bluuebunny/crossref_metadata_2025 huggingface dataset:
The prognostic impact of
SLFN11
gene expression in metastatic colorectal cancer (mCRC).
Authors: Arai Hiroyuki , Yang Yan , Millstein Joshua , Ashouri Karam , Ou Fang-Shu , Innocenti Federico , Battaglin Francesca , Algaze Sandra , Soni Shivani , Zhang Wu , Venook Alan P. , Lenz Heinz-Josef
Published: January 2025

254

Background:
SLFN11 was recently identified as a dominant determinant of response to DNA-damaging anticancer agents. Several studies showed SLFN11 expression led to better sensitivity to topoisomerase inhibitors and PARP inhibitors. However, clinical evidence in mCRC has been lacking.
Methods:
Two independent cohorts (CALGB/SWOG 80405 trial and a real-world patient [Caris CODEai] cohort) were included in this study. Patients were stratified into
SLFN11
-high and -low groups based on the median
SLFN11
gene expression levels. Survival outcomes were compared between
SLFN11
-high and
SLFN11
-low in irinotecan-treated and oxaliplatin-treated patients. Median time was estimated using Kaplan-Meier method and Cox models were used for covariate adjustment. Endpoints of interest were progression-free survival (PFS) and overall survival (OS).
Results:
In the CALGB/SWOG 80405 trial cohort, 433 patients were included (110 treated with FOLFIRI-based chemotherapy and 323 treated with FOLFOX-based chemotherapy). In patients treated with FOLFIRI-based chemotherapy,
SLFN11
-low patients exhibited numerically better PFS (median PFS, 13.4 vs 11.2 months, log-rank
p
= 0.03, adjusted hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.55-1.39,
p
= 0.50) and OS (median OS, 39.6 vs 30.3 months, log-rank
p
= 0.02, adjusted HR = 0.73, 95% CI 0.46-1.16,
p
= 0.19) compared to
SLFN11
-high patients. In patients treated with FOLFOX-based chemotherapy,
SLFN11
-low patients exhibited numerically better PFS (median PFS 11.2 vs 9.8 months, log-rank
p
= 0.03, adjusted HR = 0.83, 95% CI 0.65-1.05,
p
= 0.12) and OS (31.1 vs 26.1 months, log-rank
p
= 0.07, adjusted HR = 0.84, 95% CI 0.65-1.08,
p
= 0.16) compared to
SLFN11
-high patients. No significant interaction was observed between treatment and
SLFN11
expression in terms of PFS (
p
= 0.69) and OS (
p
= 0.44). In the Caris CODEai cohort, a better OS in
SLFN11
-low patients than in
SLFN11
-high patients was observed in irinotecan-treated patients (
N
= 2906) (median OS, 25.5 vs 21.7 months, HR = 0.90, 95% CI 0.82-1.00,
p
= 0.048). However, no significant difference in OS between
SLFN11
-low and SLFN11-high was observed in oxaliplatin-treated patients (
N
= 4428) (median OS, 39.5 vs 35.8 months, HR = 0.98, 95% CI 0.90-1.06,
p
= 0.56).
Conclusions:
Low
SLFN11
expression showed a potential for better prognosis in mCRC patients receiving irinotecan- and oxaliplatin-containing chemotherapies. These findings are not consistently aligned with preclinical data and clinical evidence in other cancer types previously reported. Further investigation is warranted to better understand the biological role and clinical implication of SLFN11 in mCRC.
Acquired gene alterations potentially related to resistance to anti-HER2 therapy in HER2-positive metastatic colorectal cancer (mCRC).
Authors: Hoyek Celine , Zheng-Lin Binbin , Pirozzi Angelo , Abidoye Oluseyi , Eslinger Cody , Iida Naoko , Nakamura Yoshiaki , Ramaker Ryne , Sonbol Mohamad Bassam , Wu Christina , Borad Mitesh J. , Ahn Daniel H. , Ikeda Masafumi , Shibuki Taro , Yoshino Takayuki , Strickler John H , Bekaii-Saab Tanios S.
Published: January 2025

