NOCC to Host Annual “Walk To Break The Silence On Ovarian Cancer” in the Greater Washington, D.C. Area

The National Ovarian Cancer Coalition (NOCC) Central Maryland Chapter announces its annual “Walk to Break the Silence on Ovarian Cancer” to be held on Sunday, September 18, 2011 at Quiet Waters Park, located in Annapolis, Maryland.

The National Ovarian Cancer Coalition (NOCC) Central Maryland Chapter announces its 2nd Annual “Walk to Break the Silence on Ovarian Cancer” to be held on Sunday, September 18, 2011 at Quiet Waters Park, located in Annapolis, Maryland. This event will be held “rain or shine.”

Registration will open at 7:30 a.m. at the Blue Heron Center located within the park. The 5K Run will begin at 9:30 a.m. The 3K Walk is scheduled to kick off at 9:35 a.m. All participants will receive a T-shirt. The race will be timed and various age awards will be presented.

To view a complete schedule of events, click here. To view the event brochure, click here. To view a video from last year’s event, click here.

September is Ovarian Cancer and Gynecologic Cancer Awareness Month. “We walk and run to raise funds but just as importantly we walk and run to raise awareness”, said Nancy Long, Co-president of the Central Maryland Chapter. “There is no early detection test for ovarian cancer. That is why education and awareness are currently our best defense against this disease.”

Survivors are celebrated at the Run/Walk, so please visit the survivors’ tent for gift bags. In addition, you can commemorate the occasion with a special survivors’ photo. Bring a photo of yourself, a survivor you know, or a lost loved one for the survivor/memory banner.

Quiet Waters Park - South River Overlook, Annapolis, Maryland

Quiet Waters Park - Bridge & Fountain, Annapolis, Maryland

More than 20,000 women are diagnosed with ovarian cancer each year, and approximately 15,000 women die from the disease annually. Unfortunately, most cases are diagnosed in late stages when the prognosis is poor.  However, if diagnosed and treated early, when the cancer is confined to the ovary, the five-year survival rate is over 90 percent.

There is currently no early detection test for ovarian cancer, and Pap tests do not detect the disease.  That is why it is imperative that the early signs and symptoms of the disease are recognized, not only by women, but also by their families and the medical community.

Symptoms of ovarian cancer may include bloating, pelvic or abdominal pain, trouble eating or feeling full quickly, and feeling the need to urinate urgently or often. Other symptoms of ovarian cancer may include fatigue, upset stomach or heartburn, back pain, pain during intercourse, constipation, and menstrual changes. Women who experience these symptoms for longer than two weeks, especially if these symptoms are new to them, are encouraged to visit their health care provider.

Many women attending this NOCC event are anxious and willing to tell their stories of, or related to, diagnosis, misdiagnosis, the hardships of treatment, the potential for inherited genetic mutations, and the fears and joys of being a survivor.

To register for the NOCC Central Maryland Chapter’s “Walk to Break the Silence on Ovarian Cancer,” please call 443-433-2597 or visit www.nocc.kintera.org/mdcentral.

Nancy Long and Paula Kozik are the Co-presidents of the NOCC Central Maryland Chapter. Libby’s H*O*P*E*™ will be featuring the inspirational stories of these two amazing women as part of its Vox Populi (“voice of the people”) feature during National Ovarian Cancer Awareness Month.

About the National Ovarian Cancer Coalition

The mission of the National Ovarian Cancer Coalition, a 501 (c)(3) charitable organization, is to raise awareness and promote education about ovarian cancer. The Coalition carries out its mission through a toll-free Help Line, local NOCC Chapters, a comprehensive website, peer support, written publications, and awareness/educational programs. The Coalition is committed to improving the survival rate and quality of life for women with ovarian cancer. If you would like more information about the “Break the Silence” campaign, or wish to contact one of the local NOCC Chapters, visit www.ovarian.org or call 1-888-OVARIAN (1-888-682-7426).


