Molecular Profiling of Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer death in the United States, with an estimated 21,290 new cases and 14,180 deaths estimated for 2015 (ACS 2015). The vast majority of women are diagnosed with advanced stage EOC. Current practice consists of aggressive surgical removal of tumors, followed by platinum–taxane based chemotherapy (Muggia 2009). Despite initial aggressive treatment, most tumors recur, and the overall 5-year survival rate is 44% (Siegel, Naishadham, and Jemal 2012).

Emerging knowledge about underlying molecular alterations in ovarian cancer could allow for more personalized diagnostic, predictive, prognostic, and therapeutic strategies. Approximately 10–20% of high grade ovarian cancers are associated with germline mutations in BRCA1/2 (Pal et al. 2005). Somatic alterations in BRCA1/2 and other genes associated with DNA repair are seen in approximately 50% of high grade ovarian cancers (TCGA 2011) and tumors with a ‘BRCAness’ molecular profile are relatively sensitive to treatment with DNA damaging agents cisplatin and PARP inhibitors (Konstantinopoulos et al. 2010).

More recently, EOC tumors have been broadly classified into two distinct groups with unique histological, clinical and molecular profiles (Table 1). Type I tumors have low grade serous, clear cell, endometrioid, and mucinous histological features. Typically, these tumors are slow growing and confined to the ovary, and are less sensitive to standard chemotherapy. BRAF and KRAS somatic mutations are relatively common in these tumors, which may have important therapeutic implications.

Type II tumors are high grade serous cancers of the ovary, peritoneum, and fallopian tube. Other high grade endometrioid and poorly differentiated ovarian cancers as well as carcinosarcomas are included in the type II group. These tumors are clinically aggressive and are often widely metastatic at the time of presentation. High grade serous EOC tumors display high levels of genomic instability with few common mutations, other than TP53, which is altered in over 90% of the cases (Kurman and Shih 2011Landen, Birrer, and Sood 2008TCGA 2011). PIK3CA and RAS signaling pathways are altered in 45% of the cases, but somatic mutations are rare and gene amplifications are far more common (TCGA 2011).

Currently, the most common ‘actionable’ alterations with potential for small molecule targeted therapy in EOC tumors are in the PIK3CA/PTEN and KRAS/BRAF signaling pathways.

Read the entire article on MyCancerGenome.org here.

Molecular Profiling As a Necessity for Uncommon Ovarian Cancers

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By: Laura Shawver, PhD

In 1998, Herceptin was approved for women with breast cancer whose tumors have extra copies of the Her2/ERBB2 gene and since that time, there have been more than 25 drugs approved to treat cancers with specific genetic alterations. These so called targeted drugs have changed the lives of many people with cancer. For example, lung cancer is now treated based on the tissue type (called histology) that it resembles and also the underlying molecular alteration that is predicted to be driving cancer growth. Ovarian cancers can be more than five different histology types (for example, high grade serous, low grade serous, clear cell, endometrioid, mucinous) and the molecular changes that are found in them mirror those found in other cancers. In spite of this complexity, there is typically one front-line therapy (platinum + taxane doublet) that is administered to all patients with advanced stage ovarian cancer, regardless of her cancer’s histology. While more than 70% of patients diagnosed with high grade serous ovarian cancer (the most common type) have good responses to platinum-based treatment, it has been established that this standard treatment is not as effective against other histologies such as clear cell and mucinous and carcinosarcoma of the ovary. For example, only 11% of clear cell ovarian tumors respond well to platinum-based treatment (http://theoncologist.alphamedpress.org/content/11/10/1089.full).

