Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer.

OBJECTIVE: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described. DESIGN: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin. RESULTS: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFßi, mTORi and SRCi) for EpiC groups. CONCLUSION: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.

APC and PIK3CA Mutational Cooperativity Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colorectal Liver Metastases.

OBJECTIVE: The aim of the study was to determine the prognostic impact of co-existence of APC and PIK3CA mutations in patients undergoing preoperative chemotherapy and resection for colorectal liver metastases (CLM). BACKGROUND: Co-occurring genetic events have been shown to drive carcinogenesis in multiple malignancies. METHODS: We identified 396 patients with primary colorectal cancer and known somatic mutation status by next-generation sequencing who underwent hepatectomy for CLM (2005-2015). Survival after hepatectomy in patients with double mutation of APC and PIK3CA and others was analyzed. Predictors of pathologic response and survival were determined. The prognostic value of double mutation was evaluated with a separate cohort of 157 patients with CLM undergoing chemotherapy alone. RESULTS: Forty-five patients had double mutation of APC and PIK3CA; 351 did not. Recurrence-free survival (RFS) and overall survival (OS) after hepatectomy were worse in patients with double mutation (3-year RFS, 3.1% vs 20% [P < 0.001]; 3-year OS, 44% vs 84% [P < 0.001]). Independent predictors of major pathologic response were bevacizumab use (odds ratio [OR] 2.22; P = 0.001), tumor size <3 cm (OR 1.97; P = 0.004), wild-type RAS (OR 2.00; P = 0.003), and absence of double mutation (OR 2.91; P = 0.002). Independent predictors of worse OS were primary advanced T category (hazard ratio [HR] 2.12; P = 0.021), RAS mutation (HR 1.74; P = 0.015), and double mutation (HR 3.09; P < 0.001). In the different medical cohort, patients with double mutation had worse 3-year OS of 18%, compared with 35% without double mutation (P = 0.023). CONCLUSIONS: Double mutation of APC and PIK3CA predicts inferior response to preoperative chemotherapy and poor survival in patients with CLM.

Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases.

OBJECTIVE: To assess the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (CLM). BACKGROUND: Patients undergoing CLM resection have heterogeneous outcomes, and accurate risk stratification is necessary to optimize patient selection for surgery. METHODS: Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing CLM resection. Missense TP53 mutations were classified by the evolutionary action score (EAp53)-a novel approach that dichotomizes mutations as low or high risk. RESULTS: The most frequent somatic gene mutations were TP53 (65.6%), followed by KRAS (48.1%) and APC (47.4%). Double mutation in RAS/TP53, identified in 31.4% of patients, was correlated with primary tumor location in the right colon (P = 0.006). On multivariable analysis, RAS/TP53 double mutation was an independent predictor of shorter overall survival (hazard ratio 2.62, 95% confidence interval 1.41-4.87, P = 0.002). In patients with co-mutated RAS, EAp53 high-risk mutations were associated with shorter 5-year overall survival of 12.2%, compared with 55.7% for TP53 wild type (P < 0.001). The negative prognostic effects of RAS and TP53 mutations were limited to tumors harboring mutations in both genes. CONCLUSIONS: Concomitant RAS and TP53 mutations are associated with decreased survival after CLM resection. A high EAp53 predicts a subset of patients with worse prognosis. These preliminary analyses suggest that surgical resection of liver metastases should be carefully considered in this subset of patients.

Embryonic Origin of Primary Colon Cancer Predicts Pathologic Response and Survival in Patients Undergoing Resection for Colon Cancer Liver Metastases.

BACKGROUND: The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM). METHODS: We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy. RESULTS: Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs 27%, P < 0.001; OS rate at 3 years: 46% vs 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value ≥5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs 78%, P = 0.003). CONCLUSIONS: Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status.

Impact of RAS Mutations in Metastatic Colorectal Cancer After Potentially Curative Resection: Does Site of Metastases Matter?

BACKGROUND: RAS mutation status is an important prognostic factor after resection of liver metastases (LiM) from colorectal cancer (CRC). The prognostic significance of RAS after resection of lung (LuM) and peritoneal (PM) metastases from CRC is unknown. METHODS: Between 2005 and 2014, all consecutive patients with known RAS status who underwent potentially curative resection for LiM, LuM, or PM were evaluated. RESULTS: A total of 720 patients with known RAS status underwent resection of LiM (n = 468), LuM (n = 102), and PM (n = 150). RAS mutations were identified in 63 and 58% of patients with LuM and PM, respectively, compared with 41% of patients with LiM (p < 0.001). Five-year overall survival (OS) after resection of PM was 45%, compared with 52% after resection of LiM (p = 0.018) and 64% after resection of LuM (p = 0.005). RAS mutations were associated with significantly worse OS after resection of LiM (p < 0.001), but did not affect OS among patients undergoing resection of LuM (p = 0.41) and PM (p = 0.65). CONCLUSIONS: RAS mutations are more prevalent among patients undergoing resection of LuM and PM than LiM but do not affect survival after lung and peritoneal metastasectomy, as they do after hepatectomy. These results suggest that the prognostic significance of RAS mutations after resection of metastatic CRC depends on the specific site of metastases.

