bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytoplasmic cyclin E independently predicts recurrence in older patients with primary breast cancer.
Authors: Johnston Simon , Parks Ruth , Syed Binafsha Manzoor , Green Andrew R. , Hunt Kelly , Keyomarsi Khandan , Ellis Ian O. , Cheung Kwok-Leung
Published: May 2019

3128

Background: Primary breast cancer in the older ( > 70 years) population has distinct biological characteristics associated with favourable outcome, such as higher rate of estrogen receptor (ER) positivity. Due to comorbidities, older patients with primary breast cancer are more likely to die of non-breast cancer-related causes compared to their younger counterparts. Biomarkers that may influence treatment strategy therefore require interpretation in the specific biological and clinical context of older women. Cyclin E regulates cell cycle transition from G1 to S phase, and its deregulation is implicated in breast cancer pathogenesis. Tumour-specific isoforms of cyclin E localise to the cytoplasm. Expression of cytoplasmic cyclin E (c-cyclin E) is linked with poor clinical outcome. We now present multivariate analysis of breast cancer-specific survival (BCSS) by c-cyclin E and clinical markers of disease biology from a cohort of older women. The primary outcome, BCSS, excludes deaths from competing causes and is used as a surrogate for tumour biology. Methods: Between 1973 and 2010, 813 older women underwent initial surgery for early breast cancer and were followed up in a dedicated clinic in Nottingham. Excised tumours from 517 of these patients were successfully incorporated into a tissue microarray (TMA). Expression of c-cyclin E was assessed by IHC using an assay developed at MDACC, along with a panel of 24 biomarkers. Of these, ER, progesterone receptor (PR), human epidermal growth factor 2 (HER2) and Ki67 are in current clinical use and are analysed alongside c-cyclin E. Grade was assessed from the primary tumour. Multivariate analysis of BCSS was performed by Cox proportional hazard test. Results: In multivariate analysis alongside markers of disease biology currently used in the clinic (ER, PR, HER2, Ki67 and grade), c-cyclin E is the only factor that independently predicts BCSS in this cohort of older women (HR 5.0, 95% CI 2.1 – 12.0; p< 0.001). Conclusions: In the older population with primary breast cancer, c-cyclin E expression is the only independent biological marker of BCSS. Patients with low c-cyclin E expression are unlikely to die of breast cancer. These data have potential to influence treatment strategy in older patients. For example, patients with ER+, c-cyclin E negative disease plus multiple co-morbidities may be suitable for primary endocrine therapy. This hypothesis warrants prospective clinical evaluation.
The Cancer Molecular Screening and Therapeutics Program (MoST): Actionable mutation frequencies in a population with rare and less common cancers.
Authors: Thavaneswaran Subotheni , Ballinger Mandy L. , Grady John , Cowley Mark , Joshua Anthony , Sebastian Lucille , Collignon Emily , Silvestri Audrey , Kansara Maya , Pinese Mark , Sjoquist Katrin Marie , Hague Wendy , Lee Chee Khoon , Simes John , Thomas David Morgan
Published: May 2019

3136

Background: Personalizing therapy will arguably have no greater impact than on patients (pts) with rare (< 6 per 100,000 population) or less common cancers (6-12/100,000). MoST combines a molecular screening platform and biomarker-driven treatments for pts with advanced cancer, with a particular focus on rare and less common cancers (RLC). Methods: Molecular screening was performed using in-house and commercial panels on archival tumor tissue. A Molecular Tumor Board by consensus reported on pathogenic variants with potential therapeutic actionability. Tiers of actionability were defined as: Tier 1–eligible for a MoST substudy; Tier 2–clinical evidence of efficacy in any cancer type, Tier 3—preclinical evidence. The clinical and molecular characteristics of the first 1,000 pts are presented here. Results: Pts were recruited from Sept 2016 to Dec 2018. A report was issued in 94% of cases in a median of 7.7 weeks from consent. In 6%, there was insufficient tissue. The median age at cancer diagnosis was 35 years (range 4-85 years), and 49% were male. Pts had a median of 2 lines of prior systemic therapy (0-11), and a median baseline ECOG performance status of 0 (range 0-3). 82% of pts had RLCs. A total of 2642 pathogenic variants were reported, of which 1144 (43%) were deemed therapeutically actionable. 651(57%) of actionable variants (AVs) occurred in RLC (Table). Most commonly, AVs were found in the cell cycle, homologous recombination repair (HR) and fibroblast growth factor (FGF) pathways. 559(66%) of pts had at least one AV identified, 30% tier 1, 63% tier 2 and 6% tier 3, including 66% of RLC. In 30% of cases, a tumor mutational burden >11 mutations/ megabase was reported. Conclusions: Here we report a high frequency of AVs in RLC, providing a rational basis for assessing the potential of personalized therapy in a population with a historically unmet need for effective treatment. Clinical trial information: ACTRN12616000908437. [Table: see text]
Effects of immune architecture on response to adjuvant capecitabine in triple-negative breast cancer (FinXX trial).
Authors: Chumsri Saranya , Asleh Karama , Brauer Heather Ann , Hinerfeld Douglas , Kachergus Jennifer M. , Lauttia Susanna , Lindman Henrik , Nielsen Torsten , Joensuu Heikki , Thompson E. Aubrey
Published: May 2019