Therefore, it is of utmost importance that alternative treatment paradigms be developed. Typically, women with recurrent ovarian cancer receive additional chemotherapy (such as Doxil, taxane, gemcitabine, topotecan) regardless of the histology of their cancer. Because they are inherently resistant to chemotherapy, this leads to a shorter survival for patients with these uncommon histologies. But, molecular profiling may provide a path to better outcomes. A case study was just published by Castro et al (http://www.gynoncrp.com/content/2/1/4) in which Clearity’s scientific director, Deb Zajchowski, PhD, participated as a co-author. Profiling identified KRAS and PIK3CA mutations in the tumor of a woman with a clear cell ovarian carcinoma.   Based on this information, her doctors treated her with a MEK inhibitor (trametinib) and metformin and she experienced dramatic disease regression. She had already had her cancer progress following platinum, taxane, pemetrexed and bevacizumab treatments. This case highlights the utility of combining individual molecular diagnosis with rational therapeutic intervention especially for uncommon ovarian cancers. The genomic analysis was arranged by Clearity Foundation and included sequencing analysis at Foundation Medicine, Inc. as part of the comprehensive molecular analysis that was carried out.

When Clearity Foundation was launched in 2008, we removed the cost barrier to profiling by paying for the tests when insurance did not cover the costs or if a woman needed help with her co-pay. Today, one major cost barrier is for drug access when insurance does not cover it. In these uncommon histology cases, where it is unlikely that standard chemotherapy will be effective, access to a molecular targeted treatment may be more appropriate and arguably could be employed in treatment early in the disease course. Unfortunately, many insurance companies will not cover the cost until women have failed the list of chemotherapy drugs in the NCCN guidelines. This means that women are exposed to considerable toxicity with little, if any, benefit.

If you have a rare ovarian cancer histology, please contact us so that we can assist in your tumor profiling. In addition, we have launched a pilot program to subsidize the cost of molecular targeted agents that match your tumor profile if the oncologist prescribes it but insurance is not willing to reimburse. Clearity takes this as a call to action just as we did 7 years ago when profiling was unavailable to most women battling ovarian cancer!

Ovarian Tissue Transplants Help Women Have Children After Cancer, Study Shows

A new procedure shows promise

An experimental procedure in which women who survive cancer receive transplants of their own ovarian tissue has helped some women have babies, a new study shows. The study is the largest to be done on this procedure so far.

The Denmark study, published in the journal Human Reproduction, focused on women who had one ovary removed and frozen when they found out that they had cancer. After receiving treatment and recovering from cancer, doctors transplanted the preserved ovarian tissue onto the women’s remaining ovary, the Associated Press reports.

The study looked at 41 women with cancer who had the procedure between 2003 and 2014. The results showed that among the 32 women who wanted to get pregnant, 10 did conceive and gave birth. The findings suggest the procedure could help 1 in 3 women successfully have a baby.

According to the AP, over 36 babies have been born after ovarian transplants including 14 in Denmark.

“Freezing ovarian tissue is now gaining ground as a valid method for fertility restoration and for providing ovarian activity with cycling levels of sex hormones for several years,” the study authors conclude. “The level of safety appears to be high, with no relapse due to transplantation of ovarian tissue recorded to date.”

Read the full article on Time.com.

Advance In Photodynamic Therapy Offers New Approach To Ovarian Cancer

Researchers at Oregon State University have made a significant advance in the use of photodynamic therapy to combat ovarian cancer in laboratory animals, using a combination of techniques that achieved complete cancer cell elimination with no regrowth of tumors.

The findings were just published in the journal Nanomedicine: Nanotechnology, Biology and Medicine, and after further research may offer a novel mechanism to address this aggressive and often fatal cancer that kills 14,000 women in the United States each year.

Ovarian cancer has a high mortality rate because it often has metastasized into the abdominal cavity before it’s discovered. Toxicity and cancer-cell resistance can also compromise the effectiveness of radiation and chemotherapy that’s often used as a follow-up to surgery.

The new approach being developed by researchers from the OSU College of Pharmacy and the University of Nebraska takes existing approaches to photodynamic therapy and makes them significantly more effective by adding compounds that make cancer cells vulnerable to reactive oxygen species, and also reducing the natural defenses of those cells.

