Ultra-deep amplicon sequencing to identify actionable mutations in matched plasma/tumor specimens from 44 patients with colorectal cancer of UICC stage III and IV.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3634-3634
Author(s):  
Paulina Pechanska ◽  
Matthias Pross ◽  
Cornelia Radke ◽  
Frank Marusch ◽  
Hartmut Lobeck ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Primary Tumor ◽  
Stage Iv ◽  
Amplicon Sequencing ◽  
Stage Iii ◽  
Plasma Samples ◽  
High Quality ◽  
Primary Tumors ◽  
Dna Yield ◽  
Matched Primary Tumor

3634 Background: Circulating cell-free DNA (cf-DNA) isolated from plasma samples of cancer patients (pts) is a promising source for noninvasive examination of tumor-specific mutation patterns. We examined the efficiency of ultra-deep amplicon sequencing (UDAS) of cf-DNA isolated from plasma and tumor DNA isolated from matched primary tumor tissue of pts with colorectal cancer (CRC). Methods: Blood was drawn prior to surgery from 44 pts: 20 male, 24 female; 44-79 years of age (median: 67.5); 11 stage III, 33 stage IV; 36 colon, 8 rectum tumors; no neo-adjuvant therapy. Cf-DNA was isolated from 2 ml of EDTA plasma. UDAS was applied to 72 DNA samples (44 plasma, 28 matched snap-frozen primary tumors) using the MiSeq platform (Illumina). A panel of 49 highly multiplexed amplicons was designed (Life Technologies) representing 9 cancer genes frequently mutated in CRC. For 16 primary tumors the mutation profile was determined using the TruSeq Amplicon Cancer Panel (Illumina). Results: Median cf-DNA yield was 310 ng / 2 ml plasma (1ng – 6.600 ng). There was no significant relation between cf-DNA yield and any clinical characteristic. Median amplicon coverage was 20.162 reads per bp (2.913 - 115.782). 33/49 amplicons (67%) had a coverage of > 10.000 reads. Altogether 61 high quality COSMIC-cited mutations were confirmed in plasma of 29/44 (66%) pts: 24/33 (73%) pts in stage IV, 5/11 (45%) pts in stage III. Confirmed mutations are: APC-17; BRAF-2, FBXW7-1, KRAS-15, NRAS-1, PIK3CA-4, SMAD4-2, and TP53-19 mutations. No high quality mutations were found in CTNNB1 and HRAS. Moreover two pts exhibited four high quality plasma mutations which were not detected in the matched primary tumor: APC (R216X), KRAS (Q61K), and SMAD4 (D355E); PIK3CA (E545K). Conclusions: Ultra deep amplicon sequencing is suitable to detect mutations in plasma samples of CRC pts with a high concordance to matched primary tumors. The concordance rate can be further increased by extending the spectrum of analyzed mutations or by the enrichment of cf-DNA tumor copies. This method could be applied to detect and monitor metastasis thus opening a new paradigm for the selection of pts for targeted therapies.

Clinical trials versus clinical practice in colorectal cancer: Equivalent populations?

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 802-802
Author(s):  
Alejandra Magdaleno Cremades ◽  
María del Carmen Ors Castaño ◽  
María Ballester Espinosa ◽  
Marta Llopis Cuquerella ◽  
María del Rocío Ramirez Belloch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Adjuvant Treatment ◽  
Combination Treatment ◽  
Primary Tumor ◽  
Stage Iv ◽  
Stage Iii ◽  
Stage Iii Colon Cancer

