bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroOrganoSpheres as a clinically applicable precision oncology platform for the discovery of novel therapies in colorectal cancer.
Authors: Dayanidhi Divya Lakshmi , Rupprecht Gabrielle , Watlington Wylie , Mantyh John , Kim So Young , McCall Shannon J. , Somarelli Jason A. , Hsu Shiaowen David 
Published: June 2023

3592 Background: Patient-derived models of cancer, such as cell lines, patient-derived organoids, and patient-derived xenografts, are useful models of patient response in the clinic. However, these models are often not clinically applicable within the time periods necessary to inform clinical decision making, as they can take weeks to months to develop. An ideal platform using patient-derived models would be generated from a core biopsy with a subsequent drug screen within 10-14 days to minimize delay in therapy. We recently reported the development of MicroOrganoSpheres (MOS) that can be used in drug screens within 14 days of obtaining a biopsy. In the current study, we use this MOS system as precision oncology platform in colorectal cancer (CRC) to identify new therapies and predict response to therapy. Methods: CRC patient tissue samples were collected under a Duke Institutional Review Board approved protocol (Pro00089222). Resections or biopsies were mechanically and enzymatically digested to obtain a single cell suspension. Cells were then plated in Matrigel at a ratio of 20,000 cells:5 µL Matrigel to establish “mini-bulk” organoid cultures. After establishment for 5-7 days, cultures were harvested with subsequent generation of MOS at a ratio of 50 cells per MOS. After growing for 3-4 days, MOS were used for dose-response curves using oxaliplatin, SN38, and 5-Fluorouracil (5-FU) as well as high-throughput drug screens with the NCI Approved Oncology Drugs Set VI library. Results: We developed and optimized a MOS pipeline on over 50 CRC specimens, including 9 primary rectal, 35 primary CRC, 12 CRC liver metastasis, and 1 CRC lung metastasis lines with a success rate of 80% and an average of 10-21days from biopsy to MOS generation. The high success of generating CRC MOS in a clinically applicable time frame led to the next phase of the project where a total of 10 CRC MOS were tested against standard of care chemotherapy agents used in CRC (oxaliplatin, irinotecan and 5-FU) as well as the NCI Approved Oncology Drugs Set VI within 14-21days of establishment. We noted a range of sensitivity of approximately 100-fold for standard of care agents. The most sensitive drugs found in the high-throughput screen were Bortezomib, Carfilzomib, and Panobinostat and the most resistant were Gefitinib, Chlorambucil, and Procarbazine hydrochloride. Conclusions: These results demonstrate that our MOS pipeline can be used as a precision oncology platform within a clinically applicable time frame to potentially guide therapy. We are now in the process of correlating drug response in MOS to patient outcome data and these findings will be presented at the annual meeting.
VIC regimen (vemurafenib/irinotecan/cetuximab) versus bevacizumab plus chemotherapy as first-line treatment for BRAF V600E-mutated advanced colorectal cancer.
Authors: Chen Yijiao , Zhu Dexiang , Wei Ye , Xu Jianmin 
Published: June 2023

3596 Background: The need for safe and effective therapies for untreated, BRAF V600E-mutated, unresectable locally advanced or metastatic colorectal cancer remains unmet. The purpose of this study was to compare the efficacy and safety of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen versus bevacizumab plus chemotherapy as first-line setting in Asian patients. Methods: In the single-center prospective cohort study, 78 untreated, BRAF V600E-mutant, locally advanced or metastatic CRC patients were enrolled. Every two weeks, the VIC regimen and bevacizumab plus doublet or triplet chemotherapy are administered. We evaluated the objective response rate (ORR), the disease control rate (DCR), and the conversion resection rate. In progression-free survival (PFS) and overall survival, the Kaplan-Meier method was utilized (OS). Results: In the evaluable population, 32 patients received VIC regimen and 35 patients received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 68.8% versus 40.0%, P = 0.018; DCR: 100.0% versus 80.0%, P = 0.023). The VIC regimen was significantly superior to bevacizumab plus chemotherapy for PFS (median, 11.9 vs 7.9 months; hazard ratio [HR] = 0.48, 95% CI, 0.27-0.87; P = 0.012) and OS (median, 24.5 vs 14.4 months; HR = 0.36, 95% CI, 0.16-0.78; P = 0.007). In the VIC group, the conversion resection rate for liver metastases was 42.1% (8 of 19 patients), and for local CRC it was 66.7% (6 of 9 patients with initially unresectable local CRC). Rates of treatment-related adverse events of Grade 3 to 4 were 32.4% and 31.1% for the VIC regimen and bevacizumab plus chemotherapy, respectively. Conclusions: Among Asian patients with BRAF V600E-mutated advanced CRC, the VIC regimen was superior to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting. Clinical trial information: NCT05540951 .