Impact of Prior Hepatectomy History on Local Tumor Progression after Percutaneous Ablation of Colorectal Liver Metastases.

PURPOSE: To test the hypothesis that, given the current resection eligibility criteria for colorectal liver metastasis (CLM), prior hepatectomy would be associated with improved local tumor control and survival after percutaneous ablation of CLMs. MATERIALS AND METHODS: This single-institution retrospective study included 82 consecutive patients with 97 CLMs treated with ablation (radiofrequency ablation, microwave ablation, or cryoablation) from January 2005 to December 2014. Local tumor progression-free survival (LTPFS), recurrence-free survival (RFS) at any organ, and overall survival (OS) were calculated using the Kaplan-Meier method from the time of ablation and compared between patients with (n = 49) and without (n = 33) prior hepatectomy. Cox regression models were used to identify LTPFS predictors. RESULTS: Median overall follow-up period was 28 months (range, 4.5-132 months). Three-year actuarial LTPFS (patient level: 73% vs 34%, P < .001) was significantly higher in patients with than without prior hepatectomy, respectively. Similarly, 3-year RFS (23% vs 9.1%, P = .026) and OS (78% vs 48%, P = .003) were improved in patients with prior hepatectomy. At multivariate analysis, predictors of worse LTPFS were: no prior hepatectomy (hazard ratio [HR] 2.35, 95% confidence interval [CI] 1.02-5.45; P = .045), minimal ablation margin < 5 mm (HR 2.4, 95% CI 1.18-4.87; P = .016), and RAS-mutant tumor (HR 2.65, 95% CI 1.18-5.94; P = .019). CONCLUSIONS: Prior hepatectomy for CLMs is associated with improved local tumor control after percutaneous ablation of post-resection-developed CLMs.

RAS Mutation Predicts Positive Resection Margins and Narrower Resection Margins in Patients Undergoing Resection of Colorectal Liver Metastases.

BACKGROUND: In patients undergoing resection of colorectal liver metastases (CLM), resection margin status is a significant predictor of survival, particularly in patients with suboptimal response to preoperative therapy. RAS mutations have been linked to more invasive and migratory tumor biology and poor response to modern chemotherapy. OBJECTIVE: The aim of this study was to evaluate the relationship between RAS mutation and resection margin status in patients undergoing resection of CLM. METHODS: Patients who underwent curative resection of CLM from 2005 to 2013 with known RAS mutation status were identified from a prospectively maintained database. A positive margin was defined as tumor cells <1 mm from the parenchymal transection line. RESULTS: The study included 633 patients, of whom 229 (36.2 %) had mutant RAS. The positive margin rate was 11.4 % (26/229) for mutant RAS and 5.4 % (22/404) for wild-type RAS (p = 0.007). In multivariate analysis, the only factors associated with a positive margin were RAS mutation (hazard ratio [HR] 2.439; p = 0.005) and carcinoembryonic antigen level 4.5 ng/mL or greater (HR 2.060; p = 0.026). Among patients presenting with liver-first recurrence during follow-up, those with mutant RAS had narrower margins at initial CLM resection (median 4 mm vs. 7 mm; p = 0.031). A positive margin (HR 3.360; p < 0.001) and RAS mutation (HR 1.629; p = 0.044) were independently associated with worse overall survival. CONCLUSION: RAS mutations are associated with positive margins in patients undergoing resection of CLM. Tumors with RAS mutation should prompt careful efforts to achieve negative resection margins.

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. SIGNIFICANCE: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897.

Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases.