30-Day Mortality Associated With Primary Cytoreductive Surgery In Elderly Advanced Ovarian Cancer Patients Much Higher Than Previously Reported

Researchers affiliated with the University of Washington have determined that the 30-day mortality rate associated with primary cytoreductive surgery in elderly patients with advanced ovarian cancer is much higher than previously reported.

Researchers affiliated with the University of Washington have determined that the 30-day mortality rate associated with primary cytoreductive surgery in elderly patients with advanced ovarian cancer is much higher than previously reported. There research is based upon the analysis of statistics obtained from the National Cancer Institue (NCI) Surveillance, Epidemiology, and End Results (SEER) database (collectively, the NCI SEER database).

Melissa M. Thrall, M.D., Lead Study Author; Fellow, Department of Obstetrics & Gynecology, University of Washington School of Medicine

The lead author of the study is Melissa M. Thrall, M.D., a Fellow in the Department of Obstetrics & Gynecology, University of Washington School of Medicine.

The researchers used the NCI SEER database to identify a cohort of 5,475 women aged 65 and older, who had primary debulking surgery for stage III or IV epithelial ovarian cancer which was diagnosed from 1995 through 2005. Women were stratified by acuity (i.e., average severity of illness) of hospital admission. Multivariable analysis was performed to identify patient-related and treatment-related variables associated with 30-day mortality.

The overall 30-day mortality rate was 8.2% for the 5,475 women who had surgery for advanced ovarian cancer. Women admitted on an elective basis experienced a 30-day mortality rate of 5.6% (251/4,517), while those patients admitted on an emergency basis experienced a 30-day mortality of 20.1% (168/835).  The researcher determined that 84.4% of patients were admitted on an elective basis, 15.6% of patients were admitted on an emergency basis, and 2.2% of patients had an unknown admission status.

Emergency admission was associated with older age (median of 76.9 vs. 75.1 for elective admission), higher comorbidity scores, and stage IV disease (41.9% vs. 32.9%). Women admitted on an emergency basis had surgery performed more frequently in low-volume hospitals, by low-volume surgeons, and by surgeons other than gynecologic oncologists (p value <0.001). Emergency admission was also associated with significantly less use of neoadjuvant chemotherapy (2.99% vs. 13.39%, p <0.001).

Advancing age, increasing disease stage, and increasing comorbidity score were all associated with an increase in 30-day mortality (p <.05) among elective admissions. The mortality risk was not influenced significantly by race, income, marital status and other demographic and clinical factors.

A group of women at high risk who were admitted on an elective basis included those aged 75 or older with stage IV disease, and women aged 75 or older with stage III disease and a comorbidity score of 1 or more. The high risk group experienced a 30-day mortality rate of 12.7% (95% confidence interval: 10.7%–14.9%), and accounted for 25.7% of the study population and approximately 50% of the deaths.

Low-risk patients were defined by age 65 to 74, stage III or IV disease, and a morbidity score of less than or equal to one. The low-risk patients accounted for 48.7% of the study population and experienced a 30-day mortality rate of 3.64%. The remaining intermediate patients experienced a mortality rate of 6.05%.

Based upon their analyses, the researcher concluded that age, cancer stage, and comorbidity scores may be helpful to stratify patients admitted on an elective basis by predicted postoperative mortality risk. If validated in a prospective cohort study, these factors may help identify women who may benefit from alternative treatment strategies, such as neoadjuvant chemotherapy.

The study was supported by the Marsha Rivkin Center for Ovarian Cancer Research and by the National Cancer Institute.

Sources:

Related WORD of HOPE Ovarian Cancer Podcast

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

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

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

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

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

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

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

Background

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

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

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

Olaparib Phase 2 Study Design

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

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

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

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

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

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

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

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

Olaparib Phase 2 Study Results

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

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

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

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

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

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

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

Expert Commentary

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

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

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

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

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

Study Relationship Disclosures

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

Libby’s H*O*P*E* Commentary

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

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

References

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

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

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

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

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

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

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

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

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

Additional Sources:

PARP Inhibitor Clinical Trial Information

Related Libby’s H*O*P*E* Posts

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

Related WORD of HOPE Ovarian Cancer Podcast

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

U.K. Researchers Launch Clinical Trial of Mercaptopurine (6-MP) In Women with Hereditary Breast and Ovarian Cancer

A Cancer Research UK-funded clinical trial of a new drug for patients with advanced breast or ovarian cancer due to inherited BRCA gene mutations has been launched at the Experimental Cancer Medicine Centre at the University of Oxford.

