bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulating the tumor microenvironment to enhance efficacy of PARP inhibitors.
Authors: Mehibel Manal , Xu Jimmy , Diep Anh , Thakkar Kaushik , Li Caiyun G , Xiao Yiren , Rankin Erinn , Giaccia Amato
Published: May 2019

e14715

Background: PARP inhibitors (PARPi) have demonstrated activity in HR deficient tumors through synthetic lethality. However, their clinical efficacy has not been highly promising, with response rates ranging between 30-60% for Olaparib, Talazoparib and Veliparib (1). This highlights the necessity to understand the mechanisms of resistance and how these agents work in the context of the tumor microenvironment. In this study, we explore the effect of hypoxia on the efficacy of PARPi in a range of HR-deficient tumors. Hypoxia is known to downregulate genes of homologous recombination (2) but its role in HR deficiency in still unknown. Methods: HR deficient tumor cell lines were treated with PARPi under both aerobic and hypoxic conditions. DNA damage markers such as γH2AX, 53BP1 and RIF1 were detected by immunofluorescence. Tumor xenografts were grown to 100 mm3 prior to treatment with vehicle, PARPi, hypoxia activated cytotoxin, or the combination and tumor volumes were measured. Co-localization of apoptosis and hypoxia was detected by IHC. Finally, hypoxic signature in breast PDX models was correlated with their sensitivity to PARPi. Results: We found that hypoxic cells are significantly more resistant to PARPi in cell culture models. Efficiency of inhibition of PARP activity by these agents was similar under both air and hypoxia. The DNA damage marker γH2AX increased in cells treated in air, but not under hypoxia. There was no loss of 53BP1 protein that regulate engagement of the c-NHEJ pathway, indicating that HR has not been restored in these cells (3). However, it’s binding partner RIF1 was lost in hypoxia upon treatment indicating deficient signaling downstream of 53BP1. RIF1 is known to inhibit 5’ resection and its loss leads to resistance to PARPi in BRCA-deficient cells (4). In vivo, combining PARPi with hypoxia activated prodrugs led to substantial tumor growth delay in three xenograft models. DNA damage and apoptosis in these tumors was only detected outside of hypoxic regions positive for pimonidazole. In the breast PDX models, there was a strong correlation between the level of hypoxia in these tumors and their sensitivity to Olaparib. Conclusions: The significant increase in anti-tumor effects with the combination of PARPi and hypoxia-targeting cytotoxins leads us to propose a new strategy for tumors which are not responsive to PARPi alone. 1. Brown JS et al. Br J cancer 2016, 114, 713-5 2. Chan N et al. Cancer Res 2010, 70,8045-54 3. Bunting SF et al. Cell 2010, 141, 243-54 4. Chapman JR et al. Mol Cell 2013, 49, 858-71.
Multiplex genomic testing (MGT): Four-year real-world experience of two community oncology practices in central rural Nebraska.
Authors: Copur Mehmet Sitki , Jonglertham Pornchai , Zusag Thomas , Springer Carlene R. , Molnar Sally , Robbins Leslie , Peterson Tonya , Arbogast Jessica , Muske Chandra , Shipman Stacia , Fakkema Emily
Published: May 2019

e14728

Background: MGT forms the basis of precision oncology. More and more community oncology practices are utilizing MGT to identify somatic Actionable Alterations (AA) in solid tumors. This information is increasingly being used to choose FDA and/or guideline approved treatment options, or clinical trials. Methods: From July 2014 to July 2018, MGT (Foundation Medicine) data of patients (pts) with solid tumors at two community hospital-based oncology practices in central rural Nebraska were retrospectively analyzed. Study population consisted of advanced solid tumor pts (ECOG 0-2) with an available MGT result who had progressed on standard treatment regimens. Treating community oncologists directed treatment choices based on MGT results. Results: 360 pts underwent MGT. Average (avg) turn-around time from order to reporting was 20.19 days. Reimbursements were through commercial insurance (27 %), Medicare (66%), Medicaid (3%), self-pay (2 %) and financial assistance by company (2%). Most common cancer types were non-small cell lung (27%), pancreas (9%), colon (8%), unknown primary (4%), sarcoma (4%), breast (4%), gastro-esophageal (2%) and kidney (1%). 79% of samples had at least one AA. In 69 (19%) pts these alterations were matched to one or more on/off label FDA and/or guideline approved targeted therapies. Only 26/69 pts (37%) in this group were able to have a therapy that was new. 43 (12%) of pts qualified and went on locally available clinical trials (MATCH, LUNG-MAP and TAPUR). Conclusions: Our analysis reflects a 4-year real-world MGT experience in two community oncology practices in central rural Nebraska. In addition to established barriers of cost, long turnaround time, adequate tissue, the low yield of new FDA and/or guideline approved treatments decreases the utility of MGT. Increased variety and availability of precision medicine clinical trials with improved patient access in the rural setting may improve this shortcoming.[Table: see text]
The prognostic role of a novel TP53 mutation classifier in resectable esophageal squamous-cell carcinoma.
Authors: Su Dan , Huang Minran , Jin Jiaoyue , Wu Yingxue , Ying Lisa , Zhang Fanrong , Chen Kaiyan
Published: May 2019

