bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival after primary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (FFCD ACHBTH AURC 9002 trial and EORTC Intergroup trial 40983).
Authors: Schimanski Carl Christoph , Kasper Stefan , Hegewisch-Becker Susanna , Schroeder Jan , Overkamp Friedrich , Kullmann Frank , Bechstein Wolf Otto , Voehringer Matthias , Oellinger Robert , Lordick Florian , Heinemann Volker , Geissler Michael , Schulz-Abelius Armin , Linz Bernhard , Bernhard Helga , Potthoff Karin , Schmidtmann Irene , Moehler Markus Hermann
Published: May 2019

e15019

Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term survival and cure after hepatic metastasectomy. The optimal treatment after primary liver resection remains controversial. Here we compare results from the LICC trial with historical controls, the FFCD ACHBTH AURC 9002 trial (FFCD; Portier et al., 2006) and the EORTC Intergroup trial 40983 (EORTC; Nordlinger et al., 2008, 2013). The three trials investigated pts with mCRC LLD who underwent primary hepatic resection. Methods: LICC, FFCD and EORTC were compared regarding pts characteristics, treatment, surveillance and efficacy outcomes. LICC pts received the adjuvant antigen-specific cancer vaccine tecemotide (L-BLP25) or placebo after primary LLD resection for up to 2 years. The FFCD trial compared postoperative 5-FU/leucovorin and the EORTC trial perioperative FOLFOX versus surgery alone. Results: Primary resected pts in LICC (n = 80; R0 n = 76), FFCD (R0 n = 171; postoperative chemotherapy n = 86) and EORTC (n = 364) showed different pt characteristics concerning median age (60, 63 and 63 years) and rate of synchronous metastases (46.8%, 27.9% and 34.0%). In LICC, > 5 liver metastases were resected in 11.6% of pts, in FFCD and EORTC all eligible pts had < 5 liver metastases resected. In contrast to EORTC, LICC and FFCD had a close surveillance until recurrence or a maximum of 2 years. Median OS (mOS) in LICC was not yet estimable in primary resected pts (tecemotide arm: 62.8 months; placebo arm: not yet estimable). In the FFCD and the EORTC trial, mOS was 62.1 and 61.3 months, respectively. Further details will be presented. Conclusions: Despite unfavorable disease characteristic in LICC compared with the earlier EORTC and FFCD studies, primary liver resection without adjuvant chemotherapy led to surprisingly good survival outcomes. Improvements in imaging-based pt selection and liver resection techniques might in part explain our finding. Surgery alone appears to be an option for selected pts with resectable LLD. Better systemic chemo(immune-)therapy may have also contributed to the OS benefit. Clinical trial information: LICC: NCT01462513; EORTC: NCT00006479; FFCD: not registered.
A phase ib trial to evaluate the safety and efficacy of quinacrine plus capecitabine in patients with refractory metastatic colorectal cancer.
Authors: Winer Arthur , Vijayvergia Namrata , Cohen Steven J. , Denlinger Crystal S. , Astsaturov Igor A. , Dotan Efrat , Gallant Jean-Nicolas , Wang Edward W , Kunkel Miriam , Lim Bora , Harvey Harold A. , Sivik Jeffrey Michael , Zhou Lanlan , Korzekwa Kenneth , Ruth Karen , Ross Eric A. , El-Deiry Wafik S.
Published: May 2019

e15020

Background: Acridines emerged from a cell-based screen for p53-pathway restoring compounds. Quinacrine, an acridine demonstrating p53 pathway restoration properties, displayed preclinical anti-tumor effects when used as monotherapy in colorectal cancer (CRC) cell culture and in vivo xenografts. Quinacrine suppresses survival pathways by inhibiting Mcl-1 expression, NFkB, STAT3, and angiogenesis. The combination of quinacrine plus 5-FU showed in-vivo preclinical efficacy against CRC with mutant KRAS, BRAF, or p53. Capecitabine, an oral 5-FU prodrug, is FDA-approved to treat metastatic (m)CRC. This phase I trial evaluated the safety and efficacy of quinacrine plus capecitabine in patients with refractory mCRC. Methods: Patients ≥18 years old with histologically confirmed mCRC refractory to standard therapy or with no standard therapy options available were eligible for the study. Using a modified 4B Simon’s accelerated titration design, patients were treated with a fixed dose of capecitabine 1000 mg/m2 twice daily (bid) for 14 days of a 21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg bid, and 200 mg bid for 21 days. The primary endpoint was to identify the maximum tolerated dose (MTD) of quinacrine in combination with capecitabine and to determine their tolerability and safety. Results: Ten patients were enrolled, median age 60-years old (range: 56-79). Quinacrine 100 mg daily and 100 mg bid were well tolerated by the first two patients. Dose Limiting Toxicities (DLTs) were seen in 3 patients treated with quinacrine 200 mg bid and included hyperbilirubinemia, transaminitis, increased alkaline phosphatase, hypokalemia, diarrhea, vomiting, and dehydration. No grade 4 or 5 toxicities were seen. 5 additional patients tolerated treatment with quinacrine 100 mg bid and capecitabine without further DLTs making this the MTD. The median time on treatment was 63 days. Three patients came off study prior to their first response evaluation. In 7 patients evaluable for response, 4 had stable disease (57%), while 3 (43%) had disease progression. Median overall survival was 196.5 days. Conclusions: Capecitabine and quinacrine can be safely administered at the MTD of capecitabine 1000 mg/m2 PO bid D1-14 and quinacrine 100 mg PO bid D1-21 of a 21-day cycle for patients with mCRC. A phase II study is ongoing. Clinical trial information: NCT01844076.
Investigation of an ethnic predisposition to developing brain metastases (BM) in Asian patients with colorectal cancer (CRC).
Authors: McGovern Kerri , Rodriguez Teresa , Smith Melissa H , Maloney Antonia , Saif Wasif M.
Published: May 2019

