer among postmenopausal African-American women.

Continue reading

Photodynamic Therapy Can Potentially Target Ovarian Cancer

Oleh Taratula,PhD Assistant Professor Oregon State University/Oregon Health & Science University College of PharmacyMedicalResearch.com Interview with:
Oleh Taratula, PhD Assistant Professor
Oregon State University/Oregon Health & Science University College of Pharmacy

MedicalResearch: What is the background for this study?

Dr. Taratula: The background for the study consists of previous work we had published in the lab using photodynamic therapy (PDT) as the stand alone treatment modality. We were successful in synthesizing and incorporating the photodynamic nanoplatform in the treatment for ovarian cancer, but our current graduate student, Canan Schumann said he could make the therapy more efficient using his current research on gene therapy. The gene therapy he is currently working on is the delivery of siRNA targeted to the multifaceted oncogenic protein DJ-1 which has been implicated in antioxidative stress defense as well as the overall survival of ovarian cancer. Cancer is highly intelligent able to adapt quickly to new insults that it comes across, even ROS formed inside the cell. Cancer cells can even upregulate a whole host of antioxidant stress response proteins to combat the formation of or scavenge already created ROS. The idea was can we combine our currently used PDT, which uses the generation of reactive oxygen species (ROS) as its cytotoxic mechanism of action, coupled with gene therapy targeted to DJ-1, in hope to drastically increase ROS inside the cell leading to a more pronounced cell death.

Continue reading

Panel Testing Identifies More Management-Changing Genes Than BRAC1/2 Alone

Leif W. Ellisen, M.D., Ph.D Professor of Medicine, Harvard Medical School Program Director, Breast Medical Oncology Co-Leader, Breast Cancer Program MGH Research Scholar MGH Cancer Center  Boston, MA 02114MedicalResearch.com Interview with:
Leif W. Ellisen, M.D., Ph.D
Professor of Medicine, Harvard Medical School
Program Director, Breast Medical Oncology
Co-Leader, Breast Cancer Program
MGH Research Scholar MGH Cancer Center
Boston, MA 02114

Medical Research: What is the background for this study? What are the main findings?

Dr. Ellisen: The traditional approach to genetic testing for women with suspected hereditary breast and/or ovarian cancer risk is to test for BRCA1 and BRCA2 alone. Recent studies have shown that testing with a multi-gene panel finds relevant risk gene mutations in substantially more women than does testing for BRCA1 and BRCA2 alone. However, one of the concerns about broader multi-gene testing has been that the results really wouldn’t change what you told women about their risk and management – either because the risk associated with the other genes may not be as high as for BRCA1/2, or because the clinical practice guidelines associated with some of the other genes are less specific.

Our study sought to determine how often testing such women using a multi-gene panel would find mutations in genes other than BRCA1/2, and more importantly to ask whether finding those mutations would change how you would manage the patient and their family. We found that multi-gene panel testing finds relevant risk gene mutations in substantially more women (approximately 40% more) than does testing for BRCA1 and BRCA2 alone. Furthermore, in a case-by-case analysis we showed that finding mutations in these other genes is likely to change the clinical management that is considered or recommended for the majority of the mutation-positive women and their families.  Notably, our analysis of the predicted management change is based not just on the gene mutation alone, but on how the gene appears to be behaving in that particular family.

Continue reading

Molecule May Help Ovarian Cancer Patients Overcome Chemotherapy Resistance

Wei Zhang, Ph.D., Professor Department of Pathology Director, Cancer Genomics Core Lab University of Texas MD Anderson Cancer Center Houston, Texas 77030MedicalResearch.com Interview with:
Wei Zhang, Ph.D., Professor

Department of Pathology
Director, Cancer Genomics Core Lab
University of Texas MD Anderson Cancer Center
Houston, Texas 77030

Medical Research: What is the background for this study? What are the main findings?