277

Background:
While HER2-targeted therapies benefit patients (pts) with advanced HER2-positive mCRC, the development of resistance remains inevitable. This study aims to explore the landscape and frequency of genetic alterations putatively associated with acquired resistance to anti-HER2 therapy in HER2-positive mCRC.
Methods:
In this retrospective-multicenter international study involving Mayo Clinic, Duke Cancer Center and National Cancer Center Hospital East (Japan), we descriptively compared comprehensive genomic analyses from tissue or blood samples of pts with HER2-positive CRC pre-treatment and post-treatment with HER2-targeting agents.
Results:
A total of 36 pts were included in this study. 29 (80%) had HER2-positive mCRC as confirmed by immunohistochemistry (IHC) and fluorescent in situ hybridization (ISH), the remaining pts had HER2 amplification detected on blood or tissue . 34/36 (94%) pts were administered their first anti-HER2 agent after progressing on ≥2 prior lines of treatment. The most common anti-HER2 regimen administered was trastuzumab/pertuzumab (50%, 18/36), followed by trastuzumab-tyrosine kinase inhibitors (TKIs) (tucatinib or neratinib) (30%, 11/36) and trastuzumab deruxtecan (14%, 5/36). Putative genomic mechanisms of acquired resistance were detected in 72% (26/36), while the remaining pts lacked new genomic alterations that might explain resistance to anti-HER2 therapy, suggesting alternative escape mechanisms. Acquired alterations in downstream or alternate bypass pathways were identified in 72% (26/36) of pts; most commonly in the RAS/RAF pathway and in EGFR (34.6%, 9/26 each), followed by 27% (7/26) of pts with
MET
point mutations (mts) and amplification; activating muts in PI3K/AKT and in 27% (7/26), most commonly CDK12 (60%, 4/7)
.
HER2 receptor alterations were detected in 3 pts (8.3%), all of whom received trastuzumab-tucatinib and included
HER2 L755S, HER2 V777L, HER2 D769Y, HER2 G727A
and
HER2 S310F,
which are known to cause resistance to , however, information about tucatinib resistance is not yet available. Other altered pathways included AR, RB, NOTCH and HRD. Two pts lost HER2 expression on blood and tissue NGS post anti-HER2 therapy.
Conclusions:
The emergence of resistance might be in part related to acquired alterations that constitutively activate signaling pathways parallel or downstream of HER2, bypassing HER2 inhibition. Additional histologic studies, deep mutational scanning, larger populations and correlative analysis are needed to validate these findings.
Clinical-pathologic characteristics in young patients with metastatic colorectal cancer: Experience from a specialized cancer institute in Peru.
Authors: Veramendi Cabana Eder Christian , Chaupis Acosta Stephanie Elizabeth , Calle Cindy , Sanchez Yarleque Armando MARTIN , Mejía Paola , Macetas Jackeline , Leonardo Angela , Haro Varas Juan Carlos Carlos , Paitan Amaro Victor Roman , Pacheco Cristian , Calderon Monica , Castro Oliden Victor
Published: January 2025

279

Background:
Colorectal cancer (CRC) represents the third cause of malignant neoplasm in the world and the second in terms of mortality. CRC is a major cause of cancer-related morbidity and mortality in Peru. Diagnosis at younger ages represents a challenge. In this study, we evaluated prognostic factors in patients who were metastatic at diagnosis or progressed to metastatic disease during follow-up.
Methods:
A descriptive cross-sectional study, between 2013 and 2022, 66 patients under 40 years old and stage IV at diagnosis were analyzed. Parameters evaluated were age, gender, comorbidity, performance status and stage of the disease at the diagnosis, localization, surgery undergone, systemic treatment regimen, response to first-line treatment, incidence of K-RAS, sites and number of metastases, expression of tumor predictors (CEA levels), and survival times. A multivariate analysis was conducted with factors that were considered statistically significant in the univariate analysis.
Results:
Median age was 35 years [29.25-37] and the female/male ratio was 34/32. From 66 patients at stage IV disease, 30 patients (45.5%) were right-side, 36 (54.5%) were left-side colon cancer. At the end of follow-up, 51 patients had died, and 15 survived. Overall survival (OS) was significantly better in patients older than 35 years old (p<0,05), those who underwent primary tumor surgery (p<0,001), negative perineural invasion (p<0.0045). The treatment most common was CAPOX with a median OS of 17 months (p<0.013). The multivariate analysis shows that patients who did not undergo primary surgery had worse disease-specific OS (hazard ratio, CI 2.21.95% [1.15-4.25], p< 0.018) and there was no statistical difference between chemotherapy regimens and treatment line.
Conclusions:
In young patients with metastatic CRC, Primary tumor surgery and negative perineural invasion are significant factors influencing overall survival. Patients older than 35 years and those who underwent surgery showed better survival. These findings reflect the importance of early colorectal cancer screening and improve the risk assessment.
Genetic differences in colorectal cancer across race and ethnicity.
Authors: Sha Carrie , Chen Zhengming , Qadri Fatima , Sidhom John-William , Hissong Erika , Hyun Jini , Khan Uqba , Shah Manish A.
Published: January 2025