e14749

Background: TP53 is the most recurrently mutated gene in esophageal squamous-cell carcinoma (ESCC). However, the effect of TP53 mutation status on the prognosis for patients with ESCC remains controversial. Also, there has been no consensus on the minimal genomic region necessary for clinical TP53 genetic testing. Methods: We retrospectively examined somatic mutations in all coding exons of the TP53 gene in 161 resectable ESCC patients by next-generation sequencing. We then stratified patients by multiple TP53 mutation classifiers based on different mutant features and analyzed its association with clinicopathological features and disease outcome by univariable and multivariable analysis. Results: We detected TP53 mutations in 138 of the 161 patients (85.7%), among which 61 patients harbored a non-disruptive mutation in the DNA-binding domain (DBD). The presence of TP53 mutation, hotspot mutant, and the mutation number alone was not predictive of any disease features and prognosis. We identified a prognostic effect of harboring the non-disruptive and DBD mutation of TP53 with an HR 0.362 (95% CI: 0.212–0.620, P < 0.001) and 0.486 (95% CI: 0.277–0.853, P = 0.012) for 5-year progression-free (PFS) and overall survival (OS), respectively. Multivariable analysis revealed it as an independent prognostic predictor for PFS (HR: 0.414, 95% CI: 0.230–0.746, P = 0.003) and OS (HR: 0.414, 95% CI: 0.207–0.825, P = 0.012). In particular, this TP53 mutation classifier defined a patient subset more beneficial from peri-operative radiotherapy with improved 5-year PFS (P = 0.020) and OS (P = 0.036). Conclusions: It is of clinical importance to examine and identify the non-disruptive somatic mutation in DBD of the TP53 gene for resectable ESCC.
Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability.
Authors: Moreira Aurelie , Vacher Sophie , Morel Claire , Lecerf Charlotte , Frelaut Maxime , Sablin Marie Paule , Loirat Delphine , Ricci Francesco , Hescot Segolene , Borcoman Edith , Torossian Nouritza , Masliah-Planchon Julien , Callens Celine , Servant Nicolas , Salomon Anne Vincent- , Bieche Ivan , Le Tourneau Christophe , Kamal Maud
Published: May 2019

e14750

Background: SIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT. Methods: All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test. Results: The 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1 mo in IIIA; 1.7 mo in IIIB, and 3.2 mo in IVA (p = 0.13). Median OS was 11.7 mo in tier II, 11.2 mo in IIIA, 6.3 mo in IIIB, and 12.1 mo in IVA (p = 0.002). Conclusions: The majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway.
Type 2 diabetes as a potential risk marker for early onset colorectal cancer.
Authors: Young Joanne , Price Timothy Jay , Hardingham Jenny , Symonds Erin , Smith Eric , Ruszkiewicz Andrew , Townsend Amanda Rose , Palethorpe Helen , Tomita Yoko , Wittert Gary , Young Graeme P. , Hewett Peter , Roder David , Drew Paul , Jesudason David , Poplawski Nicola
Published: May 2019

e15005

Background: Colorectal cancer (CRC) is rising in incidence in young adults. Because they are not included in population screening, and are more likely to present at an advanced stage, there is a need to identify young adults at increased risk for CRC. An association has been reported between type 2 diabetes (T2D) and CRC in the general population. Though lifestyle risk factors may be involved, the early occurrence of CRC in young adults suggests that there may also be a role for inherited predispositions. We therefore investigated whether having a personal and/or first-degree family history of T2D was a potential risk marker for early onset CRC. Methods: The South Australian Young Onset (SAYO) CRC study is an unselected series of young adults with CRC up to age 55. Fifty unrelated young adults (31/50 or 62% female) diagnosed with CRC were recruited to the study. Personal history of T2D was confirmed. Detailed family history of T2D was recorded. 253 patients with clear colonoscopies and no known CRC predisposition served as controls for personal history studies of T2D. Diabetes status was recorded on admission for colonoscopy controls. Associations were explored using a chi-squared statistic. Results: CRC patients ranged in age from 23-54 years (median age 42) and controls from 18-54 (median age 45). Six patients (12%) met the WHO clinical criteria for serrated polyposis, and two (4%) carried a Lynch syndrome mutation. CRC was present in the distal colon in 15/19 males (79%) and 17/31 females (55%) (p = 0.12). A personal history of T2D was confirmed in 12/50 (24%) CRC patients compared with clear colonoscopy controls under 55 years (13/258 or 5% P < 0.001; OR = 5.9; 95%CI 2.5-13.8). T2D was seen in 7/31 or 23% females and 5/19 or 26% males. Young adults with CRC frequently reported at least one first-degree relative with T2D (24/47 or 51%). All patients with personal history of T2D also had first-degree relatives with T2D. A first-degree family history of T2D was observed in 12/27 (44%) CRC patients aged under 45 yrs and 12/20 (60%) of CRC patients aged between 45 and 54 yrs having this characteristic (p = 0.29), and was present in both males and females (10/17 or 58% and 13/30 or 43% respectively; p = 0.37). Conclusions: Though the mechanism remains unclear, given the prevalence of T2D in those aged < 55yrs is 5% in Australia, our observations suggest that there is a striking enrichment for personal and first-degree family history of T2D in young adults with CRC. These features could potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate.
Aflibercept (Afl) for patients (pts) with metastatic colorectal cancer (mCRC): Clinical predictors of nonhematologic (nonhem) toxicity.
Authors: Vladimirova Liubov Yu , Fedyanin Mikhail , Chubenko Viacheslav , Fakhrudinova Olga , Bolotina Larisa , Moiseenko Fedor Vladimirovich , Khasanova Alfiya , Belonogov Alexandr , Musaeva Hedi , Novikova Olga , Stradaeva Irina , Mukhametshina Guzel , Orlova Rashida , Feoktistova Polina , Kuzmina Evgeniya , Karabina Elena , Nekrasova Oksana , Sherstnev Viktor , Micshenko Andrey , Tjulandin Sergei
Published: May 2019

