bluuebunny/crossref_metadata_2025 huggingface dataset:
Metastases resection in colorectal cancer patients with mutation in oncogene BRAF or tumors located on the right side: Experience at the HGUGM.
Authors: Ortega Laura , Bringas Beranek Marianela , Gutiérrez Alonso Natalia , Soto Alsar Javier , Alva Bianchi Manuel , Arregui Valles Marta , Aparicio Salcedo Inmaculada , Gallego Gallego Iria , García González Gonzalo , Torres Pérez-Solero Gabriela , Muñoz Martín Andres J. , Calvo Ferrándiz Aitana , Blanco-Codesido Montserrat , Martin Miguel , Garcia-Alfonso Pilar
Published: May 2020

4041

Background: Approximately 25% of patients with colorectal cancer (CRC) debut with metastatic disease. In addition, 25-35% of patients with localized disease at diagnosis develop metastatic lesions during the evolution of their disease. Consequently, approximately 50-60% of patients with CRC will present metastatic lesions at some point in their lives. Metastasis resection has improved the prognosis of these patients, achieving overall survival (OS) that exceed 40 months. However, there are doubts about the benefit of this approach in patients with mutations in oncogene BRAF or tumors located on the right-side, due their poor prognosis. The aim of the study is to analyze the impact of metastases resection on OS of these populations. Methods: We conducted a retrospective analysis of patients with mCRC attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Spain) between January 2010 and 2018. Results: 487 patients were identified and included in the analysis. Median age was 71 years (62-81). Most patients were males (62.4%). 55.2% had metastatic lesions at diagnosis. Most patients had ECOG 0-1 at diagnosis of metastatic disease (91.0%). 8.9% of patients had BRAF mutations (n = 21) and 31.8% of patients had primary tumors located on the right-side (n = 152). 474 patients received first-line chemotherapy (97.3%). OS of the entire cohort was 29.67 months; 30.69 months in BRAF mutated patients vs 35.89 in wild-type patients (p = 0.161); 25.29 months in right-side tumors vs 31.02 in left-side tumors (p = 0.044). 306 patients (62.8%) underwent metastases resection. Most common location was liver (51.4%). 147 patients (30.2%) underwent a second metastases resection. Mean number of metastases surgeries was 1.35 (+/-1.40). OS since metastases resection was 24.83 months in BRAF mutated patients vs 41.55 months in wild-type patients (p = 0.020). According to location, it was 35.49 months in right-side tumors vs 43.78 months in left-side tumors (p = 0.106). In BRAF mutated patients, OS was 38.19 months in patients underwent metastases resection vs 18.52 months in non-surgical patients (p = 0.043); 41.51 months vs 16.18 months respectively in patients with tumors located on the right-side (p < 0.001). Conclusions: Metastases resection has a positive impact on overall survival of patients with mutations in oncogene BRAF or right-side tumors, even though their prognosis is still poor compared to patients without these alterations.
TAS-116, an oral HSP90 inhibitor, in combination with nivolumab in patients with colorectal cancer and other solid tumors: An open-label, dose-finding, and expansion phase Ib trial (EPOC1704).
Authors: Kawazoe Akihito , Yamamoto Noboru , Kotani Daisuke , Kuboki Yasutoshi , Taniguchi Hiroya , Harano Kenichi , Naito Yoichi , Suzuki Mitsuko , Fukutani Miki , Shima Hikari , Higuchi Tsukiko , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Nishikawa Hiroyoshi , Shitara Kohei
Published: May 2020

4044

Background: Regulatory T cells (Tregs) potentially induce the resistance of anti-PD1/PD-L1 inhibitors (A-PD1). TAS-116, a novel HSP90 inhibitor, enhanced antitumor immunity via reducing Tregs in vitro and in vivo. Combination of TAS-116 plus A-PD1 showed a superior tumor growth suppression compared with either treatment alone in vivo. Based on the above, we investigated safety and efficacy of TAS-116 in combination with nivolumab in patients with solid tumors. Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the maximum tolerated dose and the recommended phase 2 dose (RP2D). Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80mg on level 1, 120mg on level 2, and 160mg on level 3) was administrated for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLTs) during the first cycle (4 weeks). PD-L1 combined positive score (CPS) and tumor mutation burden (TMB) were assessed. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 44 patients with colorectal cancer (CRC, n = 29), gastric cancer (GC, n = 8), sarcoma (n = 5), non-small cell lung cancer (NSCLC, n = 1) and melanoma (n = 1) after standard of cares were enrolled. One patient had MSI-H CRC, but all other patients had MSS tumors. No DLTs were observed at all levels and TAS-116 160 mg was determined as RP2D. The common grade 3 or worse treatment-related adverse included AST/ALT increased (7%), creatinine increased (5%) and platelet count decreased (5%). Objective tumor response was observed in 6 patients including 4 MSS CRC, 1 MSI-H CRC and 1 sarcoma, resulting in objective response rate (ORR) of 16% in MSS CRC without prior A-PD-1. PD-L1 CPS and TMB could be evaluated in 18 and 17 MSS CRC without prior A-PD-1, respectively. ORR was 27% in patients with CPS ≥1 and 0% in patients with CPS < 1. ORR was 33% with TMB-high (median as the cut-off) and 12% with TMB-low. Analysis of tumor-infiltrating lymphocytes before treatment and after TAS-116 monotherapy demonstrated reduction of FoxP3hiCD45RA−Tregs fraction in the tumor microenvironment. Conclusions: The combination of TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients, which warrants further investigations in a large cohort. Clinical trial information: UMIN000032801 .
Patient-reported gastrointestinal outcomes in patients with anal cancer.
Authors: Kouzy Ramez , Abi Jaoude Joseph , Lin Daniel , El Alam Molly Blue , Minsky Bruce D. , Koay Eugene Jon , Das Prajnan , Holliday Emma B. , Klopp Ann , Colbert Lauren Elizabeth , Taniguchi Cullen M.
Published: May 2020

