The Emerging Field of Oncofertility

“Welcome to the burgeoning world of oncofertility. As cancer survival rates climb and patients focus on quality-of-life issues, especially fertility, Dauer and others like her are forcing two very different medical specialties-oncology and assisted reproduction-to come together. ‘The narrative of cancer is no longer that it’s a death sentence; it’s a bump in your medical history that you overcome and go back to what we hope is a healthy lifestyle,’ says Teresa Woodruff of Northwestern University’s Feinberg School of Medicine …”

“When Annie Dauer’s oncologist told her she’d need a stem-cell transplant to cure her non-Hodgkin’s lymphoma, Dauer’s first thought wasn’t about death but about life. ‘I asked what would happen to my fertility,’ she says. Her oncologist dismissed the question: ‘Honey, you’re fighting for your life; forget the fertility at this point,’ she told me. But Dauer, then 30 and newly married, pressed the subject until the oncologist referred her to a fertility specialist. Since Dauer’s chemotherapy regimen would most likely destroy her body’s egg supply, the specialist, in an experimental procedure, removed one of her ovaries, froze it and reimplanted it when Dauer recovered. Three years later, Dauer, now cancer-free, and her husband, Greg, have a 2-year-old daughter, Sienna, and a second baby on the way.

Welcome to the burgeoning world of oncofertility. As cancer survival rates climb and patients focus on quality-of-life issues, especially fertility, Dauer and others like her are forcing two very different medical specialties-oncology and assisted reproduction-to come together. ‘The narrative of cancer is no longer that it’s a death sentence; it’s a bump in your medical history that you overcome and go back to what we hope is a healthy lifestyle,’ says Teresa Woodruff of Northwestern University‘s Feinberg School of Medicine, who last fall received a first-of-its-kind $21 million NIH grant to develop ways of protecting cancer patients’ reproductive health.

Of the 125,000 people under the age of 45 who are diagnosed with cancer each year, roughly half will receive treatments that will affect their fertility. The cancers that most commonly strike the young-leukemias, lymphomas and breast cancers-require some of the most toxic forms of chemotherapy, which target rapidly growing and fragile cells like hair follicles, sperm and eggs. The good news: patients who would like to become parents have a growing array of options. Men are benefiting from a procedure that allows urologists to find a single live sperm to bank, which can then be used in an in vitro fertilization method that requires just one sperm. Women can freeze eggs or ovarian tissue, though success rates are still low. Those with partners (or donor sperm) can freeze embryos, the procedure with the best track record, though, like egg freezing, it’s available only to patients who have two to six weeks before starting treatment. On the horizon are less toxic chemotherapy agents as well as methods of shielding eggs and sperm from harm.

Up to now, few oncologists passed this vital information to patients, either because they were not aware of fertility advances, or because they were understandably preoccupied with saving lives. As the field grows (at least 50 centers now provide oncofertility services), more cancer docs are tackling the issue, and even altering treatments to aid fertility. Advocacy groups like Fertile Hope, which educate cancer patients about assisted reproduction, deserve credit for spreading the word. ‘It’s being talked about more,’ says Nancy Lin, an oncologist at Boston’s Dana-Farber Cancer Institute. ‘There’s a growing awareness among doctors, and patients are more proactive.’

Two years after Dauer completed her cancer treatment, her doctor, Kutluk Oktay, founder of New York City’s Institute for Fertility Preservation, sutured a one-inch strip of ovary, containing tens of thousands of microscopic eggs, under the skin just below Dauer’s belly button. ‘Every month, I would feel little eggs, sometimes pea-sized, sometimes as big as a quarter,’ says Dauer. Normally, Oktay, who pioneered this procedure, would have harvested mature eggs, fertilized them with Greg’s sperm and implanted them into Dauer’s uterus. But in an unexpected development, Dauer became pregnant naturally; somehow, the implanted ovary jump-started her remaining, inactive ovary and she began to ovulate. Oktay is at a loss for an explanation. ‘The healthy ovary may contain signals or hormones that may enable the [dormant] ovary to regenerate eggs,’ says Oktay. ‘That’s the theory, other than a miracle.’

