Each spring, thousands of cancer researchers from around the world gather for the annual meeting of the American Society of Clinical Oncology (ASCO). Many new studies on or related to ovarian cancer were presented at this year’s ASCO meeting. You can click on the links below to jump to a particular section, or scroll to read about all of the research presented at ASCO.
Our thanks to Patsy Hinson, Susan Leighton, Regina Parker, Alison Silberman, Cara Tenenbaum and Cheryl Trepagnier for reporting from ASCO.
Ovarian Cancer—Molecular Classification, Pathways and Subtypes
Quality of Life and Side Effects
Cost of Care
Nutrition and Cancer
End of Life
Also of Note
Need help defining these terms? Click here to view a glossary of commonly used acronyms.
A number of studies were presented on new molecules to treat ovarian cancer.
A study of olaparib (a PARP inhibitor) as a maintenance drug in women with a BRCA mutation showed an improvement in PFS. In women with an inherited (germline) BRCA mutation PFS was 11.2 months for women treated with olaparib versus 4.1 months for women who received the placebo. Additionally, there was evidence of a quality of life benefit. Phase III trials are planned. Women whose tumors had a BRCA mutation (a somatic mutation) also had a higher response to treatment with olaparib than women with no germline or somatic BRCA mutation.
A Phase III study of pazopanib (an angiogensis inhibitor) showed an improvement in PFS of 5.6 months in a study of almost 1000 women with ovarian cancer (17.9 months PFS compared to 12.3 months for the placebo arm). Pazopanib was used as a maintenance therapy after frontline therapy. Side effects from the drug included high blood pressure, elevated liver enzymes and low white blood cell counts. A study using pazopanib as maintenance therapy for Asian women with ovarian cancer confirmed that they had higher toxicities than non-Asian women. Further studies are needed to discover why this happens.
The use of metformin to reduce insulin levels in women with ovarian cancer and diabetes also appeared to reduce proliferation of cancer cells. When used in combination with chemotherapy, metformin improved overall survival rates. More studies, especially on non-diabetic patients, are ongoing.
A Phase III study of more than 500 women with ovarian cancer showed that chemotherapy prior to surgery (known as neo-adjuvant chemotherapy) was associated with higher rates of optimal debulking, lower rates of mortality and similar rates of survival. This approach may contribute to quality of life issues and may be a viable alternative for many women with ovarian cancer. However, further studies are necessary to control for quality of surgical procedures.
A Phase II study of vintafolide plus pegylated liposomal doxorubicin in women with platinum resistant ovarian cancer showed some benefit. Vintafolide targets cells that over-expresss folate receptors, which include most epithelial ovarian cancer cells. Phase III trials are underway.
A Phase III randomized study compared treatment with topotecan plus cisplatin, followed by carboplatin and taxol therapy, to standard treatment with carboplatin and taxol alone. The results confirmed that the first treatment protocol offered no improvement in outcomes (PFS or OS) when compared to the second treatment protocol.
A large Phase II trial of weekly versus every-three-week carboplatin plus paclitaxel showed no significant benefit in the weekly arm, but was associated with better quality of life and toxicity for patients. In the weekly arm, fewer women experienced neuropathy and half of women did not lose their hair.
A Phase II trial of volasertib versus chemotherapy in patients with platinum refractory/resistant ovarian cancer showed that volasertib did not improve disease control rate (31% versus 43% for the chemotherapy arm) or PFS (median PFS was 13.1 weeks versus 20.6 weeks). However, single agent volasertib showed antitumor activity in a range similar to chemotherapy. Exploration of a potential predictive biomarker for volasertib is underway.
Treatment in Older Women
A session on treatment for ovarian cancer in women over 65 years old covered eligibility for and outcomes of surgery.
Aggressive debulking surgery generally improves outcomes for ovarian cancer patients, however, in the elderly population this surgery increases certain risks. Women over 65 who have primary debulking surgery are at an increased risk of post-operative mortality, complications, delay/omission in administering chemotherapy and discharge to another facility (rather than their homes). Because of the potential complexities, the speaker recommended that medical oncologists, geriatricians and gynecologic oncologists cooperate to improve treatment guidelines in this population.