OBJECTIVE: To determine the impact of RAS mutation status on survival and patterns of recurrence in patients undergoing curative resection of colorectal liver metastases (CLM) after preoperative modern chemotherapy. BACKGROUND: RAS mutation has been reported to be associated with aggressive tumor biology. However, the effect of RAS mutation on survival and patterns of recurrence after resection of CLM remains unclear. METHODS: Somatic mutations were analyzed using mass spectroscopy in 193 patients who underwent single-regimen modern chemotherapy before resection of CLM. The relationship between RAS mutation status and survival outcomes was investigated. RESULTS: Detected somatic mutations included RAS (KRAS/NRAS) in 34 (18%), PIK3CA in 13 (7%), and BRAF in 2 (1%) patients. At a median follow-up of 33 months, 3-year overall survival (OS) rates were 81% in patients with wild-type versus 52.2% in patients with mutant RAS (P = 0.002); 3-year recurrence-free survival (RFS) rates were 33.5% with wild-type versus 13.5% with mutant RAS (P = 0.001). Liver and lung recurrences were observed in 89 and 83 patients, respectively. Patients with RAS mutation had a lower 3-year lung RFS rate (34.6% vs 59.3%, P < 0.001) but not a lower 3-year liver RFS rate (43.8% vs 50.2%, P = 0.181). In multivariate analyses, RAS mutation predicted worse OS [hazard ratio (HR) = 2.3, P = 0.002), overall RFS (HR = 1.9, P = 0.005), and lung RFS (HR = 2.0, P = 0.01), but not liver RFS (P = 0.181). CONCLUSIONS: RAS mutation predicts early lung recurrence and worse survival after curative resection of CLM. This information may be used to individualize systemic and local tumor-directed therapies and follow-up strategies.

BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers.

KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. We assessed the effect of sotorasib alone or in combination with DT2216 (a clinical-stage BCL-XL proteolysis targeting chimera [PROTAC]) on KRASG12C-mutated NSCLC, CRC and pancreatic cancer (PC) cell lines using MTS cell viability, colony formation and Annexin-V/PI apoptosis assays. Furthermore, the therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C tumor cell lines that partially responded to sotorasib treatment. Mechanistically, sotorasib treatment led to stabilization of BIM and co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis in KRASG12C tumor cell lines. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.

Colorectal Liver Micrometastases: Association with RAS/TP53 Co-Mutation and Prognosis after Surgery.

BACKGROUND: Micrometastases, defined as microscopic cancer cells spatially separated from the macroscopically evident metastasis, are identified in 24% to 56% of resected colorectal liver metastases (CLMs). Somatic gene mutations have emerged as independent prognostic factors in CLM. This study aimed to determine the prognostic impact and risk factors for the presence of micrometastases, including somatic gene mutations. STUDY DESIGN: Prospective evaluation for micrometastases was performed at 2 centers in the US and France from 2015 to 2019. CLM specimens were cut radially from the tumor margin to surrounding grossly normal liver for a distance of 2 cm. Depending on CLM size, 3 to 8 specimens per patient were submitted for microscopic analysis. Somatic gene mutations were detected by next-generation sequencing. RESULTS: Among 140 patients undergoing CLM resection in the US (n = 84) and France (n = 56), 36 (26%) patients were found to have micrometastases. Five-year overall and recurrence-free survival rates with micrometastases were 39% and 0%, respectively, compared with 61% and 20% without micrometastases (both p < 0.05). In multivariable analyses, the presence of micrometastases was an independent risk factor for worse overall survival (hazard ratio 2.88, 95% CI 1.46 to 5.70, p = 0.002) and recurrence-free survival (hazard ratio 1.56, 95% CI 1.01 to 2.41, p = 0.046). In binary logistic regression analysis, RAS/TP53 co-mutation was found to significantly increase the risk of micrometastases (odds ratio 2.77, 95% CI 1.15 to 6.71, p = 0.024). CONCLUSIONS: Micrometastases are associated with significantly worse survival after CLM resection. RAS/TP53 co-mutation correlated with increased risk of micrometastases. Further studies are needed to determine strategies to eradicate micrometastases.

A path to translation: How 3D patient tumor avatars enable next generation precision oncology.

3D patient tumor avatars (3D-PTAs) hold promise for next-generation precision medicine. Here, we describe the benefits and challenges of 3D-PTA technologies and necessary future steps to realize their potential for clinical decision making. 3D-PTAs require standardization criteria and prospective trials to establish clinical benefits. Innovative trial designs that combine omics and 3D-PTA readouts may lead to more accurate clinical predictors, and an integrated platform that combines diagnostic and therapeutic development will accelerate new treatments for patients with refractory disease.

Preliminary Analysis of Liquid Biopsy after Hepatectomy for Colorectal Liver Metastases.

