Category Archives: Medical Study Results

Symptoms Of Ovarian Cancer Remain Relatively Stabile Over Time As Reported By High Risk Women

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Researchers from the Fred Hutchinson Cancer Research Center reported recently that symptoms of ovarian cancer tend to be relatively stable over time for women who are at increased risk of ovarian cancer based upon family history of cancer or BRCA 1/2 gene mutation.

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2009 ASCO Annual Meeting Abstracts Now Available Online

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The 2009 Annual Meeting of the American Society of Clinical Oncology (ASCO) will be held in Orlando, Florida from May 29 through June 2, 2009. The ASCO Annual Meeting will be a forum for cutting-edge scientific and educational developments in oncology with a focus on personalizing cancer care.  The medical abstracts that will be presented at the 2009 ASCO Annual Meeting were made available for online viewing today at 6:00 P.M. EDT/3:00 P.M. PDT.  Late breaking medical abstracts will be available for viewing no later than 12:00 P.M. EDT on May 31st. Continue reading →

M.D. Anderson Study Predicts Dramatic Growth in Cancer Rates Among U.S. Elderly, Minorities

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” … Over the next 20 years, the number of new cancer cases diagnosed annually in the United States will increase by 45 percent, from 1.6 million in 2010 to 2.3 million in 2030, with a dramatic spike in incidence predicted in the elderly and minority populations, according to research from The University of Texas M. D. Anderson Cancer Center. …Given these statistics, the role of screening and prevention strategies becomes all the more vital and should be strongly encouraged, said [Ben] Smith [M.D.]. … These findings also highlight two issues that must be addressed simultaneously: clinical trial participation and the increasing cost of cancer care. Historically, both older adults and minorities have been under-represented in such studies, and, therefore, vulnerable to sub-optimal cancer treatment. Simultaneously, over the past decade in particular, the cost of cancer care is growing at a rate that’s not sustainable. …”

“Research underscores impact on health care system, importance of screenings, prevention strategies, inclusive clinical trials

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Dramatic Growth in Cancer Rates Among Elderly, Minorities

Over the next 20 years, the number of new cancer cases diagnosed annually in the United States will increase by 45 percent, from 1.6 million in 2010 to 2.3 million in 2030, with a dramatic spike in incidence predicted in the elderly and minority populations, according to research from The University of Texas M. D. Anderson Cancer Center.

The study, published online today in Journal of Clinical Oncology, is the first to determine such specific long-term cancer incidence projections. It predicts a 67 percent increase in the number of adults age-65-or-older diagnosed with cancer, from 1 million in 2010 to 1.6 million in 2030. In non-white individuals over the same 20-year span, the incidence is expected to increase by 100 percent, from 330,000 to 660,000.

Ben Smith, M.D., Adjunct Assistant Professor, Department of Radiation Oncology, The University of Texas M.D. Anderson Center

Ben Smith, M.D., Adjunct Assistant Professor, Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center

According to Ben Smith, M.D., adjunct assistant professor in M. D. Anderson’s Department of Radiation Oncology, the study underscores cancer’s growing stress on the U.S. health care system.

‘In 2030, 70 percent of all cancers will be diagnosed in the elderly and 28 percent in minorities, and the number of older adults diagnosed with cancer will be the same as the total number of Americans diagnosed with cancer in 2010,’ said Smith, the study’s senior author. ‘Also alarming is that a number of the types of cancers that are expected to increase, such as liver, stomach and pancreas, still have tremendously high mortality rates.’

Unless specific prevention and/or treatment strategies are discovered, cancer death rates also will increase dramatically, said Smith, who is currently on active military duty and is stationed at Lackland Air Force Base.

To conduct their research, Smith and his team accessed the United States Census Bureau statistics, updated in 2008 to project population growth through 2050, and the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry, the premier population-based cancer registry representing 26 percent of the country’s population. Cancer incidence rates were calculated by multiplying the age, sex, race and origin-specific population projections by the age, sex, race and origin-specific cancer incidence rates.

The researchers found that from 2010 to 2030, the population is expected to grow by 19 percent (from 305 to 365 million). The total number of cancer cases will increase by 45 percent (from 1.6 to 2.3 million), with a 67 percent increase in cancer incidence in older Americans (1 to 1.6 million), compared to an 11 percent increase in those under the age of 65 (.63 to .67 million).

With respect to race, a 100 percent increase in cancer is expected for minorities (.33 to .66 million); in contrast, in white Americans, a 31 percent increase is anticipated (1.3 to 1.7 million). The rates of cancer in blacks, American Indian-Alaska Native, multi-racial, Asian-Pacific Islanders and Hispanics will increase by 64 percent, 76 percent, 101 percent, 132 percent and 142 percent, respectively.

Regarding disease-specific findings, Smith and his team found that the leading cancer sites are expected to remain constant – breast, prostate, colon and lung. However, cancer sites with the greatest increase in incidence expected are: stomach (67 percent); liver (59 percent); myeloma (57 percent); pancreas (55 percent); and bladder (54 percent).

Given these statistics, the role of screening and prevention strategies becomes all the more vital and should be strongly encouraged, said Smith. In the study, Smith and his team site [sic]: vaccinations for hepatitis B and HPV; the chemoprevention agents tamoxifen and raloxifene; interventions for tobacco and alcohol; and removal of pre-malignant lesions, such as colon polyps.

These findings also highlight two issues that must be addressed simultaneously: clinical trial participation and the increasing cost of cancer care. Historically, both older adults and minorities have been under-represented in such studies, and, therefore, vulnerable to sub-optimal cancer treatment. Simultaneously, over the past decade in particular, the cost of cancer care is growing at a rate that’s not sustainable.

‘The fact that these two groups have been under-represented in clinical research participation, yet their incidence of cancer is growing so rapidly, reflects the need for therapeutic trials to be more inclusive and address issues that are particularly relevant to both populations,’ said Smith. ‘In addition, as we design clinical trials, we need to seek not only the treatment that will prolong survival, but prolong survival at a reasonable cost to patients. These are two issues that oncologists need to be much more concerned about and attuned to.’

Another issue that needs to be addressed is the shortage of health care professionals predicted. For example, according to a workforce assessment by American Society for Clinical Oncology (ASCO), the shortage of medical oncologists will impact the health care system by 2020. Smith said ASCO and other professional medical organizations beyond oncology are aware of the problem, and are actively engaged in efforts to try and grow the number of physicians, as well as encourage the careers of nurse practitioners and physician assistants who are part of the continuum of care, to best accommodate the increase in demand forecasted.

‘There’s no doubt the increasing incidence of cancer is a very important societal issue. There will not be one solution to this problem, but many different issues that need to be addressed to prepare for these changes,’ said Smith. ‘I’m afraid if we don’t come to grips with this as a society, health care may be the next bubble to burst.’

In addition to Smith, other M. D. Anderson authors on the study include: Thomas Buchholz, M.D., professor and chair of the Department of Radiation Oncology and the study’s senior author; Gabriel Hortobagyi, M.D., professor and chair of the Department of Breast Medical Oncology; and Grace Smith, M.D., Ph.D., assistant professor in the Department of Radiation Oncology. Arti Hurria, M.D., post-doctoral fellow in the Department of Medical Oncology, City of Hope Cancer Center, also is a contributing author on the study.”

