Circulating tumor DNA detection after neoadjuvant chemotherapy and prediction of distant relapse free survival, local recurrence, and distant recurrence in triple-negative breast cancer in the TRICIA study.
Authors: Aguilar Adriana , Roseshter Talia , Klemantovich Anna , Cavallone Luca , Lafleur Josiane , Lan Cathy , Elebute Oluwadara , Jenna Sarah , McNamara Suzan , Boileau Jean-Francois , Pelmus Manuela , Pezo Rossanna C. , Brackstone Muriel , Ng Terry L. , Basik Mark 
Published: July 2024

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Background: Patients with triple negative breast cancer who have a residual tumor at surgery (non-pCR) following neoadjuvant chemotherapy (NAC) have a very poor prognosis. Additional adjuvant capecitabine improves relapse-free survival (RFS) by 15%. There is a need for biomarkers to identify patients who may not require adjuvant capecitabine. The TRICIA trial (NCT04874064) accrued non-pCR TNBC patients for ctDNA measurements at pre-operative (T1), post-operative (T2), 3-month (T3) and 6-month (T4) time points using hospital-based tumor-specific personalized assays. Methods: Whole exome sequencing was performed on FFPE TNBC residual tumors or biopsies to select 5 variants/patient for Digital droplet PCR (ddPCR) assays. Patients with ≥1 detectable mutation were considered ctDNA positive. ctDNA detection was correlated with Relapse Free Survival (RFS), local recurrence, distal recurrence, overall survival (OS) and residual cancer burden (RCB) score. Results: 79 patients were recruited with a median follow-up of 32.9 months post-surgery. 32 of 79 patients relapsed and the median RFS for these patients was 8.7 months. The RCB score distribution was: 17 RCB1, 41 RCB2 and 21 RCB3. Of the 4 time points, ctDNA detection at T1 is the strongest prognostic factor for both RFS (HR=0.19, p<0.0001, 95% CI= 0.09 – 0.40) and OS (HR=0.19, p=0.0007, 95% CI= 0.08 – 0.5). 21/22 (95%) patients without detectable ctDNA at T1 did not have distant disease relapse, whereas 66% with detectable ctDNA (27/41) developed either local and/or distant disease relapse. The post-operative (T2) time point was not prognostic whereas the post-capecitabine time point (T4) was weakly prognostic. All 14 RCB3 patients that relapsed and had T1 plasma had detectable ctDNA at T1 while none of the 5 RCB3 patients without relapse had detectable ctDNA at T1. The one RCB1 patient with detectable ctDNA also relapsed. 53 patients received adjuvant capecitabine. ctDNA at T1 remained the strongest prognostic factor associated with RFS (HR=0.16, p<0.0001, 95% CI=0.06-0.4), with none of the ctDNA negative patients showing distant relapse. ctDNA clearance after Xeloda was not associated with prognosis. CtDNA was detectable at T1 in 3 of 4 patients who eventually developed local recurrence with a median lead time of 10 months. Detectable ctDNA was observed in 96% of patients (27/28) with distant recurrence and the median time from ctDNA appearance to recurrence was 9.1 months. Conclusions: A hospital-based tumor bespoke assay provides very strong prognostic information when performed after NAC and before surgery. Local and distant recurrence can both be predicted with a lead time of 9-10 months from the appearance of detectable ctDNA. These results validate the use of a hospital-based tumor bespoke platform for clinical testing. Clinical trial information: NCT04874064 .