4055

Background: Among patients with anal cancer, chemoradiotherapy tends to offer an excellent prognosis but is often associated with undesirable toxicities that diminish quality of life. We sought to quantify the gastrointestinal-related patient-reported outcomes (PROs) of anal cancer patients receiving chemoradiotherapy in order to improve patient-physician communication and shared decision making. Methods: We prospectively followed patients with non-metastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients reported outcomes were collected using the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before treatment and at 4 subsequent timepoints. We used descriptive statistics to summarize the patients’ characteristics and EPIC scores, then used the paired Wilcoxon test to compare EPIC scores at different timepoints. Results: The study included 21 patients (16 women and 5 men), whose median age was 57 years. Most patients (52%) had T2, and either N0 (38%) or N1 (43%) disease. Most patients (91%) received standard of care chemoradiotherapy. Compared with the patients’ median overall summary score at baseline (66), their median score at 1 week (82) was significantly higher (p = 0.009), whereas their median score at 5 weeks (54) was significantly lower (p = 0.025). However, the patients’ median overall summary score at baseline and at 3 months did not differ significantly (p = 0.919). Three months after radiotherapy, most patients (73%) reported rarely or never having bloody stools, and most (82%) reported rarely or never being bothered by bloody stools. Overall, EPIC scores show initial improvement of all domains, followed by some worsening of symptoms before returning to baseline levels. Conclusions: Anal cancer patients’ gastrointestinal-related PROs tend to fluctuate during radiotherapy but return to baseline by 3 months, at which time most patients report few or no residual side effects. Our data provide a clear timeline of gastrointestinal acute toxicity using sequential PRO measurements that will improve patient-physician communication regarding expectations for cancer treatment and help in shared decision making.
Socioeconomic status based on race in early-stage anal squamous cell carcinoma undergoing locoregional therapy.
Authors: Goksu Suleyman Yasin , Ozer Muhammet , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali , Sanjeevaiah Aravind , Hsieh David , Aguilera Todd Anthony , Maxwell Mary Claire , Sanford Nina Niu
Published: May 2020

4056

Background: Anal Squamous Cell Cancer (ASCC) is a highly curable cancer. Underserved and vulnerable populations are particularly at risk of developing this disease. We aimed to study racial disparities and overall survival (OS) in patients with ASCC who received radiation therapy (RT) or chemo-RT (CRT) using the National Cancer Database. Methods: We identified adult patients with early-stage (stage I-II) ASCC diagnosed between 2004-2016 who underwent RT or CRT. We compared the clinical and treatment characteristics of white and black patients. The chi-square test was used for categorical variables. Kaplan-Meier and Cox regression method performed for survival analyses. We used 1:1 nearest neighbor propensity score matching to eliminate selection bias. Results: A total of 10,014 patients; 90.2% were white and 9.8% were black. White patients were more likely to be female, older age, have higher rate high-school education, private insurance, higher income, and travel a longer distance (all p < .001). Black patients were more likely to be higher comorbidity score and be treated at an academic/research facility. White patients had a higher rate of CRT and significantly better overall survival (OS) as compared to black patients (5-year survival 76% vs. 70%, p < .001) which persisted after propensity score matching (5-year survival 76% vs. 70%, p = .002). This difference continued after adjusting for clinically important factors, including HPV status (unmatched p < .03, matched p = .008). In the patients who received CRT, white patients were associated with improved OS versus black patients (unmatched 77% vs. 71%, p < .001; matched 77% vs. 71%, p = .011), and even after multivariate Cox analysis (unmatched p < .001; matched .014) (Table). Conclusions: White patients had significantly better OS as compared to black patients with early-stage ASCC as well as in the patients who received CRT. White patients were associated with high education level, higher income, and private insurance. The rate of HPV positive was similar among groups. Further investigations are needed to enlighten these disparities and target the increase education of the population at risk. [Table: see text]
Utilization and trends in palliation-directed treatments for stage II-IV anal squamous cell carcinoma patients.
Authors: Radhakrishnan Srinidhi , Goksu Suleyman Yasin , Radhakrishnan Saikripa , Morales-Oyarvide Vicente , Sanford Nina Niu , Soleja Mohsin , Haff Stephen , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali
Published: May 2020