When cancer’s involved, even joy can be shadowed by uncertainty. Ronny Villarreal, 32, survived breast cancer, then, with her oncologist’s OK, stopped a common hormone-suppressing treatment early in order to conceive. Unfortunately, the cancer recurred during her second trimester of pregnancy. Villarreal’s daughter, Maddy Hunt, now 4 months old, is healthy, but Villarreal is facing more chemotherapy and a cloudy prognosis. ‘We are trying our hardest to stay positive,’ she says. ‘We have so much to live for.’ More, certainly, than if she never had the chance to get pregnant at all.”

Quoted Source: Survive Cancer, Have Baby – The emerging field of oncofertility offers hope to patients who worried that they couldn’t conceive, by Anna Kuchment, Medicine, Newsweek Magazine, Published July 26, 2008 (From the magazine issue dated Aug 4, 2008).

Additional Resources:

Non-Platinum Topotecan Drug Combination Therapy Provides No Survival Advantage Over Topotecan Monotherapy

“In women with recurrent ovarian cancer, treatment with topotecan along with etoposide or gemcitabine offers no survival advantage over topotecan monotherapy, German and Austrian researchers report in the July 1st issue of the Journal of Clinical Oncology.”

“In women with recurrent ovarian cancer, treatment with topotecan along with etoposide or gemcitabine offers no survival advantage over topotecan monotherapy, German and Austrian researchers report in the July 1st issue of the Journal of Clinical Oncology.

‘Combination therapies,’ lead investigator Dr. Jalid Sehouli told Reuters Health, ‘were associated with higher toxicity, but progression-free survival and overall survival were not significantly different.’

Dr. Sehouli, of Humboldt University in Berlin, and colleagues explain in their paper that although topotecan monotherapy is an established treatment, there was evidence to suggest that combination therapy may provide better results.

To investigate further, the researchers studied 502 women in whom ovarian cancer recurred following primary surgery and platinum-based chemotherapy. They were randomized to receive either topotecan alone or in combination with etoposide or gemcitabine.

Median overall survival was not significantly different among the groups: 17.2 months with topotecan alone, 17.8 months with the etoposide combination and 15.2 months with the gemcitabine combination. There were no differences in either median progression-free survival or objective response rates.

The researchers note that the incidence of thrombocytopenia was lower with monotherapy (13.5%) than with the etoposide combination (21.5%) or gemcitabine combination (31.3%), and they conclude that combination therapy increases toxicity and does not provide a survival advantage.

‘Based on our results,’ Dr. Sehouli warns, ‘physicians should not harm their patients with such combination regimens.’”

Quoted Source: Topotecan Combo No Extra Help in Ovarian Cancer, by David Douglas, Matria Healthcare News, July 28, 2008 (summarizing the findings of Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group; Sehouli J et. al., J Clin Oncol. 2008 July;26(19):3176-82.

Additional Information:

A Requiem Hallelujah, But Don’t Let There Be a Hole in the World Tomorrow

As many of you know, the H*O*P*E*™ weblog is dedicated to Libby, my 26 year old cousin. Libby was diagnosed with ovarian clear cell carcinoma in January 2007. I am deeply saddened to inform you that Libby lost her ovarian cancer battle this morning with her family at her side. Libby leaves behind her loving spouse, Steve, her mother Kathy, her father Dennis, and her sister Sara.

Libby and Steve are the inspiration behind H*O*P*E*™, and its contining campaign to make all women aware of the early warning signs and symptoms of ovarian cancer, as well as significant treatment developments relating to the disease. Upon hearing of Libby’s death this morning, my initial thought was to allow H*O*P*E*™ to go “dark” (from a post reporting perspective) for the next week in her honor. Immediately after that initial thought, two classic songs came to mind as a better way to honor Libby. I believe the song choices were inspired by Libby from a much better place.

The first song is a gospel ballad entitled “Hallelujah.” “Hallelujah” was written by Canadian singer-songwriter Leonard Cohen, who originally released it on his 1984 studio album entitled “Various Positions.” A general translation of the word “Hallelujah” in the Jewish and Christian faiths is “Great Praise to God.” The song “Hallelujah” is frequently used in television shows and movies during scenes involving death or heartbreak. The reason for this, I believe, is that the song evokes strong emotions that capture the struggle to love, pray, and live with faith in the midst of tragic human suffering. Libby experienced that same struggle throughout her treatment, yet continued her fight to the end with grace and courage.

