tbuckley/cabot-search huggingface dataset:
Incidence and potential prognostic implications of fibroblast growth factor receptor gene alterations and coexisting mutations in colorectal cancer.
Authors: Vivienne Lea, Stephanie Hui-Su Lim, Wei Chua, Weng Leong Ng, Bin Wang, Kate Jessica Wilkinson, Mahtab Farzin, Paul Habashy, Tara Roberts, Therese Becker, Cheok Soon Lee
Journal: Journal of Clinical Oncology (2024)

e15558 Background: The fibroblast growth factor receptor (FGFR) family comprises four tyrosine kinase receptors (FGFR1-4). FGFR1 amplification (6.3%) as well as overexpression of FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) have been demonstrated in primary colorectal cancer (CRC, incidence in brackets). The prognostic utility of testing FGFR alterations and association with response to FGFR-inhibitors are still emerging. Here, we report FGFR alteration data with clinicopathological correlations and survival outcomes from a Sydney based Local Health District in Australia. Methods: Clinicopathological data was analysed from 341 ethnically diverse patients with CRC treated at Southwestern Sydney Local Health District from 2014-2021. Next generation sequencing for point mutations, deletions, and amplifications was performed using the Qiagen 30-gene panel. Mismatch repair (MMR) status was determined using immunohistochemical staining. Demographic characteristics, histological features and survival outcomes were recorded from electronic medical records. Results: Of the 341 patients, 42 (12.3%) had FGFR alterations of which 52% were men and 48% women. 32 patients were Caucasian, 4 Middle Eastern, 5 Asian and 1 South American. Median age at diagnosis was 66 years. Of the 42 patients, FGFR1 mutations were present in 26.2%, FGFR1 amplifications in 4.7% and FGFR1 deletions in 4.7%. FGFR2 mutations were present in 16.7%, and 50% had FGFR3 mutations. One patient had concurrent FGFR1 and FGFR3 mutations. The vast majority were adenocarcinoma (81%), followed by mucinous adenocarcinoma (17%) and adenocarcinoma with neuroendocrine features (2%). 21.4% of patients with FGFR alterations had concurrent KRAS mutations, 28.6% had concurrent BRAF mutations (91.6% V600E) and MMR-deficiency was present in 19%. Median overall survival of patients with FGFR alterations was 44 months, for those who also had deficient MMR 48 months, concurrent BRAF V600E mutations 51 months and concurrent KRAS mutations 71 months. 43% (18 patients) were stage 4 at presentation. Of these 18 patients, 7 had FGFR1 mutations, 1 had a FGFR2 mutation and 10 had FGFR3 mutations. The median overall survival of patients with stage 4 disease was 11 months and those with concurrent BRAF V600E mutations 17 months. Two patients had concurrent KRAS mutations (both G12V), with median overall survival of 5.5 months and 1 patient had MMR deficiency, with an overall survival of 9 months. Conclusions: FGFR alterations were identified in 12.3% of patients with colorectal cancer in an ethnically diverse cohort in Australia. Concurrent KRAS and BRAF mutations appear to affect survival outcomes. Further multivariate analyses are underway.
Real-world impact of KRAS mutations on clinical outcomes in metastatic colorectal cancer treated with trifluridine-tipiracil in the USA.
