In patients with ovarian cancer, second-look surgery may find a role again. The evaluation of measurable residual disease (MRD) using second-look laparoscopy identified more women who had detectable MRD after front-line treatment than did circulating tumor DNA (ctDNA), according to a study presented at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer.¹

“Both MRD detection methods were able to identify women at high risk for recurrence, and those who were ctDNA-positive had a particularly poor prognosis,” said Anne Knisely, MD, a fellow in gynecologic oncology at The University of Texas MD Anderson Cancer Center, Houston. For patients who had ctDNA positivity and detectable MRD, their outlook was particularly poor, she added.

Dr. Knisely provided these background comments: “Historically, second-look laparotomy was used in advanced ovarian cancer to assess for residual disease after adjuvant chemotherapy. Although studies at that time found that negative second looks were associated with improved progression-free survival, second-look laparotomy fell out of practice, given its morbidity as a large, open surgery and the fact that extending the duration of limited chemotherapy options at the time did not appear to improve survival.”

However, treatments have changed, as targeted agents have become available and as minimally invasive surgery has become routine. Consequently, Dr. Knisely and her colleagues decided to revisit second-look procedures as a new way to identify MRD. The ultimate goal with identifying and understanding MRD, she said, is to be able to target this residual cancer “at a time when the tumor burden is lowest.”

Study Outcomes

Their single-center study included 44 patients with high-grade epithelial ovarian cancer who achieved a complete radiologic response and normalization of CA-125 after front-line treatment. Patients underwent second-look laparoscopy and concurrent plasma sampling for ctDNA evaluation. Their ctDNA assay (Signatera) is a personalized tumor-informed approach that has been validated as a prognostic marker for recurrence across numerous solid tumors.

Second-look laparoscopy revealed that 50% of the patients had surgically detected MRD, whereas ctDNA identified 34% who had dectectable MRD. Among patients with surgically detected MRD, half also had detectable ctDNA, Dr. Knisely reported.

Patients with detectable MRD at the time of second-look laparoscopy had a median progression-free survival of 9.9 months compared with 28.1 months for those with undetectable MRD (hazard ratio [HR] = 2.8; P = .009). Similar to the surgical MRD cohort, patients with ctDNA positivity at the end of upfront treatment also had significantly shorter progression-free survival, with a median of 7.4 months vs 28.1 months in those with ctDNA negativity (HR = 5.3; P < .001).

Dr. Knisely and colleagues looked at the four possible combinations of surgery and ctDNA outcomes. Patients who were identified both surgically and by ctDNA to have undetectable MRD had the best median progression-free survival, 36.4 months, whereas those who were identified as having detectable MRD by both methods had the shortest median progression-free survival, 7.4 months.

“This demonstrates the complementary nature of the two approaches,” Dr. Knisely said. “Both MRD detection methods were able to identify women at high risk for clinical recurrence, with ctDNA positivity representing a subgroup with a particularly poor prognosis. Although second-look surgery identified more women with detectable MRD, ctDNA provided a less invasive means of MRD detection.”

What’s Next?

MRD detection may help with risk stratification of patients, serve as a treatment decision-making guide, and, ultimately, serve as a surrogate endpoint in clinical trials to help move novel agents into earlier lines, Dr. Knisely predicted.

“In terms of tangible next steps, we are participating in the first multi-institutional clinical trial for front-line ovarian cancer to use surgically detected MRD as the primary endpoint. Patients are randomly assigned to receive standard-of-care neoadjuvant therapy with or without intraperitoneal interleukin-12,” she explained. “We believe this trial will serve as proof of principle for the use of MRD as a surrogate endpoint in future front-line trials, to accelerate drug development and de-risk innovation.” 

Expert Point of View

Helen Mackay, MBChB, MD

Commenting on the results from the study, Helen Mackay, MBChB, MD, said these results cover a key issue in ovarian cancer and are hypothesis-generating. Dr. Mackay is Head of the Division of Medical Oncology & Hematology, Sunnybrook Odette Cancer Centre, Toronto, Canada.

“If we can detect disease early, before clonal expansion and heterogeneity make our job harder in terms of eradicating disease, perhaps we can better assist patients,” Dr. Mackay said. “Patients with ctDNA do badly, and obviously, interventions are needed,” she added, as multiple studies have shown.

However, she pointed out, the study raises some important questions: “Do we need to do both laparoscopy and ctDNA (circulating tumor DNA) analysis? Obviously, this has challenges in more resource-constrained areas. Does it need to be a personalized approach, or is there a more off-the-shelf version? Do we use serial ctDNA measures or other blood-borne biomarkers? And looking to the future, can we think about integrated models with machine-based learning to produce individual signatures for patients?”

Dr. Mackay concluded: “We need action in this space to improve outcomes for patients diagnosed with this disease, so trials are much warranted.”

DISCLOSURE: Dr. Knisely reported no conflicts of interest. Dr. Mackay has served on advisory boards for AstraZeneca, GlaxoSmithKline, Eisai, and Merck.

REFERENCE

1. Knisely A, Lee S, Nitecki R, et al: Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Presented March 16, 2024.