e15023

Background: CRC, the third most common cancer in the United States, carries racial/ethnic disparities in both incidence and mortality. With availability of effective systemic therapies, the life of CRC patients can be prolonged which thereby increases the risk of metastases at uncommon sites, such as the brain. We report our investigation into the impact of race/ethnicity on the incidence of BM in CRC patients using retrospective data (2010 – 2018) at a single institution. Methods: We retrospectively reviewed patients diagnosed with CRC and collected data on age, race/ethnicity, stage, treatment modalities, metastatic sites, and survival. Race and ethnicity were defined in accordance with federal standards set by the U.S. Census. Following this, race/ethnicity was self-declared and/or based on the primary language declared and categorized as non-Hispanic White, Hispanic White, non–Hispanic Black, Asian, or Unknown/Other. CRC location was classified as right-sided, left-sided or rectal. Results: We identified 264 CRC patients (median age: 61; range: 38 - 99). Among them 123 identified as non-Hispanic white, 28 non-Hispanic black, 26 Hispanic white, and 9 declared Other. There were 76 (29%) who identified as Asian. Of those 76 patients, 5 (7%) developed BM. All 5 patients were male and stage IV at initial diagnosis. BM was a late stage phenomenon with rectal primary and lung metastases seemly associated with an increased risk in the specific cohort. Molecular markers such as KRAS were available in 3 patients without clear association. Median time to development of BM was 29 months (range: 26 - 33). Median overall survival after BM diagnosis was 5.5 months (range: 4 - 11). Overall survival was longest for the patient who had both radiation and surgery. Conclusions: Our study showed an incidence of BM of 7% in the Asian sub-population compared to the historical control of 0.6 – 3.2% in the overall population. These results at the least warrant further investigation in a larger patient population of BM in CRC patients with emphasis on molecular markers. Recognition of BM in CRC patients is clinically relevant secondary to multiple lines of therapy as mentioned earlier and its grave impact on outcome.
Correlation of histopathologic regression with progression free survival (PFS) in patients (pts) with RAS wildtype metastatic colorectal cancer (mCRC) under fluorouracil/folinic acid, irinotecan, and oxaliplatin (FOLFOXIRI) plus panitumumab (pmab) or FOLFOXIRI alone: Subgroup analysis of VOLFI (AIO-KRK-0109).
Authors: Noepel-Duennebacke Stefanie , Juette Hendrik , Lugnier Celine , Geissler Michael , Martens Uwe Marc , Heinemann Volker , Held Swantje , Klaassen-Mielke Renate , Modest Dominik Paul , Reinacher-Schick Anke C. , Seufferlein Thomas , Tannapfel Andrea
Published: May 2019

e15024

Background: We recently demonstrated improved objective response rate in untreated all-RAS wildtype mCRC with the addition of the anti-EGFR-antibody pmab to FOLFOXIRI. In this subgroup analysis we focused on histopathological response as a predictive marker for PFS. Additionally we analyzed chemotherapy induced steatosis hepatitis (CASH) in both treatment arms. Methods: Tissue samples from pts. achieving secondary resection of liver metastases in VOLFI were analyzed. We defined a cut-off for very good histopathological response at 20% of residual tumor cells in proportion to the total tumor area. For CASH sinusoidal obstructive syndrome, ballooning, steatosis, cholestasis, fibrosis and inflammation were determined. PFS was estimated using LIFETEST procedure. Results: Tissue of 14/19 resected pts. was evaluable (pmab-FOLFOXIRI/FOLFOXIRI: 11/3). All showed partial remission by RECIST. Median age was 56 yrs. (32–67), male/female: 7/7. All primary tumors were located in the left colon. Molecular analysis detected 1 BRAF (V600E) mutation and 1 MSI-H tumor. Median treatment duration until resection in this cohort: pmab-FOLFOXIRI 7 cycles (3-12)/FOLFOXIRI 9.5 cycles (7-11).7 pts. achieved very good histopathological response with vital tumor cells ≤20% (pmab-FOLFOXIRI/FOLFOXIRI 5/2) and 7 pts. showed vital tumor cells >20% (pmab-FOLFOXIRI/FOLFOXIRI 6/1). The cut-off correlated with an improved PFS in the group ≤20 vs >20% (median PFS 12.40; confidence interval (CI) 6.43-51.22 vs PFS 9.88; CI 6.17-15.26 months). The severity of CASH was not increased by the addition of pmab. Conclusions: In this preliminary analysis of VOLFI histopathological response seems to correlate with a better PFS after secondary resection of liver metastases. There was no relevant difference in CASH between pmab-FOLFOXIRI vs. FOLFOXIRI alone. The trial is registered with ClinicalTrials.gov, NCT01328171. Clinical trial information: AIO-KRK-0109.
Survival after secondary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (CELIM, FIRE-3).
Authors: Moehler Markus Hermann , Folprecht Gunnar , Heinemann Volker , Holch Julian , Maderer Annett , Kasper Stefan , Hegewisch-Becker Susanna , Schroeder Jan , Overkamp Friedrich , Kullmann Frank , Bechstein Wolf Otto , Voehringer Matthias , Oellinger Robert , Lordick Florian , Geissler Michael , Schulz-Abelius Armin , Linz Bernhard , Bernhard Helga , Schmidtmann Irene , Schimanski Carl Christoph
Published: May 2019

