Transcriptomic Differences between Primary Colorectal Adenocarcinomas and Distant Metastases Reveal Metastatic Colorectal Cancer Subtypes

The literature review is devoted to the analysis of the main methods of treatment of patients with colorectal cancer liver metastases. The analysis of the clinical trials results over the past 10 years has been carried out. Colorectal cancer is the common malignant neoplasm. About 20% of patients have distant metastases in the diagnosing. Liver is the most frequent targeted organ, liver metastases are detected in 14,5% of patients with colorectal cancer. Despite the encouraging results of treatment of certain groups of patients with metastatic colorectal cancer, the treatment tactics for most patients is limited to palliative chemotherapy. In recent years, the survival of patients with metastatic colorectal cancer has significantly improved due to the success of systemic therapy. The median overall survival has reached for 2 years due to combination chemotherapy based on fluoropyrimidines, oxaliplatin, irinotecan in combination with monoclonal antibodies (bevacizumab, cetuximab and panitumumab). The optimal combination and sequence of using these anticancer agents in the treatment of metastatic colorectal cancer has not yet been determined. Surgery is the standard of care for this category of patients. At the same time, until nowdays there are no clear and generally accepted criteria for choosing the optimal volume of surgical intervention, prescribing first-line chemotherapy and using other methods of antitumor treatment.

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The clonal evolution of metastatic colorectal cancer

Science Advances ◽

10.1126/sciadv.aay9691 ◽

2020 ◽

Vol 6 (24) ◽

pp. eaay9691 ◽

Cited By ~ 2

Author(s):

Ha X. Dang ◽

Bradley A. Krasnick ◽

Brian S. White ◽

Julie G. Grossman ◽

Matthew S. Strand ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Tumor Heterogeneity ◽

Clonal Selection ◽

Clonal Evolution ◽

Human Tumor ◽

Treatment Resistance ◽

Distant Metastases ◽

Metastasis Model ◽

Genomic Studies

Tumor heterogeneity and evolution drive treatment resistance in metastatic colorectal cancer (mCRC). Patient-derived xenografts (PDXs) can model mCRC biology; however, their ability to accurately mimic human tumor heterogeneity is unclear. Current genomic studies in mCRC have limited scope and lack matched PDXs. Therefore, the landscape of tumor heterogeneity and its impact on the evolution of metastasis and PDXs remain undefined. We performed whole-genome, deep exome, and targeted validation sequencing of multiple primary regions, matched distant metastases, and PDXs from 11 patients with mCRC. We observed intricate clonal heterogeneity and evolution affecting metastasis dissemination and PDX clonal selection. Metastasis formation followed both monoclonal and polyclonal seeding models. In four cases, metastasis-seeding clones were not identified in any primary region, consistent with a metastasis-seeding-metastasis model. PDXs underrepresented the subclonal heterogeneity of parental tumors. These suggest that single sample tumor sequencing and current PDX models may be insufficient to guide precision medicine.

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HER2 and HER3 expression in hepatic metastases of colorectal cancer: New targets for specific treatment approaches?

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.567 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 567-567

Author(s):

Lena-Christin Conradi ◽

Hanna Styczen ◽

Thilo Sprenger ◽

Hendrik A. Wolff ◽

Peter Middel ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Treatment Options ◽

Significant Proportion ◽

Specific Treatment ◽

Hepatic Metastases ◽

Distant Metastases ◽

Her2 Status ◽

Primary Tumors ◽

Her3 Expression

567 Background: Even though treatment options for coloretal cancer liver metastases have improved with the implementation of multimodal strategies and new agents, progression of distant metastases is still limiting the prognosis of affected patients. In this context we investigated the expression of HER2 and HER3 in patients with metastatic colorectal cancer and primary tumors. Methods: In this study 226 consecutive patients with hepatic metastases of colorectal cancer were included. HER2 and HER3 expression were determined in the tissue from resected metastases and—if available—in primary tumors. Immunohistochemical scoring (IHC 0 to IHC 3) and S-ISH-amplification-detection (for HER2) were used to determine the HER2 and HER3 status. Results: A positive HER2 status was found in 8.4% of all hepatic metastases; an overexpression of HER-3 in 74,8% of all cases. There was a high congruence of the expression pattern of HER2 and HER3 between hepatic metastases and available primary tumors (>90%). Conclusions: HER2 amplification and HER3 overexpression is detectable in a significant proportion of hepatic metastases of colorectal cancer. These results suggest that innovative new targeted treatment agents might be possible opportunities for the specific therapy of patients with HER2/HER3 positive metastatic colorectal cancer and should be further assessed within prospective clinical trials.