Early tumor shrinkage (ETS) as clinical factor to select maintenance with cetuximab (cet) monotherapy in patients (pts) with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC): A secondary endpoint analysis of the ERMES study.
Authors: Orlandi Armando , Pinto Carmine , Calegari Maria Alessandra , Normanno Nicola , Maiello Evaristo , Antonuzzo Lorenzo , Bordonaro Roberto , Zampino M. Giulia , Bergamo Francesca , Tonini Giuseppe , Tamberi Stefano , Avallone Antonio , Latiano Tiziana Pia , Rosati Gerardo , Pazzola Antonio , Ballestrero Alberto , Zaniboni Alberto , Formica Vincenzo , Barone Carlo 
Published: June 2023

3603 Background: ERMES study aimed to demonstrate non-inferior PFS of maintenance with cetuximab (cet) monotherapy (arm B) compared to FOLFIRI+cet until progression (arm A) in RAS and BRAF wt mCRC pts. Although study did not meet its primary endpoint it showed better toxicity profile and OS for cet alone and comparable ORR between arms. Here we present results of ETS, a secondary endpoint. Methods: ETS was defined as ≥20% reduction of the sum of target lesions at 8 weeks from the start of treatment, and was assessed by blinded independent central review. PFS and OS were compared between ETS+ and ETS- pts according to treatment arm in the modified Per-Protocol (mPP) population. Results: 327 of 337 (97%) pts were evaluable for ETS. In arm A, no statistically significant differences were observed between ETS+ and ETS- cohort for PFS (11.9 m, 95%CI 11.28-13.19, vs 12.2 m, 95%CI 10.82-14.93; HR 1.05, 95%CI 0.73-1.50; p 0.77) and OS (30.75 m, 95%CI 25.09-37.73, vs 25.46 m, 95%CI 19.96-34.63; HR: 0.79, 95%CI 0.50-1.24; p 0.29). In arm B, a statistically significant difference was observed between ETS+ and ETS- cohort for PFS (10.62 m, 95%CI 9.86-13.09, vs 8.52 m, 95%CI 7.89-9.37; HR 0.70, 95%CI 0.49-1.00; p 0.036) and for OS (38.88 m, 95%CI 34.53-43.25, vs27.43 m, 95%CI 20.59-36.64; HR 0.60, 95%CI 0.38-0.93; p 0.019). ETS+ pts reported no statistically significant difference between arm B and arm A in terms of PFS (HR 1.12, 95%CI 0.83-1.49; p 0.43) while experiencing a better OS for arm B compared to arm A (HR 0.72, 95%CI 0.50-1.05; p 0,08). Conclusions: In pts achieving ETS, induction treatment with FOLFIRI+cet may be de-escalated to cet alone without detrimental effect on PFS, resulting in less toxicity and better OS. These data support the hypothesis that ETS might be a clinical dynamic predictor of efficacy of a less intensive maintenance strategy, allowing to plan de-escalation to cet alone after 4 months of FOLFIRI+cet induction. Clinical trial information: NCT02484833 .
Subgroup analyses of safety and efficacy by number and types of prior lines of treatment in FRESCO-2, a global phase III study of fruquintinib in patients with refractory metastatic colorectal cancer.