e15007

Background: Afl is one of the antiagiogenic agents used for the treatment for mCRC. Cardiovascular toxicity of Afl is shown to be a main reason of the drug discontinuation but there are no studies on factors associated with nonhem adverse events(AEs). The aim of the study was to define clinical factors associated with the development of Gd.3-4 nonhem AEs. Methods: Pts with mCRC treated with FOLFIRI+Afl were included in a multicenter prospective base from 2016-18. Multivariative regression analysis was performed with Chicago, IL v.22.0. Factors studied included demographic, disease characteristics, data about concomitant diseases(CD) and concomitant medications. Results: 278 pts with mCRC from 18 centers were included. Mean age – 58.7, 48.6% were male, mean number of metastases– 2. ECOG 0-1–97.5%pts. RASm had 133 (47.8%) pts. Afl+FOLFIRI was used as the 2nd line therapy–in 67.6%. CD were in 194 (69.8%), cardiovascular–in 175 (62.9%). ORR(CR+PR)17.3%, SD-43.9%. MedPFS was 6.0 mos. Afl discontinuation due to AEs 11.9%. AE were reported in 201 (72.3%), Gd3-4 – in 69 (24.8%); nonhem AEs – in 178 (64%), Gd3-4–52 (18.8%)pts. Among Gd3-4 nonhem AEs were arterial hypertension Gd1-2–77 (27.7%), Gd3-4-in 36 (12.9%), vomiting Gd1-2–45 (16.2%), diarrhea Gd1-2–in 32 (11.5%), asthenia Gd1-2 –in 29 (10.4%), hepatotoxicity Gd1-2–in 2(5%), thrombosis–in 2 (5%) pts. Multivariate regression analysis showed that among the factors studied number of lines of treatment (OR1.4,95%CI1.1-2.1,p=0.03) and CD requiring medical support (OR 2.0,95%CI1.1-3.7,p=0.03) were found as independent factors of nonhem AE Gd3-4 development. ACE-inhibitors (OR2.2,95%CI1.2-4.3,p=0.02), calcium-channel blockers (CCB)(OR4.1,95%CI1.6-10.4,p=0.003 ) were the medical drugs considered to be significant. Conclusions: Number of lines and CD requiring medical support, especially with ACE-inhibitors or CCB, identifies a significant risk of developing cardiovascular non-hem AEs Gd3-4 with FOLFIRI + Afl.
Stereotactic body radiotherapy (SBRT) for colorectal liver metastasis: Clinical outcomes from the international multi-institutional RSSearch Patient Registry.
Authors: D'Avila Leite Pollyanna , Gaya Andrew M. , Lanciano Rachelle Marie , Yang Jun J. , Blanck Oliver , Urwin Robert , Davis Joanne N. , Mahadevan Anand
Published: May 2019

e15040

Background: We investigated factors associated with clinical outcome for liver metastases from colorectal primary tumors treated with Stereotactic Body Radiotherapy (SBRT) from a multi-center, international, prospective patient registry. Methods: A subgroup of patients with colorectal liver metastases treated with SBRT was identified from the RSSearch Patient Registry. Patient, tumor and treatment characteristics associated with outcome were evaluated. Dose fractionations were normalized to BED10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test. Results: 217 patients with 233 liver metastases from primary colorectal cancer treated with SBRT between 2005-2017 and enrolled in the RSSearch Patient Registry were included. The median follow-up was 15 months (1–75 months). 77% of patients received prior or concurrent chemotherapy. Median tumor volume was 21.95 cm3 (0.5 – 638 cc), median SBRT dose was 45 Gy (16 – 60 Gy) delivered in a median of 3 fractions (1-5). Median number of liver metastases was 1 (1-8). Median overall survival (OS) was 27 months; median local control (LC) was 41 months. One and two-year OS was 75% and 55%, respectively. One and two-year LC was 75% and 66%, respectively. Higher BED10 was associated with improved LC with median LC of 44 months for BED10 ≥ 100 Gy vs 39 months for BED10 < 100 Gy (p = 0.0007). Higher BED10 was also associated with improved OS: median of 33 months for BED10 ≥ 100 Gy vs to 18 months for BED10 < 100 Gy (p = 0.0009). Smaller tumor volume was associated with improved OS: median OS of tumor volume was 34 months for tumors < 20 cc vs 20 months for tumors ≥ 22cc (p = 0.0037). Local control was not significantly associated with tumor volume: median LC for tumor < 22 cc vs ≥ 22cc was 44 months vs 39 months, respectively (p = 0.193). Age, prior or current chemotherapy and BMI were not associated with OS or LC. Conclusions: In this multi-institutional prospective cohort, OS and LC were favorably correlated with small tumor volume and higher BED10.
Evaluation of complete pathological remission rates in surgically resected MSI-high metastatic colorectal cancers (mCRC).
Authors: Ludford Kaysia , Cohen Romain , Foo Wai Chin , Thomas Jane V , Parc Yann , Svrcek Magali , Kopetz Scott , Andre Thierry , Overman Michael J.
Published: May 2019