802 Background: Clinical trials are criticized due to inclusion of selected populations. The aim of this analysis is to compare populations included in clinical trials which justify treatment recommendations in stage III and IV colorectal cancer (CRC) to patient populations in our area. Methods: Data related to age, sex, primary tumor and stage of CRC patients consecutively diagnosed in Vega Baja Hospital and Elche University General Hospital were collected. Also data regarding the same variables were collected from the publications of clinical trials which justify adjuvant treatment in stage III colon cancer and combination treatment with chemotherapy and targeted therapies in stage IV CRC. Results: We analyzed 249 patients with stage III colon cancer and 237 patients with stage IV CRC from our area. In our experience, 56.6% of stage III colon cancer were males, and median age was 66.2 years (23 - 91), with 41.8% ≥ 70 years. In clinical trials supporting adjuvant treatment 54 - 56.1% of patients were males, and median age was 59 - 61 years (19-83), with 14 - 21.7% ≥ 70 years. In our experience 64.4% of stage IV CRC patients were males, and median age was 67.2 years (38-89), 76.4% primary tumor in colon. In clinical trials supporting combination treatment with chemotherapy and targeted therapies 60-67% of patients were males, and median age was 59.2 – 62 years, primary tumor in colon 57.9 – 81% (Table). Conclusions: Patient populations included in clinical trials which support standard treatment in CRC are younger to those in our area. This fact, added to the restrictions based on inclusion and exclusion criteria of clinical trials, justify the qualification of “selected” to these populations not being representative of our clinical practice. [Table: see text]

scholarly journals Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS): A Randomized Clinical Trial

2021 ◽  
Vol 39 (10) ◽  
pp. 1098-1107
Author(s):  
Yukihide Kanemitsu ◽  
Kohei Shitara ◽  
Junki Mizusawa ◽  
Tetsuya Hamaguchi ◽  
Dai Shida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Primary Tumor ◽  
Tumor Resection ◽  
Stage Iv ◽  
Standard Of Care ◽  
Phase Iii ◽  
Primary Tumor Resection ◽  
Primary Tumors ◽  
Intention To Treat ◽  
Unresectable Metastases

PURPOSE It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases. PATIENTS AND METHODS This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat. RESULTS Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided P = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm. CONCLUSION Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.

Mutational landscape of metastatic colorectal cancer: Aggregate insights from a molecular tumor board.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 837-837
Author(s):  
Mark Andrew Lewis ◽  
Derrick S. Haslem ◽  
Ramya Thota ◽  
Terence Duane Rhodes ◽  
Tyler Barker ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Stage Iv ◽  
Tumor Board ◽  
Primary Tumors ◽  
Multiple Metastases ◽  
Molecular Tumor Board ◽  
Generation Sequencing

837 Background: The mutational landscape of metastatic colorectal cancer (CRC) is being elucidated by next-generation sequencing of both primary tumors and metastatic foci. In this study, we examined the results of all stage IV CRC cases submitted to our molecular tumor board (MTB). Methods: We performed a retrospective analysis of all patients who had next-generation sequencing performed between January 2015 and August 2017 on either their primary tumor and/or metastasis. Cases were presented at a MTB convened twice monthly. For the purposes of this study only pathogenic mutations were notated, not variants of unknown significance (VUS). Results: Eighty-seven unique patients had 97 specimens sequenced (28 primary tumors and 69 metastases). The primaries averaged 3 mutations per specimen (range: 1-6) whereas the metastases averaged 4 (range: 1-14, p=.25). The most common anatomic sites of submitted metastatic tissue were the liver (n=35, average mutations=4), followed by the lungs (n=10, average mutations=3) and the omentum/peritoneum (n=8, average mutations=3). Two patients had both a primary tumor and a metastasis sequenced, with a 33% rate of concordance in inter-specimen mutations. Five patients had multiple metastases sequenced, with a 53% rate of concordance in inter-specimen mutations; in every case of longitudinal sequencing, mutational burden increased in metastases over time. The most common mutation was apc (21% of all mutations), followed by p53 (16%) and then kras (13%). Candidacy for EGFR-directed therapy was found in 8 cases, and mismatch repair defects were detected in 5 cases. Conclusions: In stage IV CRC cases sent to our MTB, tissue from metastases was more commonly submitted for analysis than from the primary tumors. There is not necessarily concordance between mutations in primary tumors and metastases, nor among multiple metastases in the same patient. Sequencing at multiple time points in the disease course may allow observation of clonal evolution and dynamic adaptation of therapeutic targets.