Authors: Dasari Arvind , Lonardi Sara , Garcia-Carbonero Rocio , Elez Elena , Yoshino Takayuki , Sobrero Alberto F. , Yao James C. , Garcia-Alfonso Pilar , Kocsis Judit , Cubillo Antonio , Sartore-Bianchi Andrea , Satoh Taroh , Randrian Violaine , Tomasek Jiri , Chong Geoff , Yang Zhao , Pallai Rajash , Carton Iris , Tabernero Josep , Eng Cathy 
Published: June 2023

3604 Background: Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC). Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, was evaluated in the global phase III FRESCO-2 study (NCT04322539) and demonstrated a clinically meaningful and statistically significant improvement in OS and PFS with a favorable safety profile. Here we report subgroup analyses of efficacy and safety by prior lines (PL) and types of anti-cancer treatment (Tx) for metastatic disease (MD). Methods: FRESCO-2 was conducted in the US, Europe, Japan & Australia, comparing F + best supportive care (BSC) with Placebo (P) + BSC. Pts were given 5 mg PO, QD, 3 wks on, 1 wk off, in a 28-day cycle. Eligible pts received prior chemotherapy, anti-VEGF, and if RAS wild type, anti-EGFR therapies; if BRAFV600E mutant or MSI-H, and appropriate targeted regimen; and had progressed on, or were intolerant to, trifluridine/tipiracil (TAS-102) and/or regorafenib (R). Subgroup (sbgrps) analyses for efficacy and safety were performed according to number of prior lines of tx (LOT) and by types of therapy. Results: A total of 691 pts were randomized; F:461 vs P:230. The median number of prior lines of anti-cancer tx for metastatic disease F vs P was 4 (2, 16) vs 4 (2, 12). F improved OS and PFS compared to P for all sbgrps and prior tx for MD, consistent with those of the ITT population (pop). (Table: OS reported by sbgrps and prior tx for MD). Occurrence of adverse events (AEs) and serious adverse events were generally balanced between F vs P and consistent across all subgroups. The most common ≥ G3 AEs in ≥5% of pts on F within majority of sbgrps were hypertension, asthenia and palmar plantar erythrodysesthesia and were consistent with the overall safety population. Additional analyses based on duration of prior anti-VEGF and last therapy prior to F will be presented at the conference. Conclusions: F demonstrated clinically meaningful improvement in OS, PFS with an acceptable safety profile across all sbgrps. These results were consistent with the effect observed in the overall population; irrespective of previous tx with anti-VEGF, anti-EGFR, TAS-102 and R further supporting F as a potential new tx option for pts with refractory mCRC. Clinical trial information: NCT04322539 . [Table: see text]
Cancer of unknown primary with gastrointestinal profiles: A distinct CUP subset.
Authors: Shah Aakash Tushar , Estrella Jeannelyn , Dasari Priyadarsini , Willett Anneleis , Allam Joelle , Higbie Victoria , Le Phat , Lee Michael Sangmin , Matamoros Aurelio , Lano Elizabeth A , Raghav Kanwal Pratap Singh , Huey Ryan W 
Published: June 2023

3606 Background: Cancer of unknown primary (CUP) with a “gastrointestinal (GI) profile” appears to be a clinically distinct subset, based on immunophenotyping, specifically staining with cytokeratins 20 (CK20) and 7 (CK7), a type I and II keratin, respectively and caudal type homeobox 2 (CDX2) protein, a transcription factor expressed in nuclei of intestinal epithelial cells. However, only a limited clinicomolecular account of this entity exists. Comprehensive profiling is needed to substantially impact personalized therapeutics and improve prognosis. Methods: We identified 401 pts evaluated at MD Anderson Cancer Center. Pts were classified into 3 cohorts based on immunohistochemistry: lower GI profile CUP (LGI-CUP), other-GI profile CUP (OGI-CUP), or non-GI CUP (NGI-CUP). A control group of known lower GI primary cancers was derived from MSK-IMPACT data (cBioPortal, 1075 patients, LGI-KP). Clinical and pathological data including molecular profiling, therapy and survival were logged. Fisher-exact test was used. Kaplan-Meier method was used to estimate overall survival (OS) and compared with log-rank test. Results: Among 748 pts, 401 (53.6%) had adequate immunostaining for analysis. Of these, 72 (18.0%), 226 (56.4%) and 103 (25.7%) were classified as LGI-CUP, OGI-CUP, and NGI-CUP, respectively. LGI-CUP were enriched for adenocarcinoma (88% v 86% v 35%, P < 0.0001) and good risk Culine score (59% v 51% v 37%, P = 0.02), compared to OGI-CUP and NGI-CUP, respectively. While NGI-CUP had greater proportions of poorly differentiated histology (91% v 55% vs 66%, P < 0.0001) and bone metastases (30% vs 7% v 24%, P = 0.0001) compared to LGI-CUP and OGI-CUP, respectively. Comparison of key mutations is shown in table. Median OS of LGI-CUP (14.6 months [95%CI: 12.0 – 17.2]) was similar to OGI-CUP (14.3 months [95%CI: 10.7 – 18.0]) and NGI-CUP (16.2 months [95%CI: 12.4 – 20.0]), P = 0.75, but significantly lower than LGI-KP cohort (28.6 months, [95%CI 24.4 – 32.7], p < 0.001). LGI-CUP was treated preferentially with fluoropyrimidine-based GI regimen [5-FU/capecitabine +/- oxaliplatin or irinotecan] (77% vs 43% v 5%) compared to OGI-CUP and NGI-CUP, respectively. However, median OS for LGI-CUP treated with 5-FU-based regimens was higher (16.0, 95%CI 13.0 – 19.0) than those treated with non-5-FU-based treatments (10.9, 95%CI 5.6 – 16.2), P = 0.002. Conclusions: LGI-CUP appears to be a molecularly distinct entity from and NGI-CUP, as well as lower GI CUP from known entities. LGI-CUP patients treated with 5-FU-based regimens appear to have improved survival. [Table: see text]
Predictive value of tumor-infiltrating lymphocyte (TIL) dynamics in the tumor microenvironment (TME) during preoperative chemoradiotherapy (CRT) on pathologic complete response (pCR) in microsatellite-stable (MSS) locally advanced rectal cancer (LARC).
