Targeted Therapy Shows Promise for Aggressive Form of Uterine Sarcoma
A rare, aggressive form of cancer called uterine leiomyosarcoma, which affects roughly 2,500 women every year in the U.S., is often discovered entirely by accident. The malignant smooth muscle tumor arises in the uterus and is frequently detected during a routine gynecological surgery. Most patients show no symptoms before diagnosis, but if the cancer has spread to other parts of the body, the prognosis is extremely poor.
Results of a new phase 2 clinical trial demonstrate the potential of targeted therapy in combination with chemotherapy to treat patients with uterine leiomyosarcoma. The research, presented at the annual meeting of the American Society of Clinical Oncology held online June 4-8, was led by a team at the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian/Columbia University Irving Medcial Center. The drug combination resulted in durable responses with a progression-free survival of almost 7 months in a group of patients who progressed after front-line chemotherapy.
Second-line treatment options for uterine leiomyosarcoma provide limited benefit and are usually quite toxic. Only about 10 percent of patients respond, and even then, progression-free survival typically lasts a few months at the most. The trial aimed to test a novel therapy for uterine leiomyosarcoma called olaparib, a PARP inhibitor originally developed for individuals with BRCA1 or BRCA2 mutations.
“Uterine leiomyosarcoma is a deadly disease. In the metastatic setting, it is incurable, and even when resected, recurrences are high,” says Gary K. Schwartz, MD, deputy director of the HICCC, chief of Columbia's Division of Hematology and Oncology, and a co-investigator in the clinical trial. “Chemotherapy has been tried with only a very modest effect on improving survival. So our idea is to use precision medicine to define a subset of women who would benefit from a PARP inhibitor.”
The study involved 22 patients who received olaparib along with a low dose of temozolomide, a chemotherapy drug. Six patients (27%) had a durable response that lasted an average of 12 months. Side effects of the therapy, which mostly included low blood counts, were tolerable without any serious complications. Based on these promising initial results, the team is now working on the development of a large, randomized phase 3 clinical trial to test this drug combination against the current standard of care.
“We think that this will eventually become a new standard of care for patients with uterine leiomyosarcoma and will have a profound effect for women with the disease for which there are no available therapies,” adds Dr. Schwartz.
Olaparib works by blocking a family of proteins known as PARP that help repair damaged DNA. Harmful mutations in the BRCA1 or BRCA2 genes lead to faulty DNA repair, and further inhibiting this process with olaparib can cause cancer cells that carry a BRCA mutation to die.
However, other kinds of tumors can exhibit “BRCAness,” a more general term that refers to this same kind of defect in DNA repair with or without the specific BRCA mutations. Preclinical research from HICCC and other institutions confirmed the existence of BRCAness in uterine leiomyosarcoma, as well as the potential efficacy of combining PARP inhibitors with chemotherapy.
“This is a good example of research that went all the way from the laboratory to the clinic at Columbia,” said Matthew Ingham, MD, assistant professor of medicine in the Division of Hematology and Oncology at Columbia and the trial’s lead investigator. “These two avenues came together, the fact that this type of sarcoma was found with BRCAness and at the same time in Dr. Schwartz’s lab, the combination of PARP inhibitors with chemotherapy was really synergistic and seemed to be effective across a panel of uterine leiomyosarcoma cell lines.”
The team also analyzed the tumor biopsy data for genomic signatures of BRCAness that may predict which patients would benefit from taking olaparib. Early findings suggest that such a predictive biomarker does exist, although studies remain ongoing in this area.