A Cancer Research UK-funded trial of a new drug for patients with advanced breast or ovarian cancer due to inherited BRCA gene faults has been launched at the Experimental Cancer Medicine Centre at the University of Oxford (OxFord ECMC).

Mutations in the BRCA 1 (BReast CAncer-1) and BRCA 2 genes are thought to account for around 2-5 percent of all breast cancer cases. Women carrying the BRCA1 and BRCA2 mutation have a 45-65 percent chance of developing breast cancer, and a 20-45 percent chance of developing ovarian cancer, by the age of 70. Genetic testing for faulty BRCA genes is available for women with a very strong family history.

DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. A special enzyme (shown above in color), encircles the double helix to repair a broken strand of DNA. Without molecules that can mend DNA single strand and double strand breaks, cells can malfunction, die, or become cancerous. (Photo: Courtesy of Tom Ellenberger, Washington University School of Medicine in St. Louis)

Cells lacking a properly functioning BRCA1 or BRCA2 gene  are less able to repair DNA damage. These defective cells are more sensitive to (i) platinum-based chemotherapy drugs such as cisplatin – which work by causing double-stranded DNA breaks, and (ii) PARP inhibitors, a newer class of drugs which prevent cells lacking a properly functioning BRCA gene from being able to repair damaged DNA. PARP inhibitors have shown promise in clinical trials but, as with most drugs, resistance can develop meaning some women can stop responding.

This trial, led by a team based at the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, is looking at a drug called “6MP” (a/k/a mercaptopurine; brand name: Purinethol), which is already used to treat leukemia and is often given in combination with another chemotherapy drug called “methotrexate.”

Earlier studies involving cells grown in the laboratory suggest that a class of drugs called “thiopurines,” which includes 6MP, are effective at killing cancer cells lacking BRCA – a gene which significantly increases the risk of breast and ovarian cancer – even after they have developed resistance to treatments like PARP inhibitors and cisplatin.

This trial is one of a growing number looking at matching patients to the most appropriate treatment based on their genetic makeup and that of their cancer – an approach known as “personalized medicine.”

If successful, the results will pave the way for a larger Phase 3 clinical trial, which could lead to an additional treatment option for the 15 out of every 100 women with breast and ovarian cancers, which are caused by faults in the BRCA1 or BRCA2 gene.

Trial leader Dr. Shibani Nicum, a gynecology specialist based at the Oxford ECMC, and a researcher in Oxford University’s Department of Oncology, said: “PARP inhibitors are a powerful new class of drugs developed specifically to target tumors caused by BRCA 1 and BRCA2 faults, but drug resistance remains a problem. We hope that the very encouraging results we have seen in early laboratory studies involving 6MP will lead to increased treatment options for these patients in the future.”

U.K. trial participant Suzanne Cole, 54, from Newbury, has a strong history of ovarian cancer in her family, with her sister, mother and grandmother all having been diagnosed with suspected cases of the disease at a relatively young age. But, it was not until many years later, after she herself was diagnosed with cancer, that doctors were able to trace the cause of this back to a BRCA1 mutation in her family.

Suzanne Cole said: “I was diagnosed in 2009 and initially had surgery then chemotherapy. I was then told about the trial and I went away and studied the information. The doctors were able to answer all my questions and then I agreed to sign up. I’m happy to be a part of this work as it could help others by moving treatments forward.”

Professor Mark Middleton, director of the Oxford ECMC, said: “It’s exciting to see drugs being developed for specific groups of patients who share the same underlying genetic faults in their cancer. Targeted treatments are at the cutting edge of cancer care and we’re proud to be involved in bringing such drugs a step closer to the clinic.”