3142

Background: Recent studies have demonstrated a benefit of adjuvant capecitabine, particularly in triple negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy. However, biomarkers to predict which patients are more likely to benefit from capecitabine are needed. Methods: The nanoString Breast Cancer 360 (BC360) and PanCancer Immunoncology (IO360) panels were used to quantify mRNA expression in TNBC samples in the FinXX trial. FinXX is a phase III trial which randomized high risk patients to receive either 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (Arm A: T+CEF) vs. 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (Arm B: TX+CEX). Gene signature scores were analyzed using prespecified algorithms developed by nanoString. Digital Spatial Profiling was carried out using GeoMX platform. Results: A total of 111 TNBC patients in FinXX trial were included (57 in Arm A and 54 in Arm B) with 10.2 years median follow up. There were 7 cancer- and immune-related gene signatures identified by BC360 and IO360 panels that were significantly associated with improved recurrent free survival favoring an addition of capecitabine. These include cytotoxic cell signature (HR 0.37, 95%CI 0.15-0.92, p 0.03), endothelial signature (HR 0.18, 95%CI 0.04-0.83, p 0.03), mast cell signature (HR 0.43, 95%CI 0.21-0.88, p 0.02), PDL2 gene (HR 0.29, 95%CI 0.09-0.99, p 0.05), immunoproteasome (HR 0.34, 95%CI 0.13-0.89, p 0.02), exhausted CD8 (HR 0.29, 95%CI 0.09-0.97, p 0.04), and PD1 (HR 0.44, 95%CI 0.20-1.02, p 0.05). Conclusions: Analysis of RNA abundance signatures strongly suggests that there are important immune features that are associated with benefit from capecitabine in TNBC. However, analysis of RNA extracted from whole tumor sections lacks spatial discrimination. We anticipate that a more detailed, spatially-defined analysis of protein abundance, using the novel NanoString GeoMX platform, will provide more insights and define specific immune features associated with improved outcome. Additional results of GeoMX will be reported at the meeting. Clinical trial information: NCT00114816.
Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: The efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project.
Authors: Sougklakos Ioannis , Boukovinas Ioannis , Xynogalos Spyros , Kakolyris Stylianos , Ziras Nikolaos , Vaslamatzis Michael , Athanasiadis Athanasios , Ardavanis Alexandros , Androulakis Nikolaos E. M. , Christopoulou Athina , Makrantonakis Paris , Bompolaki Iliada , Christofyllakis Charalampos , Kentepozidis Nikolaos K. , Emmanouilides Christos E. , Kouroussis Charalambos , Prinarakis Efthimios , Kalisperi Ageliki , Mavroudis Dimitrios , Georgoulias Vassilis
Published: May 2019

3500

Background: The IDEA aimed to investigate whether a 3-month (3M) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) in 3-year disease free survival (DFS) in stage high risk stage II and in stage III colon cancer (CC). Methods: HORG-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX with primary end point the 3 years DFS (3yDFS). Results: In total 1121 patients, 413 with high risk stage and 708 with stage IIICC, were randomized between May 2009 and October 2015. The median follow-up was 67 (38-126) months. There were 79 DFS events (43 in 3M and 38 in 6M arm) in high risk stage II patients leading to 3yDFS rate of 82.7 and 83.4% for 3M and 6M, respectively (HR: 1.05; 95%CI: 0.68-1.63, p = 0.829). Similarly, 214 DFS events (161 in 3M and 153 in 6M arm) has been recorded in stage III patients, leading to a 3yDFS rate of 72.9% in the 3M vs. 74.1% in the 6M (HR = 1.06; 95%CI: 0.81–1.42, p = 0.622). For high risk stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% in the 3M vs.79.3% in the 6M (HR = 1.21; 95%CI: 0.54–2.70 p = 0.641). For high risk stage II patients receiving CAPOX 3-year DFS rate was 85.4% in the 3M vs. 83.8% in the 6M (HR = 0.99; 95%CI: 0.59–1.67 p = 0.968). For stage III CC patients receiving mFOLFOX6, 3-year DFS rate was 71.5% in the 3M vs.77.3% in the 6M (HR = 1.18; 95%CI: 0.74–1.86 p = 0.479). For stage III CC patients receiving CAPOX 3-year DFS rate was 74.5% in the 3M vs. 74.7% in the 6M (HR = 0.99; 95%CI: 0.70–1.44 p = 0.991). Conclusions: The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that 3yDFS is depended on the administered adjuvant regimen, and the choice of regimen and duration should be personalized. Clinical trial information: NCT01308086.
Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the first- and second-line treatment of unresectable mCRC.
Authors: Cremolini Chiara , Antoniotti Carlotta , Lonardi Sara , Rossini Daniele , Pietrantonio Filippo , Cordio Stefano Sergio , Bergamo Francesca , Marmorino Federica , Maiello Evaristo , Passardi Alessandro , Masi Gianluca , Tamburini Emiliano , Santini Daniele , Grande Roberta , Zaniboni Alberto , Granetto Cristina , Murgioni Sabina , Aprile Giuseppe , Boni Luca , Falcone Alfredo
Published: May 2019