BACKGROUND: Liquid biopsies are increasingly tested in patients with colorectal cancer to assess tumor burden, response to therapy, and prognosis. The significance of liquid biopsy results after resection of colorectal liver metastases (CLMs) is not well-defined. STUDY DESIGN: Sixty-three patients undergoing CLM resection between 2016 and 2018 had plasma drawn postoperatively for liquid biopsy evaluation. Next-generation sequencing analysis was performed to detect somatic mutations in 70 genes. RESULTS: Liquid biopsy after CLM resection was positive in 42 of 63 patients (67%). Eleven patients (18%) had 1 gene mutation, 14 patients (22%) had 2 to 3 mutations, and 17 patients (27%) had 4 or more mutations. The most common mutation was APC, detected in 32 patients (76%), followed by TP53 (74%) and KRAS (38%). Two-year overall survival rate from date of liver resection was significantly worse among patients with a positive liquid biopsy (70% vs 100%; p = 0.005), particularly for those with 4 or more gene mutations detected, whose 2-year overall survival rate was 41%. Sixteen of the 63 patients underwent serial liquid biopsies, resulting in 100 liquid biopsies with matched serum CEA and CT scan results. Metastases were identified in 74 CT scans, which correlated with positive liquid biopsy in 77% of samples (p < 0.001) and CEA > 3 ng/mL in 45% of samples (p < 0.22). CONCLUSIONS: Liquid biopsy results provide information about disease burden and prognosis that is complementary to serum CEA and CT imaging. A positive liquid biopsy after CLM resection is associated with worse overall survival, particularly when multiple gene mutations are detected.

SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases.

INTRODUCTION: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is a key mediator in the transforming growth factor (TGF)-ß signaling pathway and SMAD4 gene mutations are thought to play a critical role in colorectal cancer (CRC) progression. However, little is known about its influence on survival in patients undergoing resection for colorectal liver metastases (CLM). METHODS: Between 2005 and 2015, all patients with known SMAD4 mutation status who underwent resection of CLM were identified. Patients with SMAD4 mutation were compared to those with SMAD4 wild type. Next, the prognostic value of SMAD4 mutation was validated in a separate cohort of patients with synchronous stage IV CRC who underwent systemic therapy alone. RESULTS: Of 278 patients, 37 (13%) were SMAD4 mutant while 241 (87%) were wild type. Overall survival (OS) after hepatic resection was worse in SMAD4-mutant patients compared to SMAD4 wild type (OS rate at 3 years, 62% vs. 82%; P < 0.0001). Independent predictors for worse OS were poor differentiation (hazard ratio [HR] 2.586; P = 0.007), multiple tumors (HR 1.970; P = 0.01), diameter greater than 3 cm (HR 1.752; P = 0.017), R1 margin status (HR 2.452; P = 0.014), RAS mutation (HR 2.044; P = 0.002), and SMAD4 mutation (HR 2.773; P < 0.0001). Among 237 patients in the validation cohort, SMAD4-mutations were significantly associated with worse 3-year OS rate (22% vs. 38%; P = 0.012) and was an independent predictor for worse OS (HR, 1.647; P = 0.032). CONCLUSION: SMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of CLM.

RAS Mutation Is Associated with Decreased Survival in Patients Undergoing Repeat Hepatectomy for Colorectal Liver Metastases.

BACKGROUND: The relationship between RAS mutation status and outcome for patients undergoing repeat hepatectomy (RH) for recurrent colorectal liver metastases (CLM) has not been defined. OBJECTIVE: The objective of this study was to evaluate the relationship between RAS mutation status and outcome in patients undergoing RH for CLM. METHODS: All patients who underwent RH for CLM with known RAS mutation status between January 2005 and November 2014 were identified, and the outcomes of patients with and without RAS mutations were compared. RESULTS: Ninety-eight patients underwent RH, of whom 34 (35 %) harbored a RAS mutation. Wild-type (WT) and mutant RAS groups had similar clinicopathologic characteristics. Median recurrence-free survival (RFS) for patients with WT and mutant RAS was 12.2 and 6.1 months, respectively (p = 0.03). Median overall survival (OS) for the WT and mutant RAS patients were 42.5 and 26.6 months, respectively (p < 0.01). On multivariate analysis, RAS mutations [hazard ratio (HR) = 1.69, p = 0.04] were associated with worse RFS, while multiple tumors (HR = 1.92, p = 0.045) and RAS mutations (HR = 2.11, p = 0.02) predicted worse OS. CONCLUSION: Patients with recurrent CLM that harbor RAS mutations have worse RFS and OS than patients with WT RAS, and RAS mutations are independently associated with worse RFS and OS. RAS mutation status should be determined prior to RH, as it may impact treatment decisions.

Planned Treatment of Advanced Metastatic Disease with Completion Ablation After Hepatic Resection.