Dr. Sally Burtles, Cancer Research UK’s director of the ECMC Network, said: “This study helps demonstrate the value of being able to pool subsets of patients who share specific rare faults in their tumor from a UK-wide network of Experimental Cancer Medicine Centres. This will be crucial as we move towards a new era of personalized medicine with treatments targeted according to the individual biological profile of a patient’s cancer.”

For more information on the trial, please visit www.cancerhelp.org.uk, or call the Cancer Research UK cancer information nurses on 0808-800-4040.

Sources:

  • Researchers trial new drug for women with hereditary breast and ovarian cancer, Press Release, Cancer Research UK, August 17, 2011.
  • Issaeva N, et al. 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. Cancer Res. 2010 Aug 1;70(15):6268-76. Epub 2010 Jul 14. PubMed PMID: 20631063; PubMed PMCID: PMC2913123.

Mesothelin Antibodies Occur In Some Women With An Epidemiologic Risk For Ovarian Cancer.

Researchers at Rush University Medical Center discover mesothelin antibodies in the bloodstream of infertile women, who possess a higher risk of ovarian cancer.

Using a new approach to developing biomarkers for the very early detection of ovarian cancer, researchers at Rush University Medical Center have identified a molecule in the bloodstream of infertile women, who possess a higher risk of ovarian cancer. This finding may be relevant in the future for screening women at high risk for the disease — or even those with early-stage ovarian cancer.

The molecule — an antibody that the human body manufactures — is an autoimmune response to mesothelin. Mesothelin a well-characterized ovarian cancer antigen and protein which is found in abundance on the surface of ovarian cancer cells, but present only in limited amounts in normal human tissue.

The study is published in the August 16 online version issue of Cancer Epidemiology, Biomarkers & Prevention, published by the American Association for Cancer Research (AACR).

Judith Luborsky, Ph.D., Lead Study Author; Professor, Pharmacology, Obstetrics & Gynecology and Preventive Medicine, Rush Medical College

“The finding is extremely important because at present medical tests are unable to detect ovarian cancer in its early stages, which is why death rates from this disease are so high,” said Judith Luborsky, Ph.D., professor of pharmacology, obstetrics and gynecology and preventive medicine at Rush and the lead author of the study.

“Our approach to discovering cancer biomarkers was unique in this study. Instead of investigating molecules specific to ovarian cancer alone, we asked what molecules women with a risk of ovarian cancer and those with ovarian cancer had in common,” Luborsky said.

The study may have enabled the researchers to explain, in part, the link between infertility and ovarian cancer that has been established in numerous epidemiological surveys.

“More important, with the discovery of the mesothelin antibody, we now have what appears to be a biomarker that can potentially be used in screening tests to help us conquer ovarian cancer,” Luborsky said.

According to the American Cancer Society’s most recent estimates, it is anticipated that 21,900 new cases of ovarian cancer will be diagnosed in the U.S. in 2011, and approximately 15,460 deaths will occur in connection with the disease. Ovarian cancer is the ninth most common cancer in women (not counting skin cancer) and ranks as the fifth highest cause of cancer death in women. It is the most lethal gynecologic cancer. The poor prognosis for women with ovarian cancer is due to the lack of both clinical symptoms when the cancer first develops and the absence of laboratory tests specific to the disease.

In the study at Rush, researchers tested for mesothelin antibodies in the bloodstream of 109 women who were infertile; 28 women diagnosed with ovarian cancer, 24 women with benign ovarian tumors or cysts, and 152 healthy women. Causes of infertility included endometriosis, ovulatory dysfunction, and premature ovarian failure. Some causes of infertility were unexplained.

Significant levels of mesothelin antibodies were found in women with premature ovarian failure, ovulatory dysfunction and unexplained infertility, as well as in women with ovarian cancer. The same results were not found in women with endometriosis, good health, or benign disease. Endometriosis is generally associated with the clear cell and endometrioid subtypes of epithelial ovarian cancer, as compared to other forms of the disease associated with infertility, which may explain why mesothelin antibodies were not found in the endometriosis cases.