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Adjunctive local therapy in metastatic colorectal cancer in an unselected cohort: Improved patient-survival in comparison to systemic therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4096 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4096-4096

Author(s):

Jan Schroeder ◽

Evrim Tasci ◽

Claus Nolte-Ernsting ◽

Peter Michels ◽

Natalie Wetzel ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Lung Metastases ◽

Local Therapy ◽

Distant Metastases ◽

Reference Population ◽

Systemic Treatments ◽

Radiofrequency Therapy ◽

Study Population ◽

Prospective Longitudinal

4096 Background: Patients with distant metastases in colorectal cancer have a poor prognosis and a low overall survival (OS). In addition to systemic treatments and irradiation, the tumor burden can be reduced by loco-regional therapeutics, including microwave ablation (MWA), radiofrequency therapy (RFA) and trans-arterial chemoembolization (TACE) available. To evaluate the benefit of such local therapies, we compared OS of a single-centre study population to a reference population of patients who underwent no loco-regional treatment within the German Tumor Registry Colorectal Cancer (TKK). Methods: The study population consists of a cohort of 51 patients (n = 51) treated loco-regionally in addition to systemic therapy. The patients were recruited in a single cancer centre in Mülheim, Germany during the years 2006 to 2015. A reference population of 788 patients was chosen from a prospective, longitudinal registry of the TKK. Time to event data analysis included the estimation of Kaplan-Meier cumulative survival probabilities and hazard ratios (HR) with corresponding 95% confidence intervals (95% CI) from Cox proportional hazards regression. Results: The median OS was 31.3 months (95% CI 26.8 - 41.6) in the study population, as compared to the reference population, where it was 21.9 months (95% CI 20.1 – 24.6). Patients with liver and lung metastases in the study population had an OS of 41.6 months (95% CI 30.5 – 78.2), the corresponding patients from the reference population 21.7 months (95% CI 16.7 – 24.6). Furthermore, patients in the reference group had a 1.79-fold death-rate, as compared to patients treated with additional loco-regional therapy (HR = 2.02; 95% CI: 1.29-3.16). Conclusions: Additional treatment with loco-regional therapies of distant metastases in patients with metastatic colorectal cancer appears to be associated with improved OS by nearly 10 months compared to systemic treatments only. [Table: see text]

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Mitochondrial DNA alteration in primary and metastatic colorectal cancer: Different frequency and association with selected clinicopathological and molecular markers

Tumor Biology ◽

10.1177/1010428317692246 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769224 ◽

Cited By ~ 4

Author(s):

Britta Kleist ◽

Thuja Meurer ◽

Micaela Poetsch

Keyword(s):

Colorectal Cancer ◽

Lymph Node ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Lymph Node Metastases ◽

Primary Tumor ◽

Distant Metastases ◽

Primary Tumors ◽

Node Metastases ◽

Mitochondrial Microsatellite Instability

This study attempts to determine whether primary tumor tissue could reliably represent metastatic colorectal cancer in therapy-guiding analysis of mitochondrial microsatellite instability. Therefore, we investigated the concordance of microsatellite instability in D310, D514, and D16184 (mitochondrial DNA displacement loop), and its association with selected clinical categories and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status between primary and metastatic colorectal cancer tissue from 119 patients. Displacement loop microsatellite instability was significantly more frequently seen in lymph node metastases (53.1%) compared to primary tumors (37.5%) and distant metastases (21.4%) ( p = 0.0183 and p = 0.0005). The discordant rate was significantly higher in lymph node metastases/primary tumor pairs (74.6%) than in distant metastases/primary tumor pairs (52.4%) or lymph node metastases/distant metastases pairs (51.6%) ( p = 0.0113 and p = 0.0261) with more gain (86.7%) than loss (61.1%) of microsatellite instability in the discordant lymph node metastases ( p = 0.0024). Displacement loop instability occurred significantly more frequently in lymph node metastases and distant metastases of patients with early colorectal cancer onset age <60 years ( p = 0.0122 and p = 0.0129), was found with a significant high rate in a small cohort of TP53-mutated distant metastases ( p = 0.0418), and was associated with TP53 wild-type status of primary tumors ( p = 0.0009), but did not correlate with KRAS, NRAS, BRAF, or PIK3CA mutations. In conclusion, mitochondrial microsatellite instability and its association with selected clinical and molecular markers are discordant in primary and metastatic colorectal cancer, which could have importance for surveillance and therapeutic strategies.