Dr. Zhang: Epithelial ovarian cancer remains the most lethal gynecological malignancy. The 5-year survival rate for patients with advanced ovarian cancer is only 30-40%, and acquired resistance to platinum is considered a major factor in disease relapse. A major challenge in cancer treatment is the resilient ability of cancer cells to repair DNA damage caused by chemotherapy agents.  In this study, we found that adding a molecule called miR-506 to standard chemotherapy can help cells overcome drug resistance, so that the chemotherapy drugs remain effective against ovarian cancer. This research supports a new combination approach, which may substantially benefit patients with this deadly disease.

Continue reading

Chemotherapy Before Ovarian Cancer Surgery May Benefit Some Patients

MedicalResearch.com Interview with:
Mr Matthew Nankivell
MRC Clinical Trials Unit at University College London
Institute of Clinical Trials and Methodology
Aviation House, London
UK

Medical Research: What is the background for this study? What are the main findings?

Response: Ovarian cancer is diagnosed in over 7000 women each year in the UK. Over 75% of these already have advanced disease, for which the standard treatment is surgery followed by platinum based chemotherapy. The prognosis for these patients remains poor however, with less than 25% surviving for 5 years. There is consistent evidence that achieving optimal debulking (meaning less than 1cm of residual tumour after surgery) is key to increasing survival. The theory tested in Chorus is that giving the chemotherapy before surgery (neo-adjuvantly) would be as least as effective as giving it post-operatively, and may in fact increase the chance of achieving optimal debulking, and subsequently living for longer.

In Chorus we randomised 552 women to receiving either the current standard of immediate surgery followed by chemotherapy, or chemotherapy followed by surgery. The trial met its primary aim of showing that neo-adjuvant chemotherapy was no worse than post-operative chemotherapy, with median survival times of 24.1 and 22.6 months respectively. The proportion of women achieving optimal debulking increased from 41% in the post-operative chemotherapy group to 73% in the neo-adjuvant chemotherapy group. Additionally we saw that fewer women experienced serious post-operative complications having had neo-adjuvant chemotherapy (14% vs 24%), and fewer women died within 28 days of surgery (<1% vs 6%).

There is a planned meta-analysis, to combine the data from Chorus with those from a similar European trial, which will allow further investigations to take place, and may allow the identification of groups of women who are more likely to benefit from one or other of the approaches.

Continue reading

Novel Combination Treatment May Help Some Patients With Ovarian and Triple-negative Breast Cancers

Dr. Victoria L. Chiou, MD Medical Oncology Fellow Women’s Malignancies Branch National Cancer InstituteMedicalResearch.com interview with
Dr. Victoria L. Chiou, MD

Medical Oncology Fellow
Women’s Malignancies Branch
National Cancer Institute

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Chiou: We studied the effects of different treatments in ovarian and breast cancer cell lines with and without BRCA1 mutation in the laboratory. Our discovery that olaparib pretreatment before carboplatin led to decreased carboplatin-induced DNA damage in tumor cells carrying BRCA1 mutation led us to a novel clinical question. We wanted to further understand whether there was an optimal way to deliver a combination of the new tablet formulation of olaparib with carboplatin chemotherapy in women with gynecologic and breast cancers.

We launched our clinical trial to test this important question. Overall, we are pleased that the drug combination of olaparib and carboplatin chemotherapy can be given safely together, with preliminary activity in women with breast and ovarian cancer associated with germline BRCA mutations. We are excited to report the findings of this study, which is the first to report preclinical and clinical data on sequence specificity for this drug combination in this patient population. Continue reading

Two Gene Mutations Linked To Deadly Ovarian Cancer

Dr. Terry Magnuson PhD Vice Dean for Research Department of Genetics, School of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27599MedicalResearch.com Interview with:
Dr. Terry Magnuson PhD
Vice Dean for Research
Department of Genetics, School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599

Medical Research: What is the background for this study? What are the main findings?