4059

Background: Anal squamous cell carcinoma (ASCC) is associated with significant symptom burden including pain, bleeding, and obstructive symptoms. However, the proportion of patients requiring palliation-directed treatments in ASCC is unknown. Palliation-directed treatments can control and improve symptoms and affect quality of life. We aimed to study trends, factors, and outcomes associated with utilization of palliation-directed treatment in ASCC. Methods: Using the National Cancer Database (NCDB), adult patients with stage II-IV ASCC diagnosed 2004-2015 were identified and stratified by receipt of palliation-directed treatments. Using chi-square test and logistic regression, we evaluated the associations of demographic, clinical, and pathological factors with palliation-directed treatment utilization. Results: Out of 17,988 ASCC patients in this study, palliation-directed treatments were used by 504 patients (2.8%) with stages II-IV ASCC as first line treatment. Two percent received palliation-directed surgery, chemotherapy, and radiotherapy, 0.3% received pain management, and 0.4% utilized combination therapy approach. On univariable analysis, palliation-directed treatments were associated with older age, lower income level ( p=0.004), Medicare insurance, and higher comorbidity score ( all other p<0.001). Palliation-directed treatments were also more frequent in academic/research facilities ( p=0.01), in East North Central USA ( p=.001), and in stage 4 versus stage 2/3 ASCC ( p<.001). Palliation-directed treatments have increased in recent years (2004-06 vs. 2013-15; p=.005) and were more frequently used within 6 months of patient death ( p<.001). On multivariable analysis stage 4 disease and life expectancy < 6 months were the only variables that maintained significance. Conclusions: In our study, palliation-directed treatments were used by 2.8% of the patients as codified by NCDB. Its use was higher in stage 4 ASCC and within the last six months of life. Palliation-directed treatment utilization has incrementally increased in recent years. Additional research is warranted in determining the phase of care wherein palliation-directed treatments are utilized in ASCC.
Tumor-infiltrating lymphocytes and tumor budding refine prognostication in patients with low- and high-risk stage III colon cancers (NCCTG N0147)[Alliance].
Authors: Sha Dan , Lee Hee Eun , Foster Nathan R. , Shi Qian , Alberts Steven R , Smyrk Thomas C. , Sinicrope Frank A.
Published: May 2020

4065

Background: Tumor infiltrating lymphocytes (TILs) and tumor budding (linked to epithelial mesenchymal transition) may influence metastatic potential and patient prognosis. We analyzed these features and their relative contribution to survival among low (T1-3 N1) and high (T4 and/or N2) risk groups, defined by the IDEA study, used to inform the duration of adjuvant chemotherapy in stage III colon cancer. Methods: Among 1,532 patients (low risk n=804; high risk n=728) treated in a phase III adjuvant trial of FOLFOX + cetuximab (x 6 months), intraepithelial TIL densities and tumor budding were quantified at microscopy in routine histologic sections. Optimal cutpoints were determined in association with 5-yr disease-free survival (DFS). Relative contribution of variables to DFS was calculated using χ2 from Harrell’s rms R package based on multivariable Cox regression models. Results: In the overall cohort, the tumor budding/TILs combined variable was more robust for predition of DFS than either alone. Budding/TILs was significantly associated with DFS in both low (HRadj, 1.59; 95% CI, 1.02-2.48; p=.0273) and high (HRadj, 2.82; 95% CI, 1.72-4.63; p<.0001) risk patients. We then determined its relative contribution (%) to DFS (Table). Among low risk, budding/TILs ranked second (24.4%) behind KRAS status (45.5%) and ahead of treatment arm (7.2%) and mismatch repair (MMR) status (6.1%). Among high risk, budding/TILs contributed the most to DFS (45.4%) followed by primary tumor sidedness (13.0%), performance status (12.0%), and MMR (10.4%). Conclusions: Tumor budding/TILs provides robust prognostic stratification by risk group to improve anatomic tumor staging. The relative contribution of budding/TILs to DFS was second only to KRAS status in low risk patients, and was the most important predictor of DFS in high risk patients. Evaluation in patients treated with 3 vs 6 mos of adjuvant chemotherapy is warranted. [Table: see text]
Prognostic importance of primary tumor resection and synchronous metastasis on overall survival in metastatic colorectal cancer: Data from the FIRE-3 (AIO KRK-0306) study.
Authors: von Einem Jobst C. , Stintzing Sebastian , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Vehling-Kaiser Ursula , Al-Batran Salah-Eddin , Heintges Tobias , Lerchenmuller Christian A. , Kahl Christoph , Seipelt Gernot , Stauch Martina , Scheithauer Werner , Hielscher Joerg , Scholz Michael , Modest Dominik Paul , Jung Andreas , Kirchner Thomas , Heinemann Volker
Published: May 2020

4070

Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In the present analysis of the FIRE-3 trial we explored the impact of primary tumor resection on outcome in relation to anti-EGFR vs. anti-VEGF treatment. Furthermore, we investigated the prognostic value of synchronous versus metachronous metastases. Results: In patients with synchronous disease no significant difference in OS was detected when comparing resected (n=339) vs. non-resected (n=97) patients (p-value: 0.29, HR: 1.17, 95%-CI: 0.88 – 1.55). In the cetuximab arm, resection (n=167) showed no significant benefit in OS when compared to non-resection (n=52) (p-value: 0.51, HR: 1.15, 95%-CI: 0.77 – 1.71). Treated with bevacizumab, similar results were present, when comparing resection (n=172) vs. non-resection (n=45); (p-value: 0.29, HR: 1.25, 95%-CI: 0.83 – 1.9). A strong trend was seen when comparing OS in treatment arms cet. (n=219) vs. bev. (n=217)) for patients with synchronous disease; (p-value: 0.05, HR: 1,26, 95%-CI: 1.0 - 1.59). 436/592 pts suffered from synchronous, 153/592 from metachronous disease (in 3/592 pts the information was not given). Median OS in pts with synchronous disease was 24.5 months and 29.5 in pts with metachronous disease (p-value: 0.02, HR: 0.76, 95%-CI: 0.6 - 0.96). In pts treated in the cetuximab arm metachronous disease (n=77) was associated with a trend towards longer OS when compared to synchronous disease (n= 219) (p-value: 0.13, HR: 0.76, 95%-CI: 0.54 – 1.1). The same effect was present in the bevacizumab arm (p-value: 0.05, HR: 0.73, 95%-CI 0.53 – 1.0) when comparing pts with synchronous disease (n=217) vs. pts. with metachronous disease (n=76). Conclusions: In the FIRE-3 study, metachronous disease was associated with superior OS compared to synchronous disease. This finding was accentuated in the bevacizumab arm. The role of resection of the primary tumor had no impact on survival. Clinical trial information: NCT00433927 .
Colorectal cancer under the age of 50 years in U.S. Department of Veterans Affairs: Is there a role of early screening?
Authors: Khan Abdul Moiz , Ajmal Zainub , Naseer Usman , Gemoets Darren , Mehdi Syed Arzoo
Published: May 2020

