Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of ...response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease has been questioned. As next-generation sequencing technology becomes more widely available for clinical use and additional molecularly targeted agents are considered as treatment options in colorectal cancer, it is important to characterize the extent of tumor heterogeneity between primary and metastatic tumors.
We performed deep coverage, targeted next-generation sequencing of 230 key cancer-associated genes for 69 matched primary and metastatic tumors and normal tissue. Mutation profiles were 100% concordant for KRAS, NRAS, and BRAF, and were highly concordant for recurrent alterations in colorectal cancer. Additionally, whole genome sequencing of four patient trios did not reveal any additional site-specific targetable alterations.
Colorectal cancer primary tumors and metastases exhibit high genomic concordance. As current clinical practices in colorectal cancer revolve around KRAS, NRAS, and BRAF mutation status, diagnostic sequencing of either primary or metastatic tissue as available is acceptable for most patients. Additionally, consistency between targeted sequencing and whole genome sequencing results suggests that targeted sequencing may be a suitable strategy for clinical diagnostic applications.
Learning Objectives
Describe the approach to patients with unresectable liver metastases from colorectal cancer.
Identify the hepatotoxicities associated with chemotherapy.
Explain what happens to ...metastatic sites when there is a response.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
The liver is a frequent site of metastatic disease for colorectal cancer patients. Approximately 15% of patients have liver metastases at diagnosis and another 50% develop metastatic disease to the liver over the course of their disease. Advances in systemic chemotherapy and surgical techniques for hepatic resection have led to longer survival times for these patients. There is no doubt that unresectable patients benefit from systemic chemotherapy. For patients who have resectable disease, the timing of chemotherapy is still not clear. This review addresses the pros and cons of presurgical chemotherapy. The benefits of preoperative chemotherapy include decreasing tumor size, controlling micrometastatic disease, assessing activity of chemotherapy, improving chemotherapy tolerance, and perhaps allowing some prediction of the success of liver resection. The risks for presurgical chemotherapy include liver toxicity, the risk for progression or growth of new sites, secondary splenomegaly, selection of resistant clones, and the possibility of leaving behind active tumor that is no longer seen because of a complete radiographic response. The challenge for the future is to develop a multidisciplinary team approach that can design the best treatment plan for patients with liver metastases.
Disclosure of potential conflicts of interest is found at the end of this article.
Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be ...prognostic biomarkers and/or predictive of drug response.
Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.
A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were
(30%),
(23%),
(20%),
(20%), and
gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including
, and
Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.
Cholangiocarcinoma is a genetically diverse cancer. Alterations in
and
are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers.
.
Hepatic resection of colorectal liver metastases is associated with long-term survival. This study analyzes actual 10-year survivors after resection of colorectal liver metastases, reports the ...observed rate of cure, and identifies factors that preclude cure.
A single-institution, prospectively maintained database was queried for all initial resections for colorectal liver metastases for the years 1992–2004. Observed cure was defined as actual 10-year survival with either no recurrence or resected recurrence with at least 3 years of disease-free follow-up. Clinical risk score was dichotomized into low (0–2) and high (3–5). Semiparametric proportional hazards mixture cure model was utilized to estimate probability of cure.
We included 1,211 patients with a median follow-up for survivors of 11 years. Median disease-specific survival was 4.9 years (95% CI: 4.4–5.3). 295 patients (24.4%) were actual 10-year survivors. The observed cure rate was 20.6% (n = 250). Among 250 cured patients, 192 (76.8%) had no recurrence and 58 (23.2%) had a resected recurrence with at least 3 years of disease-free follow-up. Extrahepatic disease (n = 88), carcinoembryonic antigen >200 ng/mL (n = 119), positive margin (n = 109), and >10 tumors (n = 31) had observed cure rates less than 10%. In cure model analysis, patients with both extrahepatic disease and high clinical risk score (n = 31) had an estimated probability of cure of 3.5%.
Actual 10-year survival after resection of colorectal liver metastases is 24% with an observed 20% cure rate. Patients with both high clinical risk score and extrahepatic disease have an estimated probability of cure less than 5%. When such factors are identified, strong consideration may be given to preoperative strategies, such as neoadjuvant chemotherapy, to help select patients for surgical therapy.
To identify predictors of oncologic outcomes after percutaneous radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLMs) and to describe and evaluate a modified clinical risk score ...(CRS) adapted for ablation as a patient stratification and prognostic tool.
This study consisted of a HIPAA-compliant institutional review board-approved retrospective review of data in 162 patients with 233 CLMs treated with percutaneous RFA between December 2002 and December 2012. Contrast material-enhanced CT was used to assess technique effectiveness 4-8 weeks after RFA. Patients were followed up with contrast-enhanced CT every 2-4 months. Overall survival (OS) and local tumor progression-free survival (LTPFS) were calculated from the time of RFA by using the Kaplan-Meier method. Log-rank tests and Cox regression models were used for univariate and multivariate analysis to identify predictors of outcomes.
