tbuckley/cabot-search huggingface dataset:
Survival impact of KRAS mutation in metastatic colorectal cancer (mCCR) under first-line treatment.
Authors: Maria Cecilia Mathias, Felippe Lazar Neto, Mariana Carvalho Gouveia, Lucas Stangler, Mateus Zapparoli Claro, Evandro Sobroza de Mello, Jorge Sabbaga, Maria Ignez Braghiroli, Camila M Venchiarutti Moniz, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2024)

3547 Background: Activating mutations in the MAPK pathway are predictive biomarkers in mCCR and 50% of patients (pts) present KRAS mutations. There is a large spectrum of molecular aberrations with a lack of data regarding tumor side correlations and their impact on treatment response and overall survival. Methods: Retrospective cohort of mCRC pts and KRAS activating mutations treated between 2019-2022 in a tertiary cancer center in Brazil. KRAS gene was analyzed by next-generation sequencing in tumor tissue samples. Electronic medical records were reviewed with case report forms registered in RedCap software. The primary endpoint was Overall survival (OS), estimated using Kaplan-Meir and compared with the log-rank test. Cox proportional models were applied to estimate hazard ratios (HR). Results: We included 490 patients with a mean age of 59 years (y), mostly male, 51.4%. Primary left-side location was present in 65.5% and liver metastasis in 66.7%. The spectrum of KRAS mutations found were G12D (31.2%), G12V (20.2%), G13D (15.1%), G12C (9.4%), G12A (4.9%), G12S (3.5%), and G12R (2%). First line regimen was 5-FU and Oxaliplatin (mFLOX) in 84.9% (n=388), with a median PFS of 9.2 months (95%CI 7.8 - 11.6) and OS of 21 months (95%CI;19-23) in this group. Treatment related outcomes in first-line therapy at first evaluation were 40% partial response, 20.4% stable disease, 30,9% disease progression and 1.3% complete response. G12S mutation was associated with better PFS 18.62 vs. 8.75m compared with other codon mutations (HR:0.52;95%CI 0.28-0.98) and OS NR vs. 21.58m HR (HR:0.48;95%CI;0.24-0.97). G12R was associated with worse PFS 5.31 vs. 9.90 m (HR:2.2;95%CI;1.09-4.47) and OS 17.89 vs. 21.88m (HR:1.61;0.79-3.24). Sideness was not associated with prolonged response or overall survival right-sided tumors 20.72 vs. vs. left-sided tumors 22.14m (HR:1.04;95%CI;0.82-1.31). Conclusions: Specific mutated codons in the KRAS gene impact PFS and OS independently of primary tumor sidedness. G12S mutation demonstrated an improved OS and PFS. [Table: see text]
Impact of delirium on outcomes among hospitalized patients with colorectal cancer: A United States population-based cohort study.
Authors: Yajur Arya, Arshi Syal, Carlo Casipit, Bruce Adrian Casipit, Akshay Ratnani, John Charles Leighton, Claudia M. Dourado
Journal: Journal of Clinical Oncology (2024)

e15524 Background: Delirium is commonly encountered among hospitalized patients. It leads to cognitive and functional decline, resulting in longer recovery time. Patients with cancer, especially those undergoing surgery, are at higher risk for delirium and its adverse effects. Our study aims to explore the impact of delirium on hospitalized patients with colorectal cancer. Methods: We utilized the 2020 National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified patients with colorectal cancer and delirium using appropriate ICD-10 diagnostic codes. We stratified patients with colorectal cancer based on the presence or absence of delirium. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of &lt; 0.05 was considered statistically significant. The aim of this study was to investigate the impact of delirium on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charge among hospitalized patients with colorectal cancer. Results: We identified a total of 77130 hospitalized patients with colorectal cancer, of which 1.91% (1475/77130) had concomitant delirium. The overall in-hospital mortality among patients with colorectal cancer was 2.74% (2115/77130). Among those with concomitant delirium, the mortality rate was significantly higher at 10.51% (155/1475, p &lt; 0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, delirium was found to be an independent predictor of increased in-hospital mortality (adjusted OR 3.34; 95% (confidence interval [CI], 2.05-5.42; p &lt; 0.001), longer LOS (coefficient 4.72; CI 3.26-6.18; p &lt; 0.001), and higher total hospitalization charge (coefficient $36247; CI $22123- $50371; p &lt; 0.001). Conclusions: Our analysis showed that delirium significantly worsens outcomes, including increased in-hospital mortality, LOS, and cost of healthcare utilization among hospitalized patients with colorectal cancer. Efforts should be made to prevent and proactively manage delirium in the inpatient setting, particularly with non-pharmacological techniques. Further prospective studies are needed to better describe these associations.