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Evaluate algorithms for identifying treatment patterns for patients with metastatic colorectal cancer using administrative claims data.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.30_suppl.299 ◽

2014 ◽

Vol 32 (30_suppl) ◽

pp. 299-299

Author(s):

Yue Zhong ◽

Rajesh Kamalakar ◽

Carl V Asche ◽

Sibyl Anderson ◽

Brian S. Seal

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Claims Data ◽

Distant Metastases ◽

Treatment Patterns ◽

New Drugs ◽

Administrative Claims ◽

Biologic Drugs ◽

Administrative Claims Data ◽

Treatment Regimens

299 Background: Administrative claims data are widely used to identify treatment patterns. However, as new drugs are brought to clinical practice, treatment regimens become more complicated for cancer patients receiving both chemotherapy and biologic agents. We evaluated the influence of using different treatment length algorithms on identification of treatment patterns for patients with metastatic colorectal cancer (mCRC). Methods: We identified patients aged 18 or older with at least one primary CRC diagnosis between 01/01/2008 and 03/31/2012 in the MarketScan databases. mCRC patients were included if claims indicated the presence of distant metastases (ICD-9-CM codes: 196.x, 197.0 to 197.4, 197.6 to 197.8, 198.x, and 199.0). All treatment claims were extracted and patients were followed for more than 6 months, until end of enrollment or study end date (03/01/2013). We identified all chemotherapy and/or biologic drugs given to a patient during 30, 60, or 90 days after initiation of treatment and compared differences in type and number of treatment lines (TLs). Results: A total of 2,046 mCRC patients received at least one TL. Using a 30-day cutoff period, 30% patients received 1 TL; 30% received 2 TLs; and 40% received ≥3 TLs. Results changed after using a 60-day cutoff period: 39% patients with 1 TL, 33% with 2 TLs, and 28% with ≥3 TLs. If using 90 days as a cutoff period, 44% received 1 TL; 35% received 2 TLs; and 22% received ≥3 TLs. For all cutoff periods, the most common first TL prescribed were FOLFOX +/- bevacizumab and 5-FU/LV. For patients receiving a second TL, FOLFOX was most frequently prescribed if using a 30-day or 60-day cutoff, while FOLFIRI/bevacizumab had a higher prescription rate with a 90-day cutoff. Regimens varied in third and fourth-line therapy using different cutoff periods and FOLFIRI +/- bevacizumab was more frequently used than other regimens. Conclusions: The cutoff period did not significantly influence treatment regimens detected for first and second TL. Using a 30-day cutoff period resulted in 30% patients with one TL and 40% with three or more TLs, while with a 90-day cutoff, 44% patients received one TL and only 22% received three or more TLs.

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Treatment patterns of patients with metastatic colorectal cancer in a large national U.S. claims-based data.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.30_suppl.268 ◽

2014 ◽

Vol 32 (30_suppl) ◽

pp. 268-268

Author(s):

Yue Zhong ◽

Rajesh Kamalakar ◽

Carl V Asche ◽

Sibyl Anderson ◽

Brian S. Seal

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitor ◽

Distant Metastases ◽

Treatment Patterns ◽

Cytotoxic Agents ◽

Line Treatment ◽

Treatment Standards ◽

Treatment Regimens ◽

The Third

268 Background: FDA approved therapeutic choices for patients with metastatic colorectal cancer (mCRC) have evolved, including cytotoxic agents such as 5-fluorouracil (5-FU)/ leucovorin or levoleucovorin (LV), capecitabine, oxaliplatin, and irinotecan, biological agents such as bevacizumab, cetuximab, panitumumab, and aflibercept, as well as regorafenib, an oral multi-kinase inhibitor. The present study examined treatment patterns among patients with mCRC. Methods: We identified patients aged 18 or older with at least one primary CRC diagnosis between 01/01/2008 and 03/31/2012 in the MarketScan databases. mCRC patients were identified if claims indicated the presence of distant metastases (ICD-9-CM codes: 196.x, 197.0 to 197.4, 197.6 to 197.8, 198.x, and 199.0). All systemic treatment claims were extracted during 60 days after initiation of treatment. Patients were followed for more than 6 months, until end of enrollment or study end date (03/01/2013) to capture type and number of treatment lines (TLs). We also assessed regimen compliance to the current National Comprehensive Cancer Network (NCCN) treatment standards. Results: Of the total 2,934 mCRC patients retained, 2,046 (69.7%) received at least one TL: 801 (39.1%) patients with one TL, 679 (33.2%) with two TLs, and 566 (27.7%) with three or more TLs. For patients receiving first-line treatment, the most common regimens prescribed were FOLFOX (19.1%), FOLFOX+ bevacizumab (18.6%), and 5-FU/LV (17.8%). For patients receiving second-line treatment (60.9%), FOLFOX (14.1%), FOLFOX+ bevacizumab (11.0%), and FOLFIRI+bevacizumab (11.0%) were most frequently prescribed. Treatment regimens varied in patients receiving three or more TLs. FOLFIRI + bevacizumab was most frequently prescribed in the third TL (16.8%). Proportion of patients receiving NCCN-recommended regimens was 81.7% for first TL, 54.4% for second TL, and 25.3% for third TL. Conclusions: About one third of mCRC patients didn’t receive any treatment. Among mCRC patients with treatment, two thirds received at least two TLs. FOLFOX (+/-biologics) was the most frequently prescribed first and second TL. Only a quarter of patients received NCCN-recommended regimens in the third TL.

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