28

Background:
Colorectal cancer (CRC) is the fourth most common cause of cancer death and cancer-related mortality is expected to increase exponentially. Ethnic minorities, in particular African Americans, have increased mortality from CRC. Although multifactorial, differences in somatic gene mutations could contribute to these racial discrepancies. Mutations in the critical oncogene KRAS are associated with worse prognosis in CRC. Recent literature suggests that in CRC patients, KRAS mutations are more frequently found in African Americans compared to Caucasians. This finding led to our hypothesis that molecular alterations across multiple races/ethnicities could explain differences in patient outcomes. This project will also inform a larger analysis using artificial intelligence learning models to predict race from tumor-specific genetic variants, as a tool to identify genetic drivers of race-specific patient outcome.
Methods:
We examined the molecular alterations in 304 patients diagnosed with CRC who had genetic testing between June 2021 and April 2023 at NYP Queens, NYP Brooklyn, and NYP Cornell. Race and ethnicity, genetic mutations, mortality, tumor location, and age, stage, and the presence of metastasis at diagnosis was collected. Patients self-identified as Non-Hispanic Black (NHB), White (NHW), Asian (NHA), American Indian (NHAI), or Hispanic, Other, or Declined. Median and interquartile range were used to summarize continuous variables, and frequency and proportion were used to summarize categorical variables. The significance of difference across ethnicity groups was tested using Kruskal-Wallis rank sum test for continuous variables and Fisher’s exact test for categorical variables. Mutational correlates of race using a multiple-instance learning artificial intelligence approach (i.e. Anaya et al., Nature Biomedical Engineering, 2023), will be presented. This method will predict race from patients' tumor-specific genetic variants, allowing us to identify specific variants and patterns predictive of race, and potential drivers of patient outcome.
Results:
Amongst the 304 CRC patients, we identified 116 NHW, 51 NHA, 40 NHB, 35 Hispanic and 1 NHAI, for a total population of 243. BRAF mutations were almost absent in NHB (2.5%) and NHA (3.9%), compared to NHW (13.8%; p=0.02). KRAS mutations were also more prevalent in underserved populations; 65.7% Hispanic, 57.5% NHB, compared with 44.8% NHW (p=0.14). We further identified substantial differences in KRAS mutations when dividing the Asian population into East Asian (62.9%) and South Asian (37.5%).
Conclusions:
We identified significant differences in key molecular drivers between ethnicities. Our findings suggest that genomic and tumor specific differences across ethnicities could in part explain differences in patient survival across these groups. Mutational correlates of race and survival using natural language processing will be presented.
Challenges in patient selection for surgical options in V600E BRAF–mutated metastatic colorectal cancer.
Authors: Maddalena Giulia , Perissinotto Eleonora , Intini Rossana , Morris Van K. , Bergamo Francesca , Newhook Timothy E. , Lonardi Sara , Kopetz Scott
Published: January 2025

