As part of the Profile research project at Dana-Farber, Brigham and Women’s Hospital, and Boston Children’s Hospital, investigators have scanned hundreds of endometrial tumor samples for genetic abnormalities associated with cancer. As more and more samples are analyzed, scientists are exploring whether endometrial cancer is a fairly uniform disease, or, more likely, whether it comprises several molecular subtypes, each with its own set of genetic flaws.
These efforts have already yielded some valuable insights. Researchers recently found, for example, that the genes ARID1A and POLE are often mutated in endometrial cancers, says Panos Konstantinopoulos, MD, PhD, of the Gynecologic Oncology Program at the Susan F. Smith Center for Women’s Cancers at Dana-Farber.
Studies also have uncovered abnormalities in certain genetic “pathways” – signaling circuits consisting of multiple genes – in some endometrial tumors. These include the PI3K pathway, which is altered in a variety of cancers and is the subject of intense efforts to attack with new drugs, and the mismatch repair (MMR) pathway, which is involved in mending damaged cell DNA. Each abnormality represents a possible weak spot in endometrial cancer’s cellular machinery and a potential target for therapies.
“As this type of research progresses, we hope to move from traditional hormonal treatments to a more personal approach based on the molecular make-up of each patient’s tumor,” Konstantinopoulos says.
He notes that because endometrial cancer is often detected in its early stages, treatment with surgery, radiation and/or chemotherapy, as well as hormonal therapy, usually cures the disease. When the disease has spread beyond its initial site, the main treatments – chemotherapy and hormonal therapy – often aren’t as successful. For these cases, targeted therapies and, possibly, future immune system-based therapies holds the greatest promise. Research at Dana-Farber has shown, in fact, that endometrial cancers with a defective MMR pathway or POLE mutation appear to be more sensitive to immune system-based therapy.