3508

Background: In the phase III TRIBE study FOLFOXIRI/bev significantly improved Response Rate (RR), PFS and OS when compared with FOLFIRI/bev as initial treatment of mCRC. However, the actual advantage by the triplet could be lower when compared with a pre-planned sequential strategy of doublets (FOLFOX, FOLFIRI). TRIBE2 (NCT02339116) is a phase III trial in which unresectable mCRC pts were randomized 1:1 to FOLFOX/bev followed by FOLFIRI/bev after PD (arm A) or FOLFOXIRI/bev followed by the reintroduction of the same regimen after PD (arm B). A pre-planned interim analysis showed a significant advantage for arm B in terms of PFS2, primary endpoint of the study, defined as the time from randomization to PD on any treatment given after first PD or death (PD2). Methods: The study had 80% power to detect a HR for PFS2 of 0.77 in favor of arm B with an overall 2-sided-α error of 0.05 (0.0131 and 0.0455 for the interim and final analyses, planned at 303 and 466 PFS2 events, respectively). Secondary endpoints included RR, 1st-PFS, i.e. the time from randomization to the first evidence of PD or death (PD1), 2nd-PFS, i.e. the time from PD1 to PD2, and OS. Results: From February 2015 to May 2017, 679 pts (arm A/B: 340/339) were enrolled in 58 Italian sites. Main pts’ characteristics were (arm A/B): right side 38%/38%, synchronous mets 89%/89%, RAS mutant 65%/63%, BRAF mutant 10%/10%. At a median follow up of 30.6 mos, 514 (arm A/B: 272/242) PD2, 594 (arm A/B: 303/291) PD1 and 408 (arm A/B: 217/191) OS events were collected. A significant advantage by upfront FOLFOXIRI/bev was confirmed in terms of PFS2 (19.1 vs 16.4 mos, HR 0.74, 95%CI 0.62-0.88, p<0.001), RR (62% vs 50%, OR 1.61, 95%CI 1.19-2.18, p=0.002) and 1st-PFS (12.0 vs 9.8 mos, HR 0.75, 95%CI 0.63-0.88, p<0.001). A significant OS benefit for pts in arm B was also observed (27.6 vs 22.6 mos, HR: 0.81, 95%CI: 0.67-0.98, p=0.033). Out of 594 pts with a PD1 event, 470 (79%, arm A/B: 251/219) received a treatment after PD. In the per-protocol analysis (N=323), pts in arm B showed significantly longer 2nd-PFS (6.5 vs 5.8 mos, HR 0.76, 95%CI 0.59-0.97, p=0.024). Conclusion: Upfront FOLFOXIRI/bev followed by the pre-planned reintroduction of the same agents after PD provided a statistically significant and clinically relevant PFS2 and OS benefit when compared with the pre-planned sequential administration of FOLFOX/bev and FOLFIRI/bev in unresectable mCRC patients. A median OS of 27.6 mos was reached despite the high percentage of pts with poor prognostic features ( RAS and BRAF mutations, right side, synchronous mets). Clinical trial information: NCT02339116.
CCTG CO.26: Updated analysis and impact of plasma-detected microsatellite stability (MSS) and tumor mutation burden (TMB) in a phase II trial of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with refractory metastatic colorectal carcinoma (rmCRC).
Authors: Chen Eric Xueyu , Jonker Derek J. , Loree Jonathan M. , Kennecke Hagen F. , Berry Scott R. , Couture Felix , Ahmad Chaudhary E. , Goffin John R. , Kavan Petr , Harb Mohammed , Colwell Bruce , Samimi Setareh , Samson Benoit , Abbas Tahir , Aucoin Nathalie , Aubin Francine , Koski Sheryl L. , Wei Alice Chia-chi , Tu Dongsheng , O'Callaghan Christopher J.
Published: May 2019

3512

Background: Targeting both PD-L1 and CTLA-4 may be synergistic immunotherapy approaches. CO.26 evaluated if dual inhibition leads to improved pt survival vs BSC alone in rmCRC. Methods: rmCRC pts were randomized 2:1 to D+T vs BSC. Treatment consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and supportive measures. Primary endpoint was overall survival (OS). Two-sided p < 0.10 was considered statistically significant. Cell-free (cf)DNA sequencing for MSI and TMB used GuardantOMNI panel and baseline plasma. Results: From 08/2016-06/2017, 180 pts were enrolled. Pt characteristics were balanced between arms. At median follow-up of 15.2 months (mos), median OS was 6.6 mos for D+T and 4.1 mos for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 mos vs 1.9 mos, respectively (HR 1.01, 90% CI 0.76 – 1.34). Disease control rate (DCR) was 22.6% for D+T and 6.6% for BSC (p = 0.006). cfDNA analysis was successful in 168/169 pts (99.4%). Two pts were MSI-high. In 166 MSS pts, OS HR was 0.66 (p=0.024; 90% CI 0.49-0.89). Excluding the MSI-H cases (TMB of 74.7 and 247.1 mts/Mb), mean TMB was 20.4 ± 16.3 mts/Mb (range: 0.96 – 114.0). In MSS pts, a pre-specified cutpoint of 20 mts/Mb stratified pts into high and low TMB groups but was not predictive for OS , PFS, or DCR (interaction p-values > 0.7). Using a minimum p-value approach, pts with TMB >28 mts/Mb (21% of MSS pts) had the greatest OS benefit (HR 0.34, 90% CI 0.18-0.63) for D+T (interaction p = 0.07). High TMB was associated with a trend in worse prognosis for OS in the BSC arm using both 20 mts/Mb (HR 1.26, 90% CI 0.76-2.12) and 28 mts/Mb (HR 2.59 90% CI 1.46-4.62) cutpoints. Conclusions: D+T significantly prolonged OS in pts with rmCRC. High TMB may select a group of MSS pts who benefit from D+T. Plasma TMB appeared prognostic in the BSC arm. This is the first study showing combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with MSS rmCRC. Updated results based on deaths in more than 90% of pts will be presented. Clinical trial information: NCT02870920.
Repeated centralized MDT resectability assessment during first-line treatment in 1086 Finnish metastatic colorectal cancer (mCRC) patients nationwide (prospective RAXO study).
Authors: Osterlund Pia J. , Kallio Raija Sinikka , Kellokumpu Ilmo , Soveri Leena-Maija , Ålgars Annika , Salminen Tapio , Murashev Maija-Leena , Lamminmaki Annamarja , Halonen Päivi , Ristamäki Raija , Lantto Eila , Ovissi Ali , Nordin Arno , Aroviita Laura , Jekunen Antti Pekka , Lindvall-Andersson Renee , Nyandoto Paul , Kononen Juha Teppo , Poussa Tuija , Isoniemi Helena ,   The RAXO Study Group
Published: May 2019