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Women of Diverse Ethnic Ancestry Have Similar Risk of Carrying BRCA Mutations as Those With Western European Ancestry

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” …The study, performed by researchers at Philadelphia’s Fox Chase Cancer Center and Myriad Genetics, Inc., analyzed the prevalence of BRCA1/BRCA2 gene mutations in patients of different ethnicities at risk for hereditary breast and ovarian cancer. The study included test results of 46,276 women during the ten-year period from 1996 to 2006. Study subjects encompassed a broad, diverse ethnic group, including individuals of European, Latin American, African, Asian and Native American ancestries. … Results of the study showed that BRCA disease-causing mutations were identified in 5,780 women tested (12.5%) across all ethnic populations. Importantly, the study demonstrated that individuals of African and Latin American ancestry had as great a risk in having BRCA mutations as women with western European ancestry, when controlled for the level of personal and family history of breast and ovarian cancer. …”

“New Study Published in CANCER Supports Use of BRACAnalysis Testing Across Broad Ethnic Populations

Women of Asian, African and Latin American Ancestry Had Similar Risk of Carrying BRCA Mutations as Those With Western European Ancestry

SALT LAKE CITY, UT, Apr 30, 2009 (MARKET WIRE via COMTEX News Network) — Myriad Genetics, Inc. (NASDAQ: MYGN) announced today that an article entitled ‘BRCA1 and BRCA2 Mutations in Women of Different Ethnicities Undergoing Testing for Hereditary Breast-Ovarian Cancer‘ will appear in the May 15, 2009 issue of the journal CANCER.  The study demonstrates that BRACAnalysis(R) testing of at-risk women across diverse ethnicities helps identify individuals who may benefit from improved surveillance, medical and surgical strategies to reduce their hereditary cancer risks.

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Gregory C. Critchfield, M.D., M.S., President, Myriad Genetic Laboratories

‘This study, the largest of its kind, shows convincingly that strong family or personal history of breast or ovarian cancer is associated with a high prevalence of BRCA mutations — irrespective of one’s ethnic heritage,’ stated Gregory C. Critchfield, M.D., M.S., President of Myriad Genetic Laboratories.

The association between ethnicity and the risk of BRCA1 or BRCA2 mutations has not been well understood in women of non-European ancestry. This study provides important information for women of Asian, African, Latin American and Native American ancestry that may impact breast cancer [and ovarian cancer] prevention and treatment efforts among women in these populations. The study, performed by researchers at Philadelphia’s Fox Chase Cancer Center and Myriad Genetics, Inc., analyzed the prevalence of BRCA1/BRCA2 gene mutations in patients of different ethnicities at risk for hereditary breast and ovarian cancer. The study included test results of 46,276 women during the ten-year period from 1996 to 2006. Study subjects encompassed a broad, diverse ethnic group, including individuals of European, Latin American, African, Asian and Native American ancestries. To date, this work represents the largest group of patients tested for BRCA mutations reported in the literature. All testing was performed at Myriad Genetics, Inc.

Results of the study showed that BRCA disease-causing mutations were identified in 5,780 women tested (12.5%) across all ethnic populations. Importantly, the study demonstrated that individuals of African and Latin American ancestry had as great a risk in having BRCA mutations as women with western European ancestry, when controlled for the level of personal and family history of breast and ovarian cancer.

Professional medical society guidelines, such as the American Society of Clinical Oncologists (ASCO), the Society of Gynecologic Oncologists (SGO), and the American College of Obstetricians and Gynecologists (ACOG), articulate risk factors for BRCA gene mutations, which include, among others, breast cancer occurring before age 50, personal or family history of ovarian cancer at any age, personal or family history of male breast cancer, Ashkenazi Jewish ancestry with breast cancer at any age, or the presence of a known BRCA mutation in the family.

About BRACAnalysis(R)

BRACAnalysis(R) is a comprehensive analysis of the BRCA1 and BRCA2 genes for assessing a woman’s risk for breast and ovarian cancer. A woman who tests positive with the BRACAnalysis(R) test has, on average, an 82% lifetime risk of developing breast cancer during her lifetime and a 44% risk of developing ovarian cancer. BRACAnalysis(R) provides important information that the Company believes will help the patient and her physician make better informed lifestyle, surveillance, preventive medication and treatment decisions. As published in the Journal of the National Cancer Institute, researchers have shown that pre-symptomatic individuals who have a high risk of developing breast cancer can reduce their risk by approximately 50% with appropriate preventive therapies. Additionally, as published in the New England Journal of Medicine, researchers have shown that pre-symptomatic individuals who carry gene mutations can lower their risk of developing ovarian cancer by approximately 60% with appropriate preventive therapies.

For more information about BRACAnalysis(R), please call 1-800-4-MYRIAD, or visit www.myriadtests.com.

About Myriad Genetics

Myriad Genetics, Inc. is a leading healthcare company focused on the development and marketing of novel molecular diagnostic and therapeutic products. Myriad’s news and other information are available on the Company’s Web site at www.myriad.com.

Myriad, the Myriad logo, BRACAnalysis, Colaris, Colaris AP, Melaris, TheraGuide, Prezeon, OnDose, Azixa and Vivecon are trademarks or registered trademarks of Myriad Genetics, Inc. in the United States and foreign countries. MYGN-G”

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Related Information:  CLICK HERE to review all Libby’s H*O*P*E*™ postings relating to BRCA gene mutations.

Novogen’s NV-128 Targets mTOR Pathway To Block Differentiation and Induce Cell Death in Ovarian Cancer Stem Cells

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“Data just presented at the Annual Meeting of the American Association for Cancer Research in Denver has demonstrated that NV-128, a Novogen, Limited (ASX: NRT NASDQ: NVGN) synthetic isoflavonoid compound, not only induces cell death in Ovarian Cancer Stem Cells (OCSCs), but also blocks their differentiation into structures which are required to support tumor growth.  In a poster presentation by Ayesha Alvero, MD, of Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Science, it was revealed that in addition to an inhibitory effect on OCSC growth, NV-128 displays a remarkable ability to inhibit differentiation of OCSCs into formation of new blood vessels. … ‘We have now demonstrated that by inhibiting the mTOR pathway in both the cancer stem cells and the mature cancer cells, we are able to inhibit development of structural elements necessary for tumor development as well as limit the number of cancer cells,’ Professor Mor said. ‘These results open a new avenue for the development of better treatment modalities for ovarian cancer patients.’ …”

“(Sydney Australia and New Canaan, Connecticut – 20 April, 2009) – Data just presented at the Annual Meeting of the American Association for Cancer Research in Denver has demonstrated that NV-128, a Novogen, Limited (ASX: NRT NASDQ: NVGN) synthetic isoflavonoid compound, not only induces cell death in Ovarian Cancer Stem Cells (OCSCs), but also blocks their differentiation into structures which are required to support tumor growth.

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Ayesha Alvero, M.D., Associate Research Fellow, Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine

In a poster presentation by Ayesha Alvero, MD, of Yale University School of Medicine, Department of Obstetrics, Gynecology and Reproductive Science, it was revealed that in addition to an inhibitory effect on OCSC growth, NV-128 displays a remarkable ability to inhibit differentiation of OCSCs into formation of new blood vessels.

The anti-proliferative effects were demonstrated to be achieved as a result of NV-128 inhibiting phosphorylation of the pro-survival mTOR pathway resulting in mitochondrial depolarisation and cell death. Time lapsed photographic morphometry revealed in graphic detail how NV-128 induces morphological changes in OCSCs after 24 hours, even when dosed as low as 1μg/ml with a progressive “clearing” of cytoplasm and condensation of nuclear material.