4072

Background: While the overall incidence of colorectal cancer (CRC) is decreasing, the rate has increased in population under 50, with higher stages at diagnosis and a greater proportion of African Americans (AA). Hence, there is an ongoing debate about the age of CRC screening. These trends have not been studied in the VA population. Methods: ICD-10 codes C18-C20 were used to identify the cases of colon and rectal cancer in National VA Cancer Cube Registry. 43,544 cases of colon cancer, 1,278 below and 42,254 above age 50, and 19,815 cases of rectal cancer, 862 below and 18,948 above age 50 were identified between 2003-17. Younger age group was defined as patients less than 50 years old. IRB approval was obtained. Results: Our data comprised > 97% of male patients. In younger group, in the 5 year periods, 2003-07, 2008-12 and 2013-17, colon cancer rate increased from 2.59% to 2.79% to 3.59%, while for rectal cancer it increased from 3.5% to 4.3% to 5.3% (p < .0001). Blacks comprise 31.6% cases of colon cancer and 27.15% cases of rectal cancer in under 50 group, compared to 18.5% and 15.9% of cases in above 50 group respectively (p < .0001). For under 50 group, 48.6% cases of colon and 42.2% cases of rectal cancer were diagnosed in stage III or IV compared to 35.7% and 34.05% cases in above 50 group respectively (p < .0001). For colon cancer, 51.87% of patients in the younger group have a < 5 year survival, worse compared to 45.05% in 50-60 group (p < .0001) and similar to 49.3% in 60-70 group (p = .08). For rectal cancer, 5 year survival showed no difference between these groups. Stage specific survival shows no difference for either colon or rectal cancer across < 50, 50-60 and 60-70 age groups. Conclusions: Rate of CRC is rising in < 50 age group with more advanced stage at diagnosis and higher proportion of African Americans. For colon cancer, < 50 group has a worse 5 year survival as compared to 50-60 age group likely due to increased proportion of patients in stage III or IV, as there is no difference in stage specific survival. For rectal cancer, the 5 year survival or stage specific survival shows no difference in < 50, 50-60 and 60-70 groups. These results add to our understanding of the trends of CRC and should be accounted for in the screening guidelines.
The role of primary tumor (PT) site as prognostic factor after resection of colorectal (CRC) liver metastases (LM): A mono-institutional cohort study.
Authors: Bensi Maria , Ardito Francesco , Di Stefano Brunella , Vellone Maria , Vivolo Raffaella , Mele Caterina , Ribelli Marta , Panettieri Elena , Camarda Floriana , Frascarelli Alessia , Calegari Maria Alessandra , Basso Michele , Pozzo Carmelo , Giuliante Felice , Tortora Giampaolo , Salvatore Lisa
Published: May 2020

4081

Background: Radical resection of LM is the only chance of cure for liver-only mCRC pts. Besides the evaluation of technical resectability, several factors must be taken into account for the evaluation of recurrence risk. Among them we should consider the Fong Risk Score and its modified version, including RAS/BRAF status (Brudvik’s score). Tumor sidedness is an important prognostic factor in CRC. The impact of PT site on the outcome of LM resection is still debated. Hence, we retrospectively analysed mCRC pts, underwent to radical LM resection at our Institution, investigating the impact of PT site on DFS and OS. Methods: Liver-only mCRC pts underwent to radical LM resection were included. The association of PT site with DFS and OS was evaluated. The following variables were collected: gender; age (≥ vs < 75 years ); ECOG PS; CEA baseline level; PT site; RAS and BRAF status; mucinous histology; grading (G1-2 vs G3); RECIST response during preoperative treatment; resected PT; synchronous vs metachronous; number of LM; bilobar vs unilobar LM; LM diameter ≥ 5 cm; R0 vs R1 resection. Univariate and multivariate analyses for DFS and OS were performed. Results: A total of 463 liver-only mCRC pts underwent to radical LM resection were included. Seventy (15%) pts had a right-sided (r-s) tumor and 393 (85%) pts a left-sided (l-s) tumor. R-s CRC pts more often had RAS/BRAF mutations in comparison to l-s tumors (76% vs 37%; p < 0.0001). Median DFS and OS was 13.1 and 41.6 months, respectively, in r-s CRC vs 16.0 (p = 0.65) and 62.2 months (p = 0.033), respectively, in l-s tumors. At the multivariate analysis no significant association with survival parameters was shown for tumor sidedness. At the multivariate analysis, R0 resection was independently associated both with better DFS and OS; RAS/BRAF wt CRC and resected PT were significantly associated with improved OS. Considering all wt CRC pts (N = 237), 14 (6%) pts had r-s tumor and 223 (94%) l-s tumor. No significant association of tumor sidedness with survival was shown (DFS r = 10.0 vs l = 16.0 months, p = 0.62; OS r = 40.3 vs l = 66.2 months, p = 0.12). Conclusions: Our results showed that a significant smaller proportion of r-s CRC underwent to radical LM resection, indirectly confirming its worse prognosis. Among radically resected pts, r-s CRC was associated to a shorter OS (significant) and DFS (not significant) compared to l-s CRC, but it was not confirmed at the multivariate analysis. We can conclude that right PT site should not be considered as a contraindication for radical LM surgery, when feasible.
The effect of aspirin on colorectal cancer incidence in African Americans.
Authors: Emiloju Oluwadunni , Djibo Djeneba Audrey , Ford Jean G
Published: May 2020