3517

Background: Resection of oligometastatic mCRC is curable in up to half and is probably underused in real-life oncology practice. In 2011, a prospective nationwide centralized evaluation of resectability was initiated to assess upfront and conversion to resectability. Methods: The RAXO-study included 1086 mCRCs referred for oncological treatments at all 21 Finnish oncology units (40% of eligible mCRCs in Finland). The MDT at Helsinki tertiary referral center (TRC) assessed resectability of liver, lung and other metastases upfront and twice during first-line therapy. Resectability evaluation was provided online and resections were performed according to clinical praxis, with major resections at TRCs. Results: Median age was 66.5 (range 24-90) yrs, 60% males, ECOG was 0 in 295 (27%), 1 in 600 (55%) and 2-3 in 191 (18%). Tumor was right-sided in 310 (29%), left in 769 (72%) and multiple in 7 (.6%). In the MDT assessment, 435 (40%) were considered resectable, 28% upfront and 12% after conversion. Resections or local ablative therapy were performed in 396 (91% of resectable, R0-1 in 74% and R2 in 17%), with 368 liver-, 91 lung- and 96 other operations. One metastatic site (n = 407), 2 (n = 369) and 3-6 (n = 310) were or became resectable in 65, 33 and 15%, respectively, and R0-1 resected in 54, 30 and 6%, respectively (P < 0.001). In multivariate analysis age < 66.5 (OR 1.51), ECOG 0 (OR 2.40); left-sided primary (OR 1.55), metachronous metastases (OR 1.49), 1-2 metastatic sites (OR 1.86) increased R0-1 resection rates; whereas primary/relapse in situ (OR 0.49), metastases in lung (OR 0.22), peritoneum (OR 0.30) or lymph nodes (OR 0.23) decreased R0-1 rates (P < 0.05). In univariate analyses BRAF wt (OR 0.34), normal CEA (OR 0.31) or normal Ca19-9 (OR 0.45) associated with R0-1 rates. Median OS was 2.4 yrs (CI95% 2.3-2.6) in all, 6.7 yrs in R0-1 (HR 0.15; CI95% 0.11-0.19), 2.8 yrs in R2 (0.50; 0.36-0.68) and 1.7 yrs in non-resected (reference group). Median PFS was 1.1 yrs (1.0-1.1) in all patients, 2.4 yrs in R0-1 (0.24; 0.20-0.28), 1.4 yrs in R2 (0.55; 0.42-0.71) and 0.8 yrs in non-resected patients. P < 0.001 for all comparisons. Conclusions: Repeated centralized MDTs in real-life mCRC patients show high resectability (40%) and resection rates (36%), even if multiple metastatic sites are present. Curative resection associates with good survival. Clinical trial information: NCT01531621.
Prognostic value of tumor deposits for disease free survival in patients with stage III colon cancer: A post hoc analysis of IDEA France phase III trial (PRODIGE-GERCOR).
Authors: Delattre Jean Francois , Cohen Romain , Henriques Julie , Falcoz Antoine , Emile Jean-François , Fratte Serge , Chibaudel Benoist , Dauba Jérôme , Dupuis Olivier Jean Marie , Bécouarn Yves , Bibeau Frédéric , Taieb Julien , Andre Thierry , Vernerey Dewi , Svrcek Magali
Published: May 2019

3519

Background: Tumor deposits (TDs) are isolated tumor foci in the pericolic, perirectal or mesocolic fat without residual lymph node (LN) tissue. TDs seem to impact the prognosis of stage III colon cancer (CC) patients (pts) but are only considered in TNM staging in the absence of LN metastases (LNM). We aimed at evaluating the prognosis value for disease free survival (DFS)of TDs in International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France phase III study (NCT00958737) that compared 3 versus 6 months of adjuvant FOLFOX or CAPOX for stage III CC pts. Methods: All pathological reports of pts included in IDEA France trial were retrospectively analyzed. DFS according to the presence or absence of TDs was evaluated using Kaplan-Meier estimator. Multivariable Cox model analysis was performed to evaluate the association between TDs and DFS. This analysis did not included immunohistochemical biomarkers. Results: Among the 2022 pts included in IDEA France study, 1942 (96%) were analyzed. 80 pts were excluded: no pathological report (n = 68), pts without treatment (n = 12). TDs were found in 184 pts (9.47%), of whom 74 with N1a/b (40%), 55 with N1c (30%) and 55 with N2 LN stage (30%). All characteristics were similar according to the presence of TDs, except for tumor/node (TN) stage (T4 and/or N2 are more frequent in pts with TDs; p = .0046). The 3-year DFS rates were 65.59% [95% confidence interval (95%CI) 58.04-72.12] and 74.71% [95%CI 72.57-76.71] for pts with and without TDs, respectively (p = 0.0079). In multivariable analysis, TDs were associated with higher risk of recurrence or death (hazard ratio (HR) = 1.36, 95%CI 1.05-1.75, p = .0201), as well as T4 and/or N2 (HR = 2.21, 95%CI 1.03-1.59, p < .001), 3 months of adjuvant treatment (HR = 1.29, 95%CI 1.09-1.52, p = .0029), obstruction (HR = 1.28, 95%CI 1.03-1.59, p = .0233) and male (HR = 1.24, 95%CI 1.04-1.46, p = .0151). Adding TDs count to the LNM count, 35 out of 1454 N1a/b/c CC pts (2.4%) were reclassified as N2 and experienced worse 3 years DFS than confirmed N1 CC pts (p = .0151). Conclusions: TD is an independent and valuable prognostic factor for DFSin stage III CC pts and should be considered whatever the LNM status.
The role of maintenance strategy in metastatic colorectal cancer (mCRC): A systematic review and meta-analysis.
Authors: Sonbol Mohamad Bassam , Mountjoy Luke , Firwana Belal , Almader-Douglas Diana , Mody Kabir , Hubbard Joleen Marie , Borad Mitesh J. , Ahn Daniel H. , Murad M. Hassan , Bekaii-Saab Tanios S.
Published: May 2019