Another speaker discussed the use of tools to help determine the course of treatment for women 65 and older. The Comprehensive Geriatric Assessment (CGA) is a multidisciplinary assessment of elderly patients used to predict complications due to chemotherapy and to make appropriate modifications for those patients at risk. Another tool in development is the Preoperative Assessment of Cancer in the Elderly (PACE), which was designed to combine the elements of the CGA and surgical risk assessment tools. Using PACE, the patient is assessed with a mini-mental state inventory, activities of daily living (basic skills required for self care, e.g. toileting, bathing), instrumental activities of daily living (skills required for independent living, e.g. cooking and doing laundry), Geriatric Depression Scale, brief fatigue inventory and other measures. The effectiveness of this tool has not yet been validated but is a step in the right direction. Some trials are now incorporating a geriatric assessment tool.
The ASCO meeting included numerous studies that sub-divided ovarian cancer by the cancer’s genetic mutations or used existing types of ovarian cancer to propose new treatments. Some of these sub-types showed survival advantages while others illuminated cancer growth pathways. Epithelial ovarian cancer is the most common form of ovarian cancer.
Epithelial Ovarian Cancer
The PI3K pathway is a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. The PI3K pathway has been shown to be activated in 70% of epithelial ovarian cancers. Members of this family have potential for targeted therapy with a variety of existing agents, however, the efficacy of these has not been proven. One protein within this pathway is the mammalian target of rapamycin or mTOR. Research is currently being done with mTOR inhibitors including metformin, a drug used in treatment of diabetes for the past thirty years.
Mucinous and Clear Cell Ovarian Cancers
Mucinous and clear cell are rare subtypes of ovarian cancer accounting for only 6-10% of tumors. Women diagnosed with those types of cancer have better outcomes generally than those diagnosed with epithelial ovarian cancer. Women diagnosed with clear cell or mucinous ovarian cancer are usually diagnosed in early stages of the disease; however, when diagnosed in later stages these sub-types of ovarian cancer are more deadly than epithelial ovarian cancer. These subtypes are not represented in The Cancer Genome Atlas (TCGA) data and more genomic data is needed to help understand them and to identify targets for treatment.
Mucinous tumors are more often diagnosed in early stages, more frequently found in younger women and not found in women with BRCA mutations. Mucinous ovarian cancer seems to be similar to other types of mucinous cancers, including gastrointestinal tumors. Half of mucinous ovarian cancers have a KRAS mutation, and about 20% have a BRAF mutation. The clinical trial GOG-241 is a 2×2 trial where half of women get a gynecologic cancer treatment and the other half get a gastrointestinal cancer treatment. Additionally, half of women on the trial will get bevacizumab. This trial is expected to take 7-10 years to accrue due to low incidence of mucinous ovarian cancer.
The genetics of clear cell is different than epithelial: clear cell is uncommon in women with a BRCA mutation and it does not have a p53 mutation, however one-third of tumors have a PIK3 mutation and half have a loss of ARID1A (a tumor suppressor gene). Potential treatments include anti-angiogenesis drugs, a drug in development for HIV treatment, Her-2 neu and others. However, there is a low incidence of the disease so accruing a clinical trial can take years. Two ongoing GOG trials investigate clear cell ovarian cancer treatments (GOG-268 and GOG-254).
One presenter discussed the data on radiotherapy for clear cell ovarian tumors. Recent studies show that radiation may be useful in this type of ovarian cancer, especially since clear cell tumors respond better to radiation than other types of ovarian cancers. Newer techniques of delivering radiation have allowed it to be given in more precise areas and smaller doses. In some forms of ovarian cancer, radiotherapy is considered curative; it also can be used as palliative therapy for bleeding and post-chemotherapy pain. Clear cell cancer resembles kidney cancer more than some forms of ovarian cancer, which may be useful for future research.
A poster that analyzed more than 10,000 women with ovarian cancer found that women with the clear cell subtype were more likely to be diagnosed with early stage disease than those with serous ovarian cancer. For women diagnosed with early stage disease, there was no survival difference but women diagnosed with late stage clear cell cancer have worse outcomes than those with late stage serous cancer.
As more studies of the genomic sequence of mucinous and clear cell tumors is are done, it is becoming apparent that there are even further subtypes within each of these subtypes. For instance, three different subtypes have been identified within the clear cell subtype.