280

Background:
V600E
BRAF mutated metastatic colorectal cancer (mCRC), which represents almost 10% of mCRC, is associated with a decreased disease-free interval and increased risk of recurrence compared to other mCRC molecular subtypes; however, data show wide outcome heterogeneity within this subgroup. Surgery is known to be associated with improved outcomes in patients with mCRC, particularly in those with liver-only disease. While many patients with
V600E
BRAF have very aggressive disease and never have the chance to undergo surgery, it is not clear how to navigate the clinical heterogeneity and choose patients that might benefit the most from loco-regional treatment.
Methods:
We retrospectively evaluated
V600E
BRAF mutated mCRC patients from two independent high-volume institutions (MDACC and IOV IRCCS) who underwent metastectomy from Oct 2009 to Oct 2023. Patients with MSI-H disease and those who had R2 surgery were excluded. Clinicopathological features, such as sex, age, histology, radicality and site of surgery, were collected from institutional datasets. Relapse free survival (RFS) was defined as the time from surgery to first relapse or progression. Overall survival (OS) was defined as the time from surgery to the date of death or last follow up. Survival was estimated with the Kaplan Meier method, and the Cox proportional Hazard model was adopted for survival comparison.
Results:
We collected data from 71
V600E
BRAF mutated mCRC patients (N=37 MDACC, N=34 IOV IRCCS); 49% were female, 61% had right-sided primary tumor and 62% had synchronous metastatic disease. Median age at metastatic disease diagnosis was 62 years old (IQR: 61-28). For 52% of patients, surgery was performed on liver-only disease; 35% involved the peritoneum. There were no emergency interventions. Median RFS was 7.9 months (95% CI: 5.4 – 10.5) and median OS was 39 months (95% CI: 28.8 – 51.7). No clinicopathological features, including sex, sidedness, histology, differentiation, presentation (synchronous, oligometastatic), or site of intervention, were associated with RFS. However, radicality (R1) was associated with worse RFS (HR=3.5 [95% CI: 1.8 – 6.5], p=0.0003) and OS (HR=2.7 [95%CI: 1.3 – 5.6], p=0.0122).
Conclusions:
In this retrospective evaluation of patients with
V600E
BRAF mutated mCRC who underwent metastectomy, only surgical radicality, observed in the post-operative setting, was associated with recurrence and survival outcomes. Therefore, while surgery should be evaluated whenever radical resection is feasible, the identification of patients with
V600E
BRAF mutated mCRC who might benefit the most from metastasectomy during pre-operative prognosis evaluation remains challenging.
Evaluation of CSF1R as a potential prognostic biomarker in colorectal cancer (Alliance).
Authors: Algaze Sandra , Yang Yan , Millstein Joshua , Battaglin Francesca , Soni Shivani , Mittal Pooja , Jayachandran Priya , Ashouri Karam , Arai Hiroyuki , Torres-Gonzalez Lesly , Zhang Wu , Ou Fang-Shu , Venook Alan P. , Lenz Heinz-Josef
Published: January 2025

285

Background:
Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC) outside of mismatch repair (MMR) deficient/microsatellite instability-high (MSI-H) tumors. Most CRC cases are MMR proficient /microsatellite stable and demonstrate resistance to ICIs, attributed to the tumor microenvironment. Colony Stimulating Factor 1 Receptor (CSF1R), a regulator of tumor-associated macrophages, has emerged as a potential target due to its association with poor prognosis in CRC.
Methods:
Data from 433 metastatic CRC (mCRC) patients in the CALGB/SWOG 80405 trial were analyzed. CSF1R RNA was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced. Patients were divided into tertiles of CSF1R expression (high, medium, low). Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Subgroup analyses were conducted based on liver metastases, treatment type (Bevacizumab, Cetuximab, FOLFOX, FOLFIRI), and MSI status.
Results:
Low CSF1R expression (CSF1R-L) was associated with significantly better survival outcomes. Median PFS was 12.9 months for CSF1R-L, compared to 11.2 and 9.2 months for CSF1R-M and CSF1R-H (p = 0.003). Median OS was 35.8 months for CSF1R-L versus 32.5 and 24.4 months for CSF1R-M and CSF1R-H (p = 0.00086). Stratification by liver metastases showed that CSF1R-L remained a strong prognostic factor only in patients with liver metastases. There were no significant survival differences based on CSF1R expression in bevacizumab-treated patients. However, in cetuximab-treated patients, CSF1R-L tumors had significantly longer PFS (12.9 vs 8.8 months, p = 0.037) and OS (35.8 vs 21.4 months, p = 0.002) than CSF1R-H tumors. Similarly, in FOLFOX-treated patients, CSF1R-L tumors showed longer PFS and OS (p = 0.018 and p = 0.013, respectively), and in FOLFIRI-treated patients, OS was significantly longer for CSF1R-L tumors (42.2 vs 24.7 months, p = 0.022) than CSF1R-H tumors.
Conclusions:
Our data suggests that CSF1R expression may serve as a prognostic biomarker in CRC, with lower expression potentially linked to improved survival, particularly in patients with liver metastases. These findings warrant further investigation of CSF1R as a possible prognostic and predictive biomarker, as well as a potential therapeutic target in CRC.
Clinical trial information: NCT00265850
.
Impact of inpatient palliative care on end-of-life care among patients with early-onset colorectal cancer.
Authors: Baskar Suriya , Lee Bohae R , Midha Rajiv , Grewal Udhayvir Singh
Published: January 2025