It is important to emphasize that the explanation as to why the presence of mesothelin antibodies in the bloodstream should be linked with ovarian cancer is not clear.

“It has been hypothesized that an autoimmune response precedes or somehow contributes to the development and progression of malignant tumors,” Luborsky said. “We think that antibodies may arise in response to very early abnormal changes in ovarian tissue that may or may not progress to malignancy, depending on additional triggering events. Or, alternatively, antibodies may bind to normal cells in the ovary, causing dysfunction and leading to infertility — and, in a subpopulation of women, to the development of ovarian cancer.”

Other researchers involved in the study were Yi Yu, MS, and Seby Edassery, MS, both from Rush, as well as a group led by Ingegerd Hellstrom, M.D., Ph.D., and Karl Eric Hellstrom, M.D., Ph.D., which included Yuan Yee Yip, BS, Jade Jaffar, BS, and Pu Liu, Ph.D. from Harborview Medical Center at the University of Washington.

The study was supported by funding from the National Institutes of Health and Fujirebio Diagnostics, Inc.

About Rush

Rush is a not-for-profit academic medical center comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health.

Rush’s mission is to provide the best possible care for its patients. Educating tomorrow’s health care professional, researching new and more advanced treatment options, transforming its facilities and investing in new technologies—all are undertaken with the drive to improve patient care now, and for the future.

Sources:

  • Luborsky JL, et al. Autoantibodies to Mesothelin in Infertility. Cancer Epidemiol Biomarkers Prev. 2011 Aug 16. PubMed PMID: 21846819 [Epub ahead of print]
  • Researchers at Rush University Medical Center Discover Antibody That May Help Detect Ovarian Cancer in its Earliest Stages, News Release, Rush University Medical Center, August 16, 2010.

Penn’s Genetically Modified T Cells Create Antitumor Effect In Mice With Folate Positive Ovarian Cancer; Clinical Trial Pending

In a recent issue of Cancer Research, researchers from the University of Pennsylvania showed for the first time that engineered human T cells can eradicate deadly human ovarian cancer in immune-deficient mice. A clinical trial involving the modified T cells is expected to be announced within the next few months.

In a recent issue of Cancer Research, Daniel J. Powell, Jr., Ph.D., a research assistant professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, showed for the first time that engineered human T cells can eradicate deadly human ovarian cancer in immune-deficient mice. Ovarian cancer is the most lethal reproductive cancer for women, with one-fifth of women diagnosed with advanced disease surviving five years. Nearly all ovarian cancers (90%) are characterized by their expression of a distinct cell-surface protein called alpha-folate receptor, which can be targeted by engineered T cells.

Daniel J. Powell, Jr., Ph.D., Research Assistant Professor of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania.

The alpha-folate receptor is expressed on the surface of ovarian cancer cells and has a high affinity for folic acid, a vitamin which helps “feed” the cancer cells, and represents an “Achilles’ Heel” for cancer researchers to target.

Until now, human T cells engineered to express an antibody fragment specific for the alpha-folate receptor protein have shown anti-tumor activity against epithelial cancers in the lab, but not in the clinic due to their inability to persist and attack tumors in the human body. The modified T cells used in this study express an engineered fusion protein – called a “chimeric antigen receptor” (CAR) — that combines the specificity of an antibody with the T cell signaling portions from two different proteins that stimulate the immune system to recognize ovarian cancer cells. These added signaling protein pieces give the engineered T cells the extra survival signals they need to do their job.

In a past clinical study, first generation engineered T cells did not shrink tumors in women with ovarian cancer because the T cells did not persist in the patients. The new second generation technology developed in the current study overcomes the limitations of the first generation approach. Specifically, the second generation T cells shrank tumors in mice, but the T cells engineered using first generation technology did not. The second generation T cells also caused tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer.

“We anticipate the opening of a genetically modified T cell clinical trial in the next few months for women with recurrent ovarian cancer,” said Powell. “Targeting the alpha-folate receptor is an opportunity for widespread clinical application.”