e15025

Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term overall survival (OS) and potential cure after complete hepatic metastasectomy. The appropriate postoperative treatment strategy is still controversial. L-BLP25 as antigen-specific cancer vaccine targeting mucin 1 (MUC1) was recently evaluated as adjuvant therapy in mCRC pts after R0/R1 LLD resection (LICC trial, NCT01462513). Here we compared the LICC surveillance program and efficacy results for secondarily resected LLD pts versus historical controls, i.e. the CELIM trial (Folprecht et al, Ann Oncol 2014) of potentially resectable LLD mCRC pts and a FIRE-3-LLD subgroup (Holch et al, Int J Cancer 2018). Methods: LICC, CELIM and FIRE-3-LLD subgroup pts with stage IV mCRC limited to liver metastases who underwent hepatic resection (R0 or R1) were compared regarding pts characteristics, surveillance and efficacy outcome. LICC pts received adjuvant L-BLP25 or placebo after secondary LLD resection as 8 weekly doses, followed by 6 week maintenance intervals and tight surveillance until recurrence or a maximum of 2 years. Results: In LICC, 41 /121 pts (33.9%) were secondarily resected, and R0 resection was achieved in 31 pts (75.6%). In CELIM, 36/106 pts (34%) with primary unresectable LLD were secondarily R0 resected. In FIRE-3-LLD, secondary resection was feasible for 29/133 pts (21.8%). After R0 resection, median recurrence free survival (mRFS) was 8.9 months in LICC, 9.9 months in CELIM and 11.5/ 12.4 months in FIRE-3-LLD in either treatment arm. In the LICC trial, median overall survival (mOS) in secondarily resected pts was 65.1 months, with 38.3 months for the R1 and is not yet reached for the R0 subgroup. In CELIM, mOS was 53.9 months for R0 resected pts. In FIRE-3-LLD, after secondary resection mOS was 56.2 months. Median age was about 5 years less in LICC. Further details will be presented. Conclusions: Secondary resected pts of LICC, CELIM and FIRE-3 showed impressive median OS with better OS for LICC and a younger patient cohort. The established tight LICC surveillance program after surgery might have had a positive impact on survival. Clinical trial information: LICC: NCT01462513; FIRE-3: NCT00433927; CELIM: NCT00153998.
Circulating tumor DNA-based mutational landscape of advanced colorectal cancer.
Authors: Yan Fang , Gao Wei , Zhu Lifei , Xie Wenzhuan , Gao Chan , Zhao Jing , Huang Mengli , Cai Shangli , Zhong Yi
Published: May 2019

e15034

Background: Alterations in oncogenic driver genes are extensively tested to guide anticancer treatment in colorectal cancer (CRC). As the repertoire of therapeutic targets continue to grow, we are interested to interrogate the possibility of resorting to circulating tumor DNA (ctDNA) where tissue samples are not readily available. Methods: Targeted next generation sequencing (NGS) was performed on ctDNA obtained from patients with advanced CRC using a 150-gene panel. Mutational profiles of ctDNA were compared with those detected in tissue samples from the 3D Medicine database as well as The Cancer Genome Atlas (TCGA) database. Genomic aberrations such as single nucleotide variations (SNVs), insertions/deletions, copy number variations, gene rearrangement and fusions were analyzed. Results: Notably, 244 of 256 samples (95.3%) were ctDNA-positive, as indicated by a maximum somatic allele frequency (MSAF) of > 0%. At least one reportable genomic alteration was detected in 96.5% of all cases, with an average of 8.12 mutations per case. The most frequently mutated genes were TP53 (47%), APC (42%), KRAS (32%) in ctDNA. A similar trend was also observed for SNVs, where TP53 (46.9% vs. 77.6% vs. 53.8%), APC (41.8% vs. 66.0% vs. 73.0%), and KRAS (30.5% vs. 48.4% vs. 43.5%) had the highest mutation frequencies across three data sets (ctDNA, tissues and the TCGA database). The SNV profiles of therapeutically relevant genes for CRC were also largely consistent between ctDNA and the tissue samples included in the 3D Medicine database: BRAF (7.0% vs. 8.7%), KRAS (30.5% vs. 48.4%), NRAS (2.7 vs. 3.1%), ERBB2 (5.1% vs. 5.2%), MLH1 (0.8% vs. 2.9%), MSH2 (2.7% vs. 3.1%), and MSH6 (3.1% vs. 3.7%). Patients harboring copy number gains had a significantly higher level of MSAF than those free of gene amplifications (p < 0.0001). Conclusions: Mutational landscape of ctDNA in general correlated with that detected in prior tissue samples as well as the TCGA database, supporting a role for ctDNA testing as a complementary approach to tissue testing in CRC.
Incidence and prognostic factors in patents (pts) with mutant BRAF (mBRAF) metastatic colorectal cancer (mCRC) in Russia.
Authors: Fedyanin Mikhail , Elsnukaeva Kheda , Demidova Irina , Stroyakovskiy Daniil , Shelygin Yury , Tsukanov Alexey , Ponomorenko Alexey , Panina Maria V , Shubin Vitaliy , Moiseenko Fedor Vladimirovich , Bolotina Larisa , Kudryavtseva Anna , Filipenko Maxim , Voscoboev Mikhail , Vladimirova Liubov Yu , Kit Oleg Ivanovich , Stroganova Anna , Dranko Svetlana , Senderovich Anastasia , Tjulandin Sergei
Published: May 2019