305

Background:
Palliative care has proven benefits in elderly patients with advanced cancer; however, the objective benefits of palliative care in younger patients with cancer remain under-studied. We sought to examine the impact of inpatient palliative care consultation on end-of-life (EOL) care among hospitalized patients with early-onset colorectal cancer (EO-CRC).
Methods:
This study analyzed all admissions in the National Inpatient Sample (NIS) between 2016 and 2020 for patients younger than 50 years old with a diagnosis of CRC and death during the admission. Patients with CRC were identified utilizing ICD-10 codes C18.x, C19.x, and C20.x. Patient cohorts were made based on if they received inpatient palliative care consultation (ICD-10 code Z515). We assessed these encounters for patient demographics, Charlson comorbidity index (CCI), utilization of mechanical ventilation, vasopressors or blood transfusion, and presence of a Do Not Resuscitate (DNR) order.
Results:
Among 4,060 patients with EOCRC, 2,425 (59.7%) received inpatient palliative care consultation. There was no significant difference in age or length of stay between groups. The cohort of patients who received palliative care consultation had more female patients (44.3% vs 39.8%, p=0.004) and had higher comorbidity burden measured by the CCI (8.6 vs 8.3, p<.001). Patients receiving inpatient palliative care consultation at EOL were significantly more likely to have a DNR order (83.3% vs 44.6%, p<.001) in place and less likely to receive aggressive interventions, including mechanical ventilation (20.4% vs 43.4%, p<.001), blood transfusion (14.8% vs 22.6%, p<.001), vasopressor use (6.2% vs 8.6%, p=.004), and surgical intervention (3.0% vs 7.3%, p<.001). There was no difference in chemotherapy use between cohorts (2.8% vs 2.9%, p=0.8). Admissions including palliative care consultation were also associated with significantly lower average hospital charges ($99,387 vs $131,993, p<.001).
Conclusions:
Inpatient palliative care consultation at EOL among patients with EOCRC was associated with lesser use of aggressive interventions and higher rates of DNR code status. We also noted significantly lower costs of hospitalization among patients receiving inpatient palliative care consultation at EOL. These results underscore the importance of integration of inpatient palliative care consultation among patients with EOCRC at EOL.

No PalliativeN=1635
PalliativeN=2425
p-value

Age (in years)
41.9 ± 6.1
42.1 ± 6.5
.28

CCI
8.3 ± 2.6
8.6 ± 2.3

<.001

Total Charges
131993 ± 206404
99387 ± 151864

<.001

DNR
730 (44.6%)
2020 (83.3%)

<.001

Blood transfusion
370 (22.6%)
360 (14.8%)

<.001

Mechanical ventilation
710 (43.4%)
495 (20.4%)

<.001

Vasopressor
140 (8.6%)
150 (6.2%)

.004

Chemotherapy
45 (2.8%)
70 (2.9%)
.800

Surgery
125 (7.3%)
75 (3.0%)

<.001
Effects of neighborhood deprivation index on survival in gastric cancers.
Authors: Bawek Sawyer , Ramesh Mrinalini , Catalfamo Kayla , Attwood Kristopher , Mukherjee Sarbajit
Published: January 2025