Response: Ovarian clear-cell carcinoma is a lethal form of ovarian cancer with limited therapeutic options. Recent patient-derived tumor sequencing studies support a strong genetic basis for the disease, but the roles of gene mutations in cancer causation are still unclear. We observed rapid induction of ovarian clear-cell carcinoma in mice that were genetically engineered to carry mutations in ARID1A and PIK3CA−the two most frequently mutated genes. Comparisons between human and mouse tumors uncovered a downstream role for the Interleukin-6 (IL-6) cytokine-signaling pathway in tumor progression. Thus, ARID1A and PIK3CA mutations cause ovarian clear-cell carcinoma and promote tumor cell growth by acting upon the IL-6 signaling pathway.

Continue reading

Ovarian Cancer: ADNEX Tool Helps Distinguish Benign From Malignant Ovarian Cysts

Ben Van Calster PhD Department of Development and Regeneration KU Leuven, Herestraat Leuven, BelgiumMedicalResearch.com Interview with:
Ben Van Calster PhD
Department of Development and Regeneration
KU Leuven, Herestraat Leuven, Belgium

 

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Van Calster: Ovarian cancer is a very common type of cancer among women, with over 200,000 new cases per year worldwide. It is the most lethal of gynecological malignancies. Research has shown that the referral of patients with ovarian cancer to specialized gynecological oncologists in high volume centers improves survival. However, audits in Europe and the United States also show that only a minority of women with ovarian cancer are appropriately triaged to receive specialist care. In addition, different types of malignancies are not treated in the same way. Hence optimal personalized management of an ovarian tumor hinges on the detailed preoperative diagnosis of its nature. Unfortunately, current prediction models focused on the discrimination between benign and malignant tumors without further specification of the likely type of malignancy.

Various prediction models and rules have been developed to help predict whether an ovarian mass is benign or malignant. A recent systematic review meta-analysis has shown that the IOTA model LR2 and simple rules perform better than any other previous test. However none of these tests give anything other than a dichotomous outcome – i.e. cancer or non-cancer. In practice the position is more nuanced.

The ADNEX model estimates the likelihood that a tumor is benign, borderline malignant, stage I cancer, stage II-IV cancer, or secondary metastatic cancer. This model is the first that is able to differentiate between benign and these four subtypes of malignancy. To do so, ADNEX uses three clinical predictors (age, serum CA-125 level, and type of center), and six ultrasound characteristics of the tumor (maximum diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites). The model is based on data from almost 6,000 women recruited at 24 centers in 10 countries.
Continue reading

Ovarian Cancer: Using a Genetic Signature To Predict Response to Bevacizumab

Sean C. Dowdy, MD, FACS Professor and Chair, Division of Gynecologic Surgery Vice-Chair for Research, Department of Obstetrics and Gynecology Co-Leader, Women’s Cancer Program Mayo Clinic College of Medicine MedicalResearch.com Interview with:
Sean C. Dowdy, MD, FACS
Professor and Chair, Division of Gynecologic Surgery
Vice-Chair for Research, Department of Obstetrics and Gynecology
Co-Leader, Women’s Cancer Program
Mayo Clinic College of Medicine

MedicalResearch.com: What are the main findings of the study?

Dr. Dowdy: This study was a collaboration between four groups in 3 countries to determine if a genetic “signature” could predict which patients with ovarian cancer benefit from Bevacizumab (a very expensive drug with marginal benefit in patients with ovarian cancer). We hypothesized that while benefit may be marginal in a large group, patients with specific genetic changes could derive significant benefit from it. Using gene expression arrays (analyzing over 18,000 genes) we separated patients into four subgroups as described by The Cancer Genome Atlas (TCGA). We show that patients in the proliferative and mesenchymal groups had a 8-10 month improvement in outcome compared to a 3 month improvement for the other two groups (immunoreactive and differentiated).
Continue reading

Irregular Menses Linked to High Risk of Ovarian Cancer

Barbara A. Cohn, Ph.D. Director, Child Health and Development Studies A Project of the Public Health Institute Berkeley, CA 94709MedicalResearch.com Interview with:
Barbara A. Cohn, Ph.D.
Director, Child Health and Development Studies
A Project of the Public Health Institute
Berkeley, CA 94709

 

MedicalResearch.com: What are the main findings of the study?