The effect of NV-128 on OCSC vessel formation was observed by plating OCSCs in high-density matrigel either without NV-128 (controls) or in the presence of 0.1 mg/ml NV-128 and observing for 48 hours. Whereas the control cultures showed differentiation of the stem cells into endothelial-type cells forming structurally intact blood vessels in the culture plates, cells cultured in the presence of NV-128 showed no differentiation and no structural elements were observed.

OCSCs represent a highly chemo-resistant cell population, allowing them to survive conventional chemotherapy. Thus these cells are considered to be the potential source of tumor induction and post-treatment recurrence.

The team from Yale University, headed by Professor Gil Mor, recently reported the identification and characterisation of OCSCs using the CD44 marker and demonstrated pronounced up-regulation of the mTOR survival pathway in these cells. They previously reported that NV-128 is able to specifically induce mTOR dephosphorylation resulting in inhibition of both mTORC1 and mTORC2 activity in mature ovarian cancer cells derived from established human cancers and cultured in vitro. In mice with human ovarian cancers established by grafting techniques (xenografts) NV-128 caused substantial cancer cell death, reducing tumor growth with no apparent toxic side-effects.

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Gil Mor, M.D., Ph.D., Associate Professor, Department of Obstetrics, Gynecology and Reproductive Science, Yale University School of Medicine

‘We have now demonstrated that by inhibiting the mTOR pathway in both the cancer stem cells and the mature cancer cells, we are able to inhibit development of structural elements necessary for tumor development as well as limit the number of cancer cells,’ Professor Mor said. ‘These results open a new avenue for the development of better treatment modalities for ovarian cancer patients.’

‘We are encouraged by these data from animal studies showing a combination of anti-cancer activities of NV-128, coupled with an apparently high safety profile,’ said Professor Alan Husband, Group Director of Research for the Novogen group. ‘This anti-angiogenic effect, coupled with the absolute effects on cell survival, demonstrate the potential for NV-128 to become a powerful new tool in prevention as well as treatment of cancer.’

Novogen has previously reported on the parallel effects of NV-128 in non-small cell lung cancer models and the Company intends to pursue this, as well as ovarian cancer, as target indications.

Novogen is currently in advanced negotiations with its majority owned subsidiary, Marshall Edwards, Inc. (MEI), to out-license NV-128 to MEI for its clinical development as a potential cancer therapeutic. To view an online abstract relating to this study, [CLICK HERE].

About NV-128

NV-128 does not rely on the traditional approach of caspase-mediated apoptosis, a death mechanism which is not effective in cancer cells that have become resistant to chemotherapy. Rather, NV-128 uncouples a signal transduction cascade which has a key role in driving protein translation and uncontrolled cancer cell proliferation. Further, NV-128 induces mitochondrial depolarisation via the novel mTOR pathway. In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies. Inhibition of the mTOR pathway appears to shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells. Animal studies have shown that NV-128 not only significantly retards tumor proliferation, inhibiting the progression of ovarian cancers-engrafted into mice, but produces this effect without apparent toxicity. This effect was shown to be due to caspase-independent pathways involving inhibition of the mTOR pathway. Unlike analogues of rapamycin, which target only mTORC1, NV-128’s capacity to inhibit mTOR phosphorylation enables it to inhibit both mTORC1 and mTORC2 activity. This blocks growth factor-driven activation of AKT and the potential for development of chemoresistance.

About Novogen Limited

Novogen Limited (ASX: NRT; NASDAQ: NVGN) is an Australian biotechnology company based in Sydney, Australia, that is developing a range of oncology therapeutics from its proprietary flavonoid synthetic chemistry technology platform. More information on NV-128 and on the Novogen group of companies can be found at www.novogen.com.

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Additional Information Re Novogen’s NV-128:

Genetic Variations In miRNA Processing Pathway & Binding Sites Help Predict Ovarian Cancer Risk

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“Genetic variations in the micro-RNA (miRNA) processing pathway genes and miRNA binding sites predict a woman’s risk for developing ovarian cancer and her prospects for survival, researchers from The University of Texas M. D. Anderson Cancer Center reported at the 100th annual meeting of the American Association for Cancer Research. … The unique study was the first to examine the association of genetic variants related to miRNA with ovarian cancer risk, overall survival for ovarian cancer patients, and platinum-based chemotherapy response. …”

“Genetic variations in miRNA processing pathway and binding sites help predict ovarian cancer risk – Several variations indicate likelihood of response to platinum-based chemotherapy

DENVER – Genetic variations in the micro-RNA (miRNA) processing pathway genes and miRNA binding sites predict a woman’s risk for developing ovarian cancer and her prospects for survival, researchers from The University of Texas M. D. Anderson Cancer Center reported at the 100th annual meeting of the American Association for Cancer Research.

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Xifeng Wu, M.D., Ph.D., Professor, Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center

‘We found a gene dosage effect, the more unfavorable variations a woman has, the greater her ovarian cancer risk and the shorter her survival time,’ said senior author Xifeng Wu, M.D., Ph.D., professor in M. D. Anderson’s Department of Epidemiology. Median survival, for example, ranged from 151 months for women with fewest unfavorable variations to 24 months for those with the most.

Several variations also indicate likely response to platinum-based chemotherapy.

‘Our findings have the potential clinical application of indicating a patient’s prognosis and showing who will respond to different therapies by analyzing a single blood sample,’ Wu said. ‘We also will incorporate this genetic information with epidemiological information to build a comprehensive model to predict susceptibility to ovarian cancer.’

The team chose the miRNA processing pathway because it is crucial to production of miRNAs, the small molecules that regulate between one third and half of all genes. The researchers also chose the binding sites on host genes where miRNAs exert their effects on gene expression.

They analyzed 219 potential functional single nucleotide polymorphisms (SNPs) – variations of a single DNA building block in a gene – in eight genes that process miRNA and at the miRNA binding sites of 129 cancer-relevant genes. The study examined genetic information from 417 cancer patients and 417 healthy controls. To minimize the possible confounding effects of ethnicity, 339 Caucasian cases and 349 controls were analyzed.

They discovered 12 SNPs to be significantly associated with ovarian cancer risk. Moreover, compared to women with five or fewer unfavorable genotypes, women with eight or more of these unfavorable genotypes were 4.5 times more likely to develop ovarian cancer and women with six to eight unfavorable SNPs were at twice the risk.

The team also found 21 SNPs significantly associated with overall survival. Median survival was 151 months for women with six or fewer unfavorable variations; 42 months for those with seven to nine unfavorable variations; and 24 months for those with 10 or more. One of the outcome risk SNPs also was strongly associated with platinum-based chemotherapy response, with those having the SNP 3.4 times less likely to respond to chemotherapy.

Wu collaborated with Dong Liang, Ph.D, in the College of Pharmacy and Health Sciences, Texas Southern University, and Karen Lu, M.D., professor in M. D. Anderson’s Department of Gynecologic Oncology, on this study.

The unique study was the first to examine the association of genetic variants related to miRNA with ovarian cancer risk, overall survival for ovarian cancer patients, and platinum-based chemotherapy response. Such a wide-ranging inquiry was made possible by M. D. Anderson’s extensive clinical and genetic data sets, Wu said.