4085

Background: From 2011 to 2016, the incidence and mortality rate of colorectal cancer(CRC) were highest among African Americans(AA), compared to other US racial/ethnic groups. Long-term aspirin use is recommended as a strategy to reduce the risk of CRC. Yet, there is scant information on the chemopreventive effect of aspirin among AA. It is imperative to assess whether the reported chemo-preventive effect also occurs in AA. Our central hypothesis is that aspirin use in AA is associated with a lower incidence of CRC, irrespective of race/ethnicity. Methods: We conducted a secondary analysis, using data from AA participants in the Atherosclerosis Risk in Communities(ARIC) longitudinal study, who did not have CRC at enrollment, from 1987 to 1998. We extracted demographic, clinical and mortality data to compare the incidence of CRC among participants taking aspirin compared to those who were not taking aspirin, stratified by age, tobacco use, and body mass index. All-cause mortality and CRC mortality will also be assessed, and we will use Cox proportional hazard regression to determine the relationship between aspirin use and CRC incidence, and mortality. Results: At baseline in 1987, 15,026 participants enrolled in the ARIC study, 25% of whom were AA, median age 54(range 44-66), including 46.7% who reported using aspirin. We analyzed follow-up data from 10,960 participants in 1996-1998, 20% of whom were AA, and 56.9% of whom were taking aspirin. Non-AA participants were more likely to report using aspirin at baseline and follow-up, compared to AA, 53% vs 30% and 59% vs 50% respectively. After 10years, the total incidence of CRC in AA participants was 1% compared with 1.1% in non-AA(p = 0.7). There was no difference in CRC incidence by aspirin use among all participants, and when stratified by race(among all participants p = 0.81, amongAA p = 0.68, among non-AA p = 0.94). Conclusions: We found no difference in the incidence of CRC among AA compared to Caucasians, by aspirin use. Investigation of consistency and/or dose of aspirin use by race may provide further insights on the relationship between aspirin use and CRC incidence, comparing AA to Caucasians.
Novel methylated DNA markers in plasma detect distant recurrence of colorectal cancer.
Authors: Xie Hao , Mahoney Douglas W. , Foote Patrick H. , Burger Kelli , Doering Karen A , Taylor William R. , Cao Xiaoming , McGlinch Maria , Berger Calise K. , Hubbard Joleen Marie , Allawi Hatim T. , Lidgard Graham P. , Ahlquist David A. , Kisiel John B.
Published: May 2020

4088

Background: Methylated DNA markers (MDMs) are broadly informative for early detection of colorectal cancer (CRC) but have not been extensively studied for post-treatment surveillance and disease monitoring. We aimed to assess the feasibility of novel CRC-associated MDMs for detection of distant recurrent CRC (rCRC) in plasma. Methods: A panel of 13 MDMs previously identified to be discriminant for primary CRC was selected. In a cross-sectional analysis of plasma samples, MDMs were assayed blindly (by target enrichment long-probe quantitative amplified signal assay) from 160 age/sex-balanced patients (60 healthy controls, 60 with resected CRC and no evidence of disease (NED), and 40 rCRC after primary tumor resection). Plasma-derived carcinoembryonic antigen (CEA) was measured on all patients. Random forest modeling was used to derive a prediction algorithm of MDMs (with and without CEA) for the endpoint of rCRC relative to healthy controls. The accuracy of the algorithm was summarized as sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CI) in the test set. Results: Median patient age was 55 (interquartile range: 49-64) years. As shown in the Table below, a single MDM with the highest AUC was significantly better than CEA ( p= 0.02). On cross validation, CEA provided no additional improvement to the performance of the panel of 13 MDMs ( p= 0.2). The cross-validated panel of MDMs detected rCRC liver metastases with 96% (79-100%) sensitivity, lung metastases with 78% (40-97%) sensitivity, and peritoneal/nodal metastases with 57% (18-90%) sensitivity. Lesions with Response Evaluation Criteria in Solid Tumors sum > 4 cm were detected with 94% (73-100%) sensitivity and ≤4 cm with 78% (52-94%) sensitivity. Conclusions: Novel MDMs in plasma detect rCRC with promising accuracy. The clinical utility of MDMs for non-invasive post-treatment surveillance and treatment monitoring in CRC warrants further evaluation in longitudinal studies with sufficient follow-up to exclude sub-clinical recurrence in those with NED. [Table: see text]
The development and validation of a novel targeted methylation sequencing technology detecting 0.003 percent tumor signal in early-stage cancer plasma.
Authors: Zhao Grace Q. , Bao Yun , Wang Heng , Wang Jianmin , Lin Shengrong
Published: May 2020