Authors: Brian William Labadie, Cierra Birch, Carol Quayle, Emil Lou, Sandra Algaze, Joanne Xiu, Soo J Park
Journal: Journal of Clinical Oncology (2024)

e15566 Background: Defining the impact of KRAS mutation status on outcomes to standard of care treatments in metastatic colorectal cancer (mCRC) is of increasing clinical relevance. We interrogated a large real-world genomic database to further explore the association between KRAS mutations and benefit to trifluridine-tipiracil (FTD-TPI) in patients with mCRC. Methods: 19,364 patients with mCRC and known KRAS mutation status were analyzed by next-generation sequencing (NextSeq, 592 Genes; NovaSeq, whole exome sequencing (WES)) at Caris Life Sciences. Real-world overall survival (rwOS) and time on treatment (ToT) was inferred from insurance claims data and calculated from time of start of treatment with FTD-TPI to last contact and time from first to last treatment with FTD-TPI with comparison done by the Kaplan-Meier test, respectively. Chi-square test was applied where appropriate, with p-value adjusted for multiple comparisons (p &lt; 0.05). Results: 764 of 10,571 (7.2%) patients with wild-type (WT) KRAS, 768 of 6,984 (11%) with KRAS G12 mutation, and 170 of 1,809 (9.4%) with KRAS G13 mutation received FTD-TPI. Age distribution was similar among groups. Sidedness of primary site was reported in 692 (40.3%) patients; an increased proportion of right-sided tumors was observed in KRAS G12 (53.4% vs. 28.3%, p &lt; 0.0001) and G13 (56% vs 28.3%, p &lt; 0.0001) groups compared to KRAS WT. An increased proportion of TP53 mutations in KRAS WT was observed compared to KRAS G12 mutation (87% vs. 70%, p &lt; 0.0001) and KRAS G13 mutation groups (87% vs. 75%, p &lt; 0.0001). KRAS G12 mutation was associated with shorter median rwOS compared to KRAS WT (7.33 vs. 8.43 months (mo), HR 1.13 (95% CI 1.11-1.42), p = 0.041). KRAS G13 mutation was associated with similar rwOS to KRAS WT. Median ToT was shorter in patients with KRAS G12 mutations than KRAS WT (1.8 vs. 2 mo, HR of 1.22 (95% CI 1.11-1.42), p &lt; 0.001). Median ToT was longer in patients with KRAS G13 versus KRAS G12 (2.3 vs. 1.8 mo, HR 0.82 (95% CI 0.68-0.98), p = 0.032). Conclusions: To our knowledge, this is the largest primarily US-based cohort of mCRC treated with FTD-TPI to be reported. KRAS G12 mutation, but not KRAS G13 mutation, was associated with shorter rwOS and ToT compared to KRAS WT, despite enrichment of TP53 and BRAF mutations in the KRAS WT group. This finding is consistent with previously published analyses of large randomized prospective trials of FTD-TPI in mCRC and further support KRAS mutation status as a predictive biomarker in this setting. [Table: see text]
Cosmetic Changes in Eyes Induced by Over-the-Counter Nasal Spray
Authors: Yusuke Kameda, Yutaka Kaneko, Karin Ishinabe
Journal: Ophthalmology (2024)

A 47-year-old man presented with apparent changes in his eyes after using an oxymetazoline hydrochloride-containing over-the-counter nasal spray for nasal congestion. No eye drops were administered. Photographs revealed that the reduced hyperemia and upper eyelid lift occurred 10 minutes after nasal spray inhalation (A, preadministration; B, postadministration). Oxymetazoline, an alpha-adrenergic agonist that stimulates alpha-1 and alpha-2 receptors, is used in nasal sprays for nasal congestion, and eye drops for eye redness or ptosis. This case highlights the need for awareness that intranasal sprays (such as steroids) may have ocular side effects. (Magnified version of Figure A-B is available online at www.aaojournal.org).
Contrasting comprehensive genomic profiles of adenocarcinomas of the appendix in younger versus older patients.