A study showed that some high-grade serous ovarian tumors have genetic mutations that make it harder for the tumor to grow its own blood supply (anti-angiogenesis).
Low-Grade Serous Ovarian Cancer
Another type of ovarian cancer is low-grade serous carcinoma of the ovary. A presenter discussed research on this type of cancer, which makes up approximately 10% of ovarian cancers. Many cases of borderline ovarian cancer recur as low-grade serous cancers. The KRAS gene mutation is found in 40% of low grade ovarian cancer, and some other pathways appear to be common in this type of cancer, which opens up possibilities for research on treatments. Low grade serous ovarian cancer is relatively resistant to chemotherapy, however patients have a relatively better prognosis: 52% of women with this subtype have no evidence of disease after the first round of chemotherapy. The CA-125 is a good marker for the majority of low grade serous tumors but imaging is not.
A European study developed an algorithm to predict the outcomes of surgery—a Surgical Outcomes Score—based on HE4 and CA-125 blood levels. This was a retrospective study of almost 200 women. Their pre-operative HE4 and CA-125 levels were measured and correlated to surgical outcomes. This study found that HE4 levels correlated with cancer cells remaining after surgery, and CA-125 correlated with cancer cells remaining after surgery in pre-menopausal patients.
A number of studies examined side effects, adherence and adverse events.
A study on why patients stop taking their oral chemotherapy pills showed that cost, side effects and behavior were the most common reasons. Non-adherence to oral medications is common and results in less effective/worse outcomes for patients. Ways to help patients continue taking their pills as directed included involving family members, simplifying the regime and counseling patients. In one study, patients under the age of 40 had the highest rate of non-adherence to prescriptions. In terms of increasing adherence, presenters recommended a focus on high risk patients, educating patients and doctors, identifying barriers (including costs) with patients, using technology and recognizing how important this is in Phase III clinical trials.
One presentation discussed the results of several studies on pain management. Due to the effects of opiates, some studies have been done using methadone as a painkiller. However, using methadone also presents challenges. The use of anti-depressants (such as Cymbalta) and NSAIDS (such as naproxen) have been shown to help certain types of pain. Studies have also shown that patient and family education help with pain management.
Opiates often cause constipation. Studies on opiate-induced constipation showed polyethylene glycol (Colace, Mirilax, and others) is superior to lactulose. The injectable drug methylnaltrexone (Relistor) gives relief within four hours, but is rarely used. Studies show that adding Colace to Senna (a nonprescription laxative) makes both drugs more effective, but using too much may cause loose stools.
Many cancer patients report anxiety and/or depression. One study showed that patients who had depression at the start of therapy, regardless of interventions, did not improve as much as those without depression. A study on conditioned anxiety (triggered by something, like nausea) or anticipatory anxiety (waiting for results) showed that mindfulness worked as a treatment for anxiety. Drugs that were effective for depression and anxiety were citalopram (Celexa) 40mg, pavoxetine (Paxil) 20mg, and duloxetine (Cymbalta) 60 mg. Steroid use raises the risk of depression.
Women diagnosed with ovarian cancer often suffer from hot flashes and joint pain due to treatment. Fluoxetine (Prozac) and megastrol have shown some benefit in addressing these. Soy, vitamin E, flaxseed and black cohosh did not show any benefit. Clonidine showed a reduction of about one fewer hot flashes per day. Both venlafaxine (Effexor) and gabapentin (Neurontin) showed the same effectiveness, but patients prefer venlafaxine to gabapentin by a two-to-one ratio. Megastrol acetate and medroxy progesterone showed approximately the same benefit.
Some posters showed the results of research related to the cost of care.
One study showed that deviating from evidence based standards of oncology care cost, on average, $25,000 per patient. That amount only includes the cost of treatment, not the cost of treating any adverse events. Another study showed that almost one-fifth of cancer patients are overwhelmed by the cost of care, and the average out-of-pocket costs for cancer patients is approximately $530 per month. The implementation of the Part D Medicare drug benefit increased the number of people with prescription drug coverage and either kept out-of-pocket costs the same or decreased them for cancer patients.