“Hallelujah” has been covered by various singers more than 120 times (counting only recorded, not live, versions). American singer-songwriter Jeff Buckley recorded one of the best-known and emotionally moving covers of “Hallelujah” for his 1994 studio album entitled “Grace.” Buckley, not wholly satisfied with any one take, recorded the song more than twenty times. In September 2007, a poll of fifty songwriters conducted by Q Magazine listed “Hallelujah” among the all-time “Top 10 Greatest Tracks,” with John Legend calling Buckley’s version “as near perfect as you can get.” A hyperlink to Jeff Buckley’s cover version of “Hallelujah” is provided below as an acknowledgment of Libby’s courageous fight against ovarian cancer.

Jeff Buckley-Hallelujah

CLICK HERE TO VIEW VIDEO

The second song is “[There’s a] Hole in the World [Tonight], which was recorded by The Eagles, a legendary U.S. rock band. In August 2001, The Eagles returned to the U.S. upon completion of a successful European tour to record a new album. The band was scheduled to begin recording on September 11, 2001. “Hole in the World” was written by the band in five part harmony to express the fear, sorrow, and future hope stemming from that tragic day. The lyrics set forth in the first verse of the song are as follows:

“There’s a hole in the world tonight.
There’s a cloud of fear and sorrow.
There’s a hole in the world tonight.
Don’t let there be a hole in the world tomorrow.”

I believe that Libby would abide by the message set forth in the last two sentences of that verse. Today, our family has a hole in its world as a result of Libby’s death, but H*O*P*E*™ cannot allow that fear and sorrow to create a hole in the world of another woman and her family through the failure to move ahead with its educational mission. Libby would tell you that “education increases survival.”

A video of The Eagles singing “Hole in the World” is provided below, as inspiration for all individuals who are involved in the fight against ovarian cancer. This fight will require perseverance through medical research, advocacy, education and fundraising until ovarian cancer is vanquished.

As an enduring tribute to Libby, H*O*P*E*™ revised the weblog homepage caption to read “Libby’s H*O*P*E*™.” We love you Libby and will forever miss you, but we will continue the fight against ovarian cancer on your behalf.

The Eagles – Hole In the World

Source: Wikipedia descriptions of the word “Hallelujah,” and Leonard Cohen’s song entitled “Hallelujah.”

From Zero to Hero: HMGB1 Protein Found to Promote DNA Repair, Prevents Cancer

“An abundant chromosomal protein [HMGB1] that binds to damaged DNA prevents cancer development by enhancing DNA repair, researchers at The University of Texas M. D. Anderson Cancer Center report online this week in the Proceedings of the National Academies of Science.”

“An abundant chromosomal protein that binds to damaged DNA prevents cancer development by enhancing DNA repair, researchers at The University of Texas M. D. Anderson Cancer Center report online this week in the Proceedings of the National Academies of Science.

The protein, HMGB1 [High mobility group box 1] , was previously hypothesized to block DNA repair, said senior author Karen Vasquez, Ph.D., associate professor in M. D. Anderson’s Department of Carcinogenesis at the Science Park – Research Division in Smithville, Texas.

Identification and repair of DNA damage is the frontline defense against the birth and reproduction of mutant cells that cause cancer and other illnesses.

Pinpointing HMGB1’s role in repair raises a fundamental question about drugs under development to block the protein, Vasquez said. The protein also plays a role in inflammation, so it’s being targeted in drugs under development for rheumatoid arthritis and sepsis.

‘Arthritis therapy involves long-term treatment,’ Vasquez said. ‘Our findings suggest that depleting this protein may leave patients more vulnerable to developing cancer.’

Long known to attach to sites of damaged DNA, the protein was suspected of preventing repair. ‘That did not make sense to us, because HMGB1 is a chromosomal protein that’s so abundant that it would be hard to imagine cell repair happening at all if that were the case,’ Vasquez said.