e15046

Background: Immune checkpoint inhibition (ICKi) for mCRC with deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H) demonstrates a high clinical activity rate that appears durable. The impact of immunotherapy on pathological tumor response in dMMR/MSI-H CRC is unknown. Our aim was to assess the pathological response and clinical outcomes following surgical resection in dMMR/MSI-H CRC patients who undergo surgical resection following immunotherapy. Methods: All dMMR/MSI-H mCRC patients treated with anti-PD1/L1 based ICKi between November 2016 and December 2018 at MD Anderson Cancer Center, Houston, Texas and Saint-Antoine Hospital, Paris, France who then underwent surgical resection were included in this retrospective analysis. MSI-H status was determined by ICH in 4 patients and by PCR and ICH in 8 patients. The primary outcome was pathological response in resected surgical specimens following at least 1 cycle of ICKi. Complete pathological response was defined as the absence of residual cancer cells in the surgical specimen. Results: 12 patients (median age at diagnosis 45 years (range 30-70); 10 germline mutations,2 sporadic) of 111 who received ICKi (11%) underwent surgical resection of primary tumor only (n = 5), metastases only (n = 6) or both primary tumor and metastases (n = 1). 42% of patients received PD1 combined with CTLA4 iCKi while 58% received PD1 monotherapy. The median time from ICKi introduction to surgery was 12 months (range 2-28). Prior to surgery 1 patient had complete radiographic response while 11 patients had residual tumor on imaging. 9 surgeries were done with curative intent and 3 with palliative intent. 11 patients achieved pCR while 1 achieved near pCR with rare viable tumor remaining (prior ICKi duration was 2 months). Median follow-up from surgery is 7 months. No patients have progressed following surgical resection. Conclusions: Complete pathological response is achievable with ICKi for dMMR/MSI-H mCRC. For these patients this data supports the curative potential of anti-PD1 based therapy and suggests that residual radiographic tumor may not require surgical resection following response to anti-PD1 based therapy.
Efficacy of PD-1/PD-L1 inhibitor-based therapies in refractory microsatellite instability (MSI)-unselected metastatic colorectal cancer (mCRC): A network meta-analysis (NMA) of randomized controlled trials (RCTs).
Authors: Wang Zi-xian , Chen Yu-tong , Zhou Yi-xin , Wu Hao-xiang , Chen Zhan-Hong , Wang Tian-tian , Wu Xiangyuan , Wang Feng , Xu Rui-hua
Published: May 2019

e15048

Background: PD-1/PD-L1 inhibitor-based monotherapies and combination therapies are being investigated to challenge microsatellite stable (MSS) mCRC. This NMA aimed to assess the efficacy of anti-PD-1/PD-L1-based therapies against active comparators (regorafenib, trifiuridine+tipiracil, and fruquintinib [R/T/F]) and negative controls (placebo and best supportive care [P/BSC]) in patients with refractory MSI-unselected mCRC, which are predominantly MSS. Methods: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and major oncology websites for relevant RCTs comparing the above therapies with each other up to Feb 15, 2019. We used the frequentist NMA to evaluate hazard ratios (HRs) for pairwise treatment comparisons in terms of overall survival (OS). Results: Seven RCTs were included, totaling nine comparisons between five therapies (durvalumab+tremelimumab [anti-PD-L1+Tre] vs. P/BSC [n = 1], atezolizumab+cobimetinib [anti-PD-L1+Cobi] vs. R/T/F [n = 1], atezolizumab [anti-PD-L1-only] vs. R/T/F [n = 1], anti-PD-L1+Cobi vs. anti-PD-L1-only [n = 1], and R/T/F vs. P/BSC [n = 5]). No significant heterogeneity was detected in the NMA (P = 0.340 in Q test; I2= 11.6%). Compared to P/BSC, OS was significantly improved with anti-PD-L1+Tre (fixed-effects model HR, 0.72 [95% confidence interval, 0.54-0.96]; P = 0.014) and anti-PD-L1+Cobi (HR, 0.70 [0.50-0.98]; P = 0.018), but not with anti-PD-L1-only (HR, 0.83 [0.57-1.21]; P = 0.172). OS with anti-PD-L1+Tre and anti-PD-L1+Cobi did not significantly differ from that with R/T/F (P = 0.565 and P = 0.500, respectively). Conclusions: In refractory MSI-unselected mCRC, anti-PD-L1 monotherapy was ineffective but anti-PD-L1+Tre and anti-PD-L1+Cobi therapies exhibited efficacies comparable to that of R/T/F.
Add-on anti-vascularendothelial growth factor agents with the second-line chemotherapy in metastatic colorectal cancer: A meta-analysis of randomized trials.
Authors: Kuan Feng-Che , Kuo Liang-Tseng , Hsieh Meng-Chiao , Chen Min-Chi , Lee Kuan-Der
Published: May 2019

e15059

Background: Whether the survival benefits of anti-VEGF agents in second-line treatment for metastatic colorectal cancer (mCRC) are confounded by clinical factors is unclear. Methods: We searched literatures from PubMed, Embase, Cochrane Library, and conference abstracts through February 2017. Results: Seven randomised controlled trials with total 4931 patients comparing add-on anti-VEGF agents and second-line chemotherapy with chemotherapy alone were included with extracted outcomes from published reports. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Anti-VEGF agents improved PFS and OS (PFS: hazard ratio [HR], 0·78; 95% CI, 0·69–0·88; OS: HR, 0·86; 95% CI, 0·78–0·95) without significant subgroup differences in age(< 65 or ≥65 years, p = 0·815), gender (p = 0·322), ECOG performance status (0 or ≥1, p = 0·514), number of metastases (1 or > 1, p = 0·903), metastasis to the liver only (yes or no, p = 0·713), second-line chemotherapy regimen (oxaliplatin- or irinotecan-based, p = 0·509), and the previous use of bevacizumab (yes or no, p = 0·185). The funnel plots showed symmetrical patterns and the result of Egger’s test was insignificant (PFS, p = 0·220; OS, p = 0·361), indicating no apparent publication bias. Conclusions: For second-line treatment in mCRC, anti-VEGF agents play an important role in PFS and OS in all subgroups of patients.
Mutational profiles and amplifications on circulating tumor DNA testing in patients with young-onset colorectal cancer.
Authors: Kamatham Saivaishnavi , Colibaseanu Dorin , Merchea Amit , Shahjehan Faisal , Kasi Pashtoon Murtaza
Published: May 2019