“Surgery and chemotherapy are the traditional approaches to ovarian cancer, but it’s very difficult to identify all of the places where a tumor has spread, and in some cases almost impossible to remove all of them,” said Oleh Taratula, an assistant professor in the Oregon State University/Oregon Health & Science University College of Pharmacy.

“Photodynamic therapy is a different approach that can be used as an adjunct to surgery right during the operation, and appears to be very safe and nontoxic,” Taratula said. “In the past its effectiveness has been limited, but our new findings may make this technology far more effective than it’s ever been before.”

Using the new approach, a patient is first given a photosensitizing compound called phthalocyanine, which produces reactive oxygen species that can kill cells when they are exposed to near-infrared light. In addition, a gene therapy is administered that lowers the cellular defense against reactive oxygen species.

Both the phthalocyanine and genetic therapy, composed of “small, interfering RNA,” are attached to what researchers call “dendrimer-based nanoplatforms,” a nanotechnology approach developed by OSU researchers. It delivers the compounds selectively into cancer cells, but not healthy cells.

Compared to existing photodynamic therapies, this approach allows the near-infrared light to penetrate much deeper into abdominal tissues, and dramatically increases the effectiveness of the procedure in killing cancer cells.

Using photodynamic therapy alone, some tumors in laboratory animals began to regrow after two weeks. But with the addition of the combinatorial genetic therapy to weaken the cancer cell defenses, there was no evidence of cancer recurrence. During the procedures, mice receiving the gene therapy also continued to grow and gain weight, indicating a lack of side effects.

“Cancer cells are very smart,” Taratula said. “They overexpress certain proteins, including one called DJ1, that help them survive attack by reactive oxygen species that otherwise might kill them. We believe a key to the success of this therapy is that it takes away those defensive mechanisms.”

The overexpression of DJ1, researchers said in their study, is associated with invasion, metastasis, resistance to cancer therapies, and overall cancer cell survival. That excess of DJ1 is silenced by the genetic therapy composed of siRNA.

The findings of this research, Taratula said, could also build upon some other recent advances in photodynamic therapy, in which a different compound called naphthalocyanine could be administered prior to surgery, causing the cancer cells to “glow” and fluoresce when exposed to near-infrared light. This provides a literal road map for surgeons to follow, showing which tissue is cancerous and which is not.

There’s no reason that approach couldn’t be combined with the newest advance, Taratula said, providing multiple mechanisms to improve surgical success and, with minimal side effects, help eradicate any remaining cancer cells that were not completely removed.

“Our study established a prospective therapeutic approach against ovarian cancer,” the researchers wrote in their conclusion. “The tumors exposed to a single dose of a combinatorial therapy were completely eradicated from the mice.”


Story Source:

The above post is reprinted from materials provided by Oregon State UniversityNote: Materials may be edited for content and length.

Read this article in full on Science Daily by clicking here.

Genes Could Hold Key To Ovarian Cancer Survival

Scientists have identified a series of genes which appear to play an important role in the longer survival of women with ovarian cancer.

It is hoped the Nottingham Trent University study could help to pinpoint genes which might act as new targets for therapies against the disease – as well as offer insight into a patient’s prognosis and their potential response to different treatments.

Fewer than one in five women with advanced stage ovarian cancer will survive beyond five years and about 4,000 UK women will die from the disease each year.

Despite rising interest in identifying targeted therapy, there has been no significant change in the disease’s outcome in the last few decades.

The Nottingham study, reported in the journal Microarrays, analysed genetic data from the tumours of different patient groups with advanced ovarian cancer, filtering out genes consistently associated with longer patient survival.

As a result, the team – based in the university’s John van Geest Cancer Research Centre – was able to identify 56 potentially significant genes out of an initial search of 37,000.

While certain genes have previously been associated with ovarian cancer, few have been verified for their clinical significance.