Co-authors with Wu, first author Liang, Ph.D., and Lu are; Jie Lin, Ph.D., Xia Pu, Yuanqing Ye, Ph.D., all in the Department of Epidemiology; and Larissa Meyer, M.D., in the Department of Gynecologic Oncology at M. D. Anderson Cancer Center. Pu is a graduate student at The University of Texas Graduate School of Biomedical Sciences at Houston, which is a joint effort of M. D. Anderson and The University of Texas Health Science Center at Houston.

This research was supported by an award by the Department of Defense Ovarian Cancer Research Program.”

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in “America’s Best Hospitals,” a survey published annually in U.S. News & World Report.

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Synergistic Anti-Tumor Effect of CRM197 & Paclitaxel in Ovarian Cancer

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CRM197, an inhibitor of heparin-binding EGF-like growth factor (HB-EGF), produces a synergistic ovarian cancer anti-tumor effect when combined with paclitaxel, according to study results published in the March 15th issue of the International Journal of Cancer.  The investigators, Dr. Shingo Miyamoto and his colleagues, are affiliated with the Fukuoka University in Japan.  “The treatment of CRM197 in conjunction with paclitaxel results in a marked synergistic anti-tumor effect in ovarian cancer cells in vivo, suggesting a novel combination therapy for ovarian cancer patients including those showing chemo-resistance.”  Accordingly, the investigators generally concluded that inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer. …

CRM197, an inhibitor of heparin-binding EGF-like growth factor (HB-EGF), produces a synergistic ovarian cancer anti-tumor effect when combined with paclitaxel, according to study results published in the March 15th issue of the International Journal of Cancer.  The investigators, Dr. Shingo Miyamoto and his colleagues, are affilitated with the Fukuoka University in Japan.

According to the researchers, HB-EGF plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, thereby making it a target for future ovarian cancer therapy. CRM197 is a non-toxic variant of the diphtheria toxin.  The investigators conducted studies in which CRM197 and paclitaxel (Taxol®) were tested against ovarian cancer cell cultures (in vitro) and overexpressing HB-EGF ovarian cancer cells which were injected into mice.

The investigators discovered that paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK, effects that were reduced by overexpression of HB-EGF. CRM197 effectively suppressed the paclitaxel-induced anti-apoptotic signals mediated by ERK and Akt and enhanced the pro-apoptotic signals JNK and p38 MAPK.

The investigators also noted that in the mice with ovarian cancer xenografts, paclitaxel and CRM197 completely blocked tumor formation at doses of 10 mg/kg paclitaxel and 5 mg/kg CRM197.

Based on the foregoing, Miyamoto et. al. concluded that “the enhancement of HB-EGF expression abrogates the antitumor effect of paclitaxel by altering the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The treatment of CRM197 in conjunction with paclitaxel results in a marked synergistic anti-tumor effect in ovarian cancer cells in vivo, suggesting a novel combination therapy for ovarian cancer patients including those showing chemo-resistance.”  Accordingly, the investigators generally concluded that inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer.

“Phase 1 [clinical] study of the use of CRM197 has already started at Fukuoka University for patients with advanced ovarian cancer under the approval of the ethical committee,” the investigators added.

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Johns Hopkins Discovers a Protein That Contributes to Ovarian Cancer Recurrence By Causing Chemoresistance

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” … Ground-breaking work on an ovarian cancer-related protein in the lab of Ie-Ming Shih at the [Johns Hopkins] School of Medicine is leading to new insights into cancer biology. … They have revealed a novel protein that creates cancer cells that are resistant to traditional cancer chemotherapies and partially revealed its mechanism of action. With all of this information, the team hopes to create drugs that can target these proteins or find out which chemotherapies currently on the market do not function in this pathway to create resistant cancer cells.”

“Ovarian cancer is a growing concern with more than 15,000 deaths occurring in 2007, making it the leading cause of death in gynecological diseases.

Ie-Ming Shih, M.D., Ph.D., Professor, Pathobiology Graduate Program, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Ie-Ming Shih, M.D., Ph.D., Professor, Pathobiology Graduate Program, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Ground-breaking work on an ovarian cancer-related protein in the lab of Ie-Ming Shih at the School of Medicine is leading to new insights into cancer biology.

The protein is nucleus accumbens-1, NAC-1, which is a transcription factor that regulates the expression of genes. Previous work has shown NAC-1 to be overexpressed in many types of cancer, specifically ovarian cancer that is resistant to chemotherapy.

A deeper understanding of its mechanism of action would allow scientists and physicians to make inroads into possibly curing the diseases.

In many cases, the first round of chemotherapy or treatment shrinks the tumor but does not cure the patient of the diseases. The cancer then grows back and can be resistant to a second round of the initial therapy.

Ovarian cancer cells that are resistant to chemotherapy have higher than normal levels of NAC-1. Shih and her [sic] team showed that the ovarian cancer cells, when exposed to a particular chemotherapy drug, were resistant compared to cancer cells with normal expression of NAC-1.

Upon further investigation into the biological pathways of interacting proteins in the nucleus, the team found that another protein [Gadd45-gamma-interacting protein 1 (Gadd45gip1)] is the target of NAC-1’s mechanism of action.

NAC-1 works by interacting with this other protein and stopping it from working and decreasing its expression inside the cell. So when NAC-1 expression is increased, the cancer cells are resistant to treatment, and the downstream target protein of NAC-1 is downregulated.

Performing further experiments, the researchers found that by making normal cancer cells overexpress the NAC-1 protein the cells were resistant to the chemotherapy drug, where previously they were not before the induced expression.

Also, the downstream target protein had reduced expression.

Conversely, if the researchers knocked down the expression of NAC-1 or increased the expression of its downstream target protein, then the cells were sensitive to cancer treatment, more so than normal cancer cells.

The scientists also wanted to uncover how the proteins interact structurally. Their work has revealed that NAC-1 is a homodimer protein, meaning it self-dimerizes – two copies of the protein come together to form the working product.

If the researchers formed a NAC-1 protein with only one of the units working properly, then the entire protein would not function and the ovarian cancer cells were sensitive to chemotherapy treatment.

Also, in this non-functional protein, it would induce the expression of its downstream target protein and increase that protein’s expression, thereby sensitizing the cells to chemotherapy.

Taken together, the researchers have paved new roads into the ever-complicating fight against cancer.

They have revealed a novel protein that creates cancer cells that are resistant to traditional cancer chemotherapies and partially revealed its mechanism of action.

With all of this information, the team hopes to create drugs that can target these proteins or find out which chemotherapies currently on the market do not function in this pathway to create resistant cancer cells.”

Source: Resistance to cancer chemotherapy is studied, by Neil Neumann, Science Section, The Johns Hopkins Newsletter, April 2, 2009 (discussing Jinawath N, Vasoontara C, Yap KL et al.  NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway.  Oncogene. 2009 Mar 23. [Epub ahead of print]).

To Screen or Not To Screen? Ultrasound + CA125 Blood Test Fail to Detect Early Stage Ovarian Cancer

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On March 10, 2009, Libby’s H*O*P*E*™ reported on the preliminary findings of a large British study that suggest that the combination of transvaginal ultrasound and CA125 blood test (a blood serum marker for ovarian cancer) can detect early ovarian cancer.  A recent U.S. study, published in the April 2009 issue of Obstetrics & Gynecology, found that the same combination screening regime did not detect early stage ovarian cancer and often resulted in unnecessary surgery. The U.S. and British studies, taken together, highlight the need to find an effective screening method to detect ovarian cancer.