e15035

Background: m BRAF mCRC has the aggressive phenotype. The incidence of such mutation in Europe and the USA is around 8-14%, in Asian countries - 4-8%. The purpose of this population-based study was to determine the incidence and identifying prognostic factors in pts with mBRAF mCRC in Russia. Methods: A multicenter retrospective analysis of clinical data and treatment results of pts with mBRAF mCRC was performed. The main method for determining mutations was a PCR. The main efficacy endpoint was progression free survival (PFS) at the 1st line. Multivariate analysis was performed using Cox regression model. Results: 437 out of 8646 pts (5%) with a known mutational status had m BRAF (V600E). Clinical data were collected from 119/437 (27.2%): female - 65.5%, average age - 60 years (28-86), MSI-H -10%; the right-sided primary tumor – in 65%, left-sided – in 17%, rectum – in 18%; the primary tumor was removed in 76%; adjuvant chemotherapy was administered in 30%; lung metastases – in 15 %, liver - 45%, peritoneal metastases – in 38%; metastasectomy was performed in 13% pts. The first line was administered in 86 (72%) pts: FOLFIRI / XELIRI - 17 (20%), FOLFOX / XELOX - 50 (58%), FOLFOXIRI - 12 (14%), monotherapy of fluoropyrimidines – in 7 (8%). Bevacizumab was added to chemotherapy at 1st line in 25 (29%) patients, anti-EGFR – in 8 (9%) pts. PFS at the 1st line was 7 months: XELOX / FOLFOX - 7, FOLFOXIRI - 7, FOLFIRI / XELIRI - 6 and fluoropyrimidines - 2 months (HR 0.9, 95% CI 0.6-1.1, p = 0.3). None of the clinical or morphological factors except the presence of metastases in the retroperitoneal lymph nodes (HR 2.6, 95% CI 1.3-5.4, p = 0.006) did not have an independent negative prognostic value. Conclusions: In contrast to Western countries the incidence of mBRAF gene in the population of pts with mCRC in the Russia is low and we found a high incidence of localization of the primary tumor in the rectum. We didn’t reveal any prognostic factors except metastases in the retroperitoneal lymph nodes, and didn’t reveal any differences between the usual duplets and standard regimen for such mutation - FOLFOXIRI in term of 1st line PFS. This suggests we need a prospective randomized study to determine the optimal regimen of chemotherapy at 1st line for mBRAF mCRC pts.
Microsatellite instability and mutations in BRAF and KRAS in small bowel adenocarcinoma.
Authors: Michalaki Vasiliki , Polydorou Andreas , Theodosopoulos Theodosios , Frangulidis George , Dafnios Nikolaos , Frangou Plemmenou Matrona , Papadimitriou Christos
Published: May 2019

e15037

Background: Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) The aim of this study was to perform a comprehensive immunohistochemical.analysis of KRAS, NRAS, V600E BRAF mutations and microsatellite instability using a cohort of surgically resected cases in our institution. Methods: A total of 17 patients (10 males and 7 females; mean age, 56.2 years old; range, 45-75 years old) received chemotherapy due to non-curative tumor resection, unresectable tumor or post-operative recurrence. Twelve patents received fluoropirimidine and oxaliplatin based first line chemotherapy. Molecular targeted agents were administered to 15 patients, for whom it was their first- or second-line therapy. Results: KRAS mutations were found in 7 cases (41%), out of which 5 (29%) were in exons 12/13. BRAFV600E mutation was observed in 1/17 pt. Microsatellite instability was identified in 3/17pt (MSI; 18%), mainly related to a loss of expression of MLH1 protein. Univariate analysis revealed a PS of 0 (P=0.0226) and treatment with platinum-based chemotherapy (P=0.0047) were significant factors for an improved prognosis. Among the 12 patients who received oxaliplatin-based chemotherapy as a first-line chemotherapy, a PS of 0 (P=0.0255) and treatment with anti-EGFR agents (P=0.0127) were significant positive prognostic factors. Toxicities due to the molecular targeted agents were not experienced. The median overall survival time was 14.3 months (range, 3-52 months), the median DFS was 14.2 months and the median OS was 32 months. Conclusions: To date, there is no standard chemotherapy regimen for advanced SBAs and little is known about their molecular characteristics. The results of the present study indicate that oxaliplatin based chemotherapy containing molecular targeted agents is a well-tolerated and effective treatment option for SBA. A better understanding of disease biology may help to identify therapeutic targets and advance precision medicine.
Efficacy of anti-EGFR-based treatment (tx) in second-line and beyond according to tumor location (TL) in RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) patients (pts): A mono-institutional retrospective analysis.
Authors: Vivolo Raffaella , Calegari Maria Alessandra , Basso Michele , Zurlo Ina Valeria , Di Stefano Brunella , Bensi Maria , Camarda Floriana , Martini Maurizio , Cocomazzi Alessandra , Pozzo Carmelo , Bria Emilio , Salvatore Lisa , Tortora Giampaolo
Published: May 2019