In a series of experiments reported in the paper, Vasquez and first author Sabine Lange, a doctoral candidate in the Graduate School of Biomedical Sciences, tracked the protein’s impact on all three steps of DNA restoration: access to damage, repair and repackaging of the original structure, a combination of DNA and histone proteins called chromatin.

First, they knocked out the [HMGB1] gene in mouse embryonic cells [HMGB1 knockout cells] and then exposed cells to two types of DNA-damaging agents. One was UV light, the other a chemotherapy called psoralen that’s activated by exposure to darker, low frequency light known as UVA. In both cases, the cells survived at a steeply lower rate after DNA damage than did normal cells.

Next they exposed HMGB1 knockout cells and normal cells to psoralen and assessed the rate of genetic mutation. The knockout cells had a mutation frequency more than double that of normal cells, however, there was no effect on the types of mutation that occurred.

Knock out and normal cells were then exposed to UV light and suffered the same amount of damage. However, those with HMGB1 had two to three times the repair as those without. Evidence suggests that HMGB1 works by summoning other DNA repair factors to the damaged site, Vasquez said.

The last step in DNA repair is called chromatin remodeling. DNA does not exist in a linear structure in the chromosome, but wraps around specialized histone proteins. This chromatin structure permits access to DNA when it is loose, or opened up, and blocks access when it is more tightly wrapped. Presence of HMGB1 resulted in a much higher rate of chromatin assembly in both undamaged and UVC-damaged cells.

Lange and Vasquez hypothesize that HMGB1 normally binds to the entrance and exit of DNA nucleosomes, so is nearby when DNA damage occurs. It then binds to and bends the damaged site at a 90-degree angle, a distortion that may help DNA repair factors recognize and repair the damage. After repair it facilitates restructuring of the chromatin.

Co-author with Lange and Vasquez is David Mitchell, Ph.D., professor of carcinogenesis.

The research was supported by grants from the National Cancer Institute and the National Institute of Environmental Health Sciences as well as an American Legion Auxiliary fellowship. 07/21/08”

Quoted Source: Once Suspect Protein Found to Promote DNA Repair, Prevent Cancer – M. D. Anderson scientists caution against targeting HMGB1 to treat other disease, M. D. Anderson News Release, July 21, 2008.

Fashion Really Can Make a Statement In the Fight Against Ovarian Cancer

Kelly Ripa and Molly Sims are fighting for a cure by doing something they love — shop! It’s all a part of Super Saturday Live on QVC. QVC will offer designer clothing, jewelry, beauty products, and accessories at 30% to 50% off of the manufacturer’s suggested retail price. All of the net proceeds benefit the Ovarian Cancer Research Fund (OCRF).

The QVC Super Saturday Live event will take place on Saturday, July 26, 2008 from 2:00 P.M. to 4:00 P.M. E.D.T. In its 11th year, the QVC Super Saturday Live event program will be hosted in the Hamptons, which is a summer playground in New York for the rich and famous. Dubbed the “Rolls Royce of Garage Sales” by The New York Times, Super Saturday 11 promises an exciting line up of over 200 top designers. It is being broadcast live for the second year on QVC.

The Super Saturday Live product line will be available through QVC by calling (800) 345-1515 or visiting www.QVC.com while supplies last.  To read ovarian cancer survivor stories on the QVC Super Saturday blog, click here.

As an organization committed to finding better ways to detect, treat, and ultimately cure ovarian cancer, the OCRF believes that future advances in ovarian cancer research lie in the hands of researchers. To promote research advancement, the OCRF sponsors young researchers with promising projects. Since 1998, the OCRF has awarded over $23 million grants to 128 of the brightest women and men in the field today at over 40 leading medical centers across the country. A brief video that describes the OCRF is provided below.

Ovarian Cancer Research Fund

TP53 Gene Mutation Found in 80% of High Grade Ovarian Serous Carcinomas; TP53 Not Directly Involved In The Development of Drug Resistance

“… [T]he [Johns Hopkins] research team concluded that the frequency of TP53 gene mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported in the medical literature. Furthermore, the research team found that TP53 is not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.”