On March 10, 2009, Libby’s H*O*P*E*™ reported on the preliminary findings of a large British study that suggest that the combination of transvaginal ultrasound and CA125 blood test (a blood serum marker for ovarian cancer) can detect early ovarian cancer.  A recent U.S. study, published in the April 2009 issue of Obstetrics & Gynecology, found that the same combination screening regime did not detect early stage ovarian cancer and often resulted in unnecessary surgery. The U.S. and British studies, taken together, highlight the need to find an effective screening method to detect ovarian cancer.

partridge-edward

Dr. Edward E. Partridge is the Director of the University of Alabama Birmingham Comprehensive Cancer Center, Birmingham, Alabama.

In a recent interview with U.S. News & World Report, the lead researcher of the U.S. study, Dr. Edward Partridge, Director of the University of Alabama Birmingham Comprehensive Cancer Center, said, “The jury is still out on the efficacy of screening with CA125 and transvaginal ultrasound in terms of reducing the mortality rate of ovarian cancer.  In this study, we do not have mortality data on the screening versus the non-screening group, so no conclusions can be made of the impact of screening with CA125 and transvaginal ultrasound.”

Partridge noted that this study only reports data on women who were screened. “We learned that the positive predictive value for the combination of tests is pretty low — in the 1 to 1.3 percent range,” he said. “A substantial number of the tests are false positives.”  In addition, screening with transvaginal ultrasound lead to a higher rate of surgery for positive findings than positive CA125, Partridge said. “Transvaginal ultrasound leads to more ‘unnecessary’ surgeries,” he said.  Partridge also noted that a high percentage of the cancers detected through screening were late-stage malignancies.  “If you detect them at a late stage, it is unlikely that you are going to impact mortality,” he said. “In order to affect mortality, one has to detect them at an earlier stage.”

As part of the study, the U.S. researchers collected data on 34,261 women who underwent annual screening for CA125 and also had transvaginal ultrasound.  A CA 125 value at or above 35 units/mL or an abnormality on transvaginal ultrasound was considered a “positive” screen.  The researchers found that  transvaginal ultrasound produced more positive findings for cancer than CA125 screening over the four years of screening, while the CA125 positive tests decreased from 60 percent in the first year to 34 percent in the third year.  Of the 89 invasive ovarian cancers diagnosed, 60 were detected through screening. In addition, 72 percent of the screen-detected cancer were late-stage cancers, the U.S. researchers reported.

Partridge told U.S. News & World Report that even detecting cancer early may not have an impact on mortality. “In any screening trial, the ultimate test of its usefulness is does it impact mortality,” he said.  Patridge added that based upon the findings of this study and The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) study published by Menon et. al. in the March 10 online edition of  The Lancet Oncology, the CA125 blood test & ultrasound screening method will not have any effect on mortality. “What we need is a more sensitive and specific screening test,” Partridge said.

In the UKCTOCS study, a British research team found that screening was able to identify most women with gynecologic cancer. The combination of the CA125 blood test and ultrasound found 90 percent of the cancers, while ultrasound alone found 75 percent of the cancers.  The researchers also found that almost 50 percent of all the cancers found were in an early stage (stage I or II).  And, 48 percent of the more invasive ovarian cancers detected were designated as being stage I tumors. By way of comparison, the British researchers pointed out that only 28 percent of ovarian cancers are identified in this early stage.

Dr. David G. Mutch, the Ira C. and Judith Gall Professor of Obstetrics and Gynecology at Washington University, St. Louis, and author of an accompanying journal editorial, agreed there is no worthwhile screening test for ovarian cancer as yet.  “Patients who were screened presented at the same stage as they would have if they were unscreened,” Mutch said. “There is no good screening test at this point.”  Mutch added that there is no reason to screen for ovarian cancer in the general population at this point. “The prevalence of the diseases is so low, one in 2,500, and the specificity of the tests are so low, that we are going to operate on a lot of patients unnecessarily,” he said.

Primary Sources:

Ovarian Cancers Detected Early May Be Less Aggressive

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“The biology of ovarian cancers discovered at an early stage may render them slower growing and less likely to spread than more aggressive cancers, which typically are discovered in an advanced stage, according to a study led by investigators in the Duke Comprehensive Cancer Center.  This finding has implications for the question of whether screening for ovarian cancer could save lives. …”

“The biology of ovarian cancers discovered at an early stage may render them slower growing and less likely to spread than more aggressive cancers, which typically are discovered in an advanced stage, according to a study led by investigators in the Duke Comprehensive Cancer Center.  This finding has implications for the question of whether screening for ovarian cancer could save lives.

berchuck-andrew

Dr. Andrew Berchuck is Director of the Duke Division of Gynecologic Oncology, Duke Comprehensive Cancer Center, Durham, North Carolina

‘Our study showed that the ovarian cancers currently detected at an early stage have gene expression profiles that correlate with favorable outcome, rather than being representative of the entire spectrum of disease aggressiveness,’ said Andrew Berchuck, MD, a gynecologic oncologist at Duke and lead investigator on this study.  ‘This highlights the potential challenges of developing a screening test for this disease, because earlier detection of aggressive cases is essential if screening is to reduce ovarian cancer deaths.’

The results of this study and the implications for screening as an approach to decreasing mortality parallel the challenges seen in lung cancer and prostate cancer.  In those cancers, while screening approaches based on radiological imaging and/or blood markers detect cancers, it remains unclear whether cancer-related deaths are prevented because screening preferentially detects more benign cancers that are much less likely to be fatal, Berchuck said.

‘While these results could be seen as discouraging, it must be remembered that this information is an important piece of the ovarian cancer puzzle, and data like these that increase our understanding of the disease hopefully will eventually lead to breakthroughs in prevention, early detection and treatment of this deadly disease,’ Berchuck said.  Although there is currently no approved ovarian cancer screening test for the general population, the CA125 blood test and transvaginal ultrasound imaging currently are being evaluated in clinical trials.

The researchers looked at gene expression patterns in 166 ovarian cancer tissue samples taken from patients who were treated at Duke, H. Lee Moffitt Cancer Center, and Memorial Sloan-Kettering Cancer Center and from the Gynecologic Oncology Group Tumor Bank.  For this study, researchers examined samples of advanced ovarian cancers from patients who had experienced long-term survival — over seven years — and patients who had done extremely poorly, and died within three years of diagnosis.  The researchers used microarrays — a method for examining thousands of snippets of DNA — with about 22,000 probe sets to examine patterns of gene expression among the samples, and identified genes that were most predictive of survival.

‘We found that certain patterns predicted long-term survival and others predicted a poorer prognosis in advanced stage cases,’ Berchuck said. ‘Cancers that were detected at an early stage almost always shared gene expression characteristics with advanced stage cases that were long-term survivors, suggesting a shared favorable biology.’

The researchers published their results in the March 24, 2009, issue of the journal Clinical Cancer Research. The study was funded by the Gail Parkins Ovarian Cancer Research Fund and the National Institutes of Health.

Other researchers involved in this study include Edwin Iversen, Jingqin Luo, Jennifer Clarke, Hisani Horne, Angeles Secord, Jason Barnett, Susan Murphy, Holly Dressman, Jeffrey Marks of Duke; Douglas Levine and Jeff Boyd of Memorial Sloan-Kettering Cancer Center in New York City, NY; Miguel Alonso of the Universidad Autonoma de Madrid; and Johnathan Lancaster of H. Lee Moffitt Cancer Center and Research Institute.”

