In a breakthrough study, Yale Cancer Center (YCC) researchers have defined the genetic characteristics of primary, metastatic and recurrent ovarian tumors and evaluated new targeted therapies to treat the disease. The findings are reported today in the Proceedings of the National Academy of Science (PNAS) online early edition.
Ovarian cancer is defined as the “silent killer”. Due to the lack of effective screening programs for early detection, it remains the most lethal gynecologic malignancy, with more than two-thirds of patients diagnosed with advanced-stage disease. It’s estimated more than 22,000 women will be diagnosed with ovarian cancer this year in the United States, with about 14,000 deaths.
In this study, the YCC team analyzed ovarian tumors from 64 primary, 41 metastatic, and 17 recurrent tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). The collaborative team—which included researchers with expertise in gynecological cancer, genomics, pathology, pharmacology and computational biology— identified a number of genes frequently mutated in primary-metastatic and chemotherapy-resistant ovarian tumors, including c-MYC and PIK3CA, which were highly prevalent and maintained in progression to metastasis and tumor recurrence.
“We have identified striking genetic similarities between primary and metastatic ovarian tumors as well as ovarian tumors arising simultaneously on both ovaries,” said senior author of the study Alessandro Santin, MD, leader of the Disease Aligned Research Team of the Gynecologic Oncology Program at Smilow Cancer Hospital. “These genetic results obtained in matched tumor samples from the same patient provide support to the view that spreading to the abdominal cavity takes place very early during the natural history of ovarian cancer.”
In this research, genetic results in simultaneously arising bilateral ovarian tumors revealed a branching structure suggesting they all share a common ancestry before evolving independently. These results, combined with the striking genetic similarity found between primary and metastatic tumors, provide a molecular explanation to why screening programs for early detection and active surveillance of ovarian cancer have so far failed.
“Ovarian tumors harbor since inception genetic characteristics which allow rapid shedding and engraftment of tumor cells from the primary site (most likely the fallopian tubes) to the abdominal cavity,” said Santin. “These findings may pose formidable clinical challenges for the early detection of ovarian cancer through active screening/surveillance.”
These findings may pose formidable clinical challenges for the early detection of ovarian cancer through active screening/surveillance.
Dr. Alessandro Santin
In the study, about 50% of patients were found to harbor a germinal or somatic damaging mutation in a homologous recombination repair (HRR) gene implicated in ovarian cancer predisposition. These data suggest that evaluation of HRR deficiency may represent a cost-effective approach for the identification of ovarian cancer patients potentially benefitting the most from PARP-inhibitor treatment. Importantly, c-MYC amplified chemotherapy-resistant ovarian cancer cell lines and xenografts were sensitive to GS-626510 in preclinical experiments, suggesting BET inhibitors as an effective class of targeted therapeutics in patients with c-MYC–amplified recurrent/chemotherapy-resistant ovarian tumors.
“The detailed study, comparing matched primary, metastatic and recurrent ovarian tumors, continues to produce new and unexpected discoveries,” said corresponding author Joseph Schlessinger, Ph.D., co-director of the Yale Cancer Biology Institute. “The findings better define the biological basis of this cancer and suggest new opportunities for personalized therapy.”
Other authors on the study include first author Charles Li, Elena Bonazzoli, Stefania Bellone, Jungmin Choi, Weilai Dong, Gulden Menderes, Gary Altwerger, Chanhee Han, Aranzazu Manzano, Anna Bianchi, Francesca Pettinella, Paola Manara, Salvatore Lopez, Ghanshyam Yadav, Francesco Riccio, Luca Zammataro, Burak Zeybek, Yang-Hartwich Yang, Natalia Buza, Pei Hui, Serena Wong, Antonella Ravaggi, Eliana Bignotti, Chiara Romani, Paola Todeschini, Laura Zanotti, Valentina Zizioli, Franco Odicino, Sergio Pecorelli, Laura Ardighieri, Dan-Arin Silasi, Babak Litkouhi, Elena Ratner, Masoud Azodi, Gloria S. Huang, Peter E. Schwartz, Richard P. Lifton, and Joseph Schlessinger.
The researchers were supported as part of a collaborative program with Gilead Sciences, Inc., as well as grants from the National Institutes of Health, the National Cancer Institute, the Deborah Bunn Alley Ovarian Cancer Research Foundation, The Honorable Tina Brozman Foundation, the Discovery to Cure Foundation, the Stand Up to Cancer Foundation, and the Guido Berlucchi Foundation.