The researchers say these genes appear to play a role in the molecular mechanisms that occur within a tumour with regards to survival length, and as such should be investigated further.

Ovarian cancer is the fifth most common cancer and the fourth most common cause of cancer-related deaths among UK women.

Its high mortality rate is attributed to the majority of incidences begin diagnosed at a late stage – and symptoms are typically vague, including back and abdominal pain, bloating and abnormal menstrual patterns. Few, if any, symptoms are evident from early-stage disease.

Treatment for ovarian cancer is most commonly a severe abdominal surgery, including hysterectomy and tumour debulking, frequently with chemotherapy.

“There is an urgent need to improve therapy for patients with advanced stage ovarian cancer,” said Clare Coveney, a researcher in Nottingham Trent University’s John van Geest Cancer Research Centre.

She said: “Hopefully we have added a useful piece to a large jigsaw. Implicating these genes should help build the growing body of knowledge about the cellular mechanics of ovarian cancer. In future work these genes will be further investigated; this will increase our understanding of how the disease works and could lead to a novel therapy target.”

Professor Robert Rees, the Director of the university’s John van Geest Cancer Research Centre, added: “Identifying genes and the proteins they code for that uniquely associate with ovarian cancer increases the likelihood of developing diagnostic tests and new therapies for this disease.

“Biomarkers that identify the presence of pancreatic cancer have recently been reported and we urgently require similar markers for ovarian cancer, which at present is largely untreatable when detected.”

Dr Suha Deen – consultant Histopathologist, Queen’s Medical Centre and visiting professor Nottingham Trent University – also collaborated in the study.

To read this article on Medical News Today, click here.

Ovarian Cancer Gets Congress’ Attention

By: Kim Lewis

FILE - Actor Angelina Jolie announced in March 2015 that she'd had her ovaries and fallopian tubes removed to prevent cancer. She also underwent a preventive double mastectomy.

The bipartisan Congressional Ovarian Cancer Caucus was launched Tuesday in Washington to bring more awareness of and research into a disease that kills more than 14,000 women each year.

Representatives Sean Duffy of Wisconsin and Rosa DeLaura of Connecticut came together after both were personally touched by ovarian cancer. DeLaura and Duffy’s sister are survivors of the disease, and Duffy lost a very good friend to the cancer.

Calaneet Balas, Ovarian Cancer National Alliance chief executive, said the caucus would will remind Congress of the need for funding.

“The alliance has been working for nearly 18 years now, and with a lot of champions on [Capitol Hill],” Balas said. “We’ve been able to raise about $2.2 billion for research and awareness, but this caucus is going to be really focused on continuing that awareness all year round on the Hill through members, as well as focusing on increasing some of those appropriations for research and education.”

The alliance says that the survival rate for ovarian cancer has improved, but that there is no test for early detection; symptoms are often confused with those of other diseases, leaving 85 percent of women diagnosed when the disease is in its later stages. More than 50 percent of these women will not live more than five years after being diagnosed.

Genetic Mutation

Balas said researchers are making progress in understanding how gene mutation might put a woman at an elevated risk for ovarian cancer. She pointed to the case of actor Angelina Jolie, whose mother died of the disease. Jolie “had that BRCA gene and had a prophylactic double mastectomy and ovariectomy” as a preventive measure.

Balas added that scientists are starting to understand the genetics of the tumors, which could lead to the development of more effective diagnoses.

Another big shift has been in treatment of ovarian cancer, such as intraperitoneal chemotherapy that is infused into the abdomen.

“That is a very new thing, really only in the last several years, and it is considered a very effective treatment … for women who can tolerate it,” Balas said.

Cancer survivor Clara Frenk, a VOA TV producer, keeps a close eye on research and development. After numerous visits to various doctors for unexplained symptoms, she was eventually diagnosed with Stage 3 ovarian cancer.