e15038

Background: Right- (R) and left-sided (L) mCRCs exhibit different clinical and molecular features. Several retrospective analyses showed that the survival benefit of anti-EGFR-based tx is limited to RAS/BRAF wt L-sided mCRC pts, with a larger effect in the first-line setting. Few data are available concerning the anti-EGFR efficacy according to TL in 2nd and following lines. Methods: Pts affected by RAS/BRAF wt mCRC treated at our Institution with anti-EGFR-based tx in 2nd and following lines were retrospectively collected. The objective of the analysis was to compare tx activity and efficacy according to TL. Primary endpoint was overall survival (OS); secondary endpoints were progression free survival (PFS) and response rate (RR). Results: A total of 47 RAS/BRAF wt mCRC pts treated with an anti-EGFR-based tx in 2nd and following lines were identified. Of those, 32 (68%) were L-sided and 15 (32%) R-sided, respectively. Pts (age, gender, PS ECOG) and tumor (number of metastatic sites) characteristics and number of tx lines were well balanced between the two 21 pts received anti-EGFR alone, 26 pts anti-EGFR plus CT. mOS was 22.3 in L-sided and 7.3 months in R-sided group (HR 2.3, 95%CI 1.02-5.14, p = 0.04). At multivariate analysis TL and PS ECOG independently correlated with OS ( p = 0.02 and p =0.0089). mPFS was 8.4 and 3.9 months in pts with L-sided and R-sided tumor, respectively (HR 1.3; 95%CI 0.64-2.80, p =0.43). RR was higher in L-sided compared to R-sided tumor (37.5 vs 13.3) ( p= 0.09). Conclusions: Our analysis, although limited by the small sample and by its retrospective nature, indicates a better OS in L-sided compared to R-sided tumors treated with anti-EGFR-based tx in 2nd and following lines. A prospective validation is warranted.
Colorectal cancer lung metastasis: Could multidisciplinary management suggest the right strategy?
Authors: Zurlo Ina Valeria , Basso Michele , Congedo Maria Teresa , Vita Maria Letizia , Petracca Ciavarella Leonardo , Salvatore Lisa , Calegari Maria Alessandra , Pozzo Carmelo , Di Stefano Brunella , Bensi Maria , Vivolo Raffaella , Barone Carlo , Cassano Alessandra , Bria Emilio , Margaritora Stefano , Tortora Giampaolo
Published: May 2019

e15039

Background: Unlike liver metastases surgery, the resection of colorectal cancer lung metastasis (CCLM) is not standardized and data are still poor. Therefore, we conducted a retrospective analysis to evaluate the management of CCLM at our Centre. Methods: We retrospectively analyzed patients (pts) with CCLM treated at our Institution from Jan-2007 to Jan-2017. Aim of the study was to evaluate the impact of clinical and pathological features with survival outcomes (DFS and OS). Differences were compared with the use of log-rank test and parameters considered statistically significant ( p value < 0.5) at univariate were compared at multivariate analysis. Results: 141 pts were included in the analysis. 87 pts received a preoperative chemotherapy (pCT) and 54 an adjuvant (a)CT. In the whole population median DFS (mDFS) was 24 m (20-24) and median OS (mOS) 54 m (46-82), while 21 m (20-34) and 65 m (45-108) for pts undergoing pCT and 15 m (20-28) and 53 m (38 – 76) for those receiving aCT respectively, without statistically significant differences (p=0.4). Age, gender, PS, disease-free interval (DFI) (> or <24 months), primary tumor sidedness, mucinous histology, grading, RAS status, timing of lung metastasis (metachronous vs synchronous), number of lesions (>2), metastasis location (uni vs bilateral) and liver resection were evaluated at univariate and multivariate analysis. DFS was correlated with DFI > 24m (p=0.02), timing (p=0.03), number (p<0,0001) of metastasis and metastasis location (p=0.01) whereas OS was associated to DFI (p=0.02), number (p=0.0005), metastasis location (p=0.037) and RAS status (p=0.05) at univariate. At multivariate analysis, number of lesions correlated to DFS (p=0.0006) while DFI (p=0.0034) and RAS status (p=0.05) to OS. Conclusions: Our single Centre retrospective experience suggests an important clinical impact from surgery of CCLM based on mOS of the whole population. These data strengthen the role of a multidisciplinary management to allow pts to achieve surgery whenever possible, regardless of previous liver surgery, metachronous vs synchronous metastasis, DFI and RAS status.
The impact of nodal metastasis on survival in stage IV colon cancer: Analysis of National Cancer Database 2004-2014.
Authors: Saha Sukamal , Elgamal Mohamed , Cherry Meghan , Buttar Robin , Wiese David , Kaushal Sunil , Alnounou Mustafa , Singh Trevor , Eilender David S. , Grewal Sandeep Singh , Arora Madan L.
Published: May 2019