  • Women with irregular menses had a statistically significant 2.4 fold increase in risk of death due to any form ovarian cancer, and a statistically significant 3-fold increase in risk of death due to late stage serous disease. Consistent with these findings, the incidence of late stage disease at diagnosis, and late stage serous cancer was increased about 2-fold in women with irregular menses.
  • Irregular menses was defined as irregular cycles (variation of 10 days or more) or infrequent cycles (>35 days) or history of annovulatory cycles identified during an in-person interview with women at an average age of 26 years or mentioned in their medical records.

    Continue reading

Ovarian Cancer and Cardiovascular Comorbidity

Anil K. Sood MD Department of Gynecologic Oncology The University of Texas MD Anderson Cancer Center Unit 1362, PO Box 301439, Houston, TX, 77030MedicalResearch.com Interview with:
Anil K. Sood MD
Department of Gynecologic Oncology
The University of Texas MD Anderson Cancer Center
Unit 1362, PO Box 301439, Houston, TX, 77030

MedicalResearch.com: What are the main findings of the study?

Dr. Sood: For women with newly diagnosed ovarian cancer, high heart rate at diagnosis (tachycardia), venous thromboembolism (VTE) occurring after diagnosis and pulmonary hypertension post-diagnosis are independently related to reduced survival after controlling for tumor stage, grade, and extent of cytoreduction.  Women with tachycardia lived an average of 4.0 years after diagnosis compared with 5.9 years for women without tachycardia, a 32% reduction in duration of survival.  Patients who experienced VTE lived a median 4.1 years after diagnosis, compared with 6.4 yrs for patients who did not experience VTE.

Continue reading

Linking of mutations in 12 genes to ovarian cancer may lead to more effective prevention

October 25 2011
More patients with ovarian carcinoma carry cancer-predisposing mutations, and in more genes, than previously thought.

A rapid experimental method for screening genomes has located mutations in 12 genes for inherited cancers of the ovary, fallopian tubes and peritoneum (the thin tissue lining the lower abdomen).

More than one-fifth of ovarian cancers arise in women with a familial predisposition, but relying on family history would have missed one-third of the cases, said Dr. Elizabeth Swisher, senior author of a paper on these findings published online ahead of print in the Proceedings of the National Academy of Sciences.

Swisher is an associate professor of obstetrics and gynecology at the University of Washington in Seattle. She directs the Breast and Ovarian Cancer Prevention program at the UW and the Seattle Cancer Care Alliance, and is an affiliate researcher at the Fred Hutchinson Cancer Research Center.

The results of her most recent study have far reaching implications beyond the important identification of mutations linked to ovarian and related cancers.

The speedy, low-cost genome analysis method her team developed could soon be applicable to patient testing for a broad range of all known breast, ovarian, colon, pancreatic and melanoma gene mutations. A single test might be able to screen a patient for susceptibility to all these cancers.

Also, the great number of specimens that this method can analyze simultaneously could allow for large scale, population studies of cancer-causing mutations. Such studies would tell who is at risk for certain cancers and how to effectively target prevention.

The UW scientists named their sequencing method BROCA, after Paul Broca, a 19th century medical scientist who was among the first to describe inherited breast and ovarian cancer. BROCA, the researchers said, is highly sensitive and can find all classes of genetic mutations, including single substitutions, small insertions and deletions, and large rearrangements of genes.

“The BROCA test is not patented,” the researchers said, and added that designs for its use in genetic studies are freely available.

At present, most tests for genes already known to be associated with breast and ovarian cancer, BRAC1 and BRAC2, are done by a lone company. The cost is about $4,000 for a non-comprehensive test accompanied by an additional test to find gene rearrangements.

