Copy number aberration burden on circulating tumor DNA predicts recurrence risk after neoadjuvant chemotherapy in patients with triple-negative breast cancer: Post-hoc analysis of phase III PEARLY trial.
Authors: Kim Min Hwan , Kim Gun Min , Kim Seul-Gi , Ahn Jin Mo , Kim Jee Hung , Kim Jeeye , Park Hyung Seok , Park Seho , Park Byeong-Woo , Kim Seung Il , Jeong Joon , Lee Ji Eun , Paik Soonmyung , Kim Sang Woo , Jung Kyung Hae , Cho Eunhae , Sohn Joohyuk 
Published: June 2022

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Background: Our previous study reported prognostic significance of copy number aberration (CNA) burden on low-pass whole genome sequencing (LP-WGS) based circulating tumor DNA (ctDNA) analysis in metastatic breast cancer patients. Here, we report the prognostic value of ctDNA CNA burden measured before neoadjuvant chemotherapy in stage II-III triple-negative breast cancer (TNBC) patients enrolled in phase III PEARLY trial (NCT02441933, BIG Supporter Study BIG 19-01, KCSG BR15-01). Methods: The PEARLY trial was performed as a randomized, open-label, multicenter, phase III study to test the efficacy and safety of adding carboplatin to (neo)adjuvant chemotherapy in patients with stage II-III TNBC. Patients were randomized in a 1:1 ratio to receive 4 cycles of AC followed by the taxane or taxane plus carboplatin (AUC 5, tri-weekly 4 cycles) as neoadjuvant or adjuvant therapy. This post-hoc baseline ctDNA analysis (before neoadjuvant chemotherapy) included only the neoadjuvant patient cohort with available baseline ctDNA results (n = 465, median follow-up 16.8 months), while it was blinded for randomization information (carboplatin or not). We used "I-score" method to estimate CNA burden of ctDNA by LP-WGS to be matched with disease-free survival (DFS) after primary surgery. Results: The baseline ctDNA I-score level was positively associated with clinical T and N stage, while baseline I-score was not different between patients with pathologic complete response (pCR) and non-pCR. We listed 465 patients in the order in which they underwent primary surgery, and then alternated patients to be assigned to exploratory cohort (n =232) and validation cohort (n = 233). The DFS was significantly shorter in high I-score (I-score ≥ 7.81) patients compared with low I-score (I-score < 7.81) patients in exploratory cohort. The high I-score independently predicted poor DFS adjusted for clinical T stage, clinical N stage, and pCR status (hazard ratio [HR] 3.88, p = 0.003). In the validation cohort, high I-score was validated to be associated poorer DFS, and multivariate Cox analysis validated the independent prognostic impact of I-score on DFS (HR 2.04 , p = 0.050). The high baseline I-score patients showed shorter DFS both in pCR-positive and pCR-negative patients. The 12-month DFS rate for pCR (+)/Low I-score patients was 98%, whereas that of pCR(-)/High I-score patients was 61.3 % in the validation cohort. Conclusions: The baseline ctDNA CNA burden on LP-WGS before neoadjuvant chemotherapy robustly predicts recurrence risk in stage II-III TNBC patients. The ctDNA I-score showed prognostic value independently from pCR status, suggesting ctDNA I-score can serve as a useful clinical determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients. Clinical trial information: NCT02441933.