Two Birds, One Stone T Cells

The double-barreled T cells are engineered to multiply, survive, recognize, and kill ovarian tumors. The modified T cells were expanded for two weeks in the lab, and then tested for reactivity by exposing them to human ovarian cancer cells to see if they destroyed the cancer cells. Researchers also tested for effectiveness by measuring cytokine production by the T cells, a sign of inflammation produced by the engineered T cells when killing cancer cells.

The new second generation engineered T cells were successful in many ways. First, they were resistant to cancer-induced cell death; that is, fewer new T cells died when exposed to cancer cells, compared to the older technology. Second, the new T cells also multiplied better and survived; therefore their numbers increased over time in in vitro experiments and in the mouse model.

A clinical trial using these T cells is pending with George Coukos, M.D., Director of the Ovarian Cancer Research Center at Penn and the principal trial investigator. Penn is the only study site identified to date. Investigators aim to recruit up to 21 patients with advanced recurrent ovarian cancer whose tumors express the alpha-folate receptor.

“This technology represents a promising advancement for the treatment of women with ovarian cancer,” said Powell. “But we will continue to work around the clock to improve this approach using other costimulatory portions and antibody-like proteins to make this the most powerful and safe approach for the treatment of the greatest number of women with this horrible disease.”

About Penn Medicine

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit the community.

About Perelman School of Medicine, University of Pennsylvania

Penn’s Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.

About University of Pennsylvania Health System

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Sources:

Song DG, et al.  In Vivo Persistence,Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB). Cancer Res. 2011 Jul 1;71(13):4617-27. Epub 2011 May 5. PubMed PMID: 21546571.

Penn Study Finds More Effective Approach Against “Achilles’ Heel” of Ovarian Cancer, News Brief, Penn Medicine, Perelman School of Medicine, University of Pennsylvania Health System, August 5, 2011.

Advanced MRI Scan May Predict Chemotherapy Benefit In Late Stage Ovarian Cancer Patients After Just One Cycle

Scientists at The Institute of Cancer Research and The Royal Marsden Hospital have developed an advanced type of magnetic resonance imaging (MRI) scan that can detect whether late-stage ovarian cancers are responding to chemotherapy treatment after just one cycle.

Scientists at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital have developed an advanced type of magnetic resonance imaging (MRI) scan that can detect whether late-stage ovarian cancers are responding to chemotherapy treatment after just one cycle, which should help doctors decide whether to continue or alter treatment.

Most ovarian cancers are detected after the tumor has already spread and although patients initially respond well to radical surgery and platinum and taxane-based chemotherapy, most relapse after an average of 18 months. Subsequent treatments generally become less effective as patients build up resistance, so scientists are looking for ways to identify non-responsive patients early in the course of treatment.

Diffusion MRI Diagnostics: Diffusion tensor imaging color map (Photo: Wikipedia)

Nandita deSouza, M.D., Ph.D., Lead Academic Radiologist, The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust.

In a paper published online this week in the journal Radiology, Professor Nandita deSouza and colleagues at the ICR and The Royal Marsden find that a technique called diffusion -weighted MRI can be used to show a change after just one 21- or 28-day treatment cycle.

“This test could allow us to predict after just one month whether a patient will benefit from the full six month course of chemotherapy,” Senior author Professor de Souza from the ICR and The Royal Marsden says. “This would help make decisions on treatment and mean that patients could avoid the unpleasant side-effects of ineffective treatments.”

From November 2008 to September 2010, forty-two women with ovarian cancer had diffusion-weighted MRI scans before and after their first and third cycles of chemotherapy. Each scan was then used to calculate a figure called an Apparent Diffusion Coefficient (ADC), a measurement of water movement within tissue, which is lower in tumor compared to normal tissue. The team found ADCs rose after just one treatment cycle for many women who were later assessed to have benefited from treatment, and did not change for patients who did not respond.

The MRI technique can also help determine the extent of the cancer, as it is able to detect tiny cancer seedlings that have spread from the ovaries into the peritoneum. Importantly, Professor de Souza says that the scans also have the potential to identify individual tumor deposits that are not responding to treatment for which other treatment options including surgical removal can be considered.