3524

Background: In mCRC, induction combination chemotherapy with targeted agents is considered the mainstay of treatment. This is typically followed by maintenance therapy vs. observation which had been examined in various trials. However, it remains unclear how best optimize maintenance strategy. We aim to evaluate comparative effectiveness to support best maintenance strategy. Methods: We searched PubMed, Embase, and Cochrane CENTRAL for randomized controlled trials (RCT) evaluating different maintenance strategies in previously untreated mCRC patients (pts): observation (obs), bevacizumab (bev), fluoropyrimidine (FP), FP+bev, or continuing induction regimen (CTX). Outcomes of interest included OS and PFS. The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White’s multivariate meta-regression to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Results: Twelve trials at low risk of bias (5540 pts) were included. Network meta-analysis shows no benefit of CTX over obs in terms of PFS (HR 0.7; 95% CI 0.46-1.09) and OS (HR 0.95; 95% CI 0.85-1.07). Compared to obs, maintenance therapy shows PFS benefit (HR 0.58; 95% CI 0.43-0.77) with only a trend in OS (HR 0.91; 95% CI 0.83-1.009). All maintenance strategies (FP, FP+bev, and bev) show significant improvement in PFS over obs. On SUCRA analysis, maintenance treatment (FP or FP+bev) has the highest likelihood of achieving better PFS (67.1% for FP and 99.8% for FP+bev) and OS (81.3% for FP and 73.2% for FP+bev). Conclusions: A maintenance strategy with at least a FP with or without the addition of bevacizumab is preferred. However, given the lack of a clear OS benefit, obs is an acceptable alternative. Optimal maintenance strategies should be dependent on factors including patient preferences, cost and toxicities. [Table: see text]
Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence: Results of an accent meta-analysis of seven studies.
Authors: Taieb Julien , Pederson Levi , Shi Qian , Alberts Steven R , Wolmark Norman , Van Cutsem Eric , De Gramont Aimery , Kerr Rachel , Grothey Axel , Lonardi Sara , Yoshino Takayuki , Yothers Greg , Andre Thierry
Published: May 2019

3525

Background: Microsatellite instable/deficient mismatch repair (MSI) metastatic colorectal cancers have been reported to be of poor prognosis. The interaction between MSI and BRAFV600E mutation complicates the picture. Methods: Patients with resected stage III CC from 7 studies with disease recurrence and data available for MSI and BRAFV600E status were analyzed. The primary endpoint was survival after recurrence (SAR) to assess the prognostic roles of MSI and BRAFV600E, respectively. Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features (data collected 12/1998 to 11/2009). Results: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI tumors (n = 220) had significantly better SAR (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.69-0.98; P = .029) than patients with microsatellite stable /proficient MMR (MSS) tumors (n = 1766). This was also observed when looking at patients treated by the standard FOLFOX adjuvant regimen only (aHR, 0.76; 0.58-1.00; P = .048). Same trends were observed when looking at MSI/dMMR patients outcome in BRAFV600E wild-type (aHR, 0.84; P = .10) and mutant (aHR, 0.88; P = .43) subgroups separately, without reaching statistical significance. As previously described poor SAR was observed in BRAFV600E mutants vs wild type patients (n = 244; aHR, 2.06; 95% CI, 1.73-2.46; P < .0001) and this was also true in BRAFV600E mutants MSI/dMMR patients (n = 77, aHR, 2.65 ; 95% CI, 1.67-4.21; p < .0001). Other factors associated with a poor SAR were : olderage, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence (by 1y increase). Conclusions: In stage III colon cancer patients recurring after adjuvant chemotherapy and before the era of immuno-oncologic agents, MSI/dMMR was associated with a better survival compared to MSS. BRAFV600E mutation seems to be a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.
Genomic alterations after EGFR blockade in patients with RAS wild-type metastatic colorectal cancer: Combined tissue and blood-based analysis from SCRUM-Japan GI-SCREEN and GOZILA.
Authors: Nakamura Yoshiaki , Yamashita Riu , Okamoto Wataru , Narita Yukiya , Komatsu Yoshito , Kagawa Yoshinori , Takahashi Naoki , Esaki Taito , Kato Takeshi , Sunakawa Yu , Denda Tadamichi , Nishina Tomohiro , Takashima Atsuo , Kobayashi Takaaki , Shiozawa Manabu , Oki Eiji , Satoh Taroh , Adachi Yuta , Odegaard Justin , Yoshino Takayuki
Published: May 2019

3528

Background: Anti-EGFR therapy (tx) in RAS wild-type (wt) metastatic colorectal cancer (mCRC) induces resistance through acquired genomic alterations. We aimed to define such alterations in Nationwide Cancer Genome Screening Project tissue and blood specimens, using next generation sequencing (NGS). Methods: Tumor specimens in patients (pts) with RAS wt mCRC were obtained from SCRUM-Japan GI-SCREEN (tissue) and GOZILA (circulating tumor DNA [ctDNA] from blood). Genomic alterations were compared using the Oncomine Comprehensive Assay (SCRUM) and Guardant360 (GOZILA), before anti-EGFR tx and after progression. Results: 373 total actionable alterations were identified in 71 pts with available matched tissue and ctDNA; 255 (68%) were acquired after anti-EGFR tx progression. Frequently seen acquired oncogenic alterations included KRAS mutations (27%) and amplifications (amps) of EGFR (41%), CDK6 (24%), BRAF (20%), MYC (17%), MET (14%), PIK3CA (11%), FGFR1 (11%), and KRAS (10%). Fusions of RET, ALK, and FGFR3 were newly acquired in 1-4%. Acquired alterations co-arose in multiple pathways, including the cell cycle, PI3K-AKT, and MAPK, although 29% of pts had none. Acquired mutations were less frequently clonal versus primary mutations (p<0.0001), but clonal acquired mutations were seen in several oncogenes, including EGFR, KRAS, and PIK3CA. A subset of acquired KRAS, MET, CCND2, and EGFR amps had high (>7) adjusted plasma copy numbers (ApCN). Acquired ERBB2 amps were identified in 3 pts (4%) with a median ApCN of 4, one of whom (ApCN=4.2), treated with dual HER2 blockade, progressed after 2 cycles. Conclusions: Our integrated analysis revealed that anti-EGFR tx of pts with RAS WT mCRC led to acquired genomic alterations in multiple oncogenic pathways. Although most acquired alterations were subclonal, a subset of oncogenic alterations had relatively high clonality and ApCN, suggesting potential targets for overcoming acquired resistance to anti-EGFR tx. Early progression in a pt with an ApCN of 4.2 suggests low-level/subclonal acquired alterations may not be effective treatment targets.
Intratumoral CD3+ and CD8+ T-cell densities in patients with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC) receiving programmed death-1 (PD-1) blockade.
Authors: Chakrabarti Sakti , Huebner Lucas J. , Finnes Heidi Diann , Muranyi Andrea , Singh Shalini , Clements June , McWilliams Robert R. , Hubbard Joleen Marie , Shanmugam Kandavel , Sinicrope Frank A.
Published: May 2019

