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Immunotherapy, cancer biology at forefront of ovarian cancer research
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Healio spoke with Jerome Strauss III, MD, PhD, professor of obstetrics and gynecology at Virginia Commonwealth University, emeritus professor of obstetrics and gynecology at Perelman School of Medicine, University of Pennsylvania, and chair of the Committee on the State of the Science in Ovarian Cancer Research, about the committee’s 2016 report on paradigm shifts in research and care, changes in the field since the report, and important areas that need more attention.
What are the most important highlights and recommendations outlined in the 2016 report?
The report highlighted five areas. The first was the biology of ovarian cancer and how it should be defined as different diseases with different characteristics. The second area was risk assessment, including screening and early detection. Ovarian cancer is frequently diagnosed at advanced stages, so this is a significant public health issue. The third area was diagnosis and treatment. At the time of the report, the therapeutic options beyond surgery and platinum-based chemotherapy were relatively limited. That is beginning to change. The fourth area was supportive care and the survivorship trajectory. Ovarian cancer can be successfully treated initially, but the disease usually recurs, particularly the high-grade serous cancers, which are the most prevalent and deadly. Knowing this trajectory, helping women with these cancers achieve a cure, if possible, or a long remission with high quality of life represent important objectives of care. The fifth area was the dissemination and implementation of new knowledge. That is important because the sponsor of the report was the CDC, and it was associated with the agency’s “Inside Knowledge” campaign, which aimed to raise the awareness of gynecologic malignancies. Ovarian cancer was highlighted in this report because, as noted above, it’s a stealth disease often diagnosed when it is disseminated, and therefore, difficult to cure.
Recommendations on risk assessment and screening in the report were very timely because the largest study ever to evaluate the existing methods of screening for ovarian cancer — the UK Collaborative Trial of Ovarian Cancer Screening — was published shortly after the report was completed. This study showed that transvaginal ultrasonography alone, or multimodal screening with transvaginal ultrasonography and serum CA-125 measurements, did not reduce mortality compared with no screening at all in average-risk women, although a secondary analysis did show some benefit of multimodal screening. This raised the question of whether routine screening using these methods for an average-risk population without a family history has value. Most organizations today believe that it does not, including the Society of Gynecologic Oncology, American College of Obstetrics and Gynecology (ACOG) and the U.S. Preventive Services Task Force, which have all issued guidelines to that effect.
Please discuss the importance of considering ovarian cancer as a group of related gynecologic malignancies rather than a single disease.
This is important because the characterization of the different types of tumors and understanding the risk factors that promote the different types of cancers have an impact on how one would screen for and implement preventive measures. One example is the understanding that high-grade serous epithelial ovarian cancers, probably in most cases, originate in the fallopian tubes. That was a paradigm shift in ovarian cancer biology because most people thought that this was a disease that originated in the ovaries. Another ovarian cancer type (endometrioid cancers) arise from the endometrium. The fallopian tube and endometrial pre-malignant or malignant cells migrate out of the female reproductive tract and find a very hospitable nesting place in the ovaries, which are very fertile soil for the proliferation of cancerous cells. This revelation helped critical crystallize the notion that ovarian cancer could be prevented in high-risk patients by removing the fallopian tubes and the ovaries after reproductive goals had been achieved.
How have research agendas changed since this report was released?
Immunotherapy for ovarian cancers was in its relative infancy at the time of the report, and there has been increasing interest in the use of immunotherapy. Several institutions have immunotherapy programs. It is not yet clear how effective this approach is going to be, but some patients have had excellent responses. These treatments are not without side effects, but they do offer the opportunity to treat disease that, in the past, was untreatable with standard chemotherapeutic approaches once the disease became resistant to standard platinum-based chemotherapy.
In terms of characterization of the types of tumors, it was noted that there were no uniform protocols to define the different types of ovarian cancers, which in some cases confounded the past literature. There was a call to standardize the way we identify and assess the extent of disease in patients with ovarian cancer. This standardized phenotyping is particularly important for improving clinical trials.
How has the prevention, treatment and management of ovarian cancer changed?
New therapeutic agents have become available: Poly (ADP-ribose) polymerase (PARP) inhibitors were approved by the FDA. They have a particular benefit in patients whose cancers have mutations in DNA repair genes. Three have been approved for the treatment of recurrent BRCA-associated ovarian cancer as well as maintenance therapy: olaparib (Lynparza, AstraZeneca); rucaparib (Rubraca, Clovis Oncology), and niraparib (Zejula, Tesaro). These are important advances that increased the therapeutic armamentarium.
At the time of the report, there was a great deal of variation in the application of genetic testing to identify individuals who are potentially high-risk. This is one of the areas where the report has had an impact, because it raised the visibility of screening for germline mutations that increase the risk of ovarian cancer, particularly BRCA1 and BRCA2 gene mutations. When the report was issued, some states had not embraced it as a universal approach to identify high-risk women. This can be done by “cascade testing” — finding an individual who has ovarian cancer or breast cancer, and screening relatives who are potentially at risk. After the report, ACOG issued practice bulletins to inform its members about the importance of cascade testing for hereditary cancers, most of which are preventable with prophylactic bilateral salpingo-oophorectomy.
What are the most important areas that still warrant attention?
The understanding of the biology of cancers. I was taught that ovarian epithelial cancer was a primary disease of the ovaries. Indeed, research was focused on the ovary up until a few years ago, when it became clear that if you carefully examined histological sections of the ovaries and the fallopian tubes in early disease, you would find that the initiating disease was often serous tubal intraepithelial carcinoma. That was a stunning revelation which has a big impact on screening strategies. Transvaginal ultrasonography is good for defining larger ovarian abnormalities but cannot identify the very small malignant lesions in the fallopian tubes. The development of methods to collect distal tubal cells and detect the characteristic molecular changes in them (the p53 oncogene signature) represents a new and viable approach for early detection of high-grade serous cancers. If these types of approaches are successful, there could be a significant change in population screening recommendations.
Ovarian cancer, particularly the type we are most concerned about because it is the most lethal — high-grade serous cancers — is a rare disease. This makes clinical trials at single centers difficult. The report called for collaboration and standardization of treatment protocols to increase clinical trial efficiency and shorten timelines.
Last, but not least, the dissemination of information and implementation of knowledge is critical. How do you implement cascade screening in an effective population-based manner so you can identify high-risk women? How can stakeholder organizations — medical societies and advocacy groups — come together and take the information that is available to make sure providers are up to date with the best approaches for disease detection and treatment? These are important issues since studies have reported better outcomes for women with ovarian cancers who are treated by experts.
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