Systematic assessment of intra- and peri-metastatic tumor budding in patients with stage IV colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 626-626
Author(s):  
Annika Blank ◽  
Sandra Burren ◽  
Inti Zlobec ◽  
Heather Dawson ◽  
Alessandro Lugli
Keyword(s):  
Colorectal Cancer ◽  
Lymph Node ◽  
Tumor Progression ◽  
Primary Tumor ◽  
Stage Iv ◽  
Distant Metastases ◽  
Metastatic Tumor ◽  
University Hospital ◽  
Tumor Budding ◽  
Primary Tumors

626 Background: Tumor budding is a strong independent prognostic factor in primary colorectal cancer (CRC). The prognosis of stage IV CRC is still poor and there is need for biomarkers to facilitate the clinical management. Data on tumor budding in colorectal cancer distant metastases (CRDM) are still missing. Therefore, the aim of this study was to analyze its role in tumor progression. Methods: 73 stage IV CRC with clinico-pathological data were retrieved from a cohort of 331 CRC patients, surgically treated between 2002 and 2013 at the University Hospital of Bern. Tumor budding was visualized immunohistochemically by pan-cytokeratin staining. Tumor budding was defined as intra- and peri-tumoral budding in the primary tumor (ITB = buds in the tumor center; PTB = buds at the tumor margin), intra- and perinodal budding (INB and PNB) and intra- and peri-metastatic tumor budding (IMB and PMB). Overall tumor budding was defined as tumor buds independent of the center and margin (OTB, ONB, OMB). The tumor bud count was assessed by calculating the mean number of tumor buds in 10 high power fields. For survival analysis a cut off of 10 tumor buds was applied to subdivide the tumors with low and high numbers of tumor buds. Results: In lymph nodes and CRDM, the tumor bud count was lower compared to primary tumors (PNB: 13; INB: 18; ONB: 21 vs PMB: 10; IMB: 21; OMB: 22 vs PTB: 23; ITB: 24; OTB: 33). For PTB/PNB and OTB/ONB, there were significant differences between primary tumor and lymph node metastasis (PTB/PNB: p < 0.001; OTB/ONB: 0.008) and primary tumor and distant metastases (PTB/PMB: p < 0.001; OTB/OMB: 0.007). The presence of PMB was predicted by INB, PNB and V1 (p = 0.032, p = 0.001 and p = 0.003). A trend towards a worse prognosis in patients with a high OMB number was observed. Conclusions: Tumor budding is present in lymph node and distant metastases of CRC, but its number is lower compared to the corresponding primary tumor. As tumor budding in local and distant metastases seems to be a predictor of tumor progression, these novel data should be considered as a basis for further analysis in large and multicentric clinical trials.

Laparoscopic surgery for palliative resection of the primary tumor in incurable stage IV colorectal cancer

2012 ◽  
Vol 26 (11) ◽  
pp. 3201-3206 ◽  
Author(s):  
Hideaki Nishigori ◽  
Masaaki Ito ◽  
Yuji Nishizawa ◽  
Atsushi Kohyama ◽  
Takamaru Koda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Laparoscopic Surgery ◽  
Primary Tumor ◽  
Stage Iv ◽  
Palliative Resection ◽  
Stage Iv Colorectal Cancer

scholarly journals Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2148
Author(s):  
Francesco Ardito ◽  
Francesco Razionale ◽  
Lisa Salvatore ◽  
Tonia Cenci ◽  
Maria Vellone ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Primary Tumor ◽  
Kras Mutation ◽  
Colorectal Tumor ◽  
Term Survival ◽  
Primary Tumors ◽  
Mutation Status ◽  
Primary Colorectal Tumor ◽  
Kras Mutation Status

If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer.

A Novel Derivation Predicting Survival After Primary Tumor Resection in Stage IV Colorectal Cancer

2017 ◽  
Vol 60 (9) ◽  
pp. 895-904 ◽  
Author(s):  
Winson Jianhong Tan ◽  
Sreemanee Raaj Dorajoo ◽  
Madeline Yen Min Chee ◽  
Wah Siew Tan ◽  
Fung Joon Foo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Primary Tumor ◽  
Tumor Resection ◽  
Stage Iv ◽  
Primary Tumor Resection ◽  
Stage Iv Colorectal Cancer
Sign in / Sign up

Export Citation Format

Share Document