4092

Background: Methylation analysis in cell-free DNA holds great potential for early cancer detection. In the plasma of early stage cancer patient, the tumor content is estimated to be less than 0.1%, therefore demands a highly sensitive assay. Targeted Methylation Sequencing (TMS) is the most promising approach; however, the current sensitivity and specificity are compromised by low efficiency and low recovery of target enrichment, and further hampered by background noise associated with large panels. The ideal solution would be an in-depth analysis using a focused small cancer-specific methylation biomarker panel, but is not supported by existing technologies. Methods: Here we present a new technology designed for TMS analysis in cfDNA: Point-n-Seq, featuring an enrichment of target molecules directly from cfDNA before bisulfite conversion and amplification. Particularly, this technology enables small focused panel that interrogates the methylation status of 1 to ~1000 markers. We designed a CRC panel covering 100 methylation markers in 3 steps: identify ~1000 CRC-specific markers from public databases; eliminate makers with high background signal in baseline cfDNA of healthy population; finalize the list with the most differentiating markers between patient and healthy cfDNA. Results: The capture of Point-n-Seq CRC panel is highly efficient resulting in high uniformity (94% > 0.5X) and on-target rate ( > 80%). For 20 ng cfDNA input, more than 1000 deduped informative reads were obtained for each marker on average, despite the high GC content ( > 80%). The output of informative reads was linear to the cfDNA input ranging from 1 ng to 40 ng. In titration studies, 0.6 pg (0.2X genome equivalent) methylated DNA in 20 ng cfDNA (0.003%) was reliably detected over cfDNA background. Using plasma samples from patients with CRC - early stage (I, n = 7; II, n = 7), late stage (III, n = 11; IV, n = 3), and control individuals (n = 105), the average fractions of methylated signal are 0.0034%, 0.013%, 0.09%, 0.17%, 0.29% for control, stage I, II, III, IV accordingly. With a simple cut-off using methylation fraction, Point-n Seq CRC panel achieved a sensitivity of 86% for stage I, 100% for stage (II-IV) at a specificity of 91%, with AUC = 0.96. Conclusions: Point-n-Seq TMS is the first hybridization based NGS technology enables the small focused methylation panel (e.g. 100 markers) sequencing using cfDNA, and it will greatly facilitate the development of practical and cost-effective methylation assays for clinical use.
APC and TP53 as potential biomarkers for EGFR sensitivity in colorectal cancer.
Authors: Thota Ramya , Yang Mingli , Davis Thomas , Schell Michael J. , Pledger Warren Jack , Yeatman Timothy Joseph
Published: May 2020

4094

Background: The Consensus Molecular Subtypes (CMS) of colorectal cancer (CRC) have prognostic and predictive value in identifying patients that derive benefit from EGFR targeted therapies. The CMS2 cohort was specifically noted to predict response to cetuximab. Besides CMS classification, we recently reported a two-gene mutation signature of APC and TP53 (AP) that predicts potential response to cetuximab. In this study, we hypothesize AP mutations, in addition to CMS cohorts, predict cetuximab sensitivity. Methods: A prespecified and validated 203 gene expression signature score measuring cetuximab sensitivity (CTX S-score) was used as a surrogate for response to cetuximab sensitivity. A cohort of 458 patients with colorectal cancer was accrued between October 2006 and September 2011. The population classified into CMS cohorts, and CTX-S scores were determined across each of the cohorts based on AP mutation status. Results: Among 458 tumor samples sequenced, AP mutations were identified as significantly associated with higher CTX-S scores. Among the CMS 1-4 cohorts identified, AP mutations were noted in 13 of 77 (17%) patients in CMS1 cohort, 87 of 116 (75%) patients in CMS2 cohort, 15 of 64 (23%) patients in CMS3 cohort, 46 of 112 (41%) patients in CMS4 cohort, indicating that AP mutations are dominant in CMS2 cohort. Further CTX-S score comparisons across CMS cohorts based on AP status show that AP mutated tumors have higher CTX-S scores than non-AP mutated tumors—irrespective of the CMS cohorts (p<0.05 unpaired, two-tailed t tests). Conclusions: In our study, we noted CMS2 cohort has high predicted sensitivity to cetuximab. Across other CMS cohorts, AP mutations were associated with higher CTX-S scores compared to those with AP wild-type tumors, suggesting both CMS2 and AP mutations contribute to CTX sensitivity.
Phase II trial of adjuvant mFOLFOX6 after metastasectomy for pulmonary metastasis of colorectal cancer: WJOG5810G.
Authors: Machida Nozomu , Okumura Takehiro , Kishimoto Junji , Boku Narikazu , Nishina Tomohiro , Suyama Koichi , Ohde Yasuhisa , Shinozaki Katsunori , Baba Hideo , Tokunaga Shinya , Kawakami Hisato , Tsuda Takashi , Kotaka Masahito , Okuda Hiroyuki , Yasui Hisateru , Denda Tadamichi , Yamazaki Kentaro , Hironaka Shuichi , Muro Kei , Hyodo Ichinosuke
Published: May 2020