e15042

Background: Lymph node (LN) metastasis (mets) is the strongest prognostic factor in colon cancer (CCa), however, its significance in Stage IV disease remains controversial. We analysed National Cancer Database (NCDB) to determine the impact of nodal mets on survival in Stage IV CCa patients (pts). Methods: From 2004-2014, NCDB pts with pathologic Stage IV CCa were divided into groups based on LN status and No. of +ve LNs. Only Stage IV CCa pts who underwent surgical resection of their primary tumor with available pathologic data as well as chemotherapy data were included. Kaplan-Meier method and log rank test were used to compare 5-year overall survival. Results: A total of 33574 pts data met the criteria of the study. Adenocarcinoma represented 82.3% of the total pts. Majority of the pts (82.61%) had +ve LN status. Mean survival was 36.3 vs 24.2 months in -ve LN vs +ve LN pts respectively. Overall 5yr survival was better in LN -ve pts ( 23.4%) versus LN +ve pts ( 10.2%) Survival for all years was inversely related to the number of +ve LN ( Table). For LN +ve or LN -ve pts, receiving any form of chemotherapy was associated with significantly improved survival when compared to no chemotherapy. Conclusions: LN status and No. of +ve LNs impact the prognosis of CCa, even in stage IV. Receiving some form of chemotherapy improves the prognosis for both pts with +ve or -ve LN status. These findings suggest that separation of Stage IV LN negative versus positive patients may be warranted in staging and treatment. 5 year survival according to LN status and No. of positive LN. [Table: see text]
A phase Ib study of pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver metastatic MSS colorectal cancer (CRC): A postoperative safety analysis.
Authors: Bassetti Michael Frederick , Turk Anita Ahmed , Lubner Sam Joseph , Uboha Nataliya Volodymyrivna , LoConte Noelle K. , Mulkerin Daniel , Kim David H. , Matkowskyj Kristina , Weber Sharon M. , Abbott Daniel , Eickhoff Jens C. , Deming Dustin A.
Published: May 2019

e15047

Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intra-tumoral and intra-lymphatic antigen release and a rapid influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence rate at 1 year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: 10 patients (median age 61.5 [range 39-69]) have been enrolled and completed the intended neoadjuvant therapy, operative management and at least 4 adjuvant cycles of Pem. All patients had received prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all patients. Mean gross tumor size targeted was 19.1cc (2.3-80.4). Any-grade post-operative AEs (>20%) attributable to Pem include diarrhea (30%), hyperbilirubinemia (20%%), and leukopenia (20%). Post-operative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity in the post-operative setting. Clinical trial information: NCT02837263.
The “effect” of T classification on colorectal liver metastasis.
Authors: Wu Lunpo , Zheng Hongjuan , Fu Jianfei , Du Jinlin , Zheng Shu , Wang Liangjing
Published: May 2019

e15049

Background: T classification is considered as a detail and credible category of the depth of tumor invasion. Generally, with the increasing T category, the risk of metastases should be continuously rising. However, there is a group of metastatic patients with early T classification, who were supposed to have a low metastatic probability. Our study aims to present the T classification on metastatic liver colorectal cancer (CRLM) in both clinical and biological aspects, and explore preoperative predictions to develop a convenient individual assessment model for clinicians to speculate whether these patients, whose prognosis is extremely poor. Methods: Tissue samples of primary colorectal cancer were obtained at our center. Patients with CRLM during 2010 to 2014 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox models were used to analyze the survival differences. We identified preoperative prognostic factors based on the Cox analysis and constructed a nomogram model. The predictive accuracy and discriminative ability were measured by concordance index (C-index) and calibration curve. Results: The mRNA array from our hospital showed that there is an obvious difference between the T1/2N0M1 subgroup and the T3/4N0M1 subgroup. Patients with early T classification (T1) were more often have tumors located in rectum, with well differentiation, with no lymph node metastasis and a higher CEA level. Further survival analysis indicated that early T classification (T1) was an independent prognostic factor with poorer survival. When the lymph node (N) status was taken into consideration, patients with T1 N+ had an obvious better survival than T1 N0 patients. A clinical nomogram was constructed based on preoperative factors. The calibration curves for probability of 1-, 2-, and 5-year overall survival showed a good agreement between nomogram prediction and actual observation. Conclusions: The prognosis of T1M1 is extremely poorer than T3/4M1. The prognosis of T1N+ is better than T1N0. It is time to pay more attention to the high-risk monitoring and screening of T1 in early colon cancer.
Reporting of patient (pt) characteristics (c) and use of stratification factors (SF) in phase III trials for metastatic colorectal cancer (mCRC): Urgent need for standardization.
Authors: Horn Robert Asa , Tannenbaum Daniel , Morris Van K. , Johnson Benny , Overman Michael J. , Parseghian Christine Megerdichian , Kopetz Scott , Eng Cathy , Rogers Jane E. , Raghav Kanwal Pratap Singh , Dasari Arvind
Published: May 2019

e15055

Background: An increasing number of pt and tumor c have predictive and prognostic implications in mCRC. However, there is no consensus on their reporting in trial results. Methods: Pt c and SF from 136 phase III trials of systemic therapies (Rx) in mCRC published between 1988 and 2018 (68,326 pts) were collected. Trials were also grouped per publication date (G1: 1988-97; G2: 98 – 2007; G3: 08-18). Patterns of reporting and trends across G were evaluated. Results: Pt c consistently reported were performance status, PS (98.5%), age (92.6%) and gender (90.4%); race (20.6%) & weight/BMI/BSA were not (13.2%). Tumor c frequently reported were metastatic (met) spread (70.6%) while time intervals related to disease course (25%) and synchronous met vs not (19.1%) were omitted. Of note, primary site was largely reported as colon vs rectum (69%) and sidedness or anatomical location was discernable only in 10.3%. Prior Rx reporting focused on chemo (58.5%) with radiation and surgery and reported in 34% & 28.7%. Reporting of prognostic factors was variable and limited: histology grade CEA, alk phos, LDH (range 10.3-15.4%). Only 11.8% of trials reported genomic factors - KRAS MT was included in all with BRAF MT in 4.4%. Of 140 trials used for SF analysis, 115 had ≥ 1 (range 1-7). Common SF were PS (60%), geography /institution (55.7%). Prior Rx (27%), met spread (24.3%) were sometimes used while primary site (7.8%), genomic factors (6.1%) rarely were. Trends across G are per Table. Conclusions: There is marked inconsistency in pt c & SF reporting in mCRC trials. Consensus guidelines will aid in standardization of trial interpretation and future meta-analyses; and will need to be updated based on emerging data. [Table: see text]
Mutational burden on circulating cell-free tumor-DNA testing as a surrogate marker of mismatch repair deficiency/microsatellite instability and/or response to immunotherapy in patients with colorectal cancer.
Authors: Kamatham Saivaishnavi , Colibaseanu Dorin , Merchea Amit , Shahjehan Faisal , Starr Jason Scott , Mody Kabir , Kasi Pashtoon Murtaza
Published: May 2019

