AT THE ANNUAL MEETING ON WOMEN’S CANCER
SAN DIEGO (FRONTLINE MEDICAL NEWS) – Following chemotherapy and surgery for gynecologic cancer, circulating tumor DNA identified recurrence in six of 32 women a mean of 7 months before it was detected on CT scan, Dr. John Martignetti reported at the annual meeting of the Society of Gynecologic Oncology. “The CT scan did not pick up cancer that ctDNA [circulating tumor DNA] did.” Meanwhile, while essentially every patient had detectable ctDNA when tumor was present on CT, only about 60% had elevated cancer antigen 125 (CA-125) levels, said Dr. Martignetti of the Icahn School of Medicine at Mount Sinai, New York.
In a subgroup of 10 patients with known survival outcomes, five with no ctDNA after primary treatment had 22-33 months progression free survival, and all were alive at up to 5.4 years follow-up. Four of the five with ctDNA after primary treatment died within 29 months; the other patient progressed immediately and was alive with disease at 4.8 years.
“We demonstrated for the first time that personalized ctDNA biomarkers in gynecologic cancers can detect the presence of residual tumor earlier than currently used serum and imaging studies and are an independent predictor of survival. [They] dynamically predict treatment response and survival in gynecologic cancers. The measurement of ctDNA in blood – dubbed liquid biopsy – is “a powerful emerging technology capable of providing accurate assessment of both tumor behavior and disease burden,” Dr. Martignetti said.
“These mutations are only made in cancer cells,” so if they are in the blood, there must be cancer somewhere, he said.
The Sinai team identified specific mutations – in, for example, P53 tumor suppression, beta-catenin, or BRAF genes – in tumor cells from 36 of 44 women, using targeted sequencing for likely mutations in 28 samples and whole exome sequencing in eight. Blood samples were checked for ctDNA in 32 women by droplet digital PCR; ctDNA was detected in 30 (94%). The patients had high-grade endometrial carcinomas or high-grade serous carcinomas of the ovary, fallopian tube, or peritoneum.
For six women, ctDNA detected recurrence 1-11 months before CT. In once case, CA-125 was within normal limits a month before bowel resection for recurrence, and a PET scan 3 months before was negative. “Seven months before her surgery, we could detect ctDNA,” Dr. Martignetti said. For the rest of the women, sensitivity and specificity correlated with CA-125 and CT.
Mount Sinai has been working on ctDNA for almost a decade, and is among the pioneers in the field. Every gynecologic cancer patient there has tumor samples collected for sequencing and blood samples for ctDNA testing.
With ctDNA, “you can monitor the evolution of tumor growth, response to treatment, acquired resistance, and development of tumor heterogeneity.” If there’s no ctDNA, it seems likely “that patients can go home and say ‘whew.’ Lingering mutations” suggest the need for closer follow-up and perhaps additional chemotherapy.
The ultimate goal of liquid biopsy is to tailor cancer treatment to specific tumor mutations. Patients with fibroblast growth factor receptor (FGFR) gene mutations could get an FGFR inhibitor; ovarian tumors with lung cancer mutations might get lung cancer drugs. The approach is being tested by the National Institutes of Health through the NCI-MATCH trial .
It seems likely there’s also a role in screening. The Sinai team detected tumor DNA mutations in the uterine lavage fluid of a woman who presented with postmenopausal bleeding. A week later, pathology identified a microscopic stage 1, grade 1 endometrial cancer in situ. “That’s the future,” Dr. Martignetti said.