Primary Source:  Spotlight:  Ovarian Cancers Detected Early May Be Less Aggressive, News Article, Duke Comprehensive Cancer Center, March 23, 2009.

Can FDA-Approved HIV Drugs Treat Chemoresistant Ovarian Cancer?

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Two recent in vitro studies conducted in the U.S. and Europe raise a provocative question:  Can FDA-approved human immunodeficiency virus (HIV) drugs be used to treat chemoresistant ovarian cancer?  Both studies were based upon the fact that HIV patients taking antiretroviral inhibitors have a lower incidence of infection-associated malignancies.  Based upon that fact, the researchers conducting both studies hypothesized that such drugs could produce anti-cancer activity.

Two recent in vitro studies conducted in the U.S. and Europe raise a provocative question:  Can FDA-approved human immunodeficiency virus (HIV) drugs be used to treat chemoresistant ovarian cancer?  Both studies were based upon the fact that HIV patients taking antiretroviral inhibitors have a lower incidence of infection-associated malignancies.  Based upon that fact, the researchers conducting both studies hypothesized that such drugs could produce anti-cancer activity.

The first in vitro study was conducted by University of Munich Hospital researchers.  The stated purpose of the German in vitro study was to determine whether nelfinavir could (i) sensitize drug resistant ovarian cancer cells to chemotherapeutic agent, or (ii) act as a monotherapy against drug resistant ovarian cancer cells.  Upon conclusion of the study, the German researchers discovered that nelfinavir induced cell death in carboplatin– sensitive and carboplatin-resistant ovarian cancer cell lines, as well as in cancer biopsies and ascites samples from patients with recurrent ovarian cancer.  The researchers noted that nelfinavir significantly changed the morphology of the ovarian cancer cells by creating the so-called “unfolded protein response” (UPR). UPR, in turn, caused ovarian cancer cell cycle arrest and death. The German researchers also observed a downregulation of cell cycle regulatory proteins after nelfinavir treatment, and hypothesized that it contributed to ovarian cancer cell death. Because nelfinavir represents a FDA-approved drug for use in humans with HIV infection, the researchers concluded that it could be tested rapidly in clinical studies as a potential treatment strategy against drug-resistant ovarian cancer.

The second in vitro study was conducted by University of Michigan researchers.  The stated purpose of the University of Michigan study was to (i) determine whether the protease inhibitor saquinavir could produce anticancer activity in ovarian cancer cell lines, and (ii) understand the mechanism through which such anti-cancer activity occurs.  Upon conclusion of the study, the University of Michigan researchers discovered that saquinavir induced cell death in chemosensitive and chemoresistant ovarian cancer cells in a time- and dose-dependent manner. Specifically, cellular morphology assessed by transmission electron microscopy (TEM) revealed apoptotic, autophagic, and necrotic cell death. The University of Michigan researchers concluded that saquinavir, as an FDA-approved drug for the treatment of HIV, could have clinical application in the treatment of chemoresistant ovarian cancer.

Comment:

There is no guarantee that the in vitro study results discussed above could be replicated in human beings.  The in vitro study results are nevertheless provocative because they were performed with drugs that are already FDA-approved, abeit for HIV, and therefore, such drugs were previously determined to be relatively safe. In addition, the findings of both in vitro studies are nearly identical despite the fact that two different FDA-approved HIV drugs were tested by two separate medical facilities. Given the chemoresistant nature of ovarian cancer, it seems that nelfinavir and saquinavir should be tested in future clinical trials.

Primary Sources:

GPs Should Suspect Ovarian Cancer in All Women With Distended Abdomen, U.K. Researchers Warn

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“GPs [General Practioners] should suspect ovarian cancer in all women presenting with abdominal distension, [U.K.] researchers have warned.  The primary care study found it was an important enough symptom on its own to warrant further investigation.  Researchers linked seven symptoms to ovarian cancer with many commonly present as much as six months before diagnosis, and warned that their study dispelled the myth that ovarian cancer was a ‘silent killer’. …”

“GPs [General Practioners] should suspect ovarian cancer in all women presenting with abdominal distension, researchers have warned.

The primary care study found it was an important enough symptom on its own to warrant further investigation.

Researchers linked seven symptoms to ovarian cancer with many commonly present as much as six months before diagnosis, and warned that their study dispelled the myth that ovarian cancer was a ‘silent killer’.

As many as 2.5% of women with abdominal distension on its own were subsequently diagnosed with ovarian cancer, and an ovarian cancer diagnosis was 240 times more likely in these women than in controls.

Urinary frequency and abdominal pain were also associated with risk, with the relative risk of ovarian cancer increasing by 16- and 12-fold respectively, although the positive predictive values of the symptoms on their own were only 0.2% and 0.3%.

Abdominal distension, urinary frequency and abdominal pain remained independently associated with cancer more than six months prior to diagnosis.

Dr. Willie Hamilton, a GP and a senior research fellow in primary care at the University of Bristol, said his preliminary results provided an evidence base for GPs to select patients for further investigation: ‘Abdominal distension is important enough to warrant investigation for ovarian cancer even without the need for other symptoms.’  ‘Ovarian cancer is not a silent killer, it’s just its noise seems to go unheard by GPs at times’, he added.

The study, presented at the Society for Academic Primary Care south west annual research meeting last week, examined the records of 212 women diagnosed with ovarian cancer at 39 practices in Devon in the year before diagnosis, and compared them with 1,030 matched controls.

Dr. Murray Freeman, a GP in Birkenhead, Merseyside and cancer lead for Wirral PCT, said the study ‘highlights how often ovarian cancer masquerades as other common illnesses’. ‘GPs should have a low index of suspicion in women over 40 with non specific symptoms – and refer or investigate early.’

Dr. Nick Brown, a GP in Chippenham, Wiltshire with an interest in cancer, said GPs desperately needed a tool to aid earlier diagnosis. ‘Small tumours are very difficult to diagnosis, even by doing a pelvic or vaginal examination. By the time tumours reach the size they can be detected it may have spread and treatment might not be that easy.’

Positive predictive values of ovarian cancer symptoms –

• Abdominal distensions – 2.5%
• Post-menopausal bleeding
• Loss of appetite – 0.6%
• Urinary frequency – 0.2%
• Abdominal pain – 0.3%
• Rectal bleeding – 0.2%
• Abdominal bloating – 0.3%

Source: Society for Academic Primary Care, South West Annual Research Meeting, March 2009, oral presentation”

Quoted Source:  Suspect Ovarian Cancer In All Women With Distended Abdomen, by Lilian Anekwe, Pulsetoday.co.uk, Mar. 9, 2009.

What’s Feeding Cancer Cells? — Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use.

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“Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature. …”

“February 15, 2009- Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature.

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

‘While we were looking for how Myc promotes cancer growth, it was unexpected to find that Myc can increase use of glutamine by cancer cells,’ says Chi V. Dang, M.D., Ph.D., the Johns Hopkins Family Professor of Oncology at Johns Hopkins. ‘This surprising discovery only came about after scientists from several disciplines came together across Hopkins to collaborate — it was a real team effort.’

In their search to learn how Myc promotes cancer, the researchers teamed up with protein experts, and using human cancer cells with Myc turned on or off, they looked for proteins in the cell’s powerhouse — the mitochondria — that appeared to respond to Myc. They found eight proteins that were distinctly turned up in response to Myc.