As more cancer-susceptibility genes are found, it is not economical to test a person for one gene mutation, and then go back and test for another, then another. Gene-by-gene testing will eventually give way to a single test that accurately identifies all classes of those gene mutations that permit tumors to grow unchecked.

At present, the price for the BROCA chemicals is about $200. The costs are shrinking for running the genome analysis, due to the increasing number of samples that can be put through the multiple “lanes” in the sequencer.

Swisher and her team concentrated on ovarian cancer gene-detection in trying this sequencing method because ovarian cancer is one of the most deadly to affect a woman’s reproductive system. It is difficult to diagnose in its early stages

Ovarian cancer and cancer of the peritoneum begin quietly. Eventually vague symptoms appear, but they mimic seemingly benign conditions, like bloating.

“Most women are not diagnosed until the cancer is has advanced to the point where the chances of a cure are small,” Swisher said. “Women with early stage ovarian cancer have a better survival than those diagnosed with late stages, but current methods of detection are not effective.”

The lack of effective early detection is why Swisher and her research team are looking for a more complete genetic picture of ovarian and related cancers. Learning the genetic mutations associated with these cancers could lead to tests to identify early on the women prone to these malignancies.

A quick, low cost, individual screening test for a variety of gene mutations linked to ovarian cancer would allow for effective preventive measures, the researchers said. For example, a woman whose genetic profile indicates high risk could consider an operation to remove her ovaries and fallopian types. This procedure has already been shown to decrease the overall death rate in women who have BRCA1 or BRAC2 mutations.

These particular mutations heighten the risk of ovarian as well as breast cancer. As this current study reveals, previously unknown mutations in other genes also occur in the population of women diagnosed with ovarian cancer.

New developments in cancer drugs that selectively wipe out cells containing certain genetic deficiencies is another major incentive for scientists to locate other mutations involved in ovarian cancer, Swisher noted. For example, the new drug class called poly-ADP-ribose polymerase (PARP) inhibitors is lethal to cells missing chemicals produced by normal BRAC1 and BRAC2 genes. The PARP drugs are showing efficacy in treating ovarian cancers in patients with mutations in these genes.

The UW scientists applied BROCA to analyze the DNA from a 360 women undergoing surgery between 2001 and 2010 at the University of Washington for cancer of the ovaries, peritoneum, or fallopian tubes, or who had cancer of the ovaries as well as the uterine lining. The women were enrolled at diagnosis. Neither age of onset of the cancer nor their family history were selection factors.

Among this group of women, the researchers found 85 mutations in 12 genes. Many were loss-of-function mutations. An example of loss of function is the inability of cells to produce chemicals to suppress tumors. As the scientists expected, women with a personal history of breast cancer had an extremely high likelihood of harboring an inherited mutation. Family history of breast, ovarian, uterine, and pancreatic cancer – but not colon cancer – were each associated with inherited mutations.

“An observation that has major implications for clinical practice was that nearly one-third of the women with inherited mutations had no prior personal history of breast cancer and no family history of ovarian or breast cancer,” Swisher noted. This high proportion of unrecognized risk, she explained, is probably due to the combined effects of small family size, female cancer genes inherited from unaffected fathers, and the simple odds of a mutated gene being inherited or not inherited.

The researcher also found that the age when these types of cancer appear was not generally associated with the likelihood of having an inherited mutation, or with the gene in which a mutation was found.

There were no significant differences in survival rates between women who had one or more of the mutations identified in this study, and women who did not have these particular mutations.

What we found overall, the researchers noted, was that more than one in five cases of ovarian carcinoma were associate with a mutation in tumor suppressor genes. In their normal form, these genes act in a way that keeps tumors from growing.

The findings of this study, the researcher concluded, point to the need to develop comprehensive testing for inherited carcinoma for all women with ovarian, peritoneal or fallopian tube cancer, regardless of their age or family history. The researchers are moving clinical science forward to a time when expensive single gene testing for thousands of dollars will be replaced by testing many genes simultaneously at low cost.