3532

Background: Colorectal cancer with dMMR display heterogeneity in the extent of intratumoral T-cell infiltration which may explain their variable responsiveness to PD-1 blockade. We examined the association of intratumoral CD3+ and CD8+ T-cell densities (TCD) with objective response rate (ORR) and response duration in patients with dMMR mCRCs receiving pembrolizumab (PEM). Methods: Record review was performed on 12 patients with dMMR mCRC treated with PEM (200 mg intravenously every 3 weeks) after failure of prior chemotherapy [median no. of regimens was 1 (range 1-4)] between 01/2015 and 12/2017. CD3+ and CD8+ TCDs were analyzed in the primary tumor core (CT) and at the invasive margin (IM) by immunohistochemistry and automated image analysis to determine density score (0 to 100) for each T-cell subtype and compartment (Ventana Medical Systems, Inc.). Patients were categorized as 1) responders [CR (complete response) + PR (partial response)] vs. non responders [SD (stable disease) + PD (progressive disease)] per RECIST version 1.1, and 2) by duration of response (< or > 12 months). Results: Median follow-up post PEM was 19.5 (9-41) months. Responders included 2 CR and 5 PR; non-responders included 4 SD and 1 PD. The ORR and median time to response were 58.3% (7/12) and 12 weeks (range 9-40), respectively. CD3+ and CD8+ TCD scores were higher in responders vs. in non-responders as well as in patients who had disease control for > 12 months; differences were greatest for CD8+ CT (Table). Conclusions: Among patients treated with PEM, data suggest higher intratumoral CD3+ and CD8+ TCDs in responders versus non-responders and in those with a longer duration of disease control. If confirmed, TCDs may potentially predict responsiveness to PD-1 blockade in dMMR mCRCs. [Table: see text]
RAS-amplified colorectal cancers: Microsatellite stability status, RAS/BRAF mutations, and prediction of anti-EGFR resistance.
Authors: Schrock Alexa Betzig , Sandhu Jaideep Singh , Wang Chongkai , Ouyang Ching , Miller Vincent A. , Ali Siraj Mahamed , Fakih Marwan
Published: May 2019

3533

Background: Pre-clinical models implicate RAS amplifications ( RASa) as a mechanism of resistance to anti-Epidermal Growth Factor Receptor (EGFR) therapies. Yet, there is little guidance on the impact of RASa, as identified by next generation sequencing (NGS), on anti-EGFR response. Methods: We investigated the Foundation Medicine (FM) database for RASa in CRC and characterized this population based on patient (pt) characteristics and other concurrent genomic alterations. We subsequently investigated City of Hope (COH) mCRC molecular data set (using FoundationOne) and described the RASa population characteristics and response to anti-EGFR. Results: FM cohort included 21,315 CRC unique pt cases. 365 (1.5%) pts had RASa, of which 123 (0.6%) had ≥ 20 copy number (CN) ( RASa≥20). The incidence of MSI-H, RAS and BRAF short variant mutations in the overall, RASa, and RASa≥20 populations were (MSI-H: 5%, 0%, 0%), ( RAS: 54%, 32%, 2%), and ( BRAF: 6%, 1%, 0%), respectively. Copy number variation inversely correlated with likelihood of RAS mutation. COH cohort included 396 mCRC. 13 pts (3.3%) had RASa. The median RAS CN was 25 (7 - 79); 8/13 pts had RASa≥20. All but 3 COH pts with RASa had a RAS/BRAF-WT tumors. Pts with concurrent RAS mutations had relatively low RAS CN (7, 8, &13). Tumors with RASa were predominantly left-sided (12/13). 7/13 pts were treated with anti-EGFR therapy. All 7 pts were RAS/ BRAF wild-type: 6 left-sided; 3 pts 1st/2nd lines (1 pt oxaliplatin-based and 2 pts irinotecan-based) and 4 pts chemo-refractory (all irinotecan-based). All 4 chemo-refractory pts had RASa≥20and progressed on anti-EGFR on 1st post-treatment CT (PFS in all pts ≤ 3 mo). One 1st line pt had SD (PFS = 4 mo). One 2nd line pt had SD (PFS = 7 mo) and one had PD as best response. Conclusions: NGS identifies RASa and RASa≥20in 1.5% and 0.6% of CRC, respectively. RASa≥20 tumors are MSS and, generally lack RAS/ BRAF mutations, and predict for resistance to anti-EGFR. This supports the potential relevance of 20-CN cut-point for the exclusion of pts from anti-EGFR. These findings would benefit from additional validation from retrospective analyses of completed prospective anti-EGFR clinical trials.
Impact of gender on the safety profile of chemotherapy plus bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies.
Authors: Zucchelli Gemma , Moretto Roberto , Schirripa Marta , Intini Rossana , Rossini Daniele , Santini Daniele , Pizzo Claudio , Antoniotti Carlotta , Borelli Beatrice , Marmorino Federica , Urbano Federica , Burgio Valentina , Libertini Michela , Prisciandaro Michele , Buonadonna Angela , Bustreo Sara , Allegrini Giacomo , Ricci Vincenzo , Cremolini Chiara , Falcone Alfredo
Published: May 2019