At the top of the list of mitochondrial proteins that respond to Myc was glutaminase, or GLS, which, according to Dang, is the first enzyme that processes glutamine and feeds chemical reactions that make cellular energy. So the team then asked if removing GLS could stop or slow cancer cell growth. Compared to cancer cells with GLS, those lacking GLS grew much slower, which led the team to conclude that yes, GLS does affect cell growth stimulated by Myc.

The researchers then wanted to figure out how Myc enhances GLS protein expression. Because Myc can control and turn on genes, the team guessed that Myc might directly turn on the GLS gene, but they found that wasn’t the case. ‘So then we thought, maybe there’s an intermediary, maybe Myc controls something that in turn controls GLS,’ says Ping Gao, Ph.D., a research associate in hematology at Johns Hopkins.

They then built on previous work done with the McKusick-Nathans Institute of Genetic Medicine at Hopkins where they discovered that Myc turns down some microRNAs, small bits of RNA that can bind to and inhibit RNAs, which contain instructions for making proteins. The team looked more carefully at the GLS RNA and found that it could be bound and regulated by two microRNAs, called miR23a and miR23b, pointing to the microRNAs as the intermediary that links Myc to GLS expression.

‘Next we want to study GLS in mice to see if removing it can slow or stop cancer growth,’ says Gao. ‘If we know how cancer cells differ from normal cells in how they make energy and use nutrients, we can identify new pathways to target for designing drugs with fewer side effects.’

This study was funded by the National Institutes of Health, the National Cancer Institute, the Rita Allen Foundation, the Leukemia and Lymphoma Society and the Sol Goldman Center for Pancreatic Cancer Research.

Authors on the paper are Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Karen Zeller, Angelo De Marzo, Jennifer Van Eyk, Joshua Mendell and Chi V. Dang, of Johns Hopkins; and Kayoko Kita and Takfumi Ochi of Teikyo University in Japan.

On the Web:
http://www.hopkinsmedicine.org/hematology/faculty_staff/dang.html
http://www.proteomics.jhu.edu/index.php
http://www.hopkinsmedicine.org/geneticmedicine/People/Faculty/mendell.html
http://www.nature.com/nature/index.html

– JHM –

Media Contacts: Audrey Huang; 410-614-5105; audrey@jhmi.edu
Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu”

______________________

Quoted Source:  What’s Feeding Cancer Cells? – Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use, Press Release, Johns Hopkins Medicine, February 15, 2009.

Primary Citation:  c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism; Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang et. al., Letter, Nature advance online publication 15 February 2009.

Two Studies Address Risk Reduction & Screening For BRCA 1/2 Gene Mutation Carriers

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“Prophylactic salpingo-oophorectomy – removal of the ovaries and fallopian tubes–reduces the relative risk of breast cancer by approximately 50 percent and the risk of ovarian and fallopian tube cancer by approximately 80 percent in women who carry a mutation in the BRCA1 or BRCA2 gene, researchers report in the January 13 online issue of the Journal of the National Cancer Institute …. Women at high risk of ovarian cancer due to a genetic predisposition may opt for either surveillance or prophylactic bilateral salpingo-oophorectomy (pBSO).  Main objective of our study was to determine the effectiveness of ovarian cancer screening in women with a BRCA1/2 mutation.  At this time,’ Dr. de Bock and colleagues advise, “prophylactic bilateral salpingo-oophorectomy from age 35-40 for BRCA1 carriers and from age 40-45 for BRCA2 carriers is the only effective strategy, as it reduces the risk of ovarian cancer by 96% and may also protect against breast cancer with a risk reduction up to 53% when performed in premenopausal women.’ They add, ‘For women who still want to opt for screening, a more effective screening strategy needs to be designed.'”

Meta-analysis Confirms Value of Risk-Reducing Salpingo-Oophorectomy
for Women with BRCA Mutations

“Prophylactic salpingo-oophorectomy – removal of the ovaries and fallopian tubes–reduces the relative risk of breast cancer by approximately 50 percent and the risk of ovarian and fallopian tube cancer by approximately 80 percent in women who carry a mutation in the BRCA1 or BRCA2 gene, researchers report in the January 13 online issue of the Journal of the National Cancer Institute .  Previous studies have shown substantial reduction in the risks of breast and ovarian or fallopian tube cancers in BRCA1/2 mutation carriers following salpingo-oophorectomy. However, the magnitude of the benefit has been unclear.

To establish a more reliable estimate of the magnitude of the benefit, Timothy Rebbeck, Ph.D., of the University of Pennsylvania School of Medicine in Philadelphia, and colleagues analyzed the pooled results of 10 published studies.  They found that risk-reducing salpingo-oophorectomy was associated with a 79 percent relative reduction in ovarian and fallopian tube cancer risk and a 51 percent relative reduction in breast cancer risk in women who carried mutations in BRCA1 or BRCA2 . When the researchers analyzed the effect of the prophylactic surgery on BRCA1 and BRCA2 mutation carriers separately, they found a similar benefit for the two groups in terms of breast cancer risk, with a 53 percent risk reduction for each group. The groups were too small to be examined independently for gynecologic cancer risk. ‘In conclusion, the summary risk reduction estimates presented here confirm that BRCA1/2 mutation carriers who have been treated with [risk-reducing salpingo-oophorectomy] have a substantially reduced risk of both breast and ovarian cancer,’ the authors write. ‘However, residual cancer risk remains after surgery. Therefore, additional cancer risk reduction and screening strategies are required to maximally reduce cancer incidence and mortality in this high-risk population.’

In an accompanying editorial, Mark H. Greene, M.D., and Phuong L. Mai, M.D., of the National Cancer Institute in Bethesda, Md., commend Rebbeck and colleagues ‘ effort and review the steps the study authors took to develop the most precise estimates of risk reduction following prophylactic salpingo-oophorectomy. The results ‘should benefit women who are trying to decide whether or not to undergo [risk-reducing salpingo-oophorectomy],’ the editorialists write. ‘We urge providers of cancer genetics counseling services to adopt the summary risk estimates developed by Rebbeck et al. as those most currently reliable when counseling BRCA mutation carriers.’

Contacts:
Article: Holly Auer, Holly.auer@uphs.upenn.edu ; 215-349-5659
Editorial: NCI Press Officers, ncipressofficers@mail.nih.gov ; 301-496-6641

Citations:
Article: Rebbeck T, et al. Meta-analysis of Risk Reduction Estimates Associated with Risk Reducing Salpingo-
Oophorectomy in BRCA1 or BRCA2 Mutation Carriers. J Natl Cancer Inst 2009;101: 80 – 87 .
Editorial: Greene M and Mai PL. What Have We Learned from Risk-Reducing Salpingo-oophorectomy? J Natl
Cancer Inst 2009;101: 7 – 71 .”

Quoted Source:  MEMO TO THE MEDIA -Meta-analysis Confirms Value of Risk-Reducing Salpingo-oophorectomy for Women with BRCA Mutations, JNCI  2009 101(2):69 (online Jan. 13, 2009).

Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?

“Women at high risk of ovarian cancer due to a genetic predisposition may opt for either surveillance or prophylactic bilateral salpingo-oophorectomy (pBSO).  Main objective of our study was to determine the effectiveness of ovarian cancer screening in women with a BRCA1/2 mutation.