Fruquintinib plus capecitabine versus capecitabine as first-line maintenance treatment of metastatic colorectal cancer (mCRC): Update results from the randomized, controlled, phase Ib/II study.
Authors: Wenhua Li, Jinjia Chang, Chenchen Wang, Junjie Peng
Journal: Journal of Clinical Oncology (2024)

3567 Background: Capecitabine (Cap) is a standard first-line maintenance treatment option for colorectal cancer. Fuquinitinib (Fru) is a highly selective small molecule tyrosine kinase inhibitor that inhibits VEGFR1/2/3, which has been approved by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and has recommended by NCCN guidelines as a standard treatment. Preliminary research results found that adding Fru to Cap as maintenance treatment was safe and improved progression-free survival (PFS, primary endpoint) for mCRC patients (pts). Methods: Eligible pts had been confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m 2 , p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was PFS 1 (defined as time from randomization to disease progression or death). Secondary were PFS 2 (defined as time from first time receiving 1L treatment to disease progression or death), ORR and DCR. Results: At data cutoff (Jan 23, 2024), 46 pts were enrolled and 38 pts who had at least one tumor assessment post treatment were randomly assigned in Fru plus Cap arm (n=20) and Cap arm (n=18). Of these pts, the median age was 59.5 (39-78) and 58.5 (32-75) years, 11 (55.0%) and 10 (55.6%) had left-sided tumors, respectively. Most pts had previously received bevacizumab therapy (65.0% /66.7%) or cetuximab (30% /22.2%). The median cycles of first-line treatment were 8 (5-12) and 8 (4-13), 8 (40.0%) and 8 (44.4%) achieved PR in the pts who had received first-line therapy, respectively. The median PFS 1 was 9.2 mo in Fru plus Cap arm and 3.1 mo in Cap arm (HR=0.385 [95% CI: 0.163 - 0.906], p=0.024). And PFS 2 was also significantly prolonged in Fru plus Cap vs Cap (16.8 vs 8.5 mo, HR=0.314 [95% CI: 0.125 - 0.788], p=0.0098). Consistently, ORR (15.0% vs 5.6%) and DCR (80% vs 55.6%) were improved in Fru plus Cap arm. The safety was similar to the previous results without new safety signals appearing. Conclusions: PFS was significantly prolonged and ORR was improved in mCRC pts treated with Fru plus Cap as first-line maintenance treatment. This trial is ongoing and updated data will be presented in the future. Clinical trial information: NCT05451719 .
The role of metastasectomy in patients with early onset metastatic colorectal cancer.
Authors: Andrea Pretta, Pina Ziranu, Eleonora Perissinotto, Raimondo Scalia, Federica Marmorino, Maria Caterina De Grandis, Paolo Ciracì, Alessandra Russo, Krisida Cerma, Chiara Cavalli, Anna Chiaramonte, Ada Taravella, Riccardo Giampieri, Rossana Berardi, Sara Lonardi, Francesca Bergamo, Filippo Pietrantonio, Chiara Cremolini, Mario Scartozzi
Journal: Journal of Clinical Oncology (2024)

3541 Background: According to the literature, metastasectomies in colorectal cancer patients can lead to a significant increase in outcomes. However, the behavior of early-onset CRC (EO-CRC), which refers to cancer occurring in adults between 18 and 49 years, when subjected to metastasectomy, remains unclear. Clinical and prognostic data on this setting are limited and conflicting. Our study aimed to evaluate clinical, prognostic, and molecular differences in early-onset colorectal cancer (EO-CRC) patients undergoing metastasectomy to identify potentially relevant differences compared to a control group of late-onset CRC (LO-CRC). Methods: We retrospectively collected data from 1123 metastatic colorectal cancer patients from 5 different Italian Institutions. 673 (59.9%) EO-CRC and 450 (40.1%) LO-CRC as a control group. All patients had one or more metastatic sites, molecular profiling available (including RAS, BRAF, and MSI status), and underwent at least one line of treatment for metastatic disease. The main objective of the study was to evaluate clinical outcomes for the EO-CRC patients undergoing metastasectomy in comparison to patients included in the control group according to molecular profile. Results: In the EO-CRC group, the median age was 44.1 (20.0-50.9), while in the control group, it was 64.4 (51.0-86.2). Among EO-CRCs patients, 388 out of 673 (57.6%) underwent metastasectomy, whereas, in LO-CRCs patients, only 181 out of 450 (40.2%) had the procedure. In the general population, patients who underwent metastasectomy demonstrated a higher median overall survival (mOS) compared to those who did not undergo the procedure. However, within the metastasectomy group, EO-CRCs patients exhibited a lower mOS compared to LO-CRCs patients (46.0 versus 60.0 months, p &lt; 0.0001). Similar results were obtained when evaluating subgroups of RAS-BRAF wild type patients (53.0 months versus 81.0 months, p &lt; 0.0001) and RAS-BRAF mutated patients (42.0 months versus 45.0 months, p &lt; 0.0001). Conclusions: Although EO-CRC patients seem more likely to undergo surgical resection for metastatic disease, our findings suggest a worse overall prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly, this seems to occur regardless of the molecular status. These observations could have a considerable impact on clinical practice and research. Further investigations will be necessary to better understand the specific clinical and molecular characteristics of this growing group of patients to better define the most appropriate therapeutic strategy.