Numerous studies are ongoing regarding food and supplements to prevent development of cancer. These include Omega-3 fatty acids and green tea. Evidence coming out of the Omega-3 trials warrants further study; there is evidence that green tea is protective for prostate cancer but not bladder cancer. While none of the studies presented at ASCO were specific to ovarian cancer, they offer interesting data from other disease states.
The Omega-3 studies included mouse or in vitro models of breast and colon cancer. Some human trials showed a decreased risk of breast cancer with higher intake of Omega-3 acid while others have shown no results. Colon cancer studies for people of average risk do not provide clear results thus far, however in people with certain familial conditions these supplements appear to decrease the number and size of polyps. These types of supplements are not FDA regulated so patients should discuss supplements with their providers.
Green tea, oolong tea and black tea have polyphenols, which may reduce inflammation or prevent cancer growth. Green tea has a unique polyphenol which is being studied as a preventive measure for some types of cancer. These studies have generally not found a preventive effect but there is some data to show that green tea may have an anti-proliferation effect.
Studies presented on soy show some reduction in risk of breast cancer. Soy is a phytoestrogen and some breast cancer tumors are hormone fueled, as are some other types of cancer. However, soy is a staple food in Asian populations which have lower rates of breast cancer. One study showed a decrease in lifetime risk when soy was ingested as an adolescent, but other studies did not confirm this. There are no clear results of soy’s effect on sex hormones or breast density.
One study examined the use of aggressive medical care at the end of life for women with ovarian cancer. The study showed that utilization of the intensive care unit, emergency departments and acute inpatient care rose significantly between 1997 and 2007 (the period examined by the study). Rates of ICU admissions rose from 6.4% to 16.6%; the rates of having more than two ED visits during the last month of life went from 19.7% to 32.1%. On the other hand, late (within seven days of death) or absent hospice referrals decreased from 63.1% to 47.8%, and chemotherapy use in the last month decreased from 8.1% to 7.1%. The authors concluded that future studies should examine whether this high-intensity health care is avoidable given evidence that high-intensity care is associated with lower patient quality-of-life near death and increased complications in bereaved caregivers.
One poster presented showed a correlation between religious beliefs and aggressive end of life treatment for cancer patients. Those who had strong religious beliefs were less worried about the end of life, were more interested in any and all treatments, did not have DNR orders and believed in a miracle, including a cure.
The Cancer Genome Atlas (TCGA) was established in 2006 to catalog genetic changes related to various cancer. Ovarian cancer was included in the original group of cancers studied, for which results were released in 2011. Currently, approximately 40 tumor types have been sequenced. This offers insights into biology of the tumors as well as a doorway to personalized medicine. Using information gained through TCGA, researchers are able to identify pathways which could be potential targets for treatment. While TCGA has expanded knowledge of cancer, it is big data and we are just beginning to understand how to use it. Many questions remain. For example, what is the significance of information stored in the “dark areas” of the genome (outside of the actual genes), its role as a driver of a gene and whether these sites could be potential treatment targets? When multiple mutations are found in a tumor genome leading to multiple pathways, how do we select the best potential target and how does the interaction of that pathway with others determine the outcome? To answer these and other questions, we need further investment to complete TCGA, expand the project to include metastasis, investigate the dark area of the genome and share data worldwide.
Dr. Margaret Hamburg, Commissioner of the Food and Drug Administration, gave remarks related to the FDA’s involvement in cancer diagnosis and treatment. She spoke about the work of the FDA in preventing and mitigating drug shortages and the new breakthrough therapy pathway for drug approval. She spent much of her time discussing the need for reliable diagnostic tests to diagnose disease and determine the appropriate course of therapy. The Commissioner specifically discussed OvaSure, a test that was brought to market without FDA approval and did not prove to be accurate in determining whether a woman had ovarian cancer. She discussed the FDA’s role in regulating these types of tests.
Approximately 30% of cancer drugs are prescribed off-label, according to Medicare records. Off-label use is when a drug is used in a different dosage or for a different condition than it has been approved for. This is legal and usually paid for as long as it is evidence based. There is speculation that off-label cancer drug prescription is more common in younger patients who may be more aggressively treated than the Medicare population.
Staging, the classification of a cancer’s spread, which has traditionally used somewhat different criteria for ovarian, tubal and primary peritoneal cancer, is now going to be done using uniform criteria across the three sites.