e15066

Background: Circulating cell-free tumor-DNA (ctDNA) testing (‘liquid biopsy’) is increasingly being employed both in clinical trials as well as clinical practice. We aimed to contrast and compare the differences in the number of somatic mutations observed on ctDNA testing between mismatch repair deficient/microsatellite instability-high (dMMR/MSI-High) versus mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancers (CRC). Methods: We had 20 patients at Mayo Clinic Florida that were dMMR/MSI-High with testing through the commercially available platform (Guardant360) that uses a 73-gene panel. Median numbers of somatic mutations were compared between the 2 subset of CRC. Results: Patients with dMMR/MSI-High CRC had a median of 8 mutations (range: 2-15) versus a median of 4 mutations (range: 1-22) in pMMR/MSS patients, p-value of 0.001. Similarly, the mean number of somatic mutations were 7.47 (S.D. ± 4.15) versus 5.02 mutations (S.D. ± 3.83) in patients with dMMR/MSI-H and pMMR/MSS, tumors respectively. Though it is simplistic, we could still potentially identify patients who may be candidates for immunotherapy by gauging the mutational burden reported (Table). Furthermore, on serial testing, decline in mutational burden as early as few weeks into therapy was predictive of response later on imaging. Conclusions: Analysis of number of somatic mutations on ctDNA testing can be complementary to MMR/MSI-testing, especially in situations when tissue is not available or safe to obtain. This can also be of value in predicting and/or following response to immunotherapy. The utility of this may go beyond CRC in identifying patients who may benefit from immunotherapy. [Table: see text]
Patterns of metastasis and second primary malignancies (SPM) in colorectal cancer: A perspective from Peru.
Authors: Leon Jorge , Namuche Fernando , Montenegro Paola Catherine , Flores Claudio J.
Published: May 2019

e15068

Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. Approximately 20% of patients with CRC already have metastases at diagnosis, and this figure has been stable over the last two decades. The lack of data makes it more difficult to manage our patients. The metastatic setting and patients with second primary malignancies are complicated scenarios. The objective of our study was to explore and describe the metastasis patterns and the second primary malignancies’ frequency in CRC patients. Methods: We retrospectively reviewed the electronic medical records of 609 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016. For the evaluation of the metastasis pattern, we selected 198 patients with metastasis at debut and the patients who had relapse of the disease. Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We evaluated the metastasis pattern according to primary tumour sidedness, age, CEA, histological grade, histological type. A survival analysis was performed with Kaplan Meier method, comparing the curves with Log Rank test for metastasectomy, biological therapy and number of sites with metastatic disease. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: At the time of diagnosis, stage IV disease accounted for 15.3% (93) of all CRC cases. 105 (stage I-III) pts had relapse disease. Regardless of the primary tumor site, the most common site for metastatic spread was the liver (42.9%), lung (12.6%), carcinomatosis (18.2%). Pts who underwent metastasectomy presented a better OS [HR, 0.284; 95% CI, 0.123-0.657; p < 0.05], as well as pts who received biologic therapy [HR, 0.641; 95% CI, 0.416-0.990; p < 0.05] and a greater number of sites with metastatic disease had worst OS [HR, 1.878; 95% CI, 1.181-2.985; p < 0.05] The incidence of SPM following CRC was 48/609 (7.8%), the more frequent localizations were: breast, prostate and lung with 14.6% each, then kidney 10.4%, bladder 8.3%. Conclusions: In mCRC metastasectomy, biological therapy and number of sites with metastatic disease play an important role in OS. The more frequent localizations with SPM were breast, prostate and lung.
A novel RAS internal tandem duplication involving the switch II domain disrupts GAP-binding and activates oncogenic signaling.
Authors: Lou Emil , Turbyville Thomas , Simanshu Dhirendra , Yang Rendong , Columbus John , Stephens Bob , Sciacca Drew , Sarver Anne , Subramanian Subbaya , Nissley Dwight , Nelson Andrew
Published: May 2019