Technique effectiveness was 94% (218 of 233). Median LTPFS was 26 months. At univariate analysis, predictors of shorter LTPFS were tumor size greater than 3 cm (P < .001), ablation margin size of 5 mm or less (P < .001), high modified CRS (P = .009), male sex (P = .03), and no history of prior hepatectomy (P = .04) or hepatic arterial infusion chemotherapy (P = .01). At multivariate analysis, only tumor size greater than 3 cm (P = .01) and margin size of 5 mm or less (P < .001) were independent predictors of shorter LTPFS. Median and 5-year OS were 36 months and 31%. At univariate analysis, predictors of shorter OS were tumor size larger than 3 cm (P = .005), carcinoembryonic antigen level greater than 30 ng/mL (P = .003), high modified CRS (P = .02), and extrahepatic disease (EHD) (P < .001). At multivariate analysis, tumor size greater than 3 cm (P = .006) and more than one site of EHD (P < .001) were independent predictors of shorter OS.
Tumor size of less than 3 cm and ablation margins greater than 5 mm are essential for satisfactory local tumor control. Tumor size of more than 3 cm and the presence of more than one site of EHD are associated with shorter OS.
To identify and compare predictors of local tumor progression (LTP)-free survival (LTPFS) after radiofrequency (RF) ablation and microwave (MW) ablation of colorectal liver metastases (CLMs).
This is ...a retrospective review of CLMs ablated from November 2009 to April 2015 (110 patients). Margins were measured on contrast-enhanced computed tomography (CT) 6 weeks after ablation. Clinical and technical predictors of LTPFS were assessed using a competing risk model adjusted for clustering.
Technique effectiveness (complete ablation) was 93% (79/85) for RF ablation and 97% (58/60) for MW ablation (P = .47). The median follow-up period was significantly longer for RF ablation than for MW ablation (56 months vs. 29 months) (P < .001). There was no difference in the local tumor progression (LTP) rates between RF ablation and MW ablation (P = 0.84). Significant predictors of shorter LTPFS for RF ablation on univariate analysis were ablation margins 5 mm or smaller (P < .001) (hazard ratio HR: 14.6; 95% confidence interval CI: 5.2-40.9) and perivascular tumors (P = .021) (HR: 2.2; 95% CI: 1.1-4.3); both retained significance on multivariate analysis. Significant predictors of shorter LTPFS on univariate analysis for MW ablation were ablation margins 5 mm or smaller (P < .001) (subhazard ratio: 11.6; 95% CI: 3.1-42.7) and no history of prior liver resection (P < .013) (HR: 3.2; 95%: 1.3-7.8); both retained significance on multivariate analysis. There was no LTP for tumors ablated with margins over 10 mm (median LTPFS: not reached). Perivascular tumors were not predictive for MW ablation (P = .43).
Regardless of the thermal ablation modality used, margins larger than 5 mm are critical for local tumor control, with no LTP noted for margins over 10 mm. Unlike RF ablation, the efficiency of MW ablation was not affected for perivascular tumors.
The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair ...and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.
A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (
, and
). Clinical variables were correlated with MMR/MSI status.
Twenty-six percent (26/100; 95% confidence interval, 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61;
= 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61;
= 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (
= 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (
= 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (
= 0.0002).
When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.
Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We ...identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.
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•Prospective targeted sequencing of 1,134 colorectal cancers in the clinical setting•Few genomic differences between primaries and metastases•Identified CTNNB1 in-frame deletions enriched in microsatellite stable cases•Differences in APC, BRAF, KRAS, and NRAS predict varied survival by tumor laterality
Yaeger et al. perform prospective sequencing of metastatic colorectal cancers (mCRCs). Right-sided primary microsatellite stable mCRCs are associated with increased oncogenic mutations whereas most left-sided tumors lack identifiable genetic mitogenic signaling alterations but highly express mitogenic ligands.
The treatment of colorectal cancer has improved considerably in recent years, but it remains the second commonest cause of cancer deaths in men and women in the United States. Better therapies have ...resulted in prolonged median survival for patients with metastatic disease and a select number of patients can now be cured.
We conducted a computerized search using PubMed and Google Scholar for reports published between January 1993 and August 2009 using mesh headings and key words relating to the treatment of colorectal cancer. If reports identified by these criteria referred to other papers not in the initial search, then these were also reviewed if relevant to metastatic colorectal cancer (MCRC).
Seven new chemotherapy agents have been licensed for the treatment of advanced colorectal cancer, with associated improved median survival from 5 months to 2 years. Complete responses are rare with systemic chemotherapy alone, but higher overall response rates to systemic and intrahepatic chemotherapies have enabled initially unresectable patients to undergo potentially curative surgical resection of metastases. Improved surgical expertise together with the adjunctive use of radiofrequency ablation has further expanded the definition of resectability. Advances in the understanding of tumor biology have resulted in the development of clinically useful biomarkers and the emergence of active biological therapies.
The multidisciplinary management of MCRC incorporating improved systemic and local therapies continues to improve median survival and enlarge the cohort of patients that can be approached with curative intent. Recent technological advances have facilitated a better understanding of tumor biology that promises continued advancements in patient care.
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