e15067

Background: There has been a concerning rise of colorectal cancer (CRC) in young individuals (<50 years). There appears to be a preponderance of left-sided tumors and rectal cancers, however, the etiology and biology is not entirely known. Our aim was to describe the results of circulating tumor DNA based (ctDNA) testing in young-onset CRC. Methods: We studied the results of 186 patients with CRC who had ctDNA testing, of whom 41 (22%) had young-onset CRC from January 2017 to January 2019 at Mayo Clinic, Florida. They were categorized based on their age at diagnosis. Results: The age distribution and the aberrations seen are summarized in the table. 25 (61%) were left sided, 9 (22%) were right sided, 7 (17%) were rectal tumors. ctDNA testing was able to identify mutations in 4 (9.8%) patients with BRAFV600E, 8 (19.5%) with RAS and categorized 29 (70.7%) as RAS/RAF wild-type. Furthermore, amplifications were detected in MYC 6 (14.6%) , MET 3 (7.3%) and ERBB2 1 (2.4%). 3(7.3%) were MSI-High and there were 4 individuals with BRCA1/2 noted on ctDNA testing. Conclusions: ctDNA testing for young onset CRC is feasible and identifies a spectrum of clinically meaningful and actionable aberrations. These can further be of use to evaluate treatment response, progression or help in selection of clinical trials. [Table: see text]
5-year survival following radiotherapy in anal cancer audit in a single center.
Authors: Morgan Stacie Joanne , Best James , Giridharan Selvaraj
Published: May 2019

e15070

Background: Anal cancer accounts for 1% of new cancer diagnoses. Incidence rates are increasing and predicted to rise. Randomised controlled trials have demonstrated superior outcomes with chemoradiation, the standard of care. The recommended dose for two phases is 50.4Gray in 28 fractions, with 5- fluorouracil (5-FU) and mitomycin C as per the UKCCCR ACT I trial. The addition of chemotherapy has been shown to improve outcomes, however is contraindicated in certain cases. Retrospective audit is important to ensure effectiveness of chemoradiation for anal cancer. Methods: Patients were identified retrospectively in a single centre, who had undergone radiotherapy for anal cancer between 2008 and 2013. The only histological subtype included was squamous cell carcinoma. Patients were included who received radiotherapy alone and concomitant chemotherapy. All TNM stages were included and patients treated with palliative intent at the outset were included. Available imaging was reviewed and staging updated in line with TNM 8th edition. 5 year survival was primarily evaluated. The proportion of patients who had a defunctioning stoma and subsequent reversal was investigated. Results: 55 patients were included in the analysis. The overall 5 year survival was 75% and 5 year relapse free survival 87%. 45 patients received chemoradiotherapy and 38 (84%) of this group received mitomycin C and 5-FU regimen. 7 (13%) patients relapsed, 3 (43%) of which were local. All of these patients proceeded to an abdomino-perineal resection. The commonest fractionation schedule used was 50.4 Gray in 28 fractions. The median stage at presentation of this cohort was T2 N0 M0. The mean age at diagnosis 61.4 years. 1 patient died whilst receiving treatment. 13 (24%) patients had a defunctioning stoma prior to radiation treatment. 3 (23%) had a subsequent reversal of the stoma. Conclusions: Chemoradiotherapy is an effective treatment for squamous cell carcinomas of the anal canal, with good relapse free survival. When a defunctioning stoma is performed prior to chemoradiation there is a low rate of reversal.
Long non-coding RNA Linc00525 as a prognostic factor to regulate proliferation and apoptosis in colorectal cancer.
Authors: Peng Peng , Zheng Qin
Published: May 2019

e15085

Background: Colorectal cancer (CRC) is one of the most common digestive system tumors and poses a serious threat to human health. More and more studies have shown that long noncoding RNAs (lncRNAs) play an important role in the occurrence and development of various tumors. They regulate a variety of cancer biology, such as proliferation, apoptosis, invasion and metastasis. Abnormally expressed lncRNAs are closely related to colorectal cancer. The purpose of this study was to find lncRNAs associated with the development of colorectal cancer and to explore its function and mechanism. Methods: (1) By analyzing the expression profile of lncRNAs in colorectal cancer-normal tissues in GEO databases, the abnormal expression of lncRNA LINC00525 was screened. Colorectal cancer tissues, adjacent normal colon tissues and colorectal cancer cell lines (HCT116, DLD1, HT-29, SW480) were detected by qRT-PCR. We analyzed the relationship between expression of LINC00525 and clinical features. (2) The biological functions of LINC00525 in HCT116, DLD1 and SW480 were peformed in vitro by MTT, clone formation assay, EDU and flow cytometry. (3) The effect of LINC00525 on tumorigenesis in vivo was evaluated by nude mice model. (4) The expression of lncRNA LINC00525 was knocked down in colorectal cancer cell lines (HCT116, SW480), and the mRNA expression levels of P15, P21, P27 and KLF2 were detected by qRT-PCR. Results: (1) Microarray data and qRT-PCR verification showed that the expression of lncRNA LINC00525 in colorectal cancer tissues and colorectal cancer cell lines was significantly upregulated. The overexpression of LINC00525 was positively correlated with clinical stage and tumor size. (2) Knockdown of LINC00525 in colorectal cancer cell lines could inhibit cancer cell proliferation and induce apoptosis. In SW480 and HCT116 cell lines, cells were arrested in G0/G1 phase after knocking down LINC00525. (3) Subcutaneous xenograft experiments in nude mice further confirmed that knockdown of LINC00525 could inhibit the tumor growth. (4) After knocking down the expression of LINC00525 in HCT116 and SW480 cell lines, the expression of mRNAs of tumor suppressor genes P15, P21, P27 and KLF2 increased. Conclusions: Our studies suggested that LINC00525 was significantly upregulated in colorectal cancer tissues. Mechanism studies had shown that LINC00525 could regulate the expression of KLF2, P15, P21 and P27 in CRC cell lines, and then affect cell proliferation and apoptosis.
Histological growth pattern as a potential marker of oligometastatic disease in patients operated for colorectal liver metastases.
Authors: Bohlok Ali , Dezes Robin , Lucidi Valerio , Bouazza Fikri , Germanova Desislava , Van Laethem Jean Luc , Hendlisz Alain , Demetter Pieter , Larsimont Denis , Donckier Vincent , Vermeulen Peter B.
Published: May 2019