4097

Background: Resection of pulmonary metastasis (PM) is widely accepted to improve the prognosis in selected patients (pts) with metastatic colorectal cancer (CRC). However, the clinical implication of adjuvant chemotherapy after metastasectomy of PM is unknown. We conducted a multi-center phase 2 trial of adjuvant chemotherapy with mFOLFOX6 after metastasectomy of PM-CRC. Methods: Main eligibility criteria were first curative metastasectomy of 4 or less PMs and no prior chemotherapy except for adjuvant chemotherapy with fluoropyrimidine monotherapy after curative resection of primary or extrathoracic CRC metastasis. The study treatment was 12 courses of mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion, every 2 w). The primary endpoint was overall survival (OS). The secondary endpoints included disease-free survival (DFS), adverse events (AEs), and recurrence sites. The sample size was determined to be 93 expecting 5-year OS rate of 50% with threshold 35% (90% power, alpha error 5%). Results: Fifty-two pts from 34 institutions were enrolled between July 2011 and July 2014. Patient enrollment was closed prematurely because of slow accrual. Four patients were ineligible after enrollment and the safety and efficacy cohort comprised 52 and 48 patients, respectively. Patient backgrounds were as follows: gender (male/female) 31/21, median age (range) 63 (42-75) years, ECOG PS (0/1) 48/4, primary site (colon/rectum) 18/34, number of PM (1/2/3/4) 36/9/5/2, synchronous/metachronous PM 11/41, and unilateral/bilateral PM 40/12. With the median follow-up time of 6.0 (1.8-7.7) years, 5-year OS rate was 86% (95% CI: 72-93) and 5-year DFS rate was 59% (95% CI: 43-71). Tumors recurred in 19 patients (13 lung, 3 liver and 7 others). Total 41 pts (79%) completed 12 courses of mFOLFOX6 (reasons for discontinuation: AEs in 3, refusal due to AEs in 8). AEs ( > Grade 3) were neutropenia 50%, fatigue 8%, peripheral sensory neuropathy 8%, appetite loss 4%, diarrhea 4%, febrile neutropenia 2% and allergic reaction 2%. There was no treatment related death. Conclusions: Adjuvant mFOLFOX6 is feasible and may be effective after metastasectomy for PM-CRC, considering much better OS than we had expected. Clinical trial information: UMIN000005693 .
Is there a benefit of oxaliplatin in neoadjuvant treatment of locally advanced rectal cancer? An updated meta-analysis.
Authors: Des Guetz Gaetan , Landre Thierry , Larrouy Anne , Panis Yves , Morere Jean F. , Mathonnet Muriel , Quero Laurent
Published: May 2020

4098

Background: Neoadjuvant fluoropyrimidine (5FU or capecitabine)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still unclear. Methods: To identify clinical trials combining oxaliplatin in preoperative CRT or perioperative chemotherapy for LARC published until December 2019, we searched PubMed, the Cochrane Library. We also search for relevant ASCO conferences. Primary endpoint was Disease-Free-Survival (DFS). Data were extracted from every study to perform a meta-analysis using Review Manager (version 5.3). Results: A total of 7 Randomized Clinical Trials (ACCORD-12, CARO-AIO-04, FOWARC, JIAO, NSABP, PETACC-6 and STAR-01) with 5782 stage II or III rectal cancer patients were analysed, including 2727 patients with OXP + 5FU regimen and 3055 patients with 5FU alone regimen. Compared with 5FU-based regimen group, OXP-based regimen group improved DFS (HR = 0.90, 95% CI: 0.81−0.99, P = 0.03) and increased pathologic Complete Response (OR = 1.21, 95% CI: 1.07−1.37, P = 0.002). Patients treated with OXP-regimen had significantly less metastatic disease (OR = 0.79; 95% CI, 0.67 to 0.94; p = 0.007). Considering Adverse Events (AEs), there was more grade 3-4 diarrhoea with OXP (OR = 2.41, 95% CI: 1.74−3.32, P < 0.00001). However, there were no significant differences grade 3-4 haematologic AEs (OR = 1.16, 95% CI: 0.87−1.57, P = 0.31). Conclusions: Combining oxaliplatin with capecitabine or 5FU in preoperative chemoradiotherapy or perioperative chemotherapy seems beneficial significantly and improved DFS. It remains necessary to identify which patients benefit most from the addition of oxaliplatin.
Clinicopathological and molecular biological characteristics of early-onset stage II/III colorectal adenocarcinoma: An analysis of 25 studies with 47,184 patients (pts) in the adjuvant colon cancer end points (ACCENT) database.
Authors: Jin Zhaohui , Dixon Jesse G. , Parekh Hiral D. , Alberts Steven R , Yothers Greg , Allegra Carmen Joseph , Kerr Rachel , Haller Daniel G. , De Gramont Aimery , Yoshino Takayuki , Van Cutsem Eric , Twelves Chris , Taieb Julien , Saltz Leonard B. , Seitz Jean-François , Andre Thierry , Mahipal Amit , Goldberg Richard M. , Shi Qian , George Thomas J.
Published: May 2020

4099

Background: Colorectal cancer (CRC) incidence and mortality has decreased since the 1970s but the incidence is increasing in young adults (age 20-49). The incidence of early onset CRC (eoCRC) will keep increasing significantly based on the trends of the SEER CRC registry data. There is limited data suggesting eoCRC may have different behaviors compared to traditional CRC (tCRC, age ≥ 50). Methods: Individual pt data of 47184 stage II/III CRC pts from 25 randomized studies in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and treatment-related data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence-free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for stage, performance status (PS), BMI and grade. Results: Using 5% difference between age groups as clinically meaningful cutoff, eoCRC had similar gender, race, ethnicity, PS, risk group, disease sidedness and T stage as tCRC. eoCRC were less likely overweight (30 vs 36%) and more pts had ≥ 12 lymph nodes resected (63 vs 51%). eoCRC had more frequent dMMR status (18 vs 12%), less BRAF mutations (5 vs 13%), and more dMMR/BRAF wild type (WT) status (17 vs 7%). Overall, eoCRC had better OS, DFS, and SAR, with the most significant differences between the < 30 and > = 70 age groups. Similar results were observed within pMMR pts. eoCRC experienced less hematological side effects, diarrhea, and stomatitis, but had more nausea and/or vomiting. Conclusions: eoCRC have unique characteristics; although statistically significant, the clinical differences in outcomes between eoCRC and tCRC are potentially due to the difference seen in extremely young and old pts. eoCRC have a different adverse events panel compared to tCRC. [Table: see text]
Randomized phase II trial of modified (m) FOLFOX6 induction chemotherapy with or without aflibercept before standard chemoradiotherapy (CRT) and total mesorectal excision (TME) in patients with high-risk rectal adenocarcinoma (HRRC): Final results of the GEMCAD 1402, and by molecular subtypes.
Authors: Fernandez-Martos Carlos , Machado Isidro , Pericay Carles , Salas Nuria , Feliu Batlle Jaime , ten Hoorn Sanne , Vermeulen Louis , Losa Ferran , Garcia Carbonero Rocio , Alonso Vicente , Vera Ruth , Gallego Javier , Capdevila Jaume , Salud Antonieta , Nogué Miguel , Maurel Joan , Layos Laura , Montagut Clara , Garcia-Albeniz Xabier
Published: May 2020

