Background: Neoadjuvant chemotherapy (NAC) is a standard approach for many patients with triple negative breast cancer (TNBC). Our group, and others, have previously reported that the detection of circulating tumor DNA (ctDNA) after NAC and surgery is a surrogate for the presence of minimal residual disease (MRD) leading to inferior survival outcomes. Further, our group has also reported that the emergence of somatic TP53 mutations in tissue samples post-NAC was associated with inferior survival outcomes. In this study, we sought to determine whether TP53 mutations detected in the plasma of patients with ctDNA-positivity after NAC was associated with inferior outcomes compared to non-TP53 mutated patients.
Methods:BRE12-158 was a phase II clinical trial which randomized early-stage TNBC patients with residual disease after NAC to post-neoadjuvant genomically-directed therapy vs treatment of physician choice. 196 patients were enrolled. Patients had blood samples collected for ctDNA at the time of post-neoadjuvant treatment assignment. ctDNA was successfully sequenced using the FoundationACT or FoundationOneLiquid Assay in 142 patients. Patients who were ctDNA positive after NAC (N=90, 63%), were selected for this comparison. Median clinical follow-up was 22.9 months. A multivariate cox proportional-hazards model was used to compare DDFS, DFS, and OS of ctDNA-positive patients with and without TP53 mutations found in the ctDNA.
Results: 90 patients in BRE12-158 were ctDNA-positive after NAC and surgery. 36/90 (40%) of those patients had TP53 mutations detected in their plasma. Patients with TP53-mutated ctDNA had significantly inferior outcomes and a significantly shorter time to recurrence when compared to those without TP53 mutations. Detection of TP53-mutated ctDNA was significantly associated with an inferior DDFS (median DDFS: 6.99 months vs. 48.69 months; HR=2.78, 95%CI: 1.41-5.49; p=0.0033). At 24 months, the DDFS probability was 36% in TP53-mutated patients as compared to 72% in non-mutated patients. Similarly, detection of TP53-mutated ctDNA was significantly associated with an inferior DFS (median DFS: 4.83 months vs. 48.69 months; HR=3.63, 95%CI: 1.76-7.48; p=0.00047). At 24 months, the DFS probability was 30% in TP53-mutated patients as compared to 72% in non-mutated patients. Lastly, detection of TP53-mutated ctDNA was significantly associated with an inferior OS (median OS: 17.8 months vs. Not Reached; HR=3.48, 95%CI: 1.51-8.01; p=0.0034). At 24 months, the OS probability was 42% in TP53-mutated patients as compared to 80% in non-mutated patients.
Conclusion: In patients with ctDNA-positivity after NAC, the presence of TP53 mutations was associated with rapid disease relapse. These data suggest that TP53 mutation status may stratify outcomes among this high-risk group of patients with ctDNA positivity in the post-neoadjuvant setting.
Citation Format: Milan Radovich, Nawal Kassem, Guanglong Jiang, Bradley A. Hancock, Bryan P. Schneider. Circulating TP53 mutations in TNBC after neoadjuvant chemotherapy is associated with rapid disease recurrence: Correlative analysis from clinical trial BRE12-158 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-06.