e15093

Background: The identification of oligometastatic profile in patients with resectable colorectal liver metastases (CRLM) would represent a major progress to improve selection for surgery. Currently, in the absence of biomarkers, the most reliable method to identify oligometastatic (OLM) and non-oligometastatic (NOLM) tumors relies on the oncological outcome after metastases-targeted surgery. The histological growth pattern (HGP) of CRLM, defined as desmoplastic (dHGP) or replacement (rHGP), has recently been shown to have prognostic value. We analyzed HGP in a series of patients operated for CRLM, characterized as OLM in case of prolonged postoperative recurrence-free survival (RFS) or NOLM in case of rapid postoperative relapse. Methods: In 357 patients operated for CRLM, we identified OLM patients as those with RFS≥5 years (N = 64), and NOLM patients as those with RFS < 1 year (N = 77). Clinicopathologic and surgical parameters were analyzed. In each CRLM, HGP was assessed in archival H&E stained tissue sections, according to international consensus guidelines. Proportions of rHGP and dHGP were determined in each metastasis. In case of multiple metastases, the mean HGP was calculated in each patient. Patients were categorized as pure (> 95% rHGP or dHGP) or dominant phenotypes (> 50% rHGP or dHGP, of the entire tumor-liver interface). Results: Preoperative characteristics of primary tumor and CRLM, and surgical data were identical in OLM and NOLM groups. In a first set of analyses, HGP was determined in 39 OLM and 52 NOLM patients. Pure dHGP was observed in 54.3% of OLM and 17.3% of NOLM patients (p = 0.001). Pure rHGP was similarly distributed among OLM and NOLM groups. Sixty-nine% of the OLM patients displayed a dHGP-dominant phenotype, whereas 57.7% of the NOLM patients presented with a rHGP-dominant phenotype (p = 0.02). Conclusions: These results confirm the potential prognostic value of HGP in patients operated for CRLM. dHGP, associated with angiogenesis and inflammation, could represent a (surrogate) marker for oligometastatic progression, whereas rHGP appears strongly associated with rapid postoperative relapse.
Utility of effect size to define populations with durable clinical outcomes across trials of metastatic colorectal cancer.
Authors: Kratz Jeremy D. , Uboha Nataliya Volodymyrivna , LoConte Noelle K. , Lubner Sam Joseph , Mulkerin Daniel , Matkowskyj Kristina , Turk Anita Ahmed , Sprackling Carley M. , Eickhoff Jens C. , Deming Dustin A.
Published: May 2019

e15104

Background: ASCO defined clinically meaningful trial endpoints in colorectal cancer (CRC) as absolute overall survival (OS) of 3-5 months and OS hazard ratio (HR) ≤0.67. Few tools predict clinically distinct subgroups from heterogeneous populations. Effect size (Glass’s delta) calculates the absolute difference in clinical outcomes relative to the standard deviation of control group. We hypothesized that effect sizes ≥1 would be useful in predicting subgroup populations of clinical significance for trials with an indeterminate HR. Methods: Prospective phase II-III trials in metastatic CRC were queried from clinicaltrials.gov and cataloged by clinical outcomes of PFS and OS. Effect size was back-calculated from trials reporting 95% confidence intervals and compared with absolute difference in clinical outcome and hazard ratio. Results: 46 prospective trials were evaluable including 49% with biomarker selection, 57% in the first-line setting, and more commonly studied with targeted therapy over chemotherapy (70 v. 30%; p < 0.001). EGFR inhibitors were studied in 34% and VEGF inhibitors in 23%. Both effect size and HR correlated similarly with PFS (correlation coefficients, R = 0.65 vs. 0.76) and OS (R = 0.83 vs. 0.84) across these studies. Of studies with an indeterminate HR (0.69-0.86; n = 24), 10 studies had a significant effect size (Glass’s delta > 1), indicating the potential for sub-populations with improved clinical benefit within the experimental treatment group. These included 4 trials with planned biomarker analyses. Remaining trials were enriched for studies investigating anti-angiogenic therapies (83% vs. 23%, p = 0.001), including bevacizumab, aflibercept, regorafenib, and ramucirumab. Conclusions: Effect size holds potential as a measure to indicate the presence of subpopulations of patients benefiting in clinical trials. Those trials with a significant effect size despite an indeterminate HR should be examined closely for such populations. In CRC, effect size indicates the potential of a subgroup of patients who benefit significantly from anti-angiogenic agents. Further investigations are needed to validate effect size as a tool to delineate improved clinical outcomes from heterogeneous populations.
Microsatellite instability status in metastatic colorectal cancer and effect of immune checkpoint inhibitors on survival in MSI-high metastatic colorectal cancer.
Authors: Okamoto Wataru , Nakamura Yoshiaki , Shiozawa Manabu , Komatsu Yoshito , Denda Tadamichi , Hara Hiroki , Kagawa Yoshinori , Narita Yukiya , Kawakami Hisato , Esaki Taito , Nishina Tomohiro , Izawa Naoki , Ando Koji , Moriwaki Toshikazu , Kato Takeshi , Nagashima Fumio , Satoh Taroh , Nomura Shogo , Yoshino Takayuki , Akagi Kiwamu
Published: May 2019