The tumor immune microenvironment features and their prognostic value in rectal and sigmoid colon signet-ring cell carcinoma.
Authors: Yang An, Lan Su, Guole Lin, Han Chen, Yuxin Liu, Jiaolin Zhou
Journal: Journal of Clinical Oncology (2024)

3544 Background: Signet-ring cell carcinoma (SRCC) of the rectum and sigmoid colon is a rare and highly malignant challenge in clinical practice. Although high PD-1+CD8+ tumor-infiltrating lymphocyte (TIL) infiltration has been reported as a positive prognostic factor in gastric cancer, pancreatic cancer, etc., its role in colorectal SRCC remains unclear. This study aims to explore the immune landscape of colorectal SRCC and its prognostic implications. Methods: The study included 34 patients with stage II-IV SRCC of the rectum and sigmoid colon. The immune contextures of tumor tissues were characterized using multiplex immunofluorescence assays and compared with a cohort of 57 cases of stage II-IV AC. The ratio density and spatial distribution of CD3 + , CD8 + , PD-1 + , PD-L1 + cells, M1/M2 macrophages, and NK cells were quantitively analyzed in both parenchymal (p) and interstitial (i) regions. Characteristics of immune cell infiltration and their prognostic value for long-term survival were investigated in SRCC cases. Results: Compared to AC, SRCC exhibited significantly higher infiltration of CD8+ and CD3+ iTILs in the interstitial region (P=0.00024; P=0.00321, respectively) and elevated CD8+ pTILs infiltration in tumor parenchyma (P=0.041). Conversely, parenchymal infiltration of TILs co-expressing PD-1 was significantly lower in SRCC than AC (PD-1+CD8+ pTILs: P=0.00035; PD-1+CD3+ pTILs: P=5.0e-05). SRCC showed significantly lower infiltration of M1 macrophages in both parenchyma and interstitium (P=0.0035; P=5.4e-09, respectively), lower interstitial infiltration of M2 macrophages (P=1.5e-05), and a borderline lower parenchymal infiltration of M2 macrophages (P=0.0522), compared to AC. Additionally, patients with high parenchymal or interstitial infiltration of PD-1+CD8+ TILs exhibited significantly longer DFS (P=0.00024; P=0.0041, respectively) and OS (P=0.011; P=0.0044, respectively) than those with low infiltration. Multivariate analysis indicated that the level of PD-1+CD8+ pTILs infiltration is an independent prognostic factor for DFS, being independent of CEA levels and TNM stage (P = 0.018; P = 0.02, respectively). Among patients with normal CEA level or of stage II-III, high level of PD-1+CD8+ pTILs infiltration was still associated with significantly improved DFS (P&lt;0.0001; P=0.00018, respectively) and OS (P=0.00021; P&lt;0.0001, respectively). Conclusions: SRCC of rectum and sigmoid colon exhibits distinct immune profiles compared to conventional AC, characterized by higher infiltration of CD8+ and CD3+ TILs, but lower infiltration of PD-1+CD8+ TILs. The unique immune landscape in SRCC, particularly the level of PD-1+CD8+ TILs infiltration and its positive predictive value for DFS and OS, provides new perspectives for immune-based stratification and therapeutic strategies for this clinically significant cancer subtype.
Therapeutic implications of acquired high tumor mutational burden (TMB-H) after targeted therapy (TT) in metastatic colorectal cancer (mCRC).