We evaluated 241 consecutive women with a BRCA1 or BRCA2 mutation who were enrolled in the surveillance program for hereditary ovarian cancer from September 1995 until May 2006 at the University Medical Center Groningen (UMCG), The Netherlands. The ovarian cancer screening included annual pelvic examination, transvaginal ultrasound (TVU) and serum CA125 measurement. To evaluate the effectiveness of screening in diagnosing (early stage) ovarian cancer sensitivity, specificity, positive and negative predictive values (PPV and NPV) of pelvic examination, TVU and CA125 were calculated.

Three ovarian cancers were detected during the surveillance period; 1 prevalent cancer, 1 interval cancer and 1 screen-detected cancer, all in an advanced stage (FIGO stage IIIc).  A PPV of 20% was achieved for pelvic examination, 33% for TVU and 6% for CA125 estimation alone. The NPV were 99.4% for pelvic examination, 99.5% for TVU and 99.4% for CA125. All detected ovarian cancers were in an advanced stage, and sensitivities and positive predictive values of the screening modalities are low. Restricting the analyses to incident contacts that contained all 3 screening modalities did not substantially change the outcomes. Annual gynecological screening of women with a BRCA1/2 mutation to prevent advanced stage ovarian cancer is not effective.”

Citation:  Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?, van der Velde NM, Mourits, MJ,  Arts HJ, et. al.; Int J Cancer 2008;Vol 124: Issue 4: 919-923.

Comment: “At this time,’ Dr. de Bock and colleagues advise, “prophylactic bilateral salpingo-oophorectomy from age 35-40 for BRCA1 carriers and from age 40-45 for BRCA2 carriers is the only effective strategy, as it reduces the risk of ovarian cancer by 96% and may also protect against breast cancer with a risk reduction up to 53% when performed in premenopausal women.’ They add, ‘For women who still want to opt for screening, a more effective screening strategy needs to be designed.'” [Source:  Annual Screening for Ovarian Cancer in BRCA1/2 Carriers Deemed Ineffective, News Article, Cancerpage.com, Feb. 23, 2009.]

European Researchers Find Estrogen Receptor Gene Amplification Occurs Rarely in Ovarian Cancer

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“… ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”

Abstract:

“Amplification of the gene encoding estrogen receptor-alpha occurs in about 20% of breast cancers and is an important mechanism for estrogen receptor overexpression in this tumor type. In ovarian cancer, overexpression of estrogen receptor protein has been described in more than two thirds of cases.

To study a potential role of estrogen receptor-alpha gene amplification for estrogen receptor overexpression in ovarian cancer, a tumor tissue microarray containing 428 ovarian cancers was analyzed by fluorescence in situ hybridization [FISH] for estrogen receptor-alpha gene amplification and immunohistochemistry [IHC] for estrogen receptor expression. The estrogen receptor-alpha gene status was successfully determined in 243 of 428 arrayed cancers.

Estrogen receptor gene amplification was found in 5 of 243 (2%) of tumors. Amplification levels were usually low, with 4-8 estrogen receptor-alpha gene copies. However, one case had a high-level amplification, with more than 30 estrogen receptor-alpha gene copies. All five amplified tumors were estrogen receptor positive, with 3 of 5 tumors showing highest (Allred score, 7-8) estrogen receptor levels. The data demonstrate that estrogen receptor-alpha amplification occurs only rarely in ovarian cancer.”

Article Discussion Points:

  • “The results of this study show that ESR1 amplification is rare in ovarian cancers (2.1%). More than one-third of ovarian tumors showed immunohistochemically detectable estrogen receptor protein expression, most abundant in serous and endometroid subtypes. This is in line with previous studies done on the classical paraffin blocks. The good concordance between our data and previous studies demonstrates the representation of our tumor tissue microarray data obtained on a 0.6 mm tissue spot per tumor and enhances the results of other studies used in this method.”
  • “A small subset of ESR1 [gene] amplified estrogen receptor-positive cases was indeed found in ovarian cancers. In comparison, some other genes showed higher rates of amplifications in these cancers. For example, the amplification of ERBB2 ranges (0-66%),  EGFR (3.65-12%),  CCND1 (0-19%), C-MYC up to 54.5,  and KRAS (31%).”
  • “The significant frequency of estrogen receptor positivity in ovarian cancers had prompted treatment efforts using hormonal therapy early on. In addition their relatively little toxicity was another provoking factor to continue going on to achieve more advance in this therapeutic field. Monotherapy studies using tamoxifen, aromatase inhibitors, and GnRH analogues had yielded variable results with objective response rates ranging between 0 and 56%.  Combinatorial treatment regimens combining tamoxifen and goserelin or tamoxifen and Gefitinib had obtained results with objective response rates of up to 11.5%.”
  • “The role of estrogen receptor expression for response prediction to anti-hormonal drugs has been much better studied in breast cancer, where a strong association between estrogen receptor positivity and response to anti-hormonal drugs is well established. … More than 20% of breast cancers had amplified or at least elevated ESR1 [gene] copy number. Possible explanations for the predictive effect of ESR1 [gene] amplification could be a particularly high expression of amplified as compared to non-amplified cancers. Alternatively, it could be speculated, that ESR1 [gene] amplified are more dependent on the estrogen receptor pathway than other tumors that express estrogen receptors together with many other growth receptors. If this latter hypothesis was true, visualization of ESR1 [gene] amplification would pinpoint toward an ‘Achilles tendon‘ of a tumor that could be most successfully targeted.”
  • “The frequency of ESR1 [gene] amplified ovarian cancers (2.1%) is much lower than that in breast cancer. Interestingly, this fraction somehow parallels the percentage of ovarian cancers reported to show strong responses to hormonal therapies.”
  • “For example, in retrospective analysis was conducted of patients who received tamoxifen at a dose 20 mg twice daily for the treatment of advanced epithelial ovarian cancer,
    • Karagol et al found that out of 29 eligible patients included in the study, there were 1 (3%) complete response, 2 (7%) partial response, 6 (21%) stable disease, and 20 (69%) progressive disease.
    • Papadimitriou et al have studied response rate in 27 patients treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n=21) and those with only increasing CA-125 serum levels (n=6) were eligible. Among the 21 patients with measurable or evaluable disease, 1 complete response (5%) and 2 partial responses were observed (10%) for an objective response rate of 15%.
    • Other studies, in which the combined regiment had been implicated, patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. In total, 26 patients entered this study, of which 17 had platinum–resistant disease, using the definition of endocrine response that included patients with stable disease of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (3.8%), two partial responses (7.7%), and 10 patients with stable disease (38.5%).”
  • “In summary, ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”

Quoted Source:  Estrogen receptor gene amplification occurs rarely in ovarian cancer, Issa RM et. al., Mod Pathol. 2009;22(2):191-196, reprinted in From Modern Pathology, Medscape Today, February 18, 2009. [Free Medscape subscription required to view full text article.]

Comment:  This study indicates that the occurrence of estrogen positivity (ER+)/ESR1 gene amplification with respect to ovarian cancer is significantly lower than such occurrence in the breast cancer area.  Nevertheless, it is prudent to request your doctor to have your ovarian cancer tumor tissue tested by a pathologist for estrogen positivity or ESR1 gene amplification (through IHC or FISH testing, respectively).  If your ovarian cancer tissue tests ER+, you may respond to anti-estrogen drugs.  Although this type of pathology testing is commonplace in the breast cancer area, it is not in the ovarian cancer area due to the much lower percentage of ER+ ovarian cancer tumors.  As the study above notes, further research of anti-estrogen therapy use within the area of ovarian cancer is needed, especially given the potential high effectiveness and low toxicity of such therapies.