e15069

Background: Recent clinical guidelines for expansion of molecular testing of oncogenic RAS mutations in colorectal carcinoma have led to increased identification of mutations in this patient population. The clinical characteristics of NRAS-mutated colorectal carcinoma have not been well established because of the lower prevalence of these mutations (< 6%) as compared to oncogenic KRAS mutations. Here, we report the discovery of a novel internal tandem duplication (ITD) mutation of NRAS, which disrupts the Switch II domain in an index case of a patient with widely disseminated colorectal cancer. Methods: Hotspot next generation sequencing of a brain metastasis using a clinical solid tumor panel identified this novel NRAS ITD and a TP53 missense mutation (p.P275F). Whole exome sequencing of the primary tumor and two metastatic lesions (lung and brain) was performed to identify other genetic factors potentially driving the disease. Results: The above approach confirmed that the NRAS ITD and TP53 mutation were conserved between the primary tumor and both metastatic tumors and identified an additional pathogenic mutation in CSMD1 (a tumor suppressor gene). No other clearly pathogenic driver mutations were identified. Structural biology and biochemical analyses demonstrated that the inserted 15 amino acids prevented binding to GAP protein, leading to sustained RAS activation and increased interaction with RAF to stimulate downstream MAPK activation. Conclusions: These genomic and biochemical studies indicate that a novel NRAS ITD was the primary driver mutation of this aggressive colorectal carcinoma. Identical or similar ITDs in NRAS and KRAS may also drive other forms of colorectal cancer and other aggressive malignancies and represent a new subset of RAS-driven drug-resistant cancers.
Structured literature review (SLR) and meta-analyses of the prevalence of microsatellite instability high (MSI-H) and deficient mismatch repair (dMMR) in gastric, colorectal, and esophageal cancers.
Authors: Amonkar Mayur , Lorenzi Maria , Zhang Jacky , Mehta Shivani , Liaw Kai-Li
Published: May 2019

e15074

Background: Pembrolizumab is approved in the US for treatment of unresectable/metastatic MSI-H/dMMR solid tumors progressing after standard prior treatment. While some data exist on MSI-H/dMMR prevalence in colorectal cancer (CRC), data on other gastrointestinal (GI) cancers is sparse. Methods: An SLR covering solid tumor types identified English language publications using immunohistochemistry (IHC) for all 4 MMR proteins or polymerase chain reaction (PCR) techniques using specified NCI or Promega marker panels. A targeted review was conducted for CRC due to larger volume of publications in this tumor type. MEDLINE, EMBASE, Cochrane databases and key cancer congresses were searched for relevant articles. Among eligible studies, meta-analyses were performed (random effects model) on the prevalence of MSI-H and dMMR among gastric, colorectal and esophageal cancers. If possible, prevalence estimates were also obtained by geography, disease stage, and histology. Results: Of 1,176 citations retrieved in the full review, 35, 17 and 6 studies reported prevalence of MSI-H and/or dMMR in gastric, CRC, and esophageal cancers, respectively. Among gastric cancers, MSI-H pooled prevalence (with 95% CI) from 32 studies (16,308 patients) was estimated at 11% (9-12%) and dMMR pooled prevalence from 4 studies (854 patients) was estimated at 8% (2-17%); in stage 4 cancers, the prevalence was 7% (4-9%; 10 studies; 383 patients). In CRC, MSI-H pooled prevalence from 14 studies (8,156 patients) was estimated at 13% (10-16%) and dMMR pooled prevalence from 4 studies (11,434 patients) was estimated at 10% (5-15%). For stage 4 CRC, the prevalence was 5% (1-10%; 4 studies; 252 patients). Among esophageal cancers, MSI-H pooled prevalence from 6 studies (731 patients) was estimated at 4% (0-11%). Conclusions: This comprehensive SLR provides prevalence estimates of MSI-H and dMMR across 3 key GI tumors based on published data. The prevalence estimates of MSI-H among gastric cancer and CRC were similar to their corresponding dMMR prevalence estimates. MSI-H prevalence appeared to be lower for advanced stage gastric cancer and CRC.
Tumor stroma percentage (TSP) and intrinsic subtypes in stage II/III colon cancer: NRG Oncology/NSABP C-07 trial.
Authors: Kim Rim S , Gavin Patrick G , Paik Soonmyung , Allegra Carmen Joseph , Jacobs Samuel A. , Pogue-Geile Katherine L. , Lucas Peter C.
Published: May 2019

e15075

Background: Recent molecular subtype studies of colorectal cancer (CRC) have identified various genomic signatures. Regardless of the variety of studies, poor prognosis is associated with stem-like or mesenchymal subtypes, which are largely contributed by stromal cells or cancer-associated fibroblasts (CAF) and are driven by transforming growth factor-beta (TGF-ß) signaling. Tumor stroma percentage (TSP) in CRC morphologically evaluated on H&E slides has been reported as an independent prognostic parameter in stage II/III colon cancer patients (pts). We tested the association of TSP with molecular subtypes in NRG Oncology/NSABP C-07, in which pts with a stem-like or mesenchymal subtype had a poor prognosis regardless of chemotherapy regimen. Methods: Ninety seven pts with available archived whole-section H&E images from C-07 were reviewed for TSP for the stromal proportion in the most invasive part of the primary tumor as stroma-high (>50%) or stroma-low (≤50%) as described in other studies. The population was selected to be enriched with stem-like subtype. Subtypes were determined by modified centroids based on Assigner (CRCA) classifier using archived nCounter data, described previously. Results: Of 23 pts, 22 (95.7%) with stroma-high tumor (TSP >50%) were classified with the stem-like subtype. One stroma-high pt had a tumor with a non-stem-like subtype. Of 56 pts with stem-like subtype tumors, 22 were classified as stroma-high, whereas 1/41 with non-stem-like tumors was classified as stroma-high (P=0.00007). Conclusions: TSP is strongly associated with stem-like subtype of poor prognosis in stage II/III CRC and identifies a subset of stem-like subtype. Further study may reveal TSP as a simple biomarker for treatment resistance and potential therapies targeting stromal cells or CAF driven by TGF-ß signaling. SUPPORT: sanofi; U10CA180868, -180822, U24CA196067, PA DoH; NSABP. No. of samples with TSP >50 according to CRCA subtypes. Clinical trial information: NCT00004931. [Table: see text]