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Antony Haddad*, Harufumi Maki, Reed Ayabe, Mateo Lendoire, Timothy E. Newhook, Hop S. Tran Cao, Yun Shin Chun, Ching-Wei D. Tzeng, Jean-Nicolas Vauthey
Hepato-Pancreato-Biliary Surgery, The University of Texas MD Anderson Cancer Center Division of Surgery, Houston, TX

Introduction: Pathologic response to preoperative chemotherapy and somatic mutation profile are both important prognostic factors for patients undergoing resection of colorectal liver metastasis (CLM). Here, we evaluate the relationship between relevant somatic mutations and pathologic response with the goal of identifying patients who may benefit from more aggressive systemic therapy regimens.
Methods: Patients with CLM who were treated with preoperative chemotherapy and curative-intent surgery from January 2004 to December 2020 were selected from a prospectively maintained database. Patients treated with >12 cycles of chemotherapy were excluded. Major pathologic response was defined as tumor viability of less than 50%. Clinicopathologic factors and mutations in RAS, BRAF, TP53, SMAD4 and FBXW7 were evaluated for association with major pathologic response and overall survival (OS).
Results: A total of 551 patients were included. Of these, 296 patients (53.7%) achieved major pathologic response. Binary logistic regression model analysis revealed that oxaliplatin-containing regimens, bevacizumab-containing regimens, and TP53 mutation were independently associated with major pathologic response (risk ratios [RR]: 2.68, 2.15, 0.47, respectively, all p-values < .001). We next evaluated the association between pathologic response and OS in patients with and without TP53 mutations. Cox regression hazard model analysis confirmed that patients with TP53 mutation with major pathologic response (HR: 0.60, p = 0.007), TP53 wild-type with minor pathologic response (HR: 0.57, p = 0.049) and TP53 wild-type with major pathologic response (HR: 0.43, p < .001) were all significantly associated with better OS compared to TP53 mutation with minor pathologic response. Other factors associated with OS included age (hazard ratio [HR]: 1.01, p = 0.047), extrahepatic disease (HR: 1.69, p = 0.003), tumor number (HR: 1.05, p = 0.030), RAS or BRAF mutation (HR: 1.41, p = 0.038) and SMAD4 mutation (HR: 2.29, p < .001).
Conclusion: The prognostic impact of pathologic response is of particular importance for patients with TP53 mutant CLM. These patients may be considered for more aggressive chemotherapy regimens to achieve major pathologic response, which is associated with improved overall survival.

Table 1. Factors Associated with Major Pathologic Response in 551 Patients

Table 2. Factors Associated with Overall Survival in 551 Patients

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