Authors: Myera Shahnawaz, Jasmine Mitchell, Jeffrey S. Ross, Alina Basnet
Journal: Journal of Clinical Oncology (2024)

3626 Background: Adenocarcinoma of the appendix (AAC) is a rare form of intestinal malignancy that can pursue an aggressive clinical course. Little is known about the clinical and biologic features of this disease when it presents in young patients under 40. Methods: 1,840 cases of clinically advanced AAC were selected and analyzed by hybrid capture based comprehensive genomic profiles (CGP) to evaluate all classes of genomic alterations (GA). MSI high status and tumor mutation burden (TMB) were determined from sequencing results and PD-L1 was measured by immunohistochemistry (Dako 22C3). Results: 135 (7.3%) of the AAC were identified in patients of 39 years of age or younger (“younger”). The mean age of the younger patients was 32.9 years and for the 40 and over (“older”) patients it was 60.4 years. The slight female gender preponderance was higher in the older patients than the younger patients (Table). The GA per sample were similar. The younger patients had a significantly higher frequency of KRAS GA (71.1% vs 60.4%; p=.017) and TP53 GA (56.3% vs 41.3%; p=.0008). The KRAS G12C mutation frequency was similarly low in both cohorts. Targetable GA in BRAF and ERBB2 were infrequent in both groups as were GA in PIK3CA, PTEN and FBXW7. GA in the APC gene was significantly more frequent in the older patients (10.8% vs 3.7%; p=.007). Biomarkers of immune-oncology (IO) drug efficacy were infrequently identified in both groups including MSI-High status, TMB levels and PD-L1 expression. Conclusions: At a 7.3% incidence, AAC is a relatively infrequent form of gastrointestinal malignancy in young patients. The data analysis shows significant differences in the genomics found in younger and older patients suffering from this disease. These results can have a crucial impact on current and future clinical trials used to design novel treatments. Further exploration into this subject can change the overall approach and even treatment guidelines for this type of cancer. [Table: see text]
Evaluation of lipopolymer as therapeutic siRNA delivery agents in non-malignant and malignant primary cells.
Authors: Aysha Ansari, Cezary Kucharski, Mahsa Mohseni, Daniel NM Sundaram, Joseph M. Brandwein, Xiaoyan Jiang, Hasan Uludag
Journal: Journal of Clinical Oncology (2024)

e15189 Background: Targeting leukemia-driving oncogenes via short interfering RNA (siRNA) offers an alternative approach to leukemia treatment that can overcome the limitations of current therapies. Low molecular weight polyethyleneimine grafted with lipids (lipopolymers) have emerged as promising carriers for siRNA delivery to leukemia cells. Lipopolymers harboring select lipids were recently shown to downregulate target oncogene leading to significant anti-leukemic activity in both in vitro and in vivo cell line-based leukemia models. The goal of this study was to evaluate these lipopolymers in (i) PBMCs obtained from healthy donors to determine the potential impact on non-malignant cells, and (ii) primary leukemia patient cells to assess therapeutic efficacy. Methods: Target gene levels were determined by RT-qPCR and the effect of treatment on progenitor cells was assessed by measuring changes in colony forming ability. Results: At day 1 post-treatment, no changes in FLT3 mRNA levels were observed in all 6 PBMC samples with the 2 candidate lipopolymers (LeuFectB and LeuFectC) tested. Among 11 PBMC samples evaluated at day 2, only one sample showed a significant reduction in oncogene transcript levels on treatment with LeuFectB. The impact of lipopolymer/siRNA complex treatment on progenitor cells in the PBMC population was then assessed. Of the 7 PBMC samples tested, significant reduction in colony numbers was observed in one sample with LeuFectB and two samples with LeuFectC. On an average, the lipopolymer/siRNA complexes were well tolerated by normal healthy cells as changes observed in oncogene expression and colony forming ability were not consistent across the whole pool. Primary acute lymphoblastic leukemia (ALL) patient cells treated with complexes targeting STAT5A showed marked reduction in STAT5A transcript levels in 4 out of 7 samples with both the lipopolymers tested. The subsequent impact of STAT5A downregulation on the clonogenicity of leukemia stem cells was observed in the significant decrease in colony numbers seen in 3 samples (out of 8) with LeuFects. Additionally, combined downregulation of STAT5A and BCR-ABL genes in BCR-ABL+ ALL patient samples led to a notable decrease in cell proliferation and viability. Moreover,2 out of 3 acute myeloid leukemia (AML) patient samples harboring the FLT3-ITD mutation showed significant retardation in their colony forming ability on treatment with FLT3-targeting siRNA complexes. Collectively, the ALL and AML primary samples demonstrated promising preliminary results, suggesting a therapeutic effect on the stem cell population which is critical for mitigating relapse or prolonging remission. Conclusions: These findings provide further proof-of-concept for clinical translation of lipopolymer mediated siRNA therapy of leukemia, showing relative safety and selectivity of these lipopolymer/siRNA complexes.