3534

Background: Based on retrospective experiences, gender seems to affect the safety profile of chemotherapy (CT), with a higher incidence of CT-related adverse events (AEs) among females than males. Here we focus on the impact of gender on the toxicity of FOLFOXIRI/bevacizumab (bev) as compared with doublets (FOLFOX or FOLFIRI)/bev in two randomized phase III studies by GONO: TRIBE and TRIBE2. Methods: The risk of experiencing CT-related AEs in males and females was estimated in univariable analysis in the overall safety population and according to treatment arms (doublets/bev and FOLFOXIRI/bev). In order to assess the independent weight of gender on the risk of developing AEs, multivariable logistic regression models were built. Results: Among 1187 patients enrolled in TRIBE and TRIBE2 studies, 1176 (684 males, 58%, and 492 females, 42%) were included in the safety population. Overall, women had a significantly higher risk of CT-related AEs, in particular gastrointestinal and hematologic AEs, asthenia and alopecia, independently of the treatment arm. The risk of CT-related AEs was increased with FOLFOXIRI/bev vs doublets/bev independently of gender (p for interaction: 0.329). Notably, among women treated with FOLFOXIRI/bev 50% and 68% experienced any grade of vomiting and nausea, respectively. Conclusions: Female mCRC patients have a higher risk to develop CT-related AEs. In women treated with FOLFOXIRI/bev the high incidence of nausea and vomiting may suggest the need for an intensification of the antiemetic prophylaxis. [Table: see text]
A randomized, double-blinded, placebo-controlled multicenter phase II trial of adjuvant immunotherapy with tecemotide (L-BLP25) after R0/R1 hepatic colorectal cancer metastasectomy (LICC): Final results.
Authors: Schimanski Carl Christoph , Kasper Stefan , Hegewisch-Becker Susanna , Schroeder Jan , Overkamp Friedrich , Kullmann Frank , Bechstein Wolf Otto , Voehringer Matthias , Oellinger Robert , Lordick Florian , Heinemann Volker , Geissler Michael , Schulz-Abelius Armin , Linz Bernhard , Bernhard Helga , Schoen Michael R. , Greil Richard , Smith-Machnow Victoria , Schmidtmann Irene , Moehler Markus Hermann
Published: May 2019

3537

Background: Hepatic metastasectomy is the only potential curative treatment option for stage IV colorectal cancer (CRC) limited to liver metastases (LM). After R0 resection of LM the high recurrence rate remains a major challenge. L-BLP25 is an antigen-specific cancer vaccine targeting mucin 1 (MUC1). The LICC trial aimed to improve survival outcome in mCRC patients (pts) after R0/R1 LM resection. Methods: This LICC trial, a binational, multicenter, double-blinded, placebo controlled phase II trial, included pts with stage IV LM limited CRC after resection of primary tumor and LM (R0/R1) within the last 8 weeks, ECOG 0/1 and adequate organ function. Pts were 2:1 randomized to receive L-BLP25 or placebo. L-BLP25 930 µg was administered as 8 weekly subcutaneous doses followed by 6 week maintenance intervals until recurrence or a maximum of 2 years. Cyclophosphamide 300 mg/m2 (CP) or matching saline (NS) was given intravenously 3 days prior to first L-BLP25/placebo. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS), secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. Differences in RFS and OS were analyzed with exploratory log-rank tests on the intention-to-treat population. Results: Of 121 pts enrolled between Oct 2011 and Dec 2014, 79 pts received L-BLP25+CP, 42 placebo+NS. Baseline characteristics were well balanced. Median age was 60 years. Median RFS was 6.1 (90% CI: 5.8-8.8) vs. 11.4 months (90% CI: 5.0-20.3) and estimated 3-year OS rate 69.1% vs. 79.1% for L-BLP25 and placebo, respectively. Two-factorial Cox regression models showed no impact of MUC1 expression or treatment on RFS or OS. The most common L-BLP25-related grade 3/4 adverse events were diarrhea, anemia and back pain. There was one death in the L-BLP25 arm due to Merkel cell carcinoma assessed by the investigator as being potentially related to vaccination. Conclusions: The LICC trial failed to meet its primary endpoint of significantly improving RFS and OS with L-BLP25. MUC1 expression was not associated with outcome. Clinical trial information: NCT01462513.
Genetic variants in RNA binding protein (RBP) to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3, TRIBE, and MAVERICC trials.
Authors: Arai Hiroyuki , Cao Shu , Loupakis Fotios , Stintzing Sebastian , Tokunaga Ryuma , Battaglin Francesca , Lo Jae Ho , Soni Shivani , Zhang Wu , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M , Weisenberger Daniel J , Liang Gangning , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz-Josef
Published: May 2019

3545

Background: RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by stabilizing or destabilizing target messenger RNA. Although alteration of RBPs affects many steps of cancer development, its clinical implication in mCRC remains unclear. Methods: We analyzed data from mCRC patients (pts) enrolled in three first-line randomized trials (FIRE-3, TRIBE, and MAVERICC). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 30 SNPs in 10 RBP genes (MSI1, MSI2, ELAVL1, RBM3, LIN28A, LIN28B, IGF2BP1, IGF2BP2, IGF2BP3, ZFP36) were tested on association with progression-free survival (PFS) and overall survival (OS). To evaluate prognostic effects and heterogeneities across treatment arms, meta-analysis approach using the METASOFT software was conducted. We also tested interaction between each SNP and treatment within each trial, i.e. FIRE-3 cohort (FOLFIRI+cetuximab (Cet) vs FOLFIRI+bevacizumab (Bev)) and MAVERICC cohort (FOLFIRI+Bev vs FOLFOX6+Bev). For multiple testing, p values were adjusted by the false discovery rate (FDR) method. Results: A total of 884 pts’ SNPs data were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 324). Meta-analysis combining three trials showed RBM3 rs926152 (adjusted p = 0.045) and RBM3 rs2249585 (adjusted p = 0.016) were significantly prognostic for PFS. Whereas, in terms of OS, only LIN28B rs314277 (adjusted p = 0.045) was significant, and RBM3 rs926152 (adjusted p = 0.057) and RBM3 rs2249585 (adjusted p = 0.059) had a trend. Interaction test showed several SNPs were potentially predictive (raw p < 0.05), although without any significance after FDR adjustment: in FIRE-3 cohort, MSI2 rs1822381, RBM3 rs926152, LIN28B rs221635, IGF2BP1 rs2969 for OS; in MAVERICC cohort, MSI1 rs1179442 and MSI2 rs3826301 for OS, ELAVL1 rs4804244 for PFS. Conclusions: Our results indicate prognostic potential of SNPs in RBP genes, such as RBM3 and LIN28B, in mCRC. However, we find no distinct evidence that these SNPs can predict differential effect between Cet and Bev, or between oxaliplatin- and irinotecan-based chemotherapy.
Modulation of autophagy: A phase II study of vorinostat (VOR) plus hydroxychloroquine (HCQ) vs regorafenib (RGF) in chemo-refractory metastatic colorectal cancer (mCRC).
Authors: Arora Sukeshi Patel , Tenner Laura LaNiel , Sarantopoulos John , Morris Jay Larry , Longoria Lisa , Liu Qianqian , Michalek Joel , Mahalingam Devalingam
Published: May 2019