Frenk offered the following advice: “Always be aware of what your body is telling you. Anything that is out of the ordinary needs to be checked by a doctor. In my case, my symptoms were so wide-ranging that you would have had to be a pretty clever doctor to connect the dots back to ovarian cancer.”

Frenk’s symptoms included intense joint and gastrointestinal pain, acid reflux, shortness of breath and, most tellingly, an extended abdomen.

“I was gaining weight like crazy, but only around my midsection,” she said. “If you look at pictures of me from that era, that period back in 2013, my face was very, very gaunt, but my abdomen was enormous. I looked like I was pregnant.”

One of the physicians she visited examined the skin over her abdomen and was able to make the connection that something was wrong.

“The bloating that one feels with ovarian cancer is not like the once-a-month bloating that women experience,” Frenk said. “It is a very tight bloating that feels like pregnancy, and the skin is very tight. So by feeling my abdomen, [the doctor] knew that there was something wrong.”

Treatment Options

After analyzing treatment options, Frenk chose one that best fit her busy lifestyle. Instead of getting aggressive chemotherapy every three weeks, which would leave her very weak and too tired to work, she chose to wear a patch that would administer the medication at a slower rate.

“I was still weak and tired, but I could function,” she said. “I could come to work. I could walk. I could go shopping. That, for me, was very important, but that might be an option that might not be available for everyone.”

Frenk shares information with others through her cancer diary blog under DCMedia Girl.

Early detection is key to surviving ovarian cancer, and as Frenk and other survivors advocate, if you detect something is wrong with your body, see a doctor and don’t give up until you get the answers you need.

To read this article on Voice of America, click here.

Why Are Many Women At Risk of Ovarian Cancer Not Aware Of It?

The statistics for ovarian cancer are frightening. Whereas early detection tests for breast cancer are relatively commonplace, 75-85% of women with ovarian cancer are diagnosed only at a late stage, when the cancer has spread and prognosis is poor.

More than 21,000 women are diagnosed with ovarian cancer each year and over 14,000 die annually from this disease. A woman has a 1 in 70 risk of being diagnosed with ovarian cancer in her lifetime.

As there is no effective surveillance technique for detecting early stage ovarian cancer, physicians are focused instead on identifying women at risk and finding effective preventive methods.

“It isn’t clear what can be done to improve the early detection of ovarian cancer,” Dr. Robyn Andersen, an expert in ovarian cancer symptoms and screening at Fred Hutchinson Cancer Research Center in Seattle, WA, told Medical News Today, adding:

“Scientists are working on tests, but there is no simple procedure or screening test to recommend right now for most women. We don’t know of anything that works really well, but there are a few things that can be done that we believe will help women in high-risk families – that’s part of the reason for making sure high-risk women know that ovarian cancer is a possible problem.”

Of particular concern to Dr. Andersen is raising awareness among women of the genetic factors that can contribute to ovarian cancer risk.

Most High-Risk Women Unaware of Their Increased Ovarian Cancer Risk

In a 2014 study published in the journal Behavioral Medicine, Dr. Andersen and her colleagues at Fred Hutchinson found that 75% of women at high risk for BRCA mutations were unaware that these gene mutations increase chance of ovarian cancer.

What is more well known, however, is that BRCA1 and BRCA2 increase risk for breast cancer.

Fast facts about ovarian cancer

  • Ovarian cancer is most commonly diagnosed among woman aged 63 and older
  • Ovarian cancer is the fifth leading cause of cancer deaths among American women
  • African-American women are at greater risk for ovarian cancer than white American women.

Learn more about ovarian cancer

Surveying 1,900 Seattle-area women ages 35-80 with family histories that suggest BRCA mutations, Dr. Andersen’s study found that only about 22% of high-risk women and 7.4% of moderate-risk women were aware that they were at increased risk of developing ovarian cancer.