Consensus molecular subtypes (CMS) as prognostic and predictive biomarkers of <i>RAS</i> wild-type (WT) metastatic colorectal cancer (mCRC): Pooled analysis of the randomized trials FIRE-1, FIRE-3, XELAVIRI, and PanaMa.
Authors: Arndt Stahler, Dominik Paul Modest, Sebastian Stintzing, Swantje Held, Ludwig Fischer von Weikersthal, Lothar Müller, Ullrich Graeven, Thomas Decker, Tobias Heintges, Christoph Kahl, Werner Scheithauer, Alexander Kiani, Florian Kaiser, Ingo Schwaner, Stefan Fruehauf, Meinolf Karthaus, Tanja Trarbach, Frederik Klauschen, David Horst, Volker Heinemann
Journal: Journal of Clinical Oncology (2024)

3529 Background: CMS were associated with prognostic relevance in RAS WT mCRC, while their role as predictive biomarker is debatable. We aimed to assess the predictive impact of CMS on treatment with anti-EGFR vs. anti-VEGF antibodies vs. cytotoxic treatment alone in a pooled analysis. Methods: Available CMS data (called by predictedCMS method) of the randomized controlled trials FIRE-1 (FUFIRI vs. mIrOx); FIRE-3 (FOLFIRI+ cetuximab vs. bevacizumab), XELAVIRI (sequential vs. initially combined FOLFIRI+bevacizumab) and PanaMa (FOLFOX+panitumumab followed by FU/FA +/- panitumumab) of RAS WT mCRC were included. Non-evaluable CMS were excluded. Kaplan-Meier estimated overall survival (OS) and progression-free survival (PFS). Uni- and multivariate Cox regression analysis (including all baseline characteristics) was used to calculate hazard ratio (HR) and 95% confidence interval (95% CI). Results: 1147 tumors had available CMS data and 746 (65.0%) were RAS wild-type (WT): CMS1, n=89; CMS2, n=346; CMS3, n=71; CMS4, n=240. CMS were significant prognostic biomarkers in terms of PFS (median months, CMS1, 6.7; CMS2, 11.1; CMS3, 8.1; CMS4, 10.0, P&lt;0.001) and OS (median months: CMS1, 14.8; CMS2, 28.7; CMS3, 19.5; CMS4, 26.5; P&lt;0.001). CMS remained significant in a multivariate backward elimination Cox regression analysis including all baseline characteristic variables and BRAF status with regard to PFS ( P=0.03) and OS ( P=0.04) Interaction of CMS and treatment was significant regarding OS ( P&lt;0.001) and PFS ( P=0.001). The longest OS was observed using anti-VEGF antibodies in CMS1 and anti-EGFR antibodies in CMS2 or CMS4 RAS WT tumors (Table). Conclusions: CMS were confirmed as prognostic biomarkers and might contain predictive information for the choice of anti-EGFR or anti-VEGF antibodies in RAS WT mCRC. Prospective validation remains mandatory. [Table: see text]
Updated efficacy and safety results from the phase Ib/II study of surufatinib combined with camrelizumab and chemotherapy in patients with advanced colorectal cancer.