e15106

Background: Tumor mismatch repair (MMR) predicts benefit of immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). We conducted a large-scale prospective observational trial on microsatellite instability (MSI) status in mCRC: SCRUM-Japan GI-SCREEN CRC-MSI. Methods: mCRC patients (pts) appropriate for systemic chemotherapy were eligible. Paired tumor and normal DNA extracted from FFPE samples were analyzed by the MSI Analysis System, which includes 5 mononucleotide markers. Tumors exhibiting ≥2 unstable markers were defined as MSI-H, while those with ≤1 were labelled MSI-L/MSS. Results: From 2/2016 to 3/2018, 1,711 pts were enrolled, and 1,696 samples were submitted. MSI status was determined in 1,676 pts (98.8%); 51 pts (3.0%) were MSI-H. For MSI-H vs. MSI-L/MSS pts: Median age (years) 64/64; male gender (%) 51.0 vs. 43.8, p=0.31; right-sided primary (%) 70.6 vs. 25.0, p<0.001; and poorly differentiated histology (%) 33.3 vs. 8.9, p<0.001. Of the 864 pts who received parallel NGS testing, median tumor mutation burdens (TMB) in MSI-H and MSI-L/MSS were 32.8 and 12.6 mt/Mb, p<0.001. High TMB, defined as >20 mt/Mb, was observed in 27/29 (93.1%) MSI-H pts. The frequency of representative gene mutations (%) for MSI-H vs. MSI-L/MSS pts were: TP53 17.2 vs. 66.1, p<0.001; PIK3CA 48.3 vs. 13.2, p<0.001; BRAF 34.5 vs. 7.5, p<0.001; MSH2 17.2 vs. 0, p<0.001; CTNNB1 17.2 vs. 0.6, p<0.001; and ERBB2 10.3 vs. 1.4, p<0.001. ERBB2 amplification was detected only in MSI-L/MSS pts (2.3%). Two-year survival rates from first-line systemic therapy in 389 pts with MSI-L/MSS, 5 pts with MSI-H treated with ICI in any-line, and 5 pts with MSI-H not treated with ICI, were 77.7, 100, and 33.3%, respectively. Conclusions: MSI-H mCRC tumors were more frequent in right-sided colon primaries and with poorly differentiated histology. Median TMB was significantly greater in MSI-H pts, and a very high burden was frequently seen. Survival in MSI-H mCRC was poor before ICIs; these agents may improve outcomes for MSI-H pts. Clinical trial #UMIN000020437.
Molecular analysis of advanced colorectal cancer in a patient cohort of Hispanics, African Americans, and Caucasians within a diverse single institution.
Authors: Ashai Nadia , Mejia Saldarriaga Mateo , Rao Devika , Stuart Matthew , Zhang Wei , Goel Sanjay , Halmos Balazs , Rajdev Lakshmi
Published: May 2019

e15121

Background: CRC survival and treatment response differences have been noted across racial and ethnic groups, particularly between Hispanics (HA), non-Hispanic AA (AA), and non-Hispanic Caucasian (CA). We examined if there are differences in molecular drivers between these groups that could explain such differences in our diverse medical center. Methods: We retrospectively examined 361 HA, AA, CA patients at Montefiore Medical Center diagnosed with metastatic CRC (mCRC) from 2007 to 2018. Mismatch repair proficiency (MMR-P), deficiency (MMR-D) was determined by immunohistochemistry. KRAS, NRAS, BRAF were determined by polymerase chain reaction or next generation sequencing. Mutations were then correlated with overall survival (OS). Results: Across subgroups, there was no differences in MMR, KRAS, NRAS, BRAF incidence (Table). Using a univariate analysis, the median survival for RAS mutated (M) patients was 33 months (ms), compared to 69 ms for RAS wild-type (WT, p = 0.01). The median OS for RAS mutated HA patients was 41 ms, compared to 41 ms and 33 ms for CA and AA respectively (p = 0.14). There was also no statistically significant difference between median OS for RAS WT HA patients (69 ms), compared to AA patients (51 ms) and CA (not reached, p = 0.75). Conclusions: In our single institution study, we found no difference in incidence of RAS (KRAS and NRAS), BRAF, MMR amongst HA, AA, and CA. Delivery of uniform care may account for similar OS outcomes in our patient population. RAS WT and M disease had improved OS compared to previously established rates in the literature. Additional studies are needed to evaluate known differences in treatment response and survival in minority populations.[Table: see text]
B7-H3 expression by immunohistochemistry as a negative prognostic biomarker in colorectal carcinoma (CRC) in a racially diverse population.
Authors: Kaumaya Meghan , Zhang Wei , Kuan Kevin , Gupta Sorab , Hu Shaomin , Rao Devika , Ohaegbulam Kim , Hwang Richard , Liu Qiang , Zang Xingxing , Goel Sanjay , Maitra Radhashree
Published: May 2019