Given that the respondents were located in an area that has high levels of education and health awareness, as well as good access to genetic counseling and testing, Dr. Andersen hypothesizes that awareness among women in areas with less education and fewer resources may be even worse.

So why is this at-risk group largely unaware of their risk for ovarian cancer, which Dr. Andersen describes as being “in many ways, the more frightening cancer”?

Dr. Andersen suggests it could partly be an issue of media representation.

“Sometimes people write about the BRCA mutations as genes for breast and ovarian cancer but often they don’t, and even when an article does include ovarian cancer as a risk, often only breast cancer makes the headline,” she says.

However, breast cancer is the more common cancer – about 1 in 8 American women develop breast cancer during their lifetime.

Also, while a BRCA1 mutation will increase risk of ovarian cancer by 50%, the increased risk of breast cancer from this mutation is higher, at 87%.

“Even in families with multiple family members affected by BRCA1- or BRCA2-linked cancers, most of the cancers in a family – frequently all of the cancers in the family – have been breast cancer,” admits Dr. Andersen. “Of course people pay attention to that.”

It may not be intuitive for women who have family members with breast cancer to assume that they are also at risk for ovarian cancer. “The connection to ovarian cancer is something that patients need to be educated about,” says Dr. Andersen, adding that it is not surprising patients do not make the connection between breast cancer and ovarian cancer if their doctors do not tell them.

“I really think this is an issue for doctors and other providers (gynecologists, internists, any primary care provider) and for medical care systems,” she stresses.

“Yes, we can also try and inform the general public that BRCA mutations are risks for both cancers, but this is an issue for a small percentage of women, and asking about a family history should be routine at least in mammography settings if not also in primary care. It seems appropriate for the doctors to provide medical advice about cancer risk based on learning a woman’s family history, just as they would provide advice when responding to her symptoms or a high blood pressure reading.”

Dr. Andersen says it should be routine for doctors to refer their patients to a genetic counselor if there are multiple relatives with breast or ovarian cancer.

Yet, in her study, only 15% of women considered to be at high-risk received genetic counseling about their cancer risk during the study period 2006-08.

New Biomarker for Ovarian Cancer Identified

An area that may allow earlier detection of ovarian cancer is screening for biomarkers. Last year, research from A*STAR’s Institute of Medical Biology in Singapore identified a new biomarker of ovarian stem cells.

This molecule, called Lgr5, resides on a subset of cells in the ovarian surface epithelium. Previously, Lgr5 has been used to identify stem cells in the intestine and stomach, but this is the first time the molecule has been identified in the ovary.

The epithelial cells that produce Lgr5 also control the development of the ovary, and detaching this biomarker should allow ovarian cancer to be diagnosed earlier.

In addition, the A*STAR researchers have conducted a bioinformatics analysis on cancer genomics data and found a gene that they believe could be an effective prognostic marker of patient survival.

This gene, called Checkpoint Kinase 2, is associated with poor response to existing cancer treatments. The researchers hope that its identification will encourage the development of personalized medicine for ovarian cancer patients.

HIPEC – New Treatment at Phase 2 Trial Stage

One new treatment that has reported positive results in initial trials is hyperthermic intraperitoneal chemotherapy (HIPEC).

HIPEC is an innovative take on chemotherapy delivery, where, instead of chemotherapy circulating throughout the body, it is delivered directly to cancer cells in the abdomen.

To do this, a chemotherapy “bath” heated to 41-42 degrees Celsius is circulated throughout the abdomen for 1.5 hours before being drained from the body.

The solution is delivered after tumor-removing surgery, with the aim of destroying any remaining, undetected cancer cells that could form into a new tumor. Heating the solution improves the ability of the chemotherapy to be absorbed into the cancer cells.

In HIPEC, because the chemotherapy is targeted to the cancerous area, without affecting the rest of the body, doctors are able to deliver higher doses of chemotherapy than normal without increasing side effects.

To read this article in its entirety, visit Medical News Today.