The TP53 gene mutation frequency in ovarian serous carcinomas has been reported to range between 50% and 80%. A research team working at the The Sidney Kimmel Comprehensive Cancer Center of The Johns Hopkins Medical Institutions (Johns Hopkins) made several important findings regarding TP53 gene mutations with respect to high grade ovarian serous carcinoma, as reported in the International Journal of Gynecological Cancer. Ovarian serous carcinoma is the most common tumor subtype within the epithelial ovarian cancer histological classification.

According to the Johns Hopkins research team, a stringent analysis of the TP53 gene using purified epithelial tumor samples has not been performed to accurately assess the TP53 gene mutation frequency and its correlation to tumor histologic grade. The research team assessed the TP53 gene mutational profile in a relatively large series of high-grade (53 primary tumors and 18 recurrent tumors) and 13 low-grade ovarian serous tumors. All samples were affinity purified, and the tumor DNA was analyzed for TP53 mutations in exons 4 through 9. In addition, the ovarian serous tumors were subjected to in vitro drug resistance testing. In vitro drug resistance assays were performed on the same tumor samples using carboplatin, cisplatin, paclitaxel, and taxotere, and the results were correlated with the TP53 mutation status.

The reported study findings are as follows:

  • TP53 mutations were detected in 57 (80.3%) of 71 high-grade carcinomas and in one (7.8%) of 13; low-grade serous tumors (an invasive low-grade serous carcinoma);
  • The mutations were predominantly missense mutations (59.6%);
  • TP53 mutations were associated with high-grade serous carcinomas and recurrent disease; and
  • There was no statistically significant correlation between TP53 mutation status and drug resistance assays or clinical stage.

Accordingly, the research team concluded that the frequency of TP53 gene mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported in the medical literature. Furthermore, the research team found that TP53 was not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.

Source: Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance; Salani R, et. al., Int J Gynecol Cancer. 2008 May-Jun;18(3):487-91. Epub 2007 Aug 10.

P.O.V. Documentary “In the Family”: One Woman’s Journey Through the Unpredictable World of Predictive Genetic Testing

“At the age of 27, filmmaker Joanna Rudnick tested positive for the BRCA mutation. Joanna now faces an impossible decision: remove her healthy breasts and ovaries or risk incredible odds of developing cancer. Armed with a positive test result that leaves her essentially “a ticking time bomb,” she balances dreams of having her own children with the unnerving reality that she is risking her life by holding on to her fertility. IN THE FAMILY follows Joanna as she takes us on a journey through the unpredictable world of predictive genetic testing.

Turning the camera on herself, Joanna bares her conflicting emotions about preventative surgery and the potential consequences. Turning the camera on her new relationship, she and her partner capture a young couple falling in love in the shadow of the mutation. Turning the camera on the company that owns the patents to the BRCA genes, she questions their control over access to the test. Along the way, she looks to other women and families dealing with the same unbelievable information.

Intensely personal and timely, IN THE FAMILY is a groundbreaking investigation that attempts to answer the question: How much do you sacrifice to survive?”

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Producer/Director: Joanna Rudnick

Co-production: Kartemquin Films and the Independent Television Service (ITVS).

Date of Completion: February 2008

Running Time: 90 Minutes

US Broadcast: PBS/P.O.V. will air the film on Wednesday, October 1, 2008 at 10:00 P.M. (to have a reminder sent to you by email, click here, then click on the “Send Me A Reminder” link)

Filmmaker’s Website: http://inthefamily.kartemquin.com

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Quoted Source: IN THE FAMILY – How much do you sacrifice to survive? (Synopsis), Press Kit, IN THE FAMILY website, accessed July 16, 2008 (Adobe Reader PDF document).

Comment: Visit the filmmaker’s website for more information about the film and upcoming screenings, by clicking on the link above. A brief video excerpt of IN THE FAMILY is provide below.

POV Website Note: “Want to hold a screening of In the Family in your community? If you are an organizer, a teacher, a young person using media to reach your peers or a PBS station employee interested in planning free local screenings of P.O.V. films, apply through P.O.V.’s Community Network and we’ll loan you a copy of the film (for free!) along with a toolkit including a discussion guide.”

Additional Resources:

P.O.V. – In the Family by Joanna Rudnick | PBS 2008