PURPOSE: The aim of this study is to describe a modified treatment strategy with image-guided percutaneous ablation after hepatic resection as a completion method to surgical eradication of liver metastases ("completion ablation [CA]"). METHODS: We conducted a retrospective analyses of patients who underwent CA within 180 days from the liver surgical resection to eradicate liver metastases present on the pre-surgical cross-sectional imaging or identified during intraoperative ultrasound that were not resected due to various reasons. Lesions treated with CA were evaluated for local tumor progression (LTP). Patients were evaluated for hepatic- and overall-recurrence-free survivals (hepatic-RFS and overall-RFS, respectively) and overall survival (OS). RESULTS: Sixteen patients (10 females; median age 55 years, range 28-69) underwent CA of 21 lesions (median size 8 mm, range 6 to 22). Indications for the use of CA were small future liver remnant in 10 (63%), inability to identify the lesion during surgical exploration in 3 (19%), and technical difficulty of resection in 3 (19%) patients. No liver-related complications were recorded following the surgical resection or the CA procedures. Primary and secondary CA efficacy rates were 95 and 100%, respectively. LTP was 0% at a median clinical follow-up of 27 months (range 4.0-108 months). Five-year hepatic-RFS, overall-RFS, and OS were 36, 16, and 51%, respectively. CONCLUSION: The use of CA as a complement to surgical resection is safe and effective. Such approach could potentially expand the surgical candidacy for patients with limited liver functional reserve and reduce postoperative morbidity and mortality in this selected patient population with more advanced disease.

Is hepatectomy justified for patients with RAS mutant colorectal liver metastases? An analysis of 524 patients undergoing curative liver resection.

BACKGROUND: RAS mutations are associated with limited overall survival after resection of colorectal liver metastases. Our aim was to determine criteria for considering hepatectomy for patients with RAS mutant colorectal liver metastases. METHODS: Of 1,163 patients who underwent liver resection for colorectal liver metastases during 2005-2014, all patients operated on with curative intent who had known RAS mutation status were included. Factors associated with overall survival were determined using multivariate analysis. RESULTS: A total of 524 patients met the inclusion criteria; 212 (40%) had mutated RAS. Mutations were located on codon 12 in 128 patients (60%) and codon 13 in 29 (14%). At median follow-up of 38 months, median overall survival was 72.6 months for wild-type RAS and 50.9 months for mutated RAS (P < .001). Median overall survival for patients with codon 12 and 13 mutations was 51.9 and 50.9 months, respectively (P = .839), significantly worse than for patients with wild-type RAS (P = .005, and P = .038 for codon 12 and 13, respectively). For patients with RAS mutation, factors associated independently with worse overall survival were node-positive primary tumor, tumor >3 cm, and >7 cycles of preoperative chemotherapy. Major and 2-stage hepatectomy were not associated independently with overall survival. Median overall survival was 57, 41, and 21.5 months for patients with 1, 2, and 3 risk factors, respectively. There were no 4-year survivors in the highest-risk group. CONCLUSION: Patients with multiple risk factors had poor overall survival after curative resection of RAS mutant colorectal liver metastases. For such patients, hepatectomy may be ill advised, and alternative therapies or further systemic therapy should be considered.

Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched-pair analysis.

PURPOSE: Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach. METHODS AND MATERIALS: From 1995 to 2003, a phase 2 protocol examined CRT with 5-fluorouracil and CB radiation therapy (52.5 Gy in 5 weeks) for patients with LARC. Seventy-six protocol patients were matched (case-control approach) for surgery type, tumor (T) stage, and clinical nodal (N) stage with patients who received standard dose (SD) CRT (5-fluorouracil, 45 Gy). A chart review was performed. McNemar's test and Kaplan-Meier analyses were used for statistical analysis. RESULTS: The SD and CB groups did not differ in tumor circumferential involvement and length, but the tumors of CB patients were closer to the anal verge (4.7 vs 5.7 cm; P = .02). Although tumor downstaging was higher in the CB cohort (76% vs 51%; P < .01), pathologic complete response rates did not differ (CB, 17.1% vs SD, 15.8%, P = 1.00). The incidence of grade ≥3 radiation-related toxicities was low and similar in both groups (CB, 10% vs SD, 3%, P = .22). Postoperative (anastomotic leak, wound complications/abscess, bleeding) and late (small bowel obstruction, stricture) complication rates did not differ between the groups (P > .05). The median follow-up was 11.9 years. The 5-year local control rates were higher for CB (100.0%) compared with SD (90.0%) patients (P = .01). CB patients had higher rates of 10-year progression-free survival (71.9% vs 57.6%, P < .01) and overall survival (71.6% vs 62.4%, P = .01) compared with SD patients. CONCLUSIONS: CRT dose escalation for patients with LARC is safe and effective. The improved T-downstaging and local control observed in CB patients should encourage further dose escalation studies.