Résumé
Background: Patients (pts) with breast cancer (BC) not achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) are at higher risk of relapse. The multicenter ALIENOR study (NCT03357120), conducted in patients who did not achieve pCR after NAC, is aiming to assess the prognostic value of serial ctDNA monitoring with a novel personalized, tumor-informed ctDNA assay predicated on detection of structural variants (SVs) in plasma. Here, we report the first of two pre-planned analyses from this study (3-years from last patient enrolled). Methods: Pts with cT2cN1, cT3cN0-1 or locally advanced (cT4cN0-3 or cT1-4cN2-3) M0 BC of any immunohistochemical subtype not reaching pCR after NAC (6 to 8 cycles) were eligible. Pts were enrolled into a 5-year plasma surveillance period (first plasma sample taken 10 to 63 days after surgery, then every 6 months for up to 5 years). A clinical assessment was performed every 6 months. Tumor blocks from surgical specimens were centrally assessed by one investigator (GMG). Tumors with >20% invasive tumor cells and at least 100 ng of DNA were evaluable. Whole genome sequencing (WGS) was performed on tumor material and personalized multiplex dPCR assays designed tracking up to 8 structural variants (SVs) for use in ctDNA analyses on all available plasma time points (SAGA Diagnostics; Lund, Sweden). Results: 119 pts were eligible for enrollment and 87 were available for ctDNA analyses. 79 of 87 pts (91%) underwent successful SV-personalized panel design (median of 7, range 4-8 SVs per patient): 463 plasma samples underwent ctDNA testing. BC subtypes included: 41 luminal HER2-, 20 HER2+ and 18 triple-negative. At a median follow-up of 54.5 months (95% CI: 53.3-56.2) from surgery, 21 of 79 pts relapsed (distant: 19 pts, locoregional: 2 pts, distant and locoregional: 1pt). Pts with detected ctDNA, whether at any time point in surveillance (n=32) or at a landmark pre-adjuvant time point (10 to 63 days post-surgery) (n=15) had shorter recurrence-free interval (RFI): HR 20.6 (95% CI 4.8-88.8; p<0.0001) and 2.5 (95% CI 1.0-6.2; p<0.05), respectively. The median lead-time from ctDNA detection to clinical relapse was 12.2 months (range 3.4-60.6). ctDNA was detected at any time-point in 90.5% (19/21) of pts who relapsed. Of 32 pts with ctDNA detected at any time point, 19 relapsed (59.4%) and 13 are still relapse-free at last follow-up. In this later group, 6 pts positive at landmark time point only, were subsequently cleared in all time points, 3 pts positive at the last visit time point only, are pending longer follow up, and 4 pts had multiple positive ctDNA time points including several with rising levels of ctDNA. Of 47 pts with no ctDNA detected, 2 relapsed (4.3%): one with local relapse; one with brain-only metastasis. The univariate analysis showed that clinical stage, BC subtype, RCB, and age were not statistically associated with RFI. Conclusions: Serial ctDNA assessment using a novel SV-based assay is predictive of relapse with lead-times of up to 61 months over clinical relapse. These data support further evaluation of this assay in prospective trials. Landmark-only ctDNA detection followed by clearance on therapy might represent micrometastatic disease controlled or eradicated by adjuvant treatment. Longer follow-up is required in cases with ctDNA detection without clinical relapse to fully characterize clinical accuracy and lead-times associated with SV-based ctDNA surveillance.
Citation Format: Hervé Bonnefoi, François-Clément Bidard, Lucas Hue, Karen Howarth, Florence Dalenc, William Jacot, Jean-Yves Pierga, Marina Pulido, Laurence Venat-Bouvet, Valérie Dumas, Marine Maréchal, Caroline Lalet, Sofia Birkeälv, Laura Salabert, Gaetan Mac Grogan. Tracking structural variants in ctDNA using a high-sensitivity assay predicts relapse in the post-neoadjuvant setting: the multicenter ALIENOR trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS9-06.