Authors: Sheng Li, Liangjun Zhu, Xiaoyou Li, Jiayuan Huang, Jun Bao
Journal: Journal of Clinical Oncology (2024)

e15547 Background: Preclinical and clinical data have demonstrated the synergistic anti-tumor effects of surufatinib, a novel VEGFR1-3, FGFR and CSF-1R inhibitor, in combination with immune checkpoint inhibitors (ICIs)/chemotherapy. A phase Ib/II, open-label study (NCT04929652) was conducted to evaluate the efficacy and safety of surufatinib plus camrelizumab (anti-PD-1), irinotecan and GM-CSF as second-line treatment in advanced colorectal cancer (CRC). In the phase Ib part, this combination showed favorable safety and efficacy profile, which was presented at ASCO 2023 in poster format (#255). Here, we reported the updated results from the phase Ib and phase II dose escalation part together. Methods: In the phase Ib, pts with CRC received surufatinib at 250mg once daily (QD) as starting dose, in combination with fixed dose of camrelizumab (200 mg, d1), irinotecan (200 mg/m 2 , d1) and GM-CSF (5ug/kg, d2-d7), every 3 weeks (Q3W). It had been reported in phase Ib that surufatinib 300 mg QD was defined as the recommended phase 2 dose (RP2D). In phase II dose expansion part, a further 36 pts were treated with the same regimen. The primary endpoint of phase II was ORR as per RECIST 1.1. Secondary endpoints included PFS, DCR, OS and safety. Results: As of Jan 18, 2024, 30 CRC pts (median age 57) were enrolled in the study with 12 pts in the phase Ib part and 18 pts in the phase II part. 70% were male and 23% had ECOG PS 1. 24/30 (80%) pts were positive for KRAS, NRAS or BRAF mutations. Among the 30 efficacy evaluable pts, the ORR was 30.0% (95% CI 14.7–49.4; 9 PR) and DCR was 93.3% (95% CI 77.9–99.2; 28 PR+SD). Pts with RAS/BRAF mutations were more likely to achieve better responses (9 PR in 24 pts, ORR-37.5%). After a median follow-up time of 11.1 months, the median PFS was 6.34 months (95% CI 4.57-9.23) and median OS was not mature. The most common grade 1-2 treatment related adverse events (TRAEs) (≥35%) were diarrhea (70%), fatigue (40%), anemia (36.7%), proteinuria (36.7%) and nausea (36.7%). Eleven pts experienced at least one grade 3 or 4 TRAEs. Grade 3 or 4 TRAEs occurred in &gt; 1 pt included diarrhea (n = 3, 10%) and neutrophil count decreased (n = 2, 6.7%). Conclusions: Surufatinib plus camrelizumab, irinotecan and GM-CSF demonstrated promising anti-tumor activity in pts with advanced CRC, with a manageable safety profile. Expansion enrollment is ongoing and updated information will be presented. Clinical trial information: NCT04929652 .
Allele-specific <i>KRAS</i> mutations as prognostic biomarkers in mucinous adenocarcinoma of the appendix and colorectal cancer.
Authors: Moh'd M. Khushman, Hassan Mohammed Abushukair, Sanad Alhushki, Michael Iglesia, Kian-Huat Lim, Xiuli Liu, Nikolaos Trikalinos, Rama Suresh, Olivia Aranha, Patrick Grierson, Benjamin R. Tan, Katrina Sophia Pedersen
Journal: Journal of Clinical Oncology (2024)

3628 Background: Kristen rat sarcoma virus ( KRAS) mutations (MT) are reported in 40-45% of colorectal cancer (CRC), and they are associated with poor prognosis. In mucinous adenocarcinoma of the appendix (MAAP), which is often treated as CRC due to its rarity, KRAS MT are reported in &gt;50% of tumors, and they are associated with favorable prognosis. We explored whether allele-specific KRAS MT are associated with overall survival (OS) in stage IV MAAP and CRC. Methods: The cBioCancer Genomics Portal was used to obtain genomic data. The prevalence of KRAS MT and the OS associated with allele-specific KRAS MT were explored in stage IV CRC (MSK, Cancer Cell 2018 cohort) and MAAP (MSK, J Clin Oncol 2022 cohort) patients. Survival analysis was performed using the Kaplan-Meier method with log-rank test comparisons. Results: The prevalence of KRASMT in stage IV MAAP (N=149) and CRC (N=1099) was 79.8% and 44.2% respectively. The prevalence of allele-specific KRAS MT (G12D, G12V, G13D and G12C) in MAAP/CRC was 42.3% / 12.4%, 18.8% / 