Authors: Imai Mitsuho , Bando Hideaki , Tsukada Yuichiro , Kato Takeshi , Komatsu Yoshito , Uemura Mamoru , Yuki Satoshi , Taketomi Akinobu , Fujisawa Takao , Nakamura Yoshiaki , Kojima Motohiro , Koyama Shohei , Oum Chiyoon , Shin Seunghwan , Ock Chan-Young , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki 
Published: June 2023

3608 Background: Preoperative CRT followed by consolidation nivolumab before surgery showed a promising pCR rate in MSS LARC; both high PD-L1 expression and an elevated CD8+ T cell/effector regulatory T cell ratio analyzed by pre-CRT samples were independently related to high pCR rate (Bando H, Clin Cancer Res. 2022). Here, we applied AI-powered spatial TIL analysis to the VOLTAGE study to investigate whether dynamic change of TIL in TME may predict pCR in MSS LARC. Methods: The VOLTAGE study is a multicenter phase I/II study to evaluate the efficacy of CRT followed by 5 cycles of nivolumab and surgery in patients (pts) with LARC. In this study, tumor samples were obtained at multiple time points; pre-CRT (B1), post-CRT/pre-nivolumab (B2), post-3 cycles of nivolumab (B3), and surgery. In this analysis, a total of 86 H&E whole-slide images (WSI) harvested at B1 and B2 time points from all the pts enrolled in the VOLTAGE study were included in the analysis. Lunit SCOPE IO (Lunit, Republic of Korea), AI-powered H&E-WSI analyzer developed based on 16,443 WSI with pathologists' annotations, was applied to quantify TIL density in TME. Results: In a total of 43 pts, pCR rate of MSS and microsatellite instability-high (MSI-H) were 28.9% (11/38) and 60% (3/5), respectively. In MSS subgroup (n = 38), which has a higher unmet need for pCR prediction, tumor samples with pCR (n = 11) had increased TIL density in TME (tTIL) in post-CRT (B2, median [IQR] 726 [249-1607] /mm2) compared to pre-CRT (B1, 598 [366-905] /mm2), whereas those without pCR (n = 27) had decreased tTIL in post-CRT (405 [148-748] /mm2), compared to pre-CRT (B1, 748 [460-1153] /mm2). Intratumoral TIL density changes were more prominent than stromal TIL density changes in MSS tumor samples with pCR (mean fold change x17.7 vs. x1.5). MSS Pts with tTIL change from B1 to B2 (during CRT) more than x1.8 times achieved 75% (6/8) pCR rate, whereas those with tTIL change less than x1.8 had 16.7% (5/30) pCR rate (p = 0.0035). Conclusions: Change of TIL density in TME during CRT was significantly correlated with favorable clinical outcome of preoperative CRT and consolidation nivolumab, resulting in high pCR rate in MSS LARC.
Combined associations of a healthy lifestyle and body mass index on colorectal cancer recurrence and survival: A cohort study.
