The decade-long paradigm shift in decoding ovarian cancer is only now beginning to make its way from research journals into clinical practice.
These changes will have a tremendous effect on the management of ovarian cancer, which is still treated as a single disease.
That’s the conclusion of Ronny Drapkin, MD, PhD, the Franklin Payne Chair in Gynecologic Oncology and director of the Penn Ovarian Cancer Research Center at the University of Pennsylvania Perelman School of Medicine in Philadelphia.
In an interview with Cancer Therapy Advisor, Dr Drapkin, who is also director, gynecologic cancer research, Basser Center for BRCA, spoke about how far management of ovarian cancer has come—and how far it still has to go.
Ovarian cancer is a heterogeneous disease. The most common subtype is high-grade serous carcinoma. Yet, unlike breast cancer, “all ovarian cancers still get treated the same way, regardless of biologic subtype,” he said. In addition, “most clinical trials still group all ovarian cancers together even though the biology is different.”
One of the greatest challenges of ovarian cancer is whether it can be detected early. With symptoms that are said to “whisper,” more than 70% of patients present with advanced disease and only 40% survive 5 years.1 In 2016, an estimated 22 280 new cases of ovarian cancer and 14 240 deaths will occur in the United States. Ovarian cancer is the leading cause of death from gynecologic cancer among US women and the fifth most common cause of cancer mortality.2
To date, no screening modalities are recommended to detect preclinical cases of ovarian cancer, and the few studies that have demonstrated increased detection have yet to show improved mortality with early detection.
Long-awaited results from the UK Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) of more than 200 000 initially cancer-free postmenopausal women, published in The Lancet, seemed to suggest that a yearly blood test may reduce ovarian cancer mortality by an estimated 20%, or 2 women for every 10. 1 It could also mean no women or 4 women for every 10. For that reason, the study—the largest ever conducted in ovarian cancer screening—will continue for another 3 years to establish the full impact.
When Dr Drapkin began working specifically in the ovarian cancer field about 15 years ago, “we knew next to nothing about it,” such as pathogenesis and genetics, he said. “Our understanding of the disease has changed dramatically in the last 5 to 10 years,” adding that “2 major advances have impacted our concept of early detection.”
“The first is the realization that many ‘ovarian’ cancers, especially high-grade serous carcinomas, actually start in the Fallopian tube. It is a tubal disease that secondarily involves the ovary. In this scenario, the ovary is a metastatic site. Therefore, early detection efforts have to focus on the Fallopian tube, rather than the ovary. Early precursor lesions have been described in the Fallopian tube and understanding the biology of those precursor lesions and how much time may elapse before they become invasive/malignant is an area of intense investigation at Penn and other places. Similarly, biomarkers for early detection will likely also come from the Fallopian tube and we have efforts in that area as well,” he told Cancer Therapy Advisor.
Somewhere between 50% and 80% of ovarian cancer is now believed to originate in the Fallopian tube, he indicated. For years, given the rarity of primary Fallopian tube cancer, few gave more than a cursory probe in cases of ovarian cancer—until the tubal fimbria were examined and cancers discovered at the distal end, “waiting for us to look in the right place.”
Dr Drapkin said that the second advance has been in genomics.
“Ovarian cancer is different than many other cancers in that it does not have many recurrent somatic mutations. The one exception is the nearly obligatory, or ubiquitous, mutation in the p53 tumor suppressor. Other than p53, there are hardly any other recurrent alterations. Rather, the disease is characterized by chromosomal derangements that include amplifications and deletions of segments or whole chromosome arms. In this regard, ovarian cancer is the most complete cancer studied to date. Therefore, searching for mutations other than p53 is not likely to be a fruitful endeavor in terms of early detection,” he said.
To date, only 2 biomarkers are approved by the U.S. Food and Administration: CA125 and human epididymis protein 4 (HE4), to monitor ovarian cancer recurrence or progression. OVA1, a multi-biomarker blood test, is FDA-approved to assess ovarian risk in the pre-surgical work-up of an adnexal mass.
Another rapidly evolving area is examining biomarker type.
“A significant effort has been focused on identifying tumor-associated proteins circulating in the blood,” he said. “There is a whole industry that revolves around serum-based biomarkers and finding 1 that works for early detection would make it easy to deploy in the clinical setting. That is why there has been so much effort on CA125. However, as we learn more about the biology of tumor cells we see that there are many other opportunities that might also contribute to early detection, including microRNA, exosomes, circulating tumor DNA (ctDNA), and tumor vascular markers.”
Currently, “there is a major effort at Penn to re-program the immune system to recognize and attack ovarian cancer,” he said. “This takes the form of adoptive cell transfer (tumor-infiltrating T cells), chimeric antigen receptors (CAR) on T cells (CART therapy), tumor vaccines, and the role of the gut microbiome, among others.
“We have also developed sophisticated animal models of ovarian cancer, including genetically engineered mouse models (GEMM) that faithfully recapitulate the clinical and genomic aspects of high-grade serous cancers.” In addition, they have created “a platform for patient-derived tumor xenograft (PDX) models, whereby the patient’s own tumor is implanted in a recipient mouse where it can grow and be expanded to do investigational drug studies,” he said.
Pointing out that only 59% of cases of ovarian cancer are detected by screening plus ultrasound, “we must and can focus on mechanisms of early cancer detection,” René H M Verheijen and Ronald P. Zweemer, of the Department of Gynaecological Oncology, Division of Surgical Oncology, UMC Utrecht Cancer Center, Utrecht, Netherlands, commented in The Lancet regarding the UKCTOCS trial.3
However, “awareness and symptom recognition for diagnosis of ovarian cancer at an early stage will be difficult to improve upon,” they wrote, adding that “screening will not be warranted until the UKCTOCS outcome has been validated in daily practice.”
- Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;387(10022):945-956.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.
- Verheijen RHM, Zweemer RP. Screening to improve ovarian cancer prognosis? Lancet. 2016;387(10022):921-923.
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