###

In addition to Swisher, the scientists on this project were Tom Walsh, Silvia Casadei, Ming K. Lee, Anne Thornton, Wendy Roeb, Sunday M. Stray, and Mary-Claire King, all of the UW Division of Medical Genetics, Department of Medicine, and Christopher Pennil, Kathy Agnew, Anneka Wickramanayake, Barbara Norquist, and Kathryn Pennington, all of the UW Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and Rochelle Garcia, UW Department of Pathology.

The study, “Mutations in 12 genes for inherited ovarian, Fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing,” was funded by the National Institutes of Health, The Breast Cancer Research Foundation, Susan G. Komen for the Cure, and the U.S. Department of Defense Ovarian Cancer Research Program.

Eurekalert University of Washington

Ovarian cancer patients survive longer with BRCA2 mutated in tumors

HOUSTON – Women with high-grade ovarian cancer live longer and respond better to platinum-based chemotherapy when their tumors have BRCA2 genetic mutations, researchers at The University of Texas MD Anderson Cancer Center and the Institute for Systems Biology report in the Oct. 12 issue of the Journal of the American Medical Association.

“BRCA2-mutated tumors are more vulnerable to these DNA-damaging agents, which is really exciting because there are a number of drugs in clinical trials now that block DNA repair that might prove effective against these tumors in combinations,” said senior author Wei Zhang, Ph.D., professor in MD Anderson’s Department of Pathology.

BRCA2 and its cousin, BRCA1, are tumor-suppressing genes involved in DNA repair that, when mutated, raise a woman’s risk for having breast or ovarian cancer.

“Uncovering the separate potential effects of BRCA1 and BRCA2 mutations takes us a step towards a more personalized approach to treating ovarian cancer, and perhaps other cancers,” Zhang said. “This paper suggests those two genes, and the many others involved in DNA repair, are prime targets for further research.”

Past studies of the possible clinical impact of BRCA1 and BRCA2 mutations tended to look at the two genes together and were limited by small sample sizes.

First author Da Yang, Ph.D., an Odyssey Fellow in MD Anderson’s Department of Pathology, said their in-depth study was made possible by The Cancer Genome Atlas project. TCGA published a study of 489 cases of high-grade serous ovarian cancer, the most common form of the disease, that combined an exhaustive analysis of each tumor’s genome with comprehensive clinical data on each patient.

“TCGA gave us enough analytical power to differentiate between BRCA1 and BRCA2 mutations and conduct a survival analysis,” Yang said.

Improved overall survival

Of 316 cases, 29 tumors had BRCA2 mutations tumors and 37 had BRCA1 mutations. Tumors were similar in grade and stage. Findings include:

  • 61 percent of patients with BRCA2 mutations survived for five years, compared with 25 percent of those with normal BRCA2 in their tumors.
  • 44 percent of those with BRCA2 mutations lived three years after surgery and platinum treatment without disease progression, compared with 16 percent of those with normal BRCA2.
  • BRCA1 mutations in tumors were not associated with survival.
  • All of those with BRCA2 mutations responded to platinum chemotherapy, compared to 82 percent with the normal gene and 80 percent whose tumors had BRCA1 mutations.
  • Their response to chemotherapy lasted 18 months, compared with 11.7 months for normal BRCA2 and 12.5 months for BRCA1 mutations.
  • Tumors with BRCA2 variations also are hypermutants – they had more genetic mutations – with 84 mutations per tumor sample compared to 52 for normal BRCA2

Zhang said this last aspect – called the hypermutator phenotype – might be both a factor in the development and growth of the tumor and a sign of its vulnerability.

BRCA2 is normally involved in the repair of double-strand DNA breaks. Cells with BRCA2 mutants are less capable of repair, allowing other genetic mutations to survive and grow, the type of genomic instability that cancer thrives upon.