4102

Background: Neoadjuvant chemotherapy (CT) followed by CRT and TME is a treatment option for clinically staged HRRC. The goal of the GEMCAD 1402 trial was to evaluate the benefit of adding an antiangiogenic drug to the neoadjuvant CT. The analysis of primary endpoint showed a better response rate in the experimental arm (Fernandez-Martos et al. Jama Oncol 2019). Here we present 3-year disease-free survival (DFS) and a retrospective analysis of consensus molecular subtypes by Immunohistochemistry (CMSs-IHQ). Methods: Patients (p) with middle or distal third, mrT3/T4/N2 rectal adenocarcinoma were randomly assigned (2:1), to mFOLFOX6 with (arm 1, n=115) or without Aflibercept (arm 2, n=65) prior to CRT (capecitabine with 50.4 Gy in 28 fractions) and TME. Tissue microarrays from 90 (58 arm1, 32 arm 2) p were stained for nine markers (CDX2, FRMD6, HTR2B, ZEB1, KER, MSH2, MSH6, PMS2 and MLH1) by IHQ using both semiquantitative and quantitative approaches. Cases were classified as CMS1-IHQ1, CMS-IHQ2/3 or CMS-IHQ 4 (immune, epithelial or mesenchymal subtypes). Results: In the intention-to-treat population after a median follow-up time of 38 months, 29 p (25%) in arm 1 had a DFS-related event, as compared with 14 p (21%) in arm 2 (HR 1.2063, 95% confidence interval 0.6374 to 2.2829, P=0.5644. The rate of DFS at three years was 75.2% (95% confidence interval, 66.1% to 82.2%) in arm 1 and 81.5% (95% confidence interval, 69.8% to 89.1%) in arm 2 (P=0.5638 by the exact stratified log-rank test). Overall 0/80/10 p were classified as CMS-IHQ1, CMS-IHQ2/3 or CMS-IHQ4 respectively. The pathological complete response (pCR) rate (ypT0N0) was achieved in 27.5% and 0% in epithelial and mesenchymal subtypes respectively. A trend towards worse survival for the mesenchymal subtype was observed. Conclusions: Adding aflibercept to induction mFOLFOX6 is not associated with an improvement in DFS. Our findings suggest that CMSs-IHQ subtypes could be predictive for pCR with this treatment strategy. Clinical trial information: NCT02340949 .
Impact of antibiotics (ATB) on the recurrence of resected colorectal cancer (CRC): Results of EVADER-1 a nation-wide pharmacoepidemiologic study.
Authors: Rousseau Benoit , Hilmi Marc , Khati Ines , Turpin Anthony , Andremont Antoine , Burdet Charles , Grall Nathalie , Vidal Joana , Bousquet Philippe Jean , Le Bihan Christine
Published: May 2020

4106

Background: Recent studies suggest that ATB increase the overall risk of CRC incidence through disruption of gut microbiota. Impact of ATB on the risk of CRC recurrence after curative resection remains unknown. Methods: Using the French nation-wide Institut National du Cancer (INCa – Système National des Données de Santé) database of cancer patients, all newly diagnozed localized CRC patients resected between 01/2012 and 12/2014 were involved. The perioperative ATB intake (6 month before until 1 year after surgery) was classified according to the spectrum, doses and period of use. The primary endpoint was 3-year Disease-Free Survival (3-DFS), stratified on chemotherapy (chemo) administration (yes/no), and assessed using multivariate Cox models. Results: Out of 219,884 CRC patients, the present study included 36,640 patients: male 53%, age≥75 years 39%, left colon/rectal 59%, exposure to chemo 44%, at least one ATB intake 74%. At 3-years, 29% of patients had recurred and 18% had died. In multivariate analysis, in patients not receiving chemo, ATB intake as an out-patient was significantly associated with better 3-DFS [HR (one ATB only) = 0.88 (0.82-0.94)]. This effect remained in the same range whatever the number of ATB or cumulative exposure to ATB. In patients receiving chemo, ATB intake as an out-patient had a significant detrimental effect on 3-DFS [HR (one ATB only) = 1.15 (1.08-1.23)], increasing with the number of ATB [HR (≥5 ATB) = 1.54 (1.39-1.71)] and longer exposure [HR ( > 30 days) = 1.39 (1.31-1.48)]. Penicillin A, quinolones and ATB combinations were associated with worse 3-DFS. The timing of ATB intake related to chemo revealed that the strongest deleterious effect was observed when ATB were taken during chemo [HR = 1.64 (1.53-1.75)]. No difference in the mean number of chemo cycle was observed comparing patients receiving ATB or not. Conclusions: This nation-wide study is the first to suggest that ATB modulate 3-DFS in resected CRC with a differential impact according to chemo exposure. Importantly, ATB intake with chemo is detrimental in a dose- and time-dependent manner suggesting that dysbiosis of gut microbiota during adjuvant chemo might increase risk of recurrence.