e15127

Background: In CRC, utility of immunotherapy (IT) remains limited to persons with microsatellite instability–high (MSI-H) status. Immunotyping of CRC patients is critical towards further establishing IT's potential. Both incidence and survival rates for CRC in the United States vary between races due to multiple factors including genetic heterogeneity. In this study, we have profiled tumor samples in a racially diverse population for the expression of four different members of the B7 family of immune check point regulators. Methods: Tissue microarray (TMA) was generated from 208 CRC patients. Formalin fixed paraffin embedded (FFPE) tissues were utilized for immunohistochemistry (IHC) post- antigen retrieval. Antibodies specific for IHC staining were used for B7-H3 (D9M2L), PD-L1(E1L3N), B7-H4/B7x(D1M81) and HHLA2(566.1). Each specimen was scored for percent staining of tumor tissue (4 quartile groups) and for intensity (1-4x), and then an overall score (1-16) was calculated. The clinical outcome of interest was overall survival (OS), measured as time from diagnosis of metastatic cancer to death. Analysis for differences in OS was by log rank test, while differences between mean staining was by t test. Race was designated as non-Hispanic white (NHW, n = 41), non-Hispanic black (NHB, n = 84), Hispanic (n = 75), and others (8). Results: B7-H3 protein expression showed strong cytoplasmic distribution. NHB patients had a mean lower expression than NHW patients (0.19 vs 0.41, p = 0.02). Correspondingly, NHB patients had a worse OS than NHW patients (606 vs 759 days). No discernible differences were found in Hispanic patients. PD-L1 showed membranous distribution with 17% expression without significant difference among patients of different racial origin. HHLA2 was more widely expressed with about 35% staining but without statistical significance. B7-H4/B7x failed to show any expression. Conclusions: Expression of B7H3 varies among patients with differential racial backgrounds. It has the potential to be a prognostic biomarker and may be a reason for worse outcome among NHB patients in our population. Other B7 immune checkpoint markers failed to show clinical relevance.
The mutational profile analysis of extramural vascular invasion in rectal cancer.
Authors: Wei Mingtian , Song Yane , Deng Xiangbing , Wu Lijia , Meng Wenjian , Yang Wanning , Mao Beibei , Yang Ying , Han Wenbo , Zhang Henghui , Wang Ziqiang
Published: May 2019

e15128

Background: Extramural vascular invasion(EMVI) is a known independent predictor of poor prognosis in rectal cancer, as evidenced by a higher risk of developing metastases and a shorter DFS compared with negative tumours. However, the molecular mechanisms of EMVI genesis remains unclear. The objective of this study is to clarify the distinct molecular characterization of EMVI-positive tumours from that of EMVI-negative tumours. Methods: DNA was extracted from FFPE tumor specimens and matched normal tissue samples from rectal cancer patients who underwent surgical resection. Comprehensive genomic profiling analysis was performed using a 2.41M size panel covering exon regions of 1,622 genes based on next generation sequencing assay. Somatic Mutations were analyzed to determine the difference of molecular features between EMVI-positive and EMVI-negative patients. Results: In this retrospective study, a total of 48 rectal cancer patients without distant metastases were included: 17 patients in the EMVI-positive group and 31 patients in the EMVI-negative group. All the EMVI-postive patients had lymph node metastasis and 15 patients had lymph node metastasis in EMVI-negative group. Among all the tumours, the most frequently mutated genes were TP53, APC, KRAS, SMAD4, CHEK2, TCF7L2 and FBXW7. Mutations of TCF7L2 and CHEK2 were more frequently observed in EMVI-positive tumours than that in EMVI-negative tumours with p < 0.05. Survival analysis (Kaplan-Meier) indicated that patients with KRAS mutations(n = 9) had a shorter DFS than patients without KRAS mutations(n = 23) in patients with lymph node metastasis (p < 0.05). In addition, age was significantly associated with DFS according to the survival analysis (p < 0.05). Conclusions: Several possible candidate genes that may be helpful to characterize the distinct mutational profile of EMVI-positive tumours from EMVI-negative tumours were identified, which may be of great significance in disclosing the molecular mechanism underlying in EMVI initiation and progression. Expanded prospective cohorts are warranted to further elucidate these findings.
The results of 3000 Fit: A prospective study led at Saint Joseph University of Beirut.
Authors: Elkaddoum Ronaldo , Eid Roland , Haddad Fady , Germanos Myrna , Mehawej Cybel , Kourie Hampig Raphael , Kattan Joseph Gergi
Published: May 2019

e15141

Background: In terms of frequency, colorectal cancer (CRC) is the 3rd cancer in Lebanon with 1093 incidences registered in 2015. To this date not a single screening campaign has been organized in the country. Fecal immunochemical test (FIT) is an advised screening technique. We found it useful to organize a screening campaign using FIT to determine the prevalence of CRC in a population of 3000 healthy Lebanese allowing the extraction of useful data. Methods: 3000 tubes were distributed to Lebanese adults (45-80 years old) at average risk of developing CRC, followed by explanations. FIT analysis was done at the medical genetics unit (UGM) of Saint-Joseph University and patients with positive FIT were asked to undergo further investigations. Results: Out of the 3000 distributed tests, 705 were returned (23.5%) with 459 fully analyzable. The age median was 56 (45-80). Sex ratio F/M 2.3. Out of the 459 patients, 278 (60.5%) showed 0ng/ml, 137 (29.8%) showed 1-79ng/ml, 3 (0.6%) showed 80-99ng/ml (intermediate risk values), 33 (7.1%) showed 100-800ng/ml considered as a positive value and finally 8 (1.7%) showed over range values. Among the 44 positive patients we contacted 41. Out of the 8 (18%) colonoscopies results received: 5 showed hemorrhoids leading to false positive, 1 ulcerative ileitis, 1 tubular adenomas and 1 carcinoma. Conclusions: While it was hard for us to quantify people for whom a free FIT was proposed, the low restitution rate among those who took the test shows the necessity of national screening and sensitization campaigns.