However, cancer cells in turn rely on DNA repair to defend themselves against DNA-damaging drugs, such as platinum-based agents. So adding drugs that inhibit DNA repair could increase the effectiveness of chemotherapy, Zhang noted. PARP-inhibitors, a new class of drug in clinical trials, block DNA repair and may also be effective in treating BRCA2 mutated ovarian cancer.

Additional studies of the function of BRCA1 and BRCA2 mutations are needed to more fully understand and exploit their findings to treat cancer, Zhang and colleagues note.

###

The Cancer Genome Atlas is a joint project of the National Cancer Institute and the National Human Genome Research Institute, both of the National Institutes of Health, to comprehensively characterize changes in genetic mutation and regulation of various cancers.

Co-authors with Zhang and Yang are Sofia Kahn, Ph.D., and Yan Sun, M.D., Ph.D., of MD Anderson’s Department of Pathology; Kenneth Hess, Ph.D., of MD Anderson’s Department of Biostatistics, Anil Sood, M.D., of MD Anderson Departments of Cancer Biology and Gynecologic Oncology and Reproductive Medicine and the Center for RNAi and Non-Coding RNA; and Ilya Shmulevich, Ph.D., Institute for Systems Biology in Seattle.

This research was funded by the National Cancer Institute; the Blanton-Davis Ovarian Cancer Research Program, MD Anderson’s NCI Specialized Program in Research Excellence in Ovarian Cancer; MD Anderson’s Odyssey Fellows Program; and an ASLA-Fulbright Research Grant.

About MD Anderson

New imaging technique visualizes cancer during surgery

Ovarian cancer is one of the most frequent forms of cancer that affect women. As tumors can initially grow unchecked in the abdomen without causing any major symptoms, patients are usually diagnosed at an advanced stage and have to undergo surgery plus chemotherapy. During the operation, surgeons attempt to remove all tumor deposits as this leads to improved patient prognosis. To do this, however, they primarily have to rely on visual inspection and palpation – an enormous challenge especially in the case of small tumor nests or remaining tumor borders after the primary tumor excision.

Yet surgeons could now be getting support from a new multispectral fluorescence imaging system developed by a team of researchers in Munich, headed by Vasilis Ntziachristos, Professor of Biological Imaging. A study carried out on nine patients with ovarian cancer has shown that the new system can be used to localize cancer cells during surgery. Before the operation, the patients were injected with folic acid chemically coupled to a green fluorescent dye. Most ovarian tumors have a protein molecule on their surface that bonds with folic acid and transports it inside the cell. This protein is known as the folate receptor alpha. During abdominal surgery, the surgeon can then shine a special laser light onto the patient’s ovaries, causing the green-labeled folic acid inside the cancer cells to emit light. Healthy tissue remains dark.

The fluorescent cancer cells, however, cannot be detected by the naked eye. Three cameras, mounted on a pivoting support arm over the operating table, detect optical and fluorescent signals at multiple spectral bands and then correct for light variations due to illumination and tissue discolorations in order to provide truly accurate fluorescence images that can be simultaneously displayed with corresponding color images on monitors in the operating room. The surgeon can thus check whether all the cancer cells have been removed by inspecting for remnant fluorescence light. In eight of the nine patients, doctors were able to remove small clusters of tumor cells that might otherwise have gone undetected. The multispectral fluorescence imaging system has thus passed its first OR test. However, it will have to prove its value to improve clinical outcome in further operations before it can be deployed for routine surgical procedures.

The researchers in Munich and Groningen also want to further develop the camera system so it can be used to detect other forms of tumors during operations. Of significant importance in future developments is the ability to offer accurate fluorescence imaging so that data collected reflect true presence of disease. “The use of advanced, real-time optical technology will allow us to standardize data collection and accuracy so that studies performed at multiple clinical centers can be accurately compared and analyzed” explains Prof. Vasilis Ntziachristos. This is important for the clinical acceptance of the technology and its approval by regulatory agencies. In the future patient selection through personalized medicine approaches, for example by obtaining a molecular profile of the tumor of each patient, would further enable custom-tailored surgical treatment of improved accuracy. The team is also planning to build a version for minimally invasive operations.