Authors: Barot Shabane , Rantanen Petri , Nordenvall Caroline , Lindforss Ulrik , Hallqvist Everhov Asa , Larsson Susanna , Lindblom Annika , Liljegren Annelie 
Published: June 2023

3609 Background: Colorectal cancer (CRC) risk is associated with modifiable lifestyle factors including smoking, physical inactivity, Western diet, and excess body weight. The impact of lifestyle factors on survival is less known. A cohort study was conducted to investigate the combined effects of a pre-diagnostic healthy lifestyle and body mass index (BMI) on prognosis following CRC diagnosis. Methods: Treatment and follow-up data were collected from the patient files of 1098 participants from the Swedish Colorectal cancer low-risk study cohort including stage I-III CRC patients. A healthy lifestyle and BMI (HL) score was computed using self-reported data on smoking status, physical activity, adherence to a Mediterranean diet pattern, and BMI five years before diagnosis, and divided into four categories ranging from least to most healthy. Survival analyses were performed to assess recurrence-free survival and overall survival across categories of exposure, using the Kaplan-Meier method and Cox proportional hazards model, the latter adjusted for age, sex, and educational level. Results: Among 1098 participants with stage I-III CRC, 233 (21.2%) had an HL score of 0-1 (least healthy), 354 (32.2%) HL score of 2, 357 (32.5%) HL score of 3 and 154 (14.0) HL score of 4 (most healthy). Participants missing follow-up data (n = 29) or relapsing ≤ 6 months (n = 29) were excluded from the recurrence-free survival analysis. 221 events of cancer recurrence were observed among 1040 participants during a median follow-up time of 4.3 years, and 542 deaths among 1098 participants during a median follow-up time of 6.3 years. Patients with the healthiest lifestyle had an improved recurrence-free survival (HL 4 vs HL0-1, HRadj 0.51 (95% CI 0.31-0.83) and overall survival (HL 4 vs HL 0-1, HRadj 0.52 (95% CI 0.38-0.70)). Stratifying these results for cancer stage (I-III) and tumor site (colon/rectum) did not alter estimated HR:s or 95% CI:s. Avoidance of smoking and being physically active were independently associated with improved recurrence-free survival and overall survival: non-smoking vs smoking HRadj 0.62 (95% CI 0.43-0.90), high vs low levels of physical activity HRadj 0.71 (95% CI 0.54-0-94)). Conclusions: Our study indicates that pre-diagnostic adherence to a healthy lifestyle may increase the recurrence-free and overall survival of patients with stage I-III CRC. Avoidance of smoking and being physically active were the strongest risk-reducing factors for these outcomes. [Table: see text]
Immunotherapy for localized MSI-H colorectal cancer: Characterizing endoscopic and imaging response.
Authors: Fox Daniel Aaron , Konishi Tsuyoshi , Kaur Harmeet , You Y. Nancy , Raghav Kanwal Pratap Singh , Ge Phillip S. , Messick Craig , Johnson Benny , Morris Van K. , Thomas Jane V , Shah Preksha , Bednarski Brian K. , Kopetz Scott , Chang George J. , Ludford Kaysia , Higbie Victoria , Overman Michael J. , Bhamidipati Deepak 
Published: June 2023

3610 Background: Early data suggests that immunotherapy (IO) for localized colorectal cancer (CRC) is associated with high rates of pathologic complete response (pCR) and durable remission. This study aims to characterize endoscopic, imaging, and pathological outcomes among patients who received IO for localized CRC. Methods: This was a single-institution retrospective analysis of patients with MSI-H CRC who received at least one cycle of anti-PD-1 therapy for localized (stage I-III) MSI-H CRC. Patient and tumor characteristics were obtained from the clinical record. Endoscopy reports were assessed using standardized criteria to determine response and imaging was assessed using RECIST v1.1 where applicable. Endoscopic complete response (endoCR) was characterized by flat, white scar and/or telangiectasia without residual ulcer or nodularity. Categorical variables were compared using Fisher’s exact test. Results: 37 patients who received a median of 8 cycles of pembrolizumab (n = 36) or nivolumab (n = 1) for localized CRC were identified, of which 16 (43%) had a rectal primary. 10 patients (27%) had mucinous features on pathology. The best endoscopic response was complete response (CR) in 13 of 30 (43%) patients, which was achieved after a median of 6 cycles. The rate of endoCR after ≤ 4 cycles of IO was similar to the rate of endoCR after > 4 cycles (29% vs 50%, p = 0.284). The best imaging response was CR in 6 of 32 (19%) of patients. The rate of CR on imaging after ≤ 4 cycles and > 4 cycles of IO was 6% and 36% respectively (p = 0.064). In cases where imaging and endoscopy were available (n = 24), discrepancy in best response was noted in 14 (58%) cases. The most common discrepancy was partial response on imaging when endoCR was noted (n = 6 cases). 16 patients proceeded to surgical resection (after a median of 8 cycles) of which 11 (69%) had pCR despite non-CR on either endoscopy (n = 7) or imaging (n = 9). The endoscopic reports indicating residual disease prior to surgery included findings such as ulceration, scarring, strictures, and an obstructing mass. Of 15 patients who did not proceed to surgery and had follow-up more than 6 months after completion of IO, 13 (87%) had no evidence of progression at a median follow-up of 19.3 months from IO start. Conclusions: Discrepancies between endoscopic, imaging, and pathological outcomes were frequent, indicating a need for improved clinical response criteria. Nevertheless, immunotherapy was associated with deep and durable responses in most patients with localized MSI-H CRC.