First author Dr. Stavroula Kyriazi from the ICR and The Royal Marsden says: “We will be starting a larger trial in four UK hospitals later this year that will assess this technique alongside the current blood tests and scans. We hope to find that it consistently detects the effects of treatment earlier, and that it provides more information about individual tumor sites than standard tests. This test can be done on existing MRI equipment, so if it is found to be effective it could potentially be used to help doctors make treatment decisions for their patients right across the country.”

The research was carried out at the Cancer Research UK and EPSRC (Engineering and Physical Sciences Research Council) Cancer Imaging Centre, Research Data Management and Statistics Unit and Department of Gynecological Oncology at the ICR and The Royal Marsden. The study was funded by Marie Curie Actions, the ICR, Cancer Research UK and EPSRC.

Dr. Julie Sharp, senior science information manager at Cancer Research UK, said: “We hope that this new approach will allow doctors to monitor tumors much more closely in the future and make quicker decisions if treatments aren’t working. Advanced ovarian cancer is difficult to treat and we’re pleased to be funding the next stage of this research that will develop this test further.”

The Institute of Cancer Research (ICR)

  • The ICR is Europe’s leading cancer research center.
  • The ICR has been ranked the UK’s top academic research centre, based on the results of the Higher Education Funding Council’s Research Assessment Exercise.
  • The ICR works closely with partner The Royal Marsden NHS Foundation Trust to ensure patients immediately benefit from new research. Together the two organizations form the largest comprehensive cancer center in Europe.
  • The ICR has charitable status and relies on voluntary income.
  • As a college of the University of London, the ICR also provides postgraduate higher education of international distinction.
  • Over its 100-year history, the ICR’s achievements include identifying the potential link between smoking and lung cancer which was subsequently confirmed, discovering that DNA damage is the basic cause of cancer and isolating more cancer-related genes than any other organization in the world.
  • The ICR is home to the world’s leading academic cancer drug development team. Several important anti-cancer drugs used worldwide were synthezised at the ICR and it has discovered an average of two preclinical candidates each year over the past five years.

For more information visit www.icr.ac.uk.

About the Royal Marsden Hospital

The Royal Marsden opened its doors in 1851 as the world’s first hospital dedicated to cancer diagnosis, treatment, research and education.

Today, together with its academic partner, The Institute of Cancer Research (ICR), it is the largest and most comprehensive cancer center in Europe treating over 44,000 patients every year. It is a center of excellence with an international reputation for groundbreaking research and pioneering the very latest in cancer treatments and technologies. The Royal Marsden also provides community services in the London boroughs of Sutton and Merton and in June 2010, along with the ICR, the Royal Marsden NHS Foundation Trust launched a new academic partnership with Mount Vernon Cancer Centre in Middlesex.

Since 2004, the hospital’s charity, The Royal Marsden Cancer Charity, has helped raise over £50 million to build theatres, diagnostic centres, and drug development units. Prince William became President of The Royal Marsden in 2007, following a long royal connection with the hospital.

For more information, visit www.royalmarsden.nhs.uk.

About Marie Curie Actions

The EU’s Marie Curie Actions provide grants at all career stages from post-graduate level to encourage international mobility among Europe’s best researchers. Every year, through the Marie Curie Actions, the EU gives 8,000 researchers the opportunity to work abroad and stimulates partnerships between research and business. The EU will allocate more than €4.5 billion under the scheme between 2007 and 2013. A total of 50,000 researchers have been supported by the Marie Curie Actions since 1996.

For more information, visit http://ec.europa.eu/research/mariecurieactions/.

About Cancer Research UK

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

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

Sources:

  • Kyriazi S, et. al. Metastatic Ovarian and Primary Peritoneal Cancer: Assessing Chemotherapy Response with Diffusion-weighted MR Imaging–Value of Histogram Analysis of Apparent Diffusion Coefficients. Radiology. 2011 Aug 9. [Epub ahead of print] PubMed PMID: 21828186.
  • Scan Predicts Chemotherapy Benefit After Just One Cycle, Press Release, The Institute of Cancer Research, August 12, 2011.