3551

Background: Agents targeting the angiogenic pathway have been a cornerstone therapy in mCRC. In chemo-refractory mCRC, RGF, an oral multikinase inhibitor with considerable angiogenic inhibition, has shown modest effects on survival. We reported that autophagy modulation using the autophagy inhibitor, HCQ, enhances the anti-cancer activity of the histone deacetylase inhibitor, VOR, via ubiquitinated protein accumulation in CRC. A phase 1b study confirmed VOR/HCQ is active and tolerated in refractory mCRC. We conducted a prospective randomized study to evaluate efficacy of VOR/HCQ vs RGF in mCRC patients (NCT02316340) and report a planned interim analysis. Methods: Randomized, controlled trial of VOR 400 mg and HCQ 600 mg PO daily vs RGF 160 mg PO daily (3 weeks on, 1 week off), Q4weeks, in advanced CRC patients. Crossover was optional after first progression. A total of 76 patients are planned. Primary endpoint: mPFS. Secondary endpoints: mOS; adverse events (NCI-CTCAEv3.0); PD analysis: 27-plex Human Cytokine Array, NGS analysis (Guardant Health) on cell-free, ctDNA. Results: At interim analysis, n = 42 patients enrolled from 2/2015-10/2017: n = 20 VOR/HCQ (5 crossed to RGF), n = 22 RGF (13 crossed to VOR/HCQ). 38 patients evaluable (at least C1 completed). Median age 58.4, 40% NH vs 60% H. mPFS on first arm: 1.90 mo VOR/HCQ vs 4.35 mo RGF [p = 0.032, HR: 2.277]. mOS: 6.77 mo VOR/HCQ vs 7.23 mo RGF [p = 0.90, HR: 1.05]. Grade 3/4 AEs (see table). In both arms, there was trend towards decreased IL-1b, IL-2, IL-6, IL-10, TNFα, IFNγ but an increase in GM-CSF after treatment. Responders (4+ cycles) had lower baseline MaxMAF versus nonresponders for both arms. In responders, there was trend toward a decrease in MaxMAF at C2 and then increase at progression. Conclusions: VOR/HCQ did not improve survival when compared to RGF. VOR/HCQ has a favorable safety profile, but further planned subgroup analysis is pending to identify biomarkers of efficacy in responders. Clinical trial information: NCT02316340. [Table: see text]
Aggressiveness of care and overall survival in young metastatic colorectal cancer patients.
Authors: Fish Madeleine , Kanter Katie , Mauri Gianluca , Horick Nora , Allen Jill N , Blaszkowsky Lawrence Scott , Clark Jeffrey William , Ryan David P. , Nipp Ryan David , Giantonio Bruce J. , Goyal Lipika , Murphy Janet E. , Roeland Eric , Weekes Colin D. , Wo Jennifer Yon-Li , Hong Theodore S. , Zhu Andrew X. , Van Seventer Emily E. , Corcoran Ryan Bruce , Parikh Aparna Raj
Published: May 2019

3563

Background: Colorectal cancer (CRC) incidence in patients younger than 50 years of age is steadily rising by 2% annually. Early-onset CRC usually presents with more aggressive features; however, data on prognosis are widely conflicting. Clinicians may hold an age-related bias in treating younger patients, but this proclivity and its effects have not been quantified. Methods: Patients with a history of metastatic CRC who consented to a departmental chart review protocol were collected between 2014 and 2018 at Massachusetts General Hospital. The cohort was divided into two groups based on age at initial diagnosis: < 50 and ≥50. Data were gathered on treatments and clinicopathological features. A log-rank test compared survival from the diagnosis of metastatic disease between age groups. The distributions of clinicopathological features were compared using Wilcoxon rank sum tests. Results: 464 metastatic CRC patients were identified. 155 patients (33%) were < 50 (median age 43, 49% female) and 309 patients (67%) were ≥50 (median age 61, 45% female). Sex did not significantly differ between the two groups (p = 0.45). Patients < 50 received more lines of therapy after metastatic diagnosis than patients ≥50 (mean 2.7 v. 2.2; p = 0.002). Younger patients also received more resections of distant metastases (mean 0.62 v. 0.48; p = 0.01). A higher rate of enrollment in clinical trials for patients < 50 approached significance (p = 0.06). Even so, patients < 50 did not see a significant survival benefit over older patients (2/5-year survival from metastatic diagnosis 77%/47% v. 73%/38%, p = 0.23). Patients < 50 had a lower proportion of right-sided tumors (p = 0.0002) and BRAF mutations (p = 0.0009). There was no difference in MSI status (p = 0.28), RAS mutational status (p = 0.40), mucinous features (p = 0.53), or signet ring features (p = 0.26). Conclusions: Overall survival in patients < 50 is similar to patients ≥50, despite patients < 50 receiving more aggressive therapy. Further study is warranted to better understand these differences. Potential areas of interest include performance status, age-related treatment bias, and biological factors.