Neoadjuvant chemotherapy for high-risk intrahepatic cholangiocarcinoma - does pathologic response mean better outcomes?

BACKGROUND: The role of neoadjuvant chemotherapy (NAC) in the management of intrahepatic cholangiocarcinoma (ICC) remains unknown. We sought to evaluate our experience treating high-risk ICC with NAC and to determine the prognostic significance of pathologic response. METHODS: Patients with ICC treated with NAC and surgery were analyzed using a prospectively maintained database. Pathologic response was graded by a blinded pathologist. Clinicopathologic/treatment variables were evaluated for associations with survival. RESULTS: Among 45 patients who received NAC followed by hepatectomy for high-risk ICC, 32(71%) were considered stage III, and 6(13%) were considered stage IV at time of diagnosis. Major response was identified in 39% of cases, including 2 with pathologic complete response. Patients with major response had a longer median NAC duration than patients with minor response (6 vs 4cycles, P=0.02). Regimen (gemcitabine/cisplatin vs gemcitabine/cisplatin/nab-paclitaxel) was not associated with response rate. Median recurrence-free (RFS) and overall survival (OS) were 11 and 45 months. Pathologic response was not associated with improved survival. CONCLUSION: Pathologic response to NAC was not associated with survival in this highly selected cohort. Nonetheless, the extended OS experienced by these high-risk patients is encouraging and suggests that NAC may help select patients who stand to benefit from aggressive resection.

Neither Surgical Margin Status nor Somatic Mutation Predicts Local Recurrence After R0-intent Resection for Colorectal Liver Metastases.

BACKGROUND: We evaluated the associations of surgical margin status and somatic mutations with the incidence of local recurrence (LR) and oncologic outcomes in patients undergoing R0-intent (microscopically negative margin) resection of colorectal liver metastases (CLM). METHODS: Patients with CLM who underwent initial R0-intent resection and analysis of tumor tissue using next-generation sequencing during 2001-2018 were analyzed. Recurrences were classified as LR (at the resection margin), other intrahepatic recurrence, or extrahepatic recurrence. Predictors and survival effect of LR were evaluated using univariate and multivariate analysis. RESULTS: Of 552 patients analyzed, 415 (75%) had R0 resection (margin width ≥ 1.0 mm), and 38 (7%) had LR. LR incidence was not affected by surgical margin width. RAS/TP53 co-mutation was associated with increased risk of intrahepatic recurrence (67% vs. 49%; p < 0.001) and overall recurrence (p < 0.001). However, incidence of LR did not differ significantly by RAS/TP53, BRAF, SMAD4, or FBXW7 mutation. Extrahepatic disease (hazard ratio [HR], 1.47; p = 0.034), > 8 cycles of preoperative chemotherapy (HR, 1.98; p = 0.033), tumor viability ≥ 50% (HR, 1.55; p = 0.007), RAS/TP53 co-mutation (HR, 1.69; p = 0.001), and SMAD4 mutation (HR, 2.44; p < 0.001) were independently associated with poor overall survival, but surgical margin status was not. CONCLUSIONS: Although somatic mutations were associated with overall recurrence, neither surgical margin width nor somatic mutations affected LR risk after R0-intent hepatectomy for CLM. LR and prognosis were likely driven by individual tumor biology rather than surgical margins.

Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer.

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.