###

Acknowledgment: The folic acid chemically coupled to a green fluorescent dye was provided by Phil Low of Purdue University.

Key function of mutation in BRCA1 gene discovered

Richmond, Va. (September 1, 2011) –It is widely known that mutations in the breast cancer susceptibility 1 (BRCA1) gene significantly increase the chance of developing breast and ovarian cancers, but the mechanisms at play are not fully understood. Now, researchers at Virginia Commonwealth University Massey Cancer Center have shown that certain BRCA1 mutations result in excessive, uncontrolled DNA repair, which challenges the prior assumption that mutations in BRCA1 only contribute to breast cancer through a reduction in function.

Recently published in the journal Aging, the study led by Kristoffer Valerie, Ph.D., discovered that certain BRCA1 mutations affecting the BRCA1 C-terminal (BRCT) binding site resulted in excessive DNA repair, or hyper-recombination, which may contribute to the development of breast and ovarian cancers. The BRCT domain is a protein binding site typically found on DNA repair proteins like BRCA1 that are responsible for maintaining genomic stability and facilitating DNA repair. This study has implications for the treatment, diagnosis and development of therapies for patients with breast and ovarian cancer.

“Our findings suggest that caution should be exercised when targeting BRCA1 for breast and ovarian cancer therapies,” says Valerie, co-leader of the Radiation Biology and Oncology program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center. “We need to better understand the biological mechanisms that lead to the development of breast and ovarian cancer before we attempt to attack it through targeted therapies aimed at causing DNA damage.”

When DNA damage occurs, various forms of BASC (BRCA1-associated genome surveillance complex) bind to the BRCT domain on BRCA1. BASC is a protein complex that in part binds to the BRCT domain and serves as a “docking site” for other proteins and enzymes to come in, effectively repair the DNA damage and leave when repair is completed. However, certain BRCT mutants unable to bind to BASC disrupt the delicate DNA repair process. Previously, it was assumed this meant that BRCA1 was unable to assist with the repair process and, thus, recombination did not occur.

Valerie and his colleagues showed through experiments with cultured breast cancer cells and tissue samples from breast cancer patients that BRCT mutants increased ubiquination of BASC, which, in turn, increased recombination several-fold over normal levels. Ubiquitin is a small protein in all living organisms that “marks” other proteins for degradation or, as more recently discovered, the participation in specific cellular processes such as recombination. The researchers proposed that the hyper-recombination resulting from increased ubiquination of the BASC might result in improperly repaired DNA and increased genomic instability, which could lead to the development and aggressive progression of breast and ovarian cancers.

“Our results point to ubiquitination as a potential therapeutic target,” says Valerie. “By disrupting ubiquitination we may be able to prevent hyper-recombination and stop the growth of cancer cells with these BRCT mutations. This might sensitize the cancer cells to radiation therapy while having little effect on cells with normal BRCA1 function.”

The researchers hope to continue studying the role of BRCA1 in DNA double-strand break repair in order to determine whether the mutations they examined are important for the onset of cancer and whether targeted therapies can be developed.

###

The full manuscript of this study is available online at: http://www.impactaging.com/papers/v3/n5/abs/100325a.html.

Valerie collaborated on this study with Seth M. Dever, Ph.D., Sarah E. Golding, Ph.D., Elizabeth Rosenberg, M.S., Bret R. Adams, Michael O. Idowu, M.D., M.P.H., John M. Quillin, Ph.D., C.G.C., Nicholas Valerie, and Lawrence F. Povirk, Ph.D., from Virginia Commonwealth University, and Bo Xu, M.D., Ph.D., from The Methodist Hospital in Houston, Texas.

Funding for this study was provided by the National Institutes of Health.