PO.CL01.22 · 临床研究
Tumor-informed circulating tumor DNA identifies high-grade serous ovarian cancer patients at highest risk for recurrence despite optimal first-line treatment with primary macroscopic complete resection
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摘要 Abstract
Background: Complete macroscopic tumor resection estimation as visualized by the surgeon is the foremost prognostic factor in high-grade serous ovarian cancer (HGSOC). Objective measures of postoperative molecular residual disease (MRD) are lacking, including serologic and radiologic evaluation. Tumor-informed circulating tumor DNA (ctDNA) has shown promise as a new approach to identify patients at higher risk for relapse.
Methods: This prospective bicentric study included advanced HGSOC patients (pts) undergoing primary debulking surgery (PDS), six cycles of chemotherapy and maintenance therapy (07/2021 - 09/2024). Whole-genome sequencing of tumor tissue identified structural variants, used to design personalized multiplex dPCR assays to detect MRD. Plasma samples were collected: perioperatively (preop, postop day[d]2 and d10), during chemotherapy (C1, C3, C6) and every 3 months (mo) until progression or 24 mo of follow up (FU). CA-125 was analyzed accordingly (cutoff 35 kU/L). Statistics included chi-square and log-rank tests, multivariate Cox model and Kaplan-Meier estimates for progression-free survival (PFS).
Results: 33/84 pts (39%) experienced relapse with a median PFS of 12.0 mo during a median FU time of 15.4 mo. ctDNA was detected in 77/82 pts (94%) at baseline and in 63/74 pts (85%) postoperatively. At postop d10, pts with complete tumor resection had significantly lower ctDNA levels than pts with postop residual disease ( p =0.0018). Median ctDNA level decreased by 94% between preop and postop d10 in pts with complete tumor resection ( p =0.0247), but not in pts with postop tumor residuals ( p =0.891). Within the pt subgroup with complete tumor resection, ctDNA clearance at C1 (20%) and C6 (70%) was associated with significantly lower recurrence risk compared to persistent ctDNA levels (C1: 80%, C6: 30%) with a stronger association at C6 (C1: HR=3.39, p =0.0470, C6: HR= 52.21, p <0.0001). Median time to recurrence in the C6 ctDNA positive group was 10.7 mo compared to 21.3 mo in the ctDNA negative group. This effect was not observed at postop d10 ( p =0.273) or for pts with residual tumor. ctDNA outperformed CA-125 for prognosis, as CA-125 levels at C1 or C6 failed to predict recurrence (C1: p =0.189; C6: p =0.165). In a multivariate analysis, ctDNA persistence at C6 (HR=14.58, p <0.0001) and postoperative residual tumor were confirmed as independent prognostic markers.
Conclusion: Tumor-informed ctDNA analysis can further accurately stratify HGSOC pts at high risk of recurrence despite primary surgery with complete macroscopic resection. ctDNA assessment at C6 may provide an opportunity window for risk-stratified treatment adjustments directly after chemotherapy, enabling new personalized maintenance strategies.
利益披露 Disclosure
M. Postl, None..
C. V. Tauber, None..
V. Glueck, None..
M. M. Gliga, None.
N. Segui,
SAGA Dx Employment, Other, Shareholder.
K. Howarth,
SAGA Dx Employment, Other, Shareholder.
M. Alcaide,
SAGA Dx Employment, Other, Shareholder.
L. Oton,
SAGA Dx Employment, Other, Shareholder.
G. Hofstetter, None..
I. Maurer, None..
A. Burges, None.
S. Mahner,
AbbVie Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
AstraZeneca Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Clovis Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Daiichi Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Eisai Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
GlaxoSmithKline Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Hubro Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Immunogen Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Medac Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
MEDiSTRAVA (Inizio Co.) Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
MSD Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Novartis Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Nykode Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Olympus Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
PharmaMar Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Pfizer Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Roche Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Seagen Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Sensor Kinesis Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
Teva, Tesaro Other, Lectures, Advisory Board, Grants, Honoraria, Congress & Travel Support.
M. Kessler, None..
M. Danisch, None..
S. Polterauer, None.
N. Concin,
AbbVie Other, Consulting/Advisory.
MSD Other, Consulting/Advisory, Educational fees.
ImmunoGen Other, Consulting/Advisory.
Seagen Other, Consulting/Advisory.
Akesobio Other, Consulting/Advisory.
EISAI Other, Consulting/Advisory.
GSK Travel, Other, Consulting/Advisory.
AstraZeneca Other, Consulting/Advisory.
Mersana Other, Consulting/Advisory.
Seattle Genetics Other, Consulting/Advisory.
eTheRNA immunotherapies NV Other, Consulting/Advisory.
Kartos Other, Consulting/Advisory, Educational fees.
Daiichi-Sankyo Other, Consulting/Advisory.
Chorus Group Other, Consulting/Advisory.
Pharma& Other, Consulting/Advisory.
Amgen Travel.
Genmab Travel.
Roche Travel.
Medtronic Travel.
Medscape Oncology, TouchIME, FOMF, Med Media Verlag und Mediaservice GmbH, MEDahead, Springer Verlag, NSGO, NOGGO, OEGGG Akademie, DOC Congress, Müller Media Other, Educational fees.
C. Grimm,
AstraZeneca ), Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
Eisai ), Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
Meda Pharma Other, Receipt of grants/research supports.
Roche Other, Receipt of grants/research supports, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
Abbvie Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
Celgene Other, Receipt of honoraria or consultation fees.
Clovis Other, Receipt of honoraria or consultation fees.
GSK Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
MSD Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
PharmaMar Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
Vifor Pharma Other, Receipt of honoraria or consultation fees.
Sandoz Other, Receipt of honoraria or consultation fees, Participation in a company sponsored speaker’s bureau.
Amgen Other, Participation in a company sponsored speaker’s bureau.
F. Trillsch,
AbbVie ).
AstraZeneca ).
Eisai ).
GSK ).
ImmunoGen ).
MSD ).
Regeneron ).
Roche ).
SAGA diagnostics ).