Authors: Celine Yeh, Emily Harrold, Fergus Keane, Jenna Cohen Sinopoli, Michael Bonner Foote, Andrea Cercek, Rona Yaeger
Journal: Journal of Clinical Oncology (2024)

3542 Background: mCRC treated w/ TT can acquire a high number of mutations at progression. TMB is used as a proxy of neoantigen load for predicting benefit from immune checkpoint blockade (ICB). In TMB-H CRC, benefit to ICB is restricted to microsatellite unstable (MSI-H) hypermutated or POL-D/E ultramutated tumors. We asked whether TT can sensitize microsatellite stable (MSS) CRCs to ICB by inducing an acquired TMB-H state. Methods: We screened the MSK-IMPACT dataset for mCRC patients (pts) who received TT and underwent pre-treatment (pre-TT) and post-progression (post-TT) tissue or liquid biopsies (LBx). We included pts who received TT against EGFR, BRAF V600E, KRAS G12C, or HER2. DNA sequencing of tissue and LBx was performed w/ MSK-IMPACT and Guardant 360. MSI status was assessed with algorithms measuring somatic changes in length of repetitive sequences (e.g., MSIsensor). Due to known discrepancies between tissue TMB (tTMB) and blood TMB (bTMB), we defined acquired TMB-H as: 1) tTMB &lt;10 mut/Mb or bTMB &lt;20 mut/Mb pre-TT; 2) ≥5-fold increase in TMB post-TT; 3) tTMB ≥10 mut/Mb or bTMB ≥40 mut/Mb post-TT. Results: We identified 26 pts w/ paired samples that had been sequenced w/ determination of TMB. 4/26 (15%) met criteria for acquired TMB-H. None had detectable pathogenic mismatch repair or DNA damage repair alterations pre-TT. All 4 post-TT samples were LBx only. One pt’s tumor acquired a somatic MLH1 mutation and converted from MSS to MSI-H. In all cases, the majority of acquired mutations were subclonal w/ many at variant allele frequencies (VAF) of ≤1% (Table). After detection of acquired TMB-H, 2/4 pts received ICB. Pt 1 had RAS wild type mCRC w/ pre-TT tTMB 6.9. She received irinotecan + panitumumab for 25.8 months. Post-TT bTMB was 40.19 and met criteria for MSI-H. She received pembrolizumab and experienced clinical + radiographic progression of disease (POD) within 49 days. Pt 2 had KRASG12C-mutant mCRC w/ pre-TT bTMB 13.4 and tTMB 4.9. She received sotorasib + panitumumab for 3.2 months w/ post-TT bTMB 145.34. She received pembrolizumab + regorafenib and experienced clinical + radiographic POD within 37 days. Conclusions: In CRC, acquisition of TMB-H at progression w/ predominantly low VAF mutations suggests activation of enhanced mutagenesis due to therapeutic pressure from exposure to TT. In this context, TMB may not be an accurate reflection of tumor immunogenicity as it does not distinguish between clonal and subclonal alterations. Our data suggest that pts w/ acquired TMB-H following TT are unlikely to benefit from ICB. [Table: see text]
Identification of a patient tissue-based phosphorylation site as a biomarker for epidermal growth factor receptor (EGFR) activity in non-small cell lung cancer.
Authors: Nithya Raman, Alexander Flohr, Daniel Pohlmann, Jonathan Woodsmith, Hartmut Juhl
Journal: Journal of Clinical Oncology (2024)

3143 Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths globally. EGFR tyrosine kinase inhibitors (TKIs) have shown promise in treating NSCLC, yet resistance to these agents is common and current biomarkers rely on genetic data alone. Therefore, identifying reliable biomarkers to more comprehensively monitor EGFR activity and predict therapeutic responses is paramount. Here, we report an uncharacterized threonine phosphorylation site within core regulator of the EGFR pathway SHP2, that is strongly predictive of EGFR activity as defined by genetic mutation status that shows potential as a clinically relevant biomarker. Methods: Using DIA mass spectrometry phosphoproteomics, we could quantify &gt;20,000 phosphosites from patient normal adjacent tumor (NAT) and primary tumor tissue. We further characterized these tissues using whole genome sequencing allowing us to define the mutational status of the EGFR. Statistical analysis was undertaken across all phospho-sites that identified a single uncharacterized phospho-site as a strong predictor of EGFR kinase activity. Finally, we generated monoclonal antibodies against the phospho-peptide and tested these in patient FFPE primary tumor tissue using immunohistochemistry to correlate phosphorylation levels with EGFR activation status. Results: Our results highlight how an individual phosphosite on SHP2 closely correlates with EGFR activity as defined by genetic mutation status in patient tissue. Interestingly, we further identify a group of patients who carry wild type EGFR yet have a phospho-signal potentially indicative of high EGFR activation without genetic aberration. These results were corroborated by a phospho-site specific antibody in FFPE tissue IHC, with strong signals observed in patients with an activating EGFR mutation (n=5), and complete absence of signal in patients harboring a wild type EGFR and no detectable mass spec signal (n=5). Conclusions: Our findings suggest that this uncharacterised SHP2 phosphosite may serve as a potent biomarker for EGFR activity in NSCLC. Further validation of the monoclonal antibodies as tools for this clinically relevant biomarker is required in larger patient cohorts to elucidate the role of the phosphosite in therapy response. This novel biomarker has the potential to guide therapeutic decision-making and contribute to personalized medicine strategies for NSCLC patients.