9%, 6.7% / 7.7% and 6% / 2.8% respectively. All other KRAS MT in MAAP/CRC were seen in 6% and 12.2% respectively. In MAAP, the median OS (mOS) in KRAS MT vs. KRAS wild-type (WT) was 147m vs. 50m (p=0.003). Compared to the mOS in KRAS WT, the mOS was 147m (p=0.004) in G12D, 74m (p=0.140) in G12V, not reached (NR) (p=0.049) in G13D and 34m (p=0.589) in G12C. In CRC, the mOS in KRAS MT vs. KRAS WT was 60m vs. 79m (p=0.012). Compared to the mOS in KRAS WT, the mOS was 58m (p=0.249) in G12D, 58m (p=0.015) in G12V, 49m (p=0.002) in G13D and 65m (p=0.437) in G12C. The mOS in MAAP vs. CRC was 50m vs. 79m (p=0.022) in KRAS WT, 147m vs. 58m (p=0.02) in G12D, 74m vs. 58m (p=0.34) in G12V, NR vs. 49m (p=0.044) in G13D and 34m vs. 65m (p=0.13) in G12C. The favorable mOS associated with G12D in MAAP remained significant after adjusting for age, grade and TP53 (p=0.028) Conclusions: KRAS MT are more common in MAAP (79.8%) than in CRC (44.2%). In contrast to CRC, KRAS MT in MAAP are associated with favorable prognosis. Allele-specific KRAS MT are associated with different mOS in MAAP and CRC. The mOS in MAAP with KRAS G12D was exceptionally favorable (147m). To our knowledge, this is the first study to explore allele-specific KRAS mutations as prognostic biomarkers in MAAP, and adds additional data to support the distinct differences between MAAP and CRC at the molecular level. [Table: see text]
Modified FOLFOXIRI plus bevacizumab as a salvage regimen for patients with refractory metastatic colorectal cancer.
Authors: Yuxuan Ou, Jianwei Zhang, Yue Cai, Huabin Hu, Xiaoyu Xie, Jiayu Ling, Yanhong Deng
Journal: Journal of Clinical Oncology (2024)

e15559 Background: The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer (mCRC) as first-line systemic treatment. However, those who progressed on standard therapies still faced the lack of optimal treatments in the third or later lines. There is a lack of data on applying triplet chemotherapy plus bevacizumab in later-line settings. We conducted a retrospective study to evaluate the efficacy and safety of modified FOLFOXIRI (mFOLFOXIRI) plus bevacizumab as a salvage regimen for patients with refractory metastatic colorectal cancer. Methods: Patients with refractory mCRC were retrospectively analyzed, who received mFOLFOXIRI plus bevacizumab in the third or later lines. The key inclusion criteria were:(1) 15-75 years old; (2) histologically confirmed mCRC; (3) treatment failure to at least two lines of treatments containing oxaliplatin, irinotecan, and 5-FU. Those with poor general condition (ECOG score &gt; 2), or continuous grade 3-4 neuropathy and allergy to oxaliplatin were excluded. The mFOLFOXIRI regimen consists of oxaliplatin 85 mg/m² intravenous infusion for 2 hours; irinotecan 150 mg/m² intravenous infusion for 90 min; following intravenous infusion of leucovorin 400 mg/m² for 2 hours then 5-FU 2400 mg/m² for 46–48 hours continuous intravenous infusion, Q2W. Bevacizumab 5 mg/kg was administered by intravenous infusion Q2W. Results: 95 patients treated between January 2020 and December 2022 were retrospectively studied. The median age at diagnosis was 50.8 years (range 23-72 years). 50.5% of the patients had previously received at least four regimens. At the last follow-up date on December 31, 2023, the objective response rate (ORR) was 11.6% (1 complete response and 10 partial responses) and the disease control rate (DCR) was 68.4% (54 stable diseases). The median progression-free survival (PFS) was 6.2 months (95% CI, 5.4-7.0) and the median OS was 13.6 months (95% CI, 12.2-14.9). The most common adverse event was neutropenia (23.2%). Grade 3-4 adverse events were reported in 37 (38.9%) patients, including neutropenia (9.5%), oxaliplatin-related allergy (7.4%), thrombocytopenia (4.2%), thrombocytopenia (4.2%), diarrhea (4.2%), anemia (3.2%), nausea (3.2%), and neuropathy (2.1%). Conclusions: Modified FOLFOXIRI plus bevacizumab is effective as a salvage regimen in patients with refractory mCRC and with an acceptable safety profile.