乌鸦传媒

CHICAGO -- The use of circulating tumor (ct)DNA analysis following upfront surgery for early-stage pancreatic cancer to guide adjuvant chemotherapy de-escalation did not appear to influence outcomes, according to a prospective study.

While median recurrence-free survival (RFS) was 22 months in ctDNA-negative patients versus 13 months in ctDNA-positive patients (HR 0.28, P=0.003), no difference was found when patients were stratified by adjuvant chemotherapy regimen (17 months with modified FOLFIRINOX vs 16 months with gemcitabine plus capecitabine; HR 0.96, P=0.86), reported Belinda Lee, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

Of note, among patients who were ctDNA-negative, those who were treated for 6 months with adjuvant chemotherapy had a median RFS of 26 months compared with 18.5 months for those who were treated for 3 to 4 months (HR 0.64, P=0.159).

"Although not statistically significant, there does appear to be a trend toward better and longer RFS in those who received 6 months of adjuvant chemotherapy," said Lee during the American Society of Clinical Oncology (ASCO) annual meeting.

Similarly, median RFS was 27 months for those who received modified FOLFIRINOX versus 18 months for those who received gemcitabine plus capecitabine in the ctDNA-negative cohort (HR=0.63, P=0.09).

In the ctDNA-positive cohort, RFS was 13 months regardless of whether patients had a treatment duration of 6 months or <6 months (HR 0.93, P=0.84), and there was no difference in median RFS between those who received modified FOLFIRINOX or gemcitabine plus capecitabine (13 vs 14.5 months; HR 0.69, P=0.29).

Any gains in survival for early pancreatic cancer "are dependent on developing better strategies that optimize adjuvant chemotherapy choices and better treatments," Lee concluded.

The findings from this study are consistent with those from previous studies showing that pancreatic tumor-informed ctDNA positivity is prognostic, said ASCO-invited discussant Stacey Cohen, MD, of the University of Washington in Seattle.

The chemotherapy heterogeneity in this study makes extrapolation of the data difficult, she noted, as bias could potentially be introduced when allowing for physician discretion.

For ctDNA-guided decision making to work, the assay needs to be optimized, the clinical scenario needs to be honed, and the treatment options need to be homogenized, she added.

While data are emerging for the use of ctDNA in pancreatic cancer "we are not ready to use this in standard practice," said Cohen, but the study provides "a great first step to question current paradigms and [should] be further evaluated in future clinical trials."

DYNAMIC-Pancreas is a prospective, multicenter, biomarker-driven treatment study in patients with localized pancreatic adenocarcinoma undergoing immediate resection and adjuvant therapy.

"With a short half-life of approximately 2 hours, ctDNA is a dynamic reflection of tumor burden," said Lee. "ctDNA is therefore also a real-time indicator of adjuvant therapy benefit. We proposed that ctDNA therefore could improve patient stratification ... to help guide treatment decisions."

A total of 102 patients undergoing curative-intent surgery who were deemed fit for adjuvant chemotherapy were included in the study. Median age was 68, 50% were men, and 72% had tumors at the head of the pancreas. Pathological nodal stage was N+ in 71% of patients, and resection margin status was R0 in 77%.

All had a blood draw for ctDNA 4 to 6 weeks after surgery. They were divided into two cohorts based on the type of adjuvant chemotherapy given. All had biomarker-informed ctDNA results and were then further divided into ctDNA-positive and -negative cohorts.

If they were ctDNA positive, the intention was that patients would receive the full 6 months of adjuvant chemotherapy. If they were ctDNA-negative, they could be de-escalated at the treating clinician's discretion (3 to 4 months).

Of the 102 patients, 98 had matched blood and suitable sufficient tumor tissue available, and KRAS mutations were identified in 94 through a tumor-informed polymerase chain reaction-based assay.

Sixty-four patients received modified FOLFIRINOX, and 34 received gemcitabine plus capecitabine. Patients had clinical follow-up every 3 months and CT imaging every 6 months.

ctDNA collection was performed at a median of 5 weeks, at which time 41% were ctDNA positive and 55% were ctDNA negative (4% had an absence of tumor mutation).

The median time to the start of chemotherapy was 6 weeks. Some 55% of clinicians said that they would de-escalate treatment if the patient was found to be ctDNA negative, "but in reality, 67% of patients in the ctDNA-negative cohort received less than 4 months of chemotherapy," Lee said. "The reasons cited for this were basically toxicity, as well as patient preference. In the ctDNA-positive cohort, the plan was to receive the full 6 months of adjuvant chemotherapy, but in reality only 50% received 6 months ... early cessation was due to toxicity in 33% and relapse in 18%."

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