Comprehensive characterization of <i>ERBB2</i> genomic alterations inlung cancer.
Authors: Talal El Zarif, Paul Stockhammer, Jacob Schillo, Sarah B. Goldberg, Katerina A. Politi, Michael J Grant
Journal: Journal of Clinical Oncology (2024)

3148 Background: ERBB2mutations () occur in 1-4% of non-small cell lung cancers (NSCLC). Trastuzumab-deruxtecan is FDA-approved for the treatment of metastatic ERBB2-mutant NSCLC based mostly on data from NSCLCs harboring tyrosine kinase domain (TKD) ERBB2mut. The genomic and clinical characteristics of NSCLC with ERBB2 mut beyond the TKD remain largely unexplored. Methods: Patients (pts) with NSCLCs with oncogenic ERBB2 mut and genomic tumor profiling data from the AACR Project GENIE database were included. The cohort was divided into pts with tumors harboring TKD, extracellular (ECD), or transmembrane (TMD) and juxtamembrane domain (JMD) ERBB2mut. Clinico-genomic characteristics were compared between the groups. The Kaplan-Meier method was used to estimate progression-free survival (PFS) with first-line systemic therapy, and log-rank tests were used for comparisons. Results: Of 483 pts with ERBB2-mutant NSCLC, 64% were female, 81% were White, and 13% were Asian. TKD, ECD, and TMD/JMD ERBB2 mut were identified in 362 (75%), 88 (18%), and 33 (7%) cases, respectively. Pts with ECD vs. TKD ERBB2mut tumors were more likely to be males (47% vs. 33%, p=0.03) and have tumors with squamous histology (7% vs. 1%, p&lt;0.0001). Among pts with (n=39), those with ECD vs. TKD ERBB2 mut tumors were more likely to have a history of smoking (100% vs. 42%, p = 0.02). The most common TKD, ECD, and TMD/JMD ERBB2 mut were in-frame ex20ins Y772_A775dup (n=224/362, 62%), missense S310F/Y (n=45/88, 51%), and missense V659E/D (n=10/33, 30%) mut, respectively. ECD vs. TKD ERBB2-mutant tumors harbored a distinct genomic phenotype with significantly higher median tumor mutational burden (11.1 vs. 5.2 mut/Mb, p&lt;0.003), median fraction of genome altered (0.2 vs. 0.1, p = 0.02), and rate of co-mut in EGFR (32% vs. 3.6%, p&lt;0.0001), KRAS (17% vs. 2.5%, p&lt;0.0001), STK11 (23% vs. 4.3%, p&lt;0.0001), KEAP1 (23% vs 5%, p&lt;0.0001) and SMARCA4 (19% vs 4.5%, p&lt;0.0001). Of 343 cases with ERBB2 copy number profiling, 32 (9.3%) harbored ERBB2 amplification. ERBB2-mutant NSCLCs with vs. without ERBB2amplifications had a higher frequency of TP53 co-mut (84% vs. 48%, p &lt;0.001). Of 39 pts with available clinical data, most had ECD (n=6) ERBB2 mut tumors and received first-line platinum-based chemotherapy (n=31). The presence of a co-mut in STK11 (HR 3.5, 0.4–27.4, p=0.03) and KEAP1 (HR 3.9, 0.7–20.6, p=0.002) conferred shorter PFS on first-line systemic therapy. Pts with ECD vs. TKD ERBB2 mut tumors had shorter PFS (HR 2.4, 95% CI 0.7–8.2, p=0.04). Conclusions: NSCLC tumors harboring ECD ERBB2 mut are associated with a distinct clinical and molecular phenotype and inferior outcomes with chemotherapy compared to pts with tumors harboring TKD mut. These findings enhance our understanding of disease heterogeneity in ERBB2-mutant NSCLC and may aid in optimizing treatment strategies for this unique population.