336

Background:
Previous studies have shown that living in disadvantaged neighborhoods resulted in poor outcomes in several malignancies. Neighborhood Deprivation Index (NDI) identifies key variables from 13 measures, including the following dimensions of socioeconomic (SES) status: wealth and income, education, occupation, and housing conditions. In this study, we aimed to investigate the effect of NDI among patients with gastric cancer (GC).
Methods:
We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database from 1996-2015. NDI was divided into two groups: less disadvantaged areas (NDI <60) and highly disadvantaged areas (NDI >60), respectively. Demographic and clinical characteristics were summarized by NDI groups. All associations were compared using Kruskal-Wallis and Chi-Square tests, respectively. Kaplan Meier curves were summarized by the NDI group for overall survival (OS) and disease-specific survival (DSS). All associations were compared using a log-rank test. Cox multivariate regression was performed to measure the association between NDI and OS/DSS. All analyses were conducted in RStudio v4.2.3 at a significance level of ≤ 0.05.
Results:
A total of 19,205 GC (11,137 patients with NDI<60 and 8,068 NDI>60) patients were analyzed. Disadvantaged areas (NDI>60) had a higher proportion of Black and Hispanic, single, uninsured, rural patients with later disease stage as compared to NDI <60. Median OS was 10.0 months for patients with NDI <60 versus 9.0 months for those with NDI >60 (p=0.0007). Median DSS was 12.0 months for NDI <60 and 10.0 months for NDI >60 (p=0.010). Multivariate analysis revealed that factors associated with worse OS included NDI >60 [HR 1.044, p=0.009], age (>60) [HR 1.28, p<0.001], male sex [HR 1.082, p<0.001], single marital status [HR 1.21, p<0.001], uninsured status [HR 1.13], p <0.001], advanced disease stage (III/IV) [HR 2.05, p<0.001], and higher grade [HR 1.32, p<0.001]. On the other hand, non-Hispanic Black [HR 0.98] and Hispanic [HR 0.94] race and urban location [HR 0.91, p<0.001] were associated with improved OS. Factors associated with inferior DSS included NDI >60 [HR 1.037, p=0.038], age (p<0.001), male sex [HR 1.05, p=0.005], single marital status [HR 1.15, p<0.001], advanced disease stage (III/IV) [HR 2.375, p<0.001], and advanced grade (III/IV) [HR 1.40, p<0.001). In contrast, Hispanic [HR 0.94], non-Hispanic Black [0.96], and urban location [HR 0.90, p<0.001] were associated with improved DSS.
Conclusions:
Patients from areas with higher NDI had worse OS and DSS for GC. Tailored healthcare policies that aim to improve healthcare delivery to areas with high deprivation may help improve GC outcomes.
Immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR)/microsatellite instability (MSI) non-colorectal cancers: Real world Indian data and the use of alternative dosing.
Authors: Vaddoriya Dishant , Ramaswamy Anant , Agarwala Vivek , Tiwari Priya , Talreja Vikas , Baghmar Saphalta , Sardana Shefali , Gupta Vineet Govinda , Bajpai Peyush , MV Chandrakanth , Ostwal Vikas S. , Raina Shivani , Shenoy Vallish , Bhargava Prabhat Ghanshyam , Lavingia Viraj Kiran
Published: January 2025

347

Background:
Immune checkpoint inhibitors, predominantly pembrolizumab and dostarlimab, have been approved in deficient mismatch repair (dMMR)/ microsatellite instability (MSI) non-colorectal cancers. There is also an emerging data to suggest significant clinical activity for low-dose ICIs (LD-ICIs) in these cancers.
Methods:
A multi-institutional retrospective analysis in Indian patients with dMMR/MSI-H advanced/metastatic non-colorectal carcinomas treated with ICIs (irrespective of dose or schedule) between 2017 and 2024 was conducted. The primary objective of the study was to evaluate 12-month Overall survival (OS) for the whole cohort as well as LD-ICI and standard dose ICI (SD-ICI) cohorts, while other secondary objectives included assessment of overall response rates (ORR) (assessed by RECIST v1.1 as per local radiological reporting), 12-month progression free survival (PFS) and incidence of immune related adverse events (IRAEs).
Results:
A total of 51 patients were available for analysis. The most common tumour types were gastrointestinal (64%, commonly gastric cancer, oesophageal cancer and cholangiocarcinoma) and endometrial cancers (23%). Eighty-four percent of patients received ICI monotherapy, while the remaining 16% received varying combinations of ICIs with chemotherapy and tyrosine kinase inhibitors. Nivolumab was used in 24 patients (47%) while pembrolizumab was used in 17 patients (33%). With a median follow-up of 14 months, 12-month OS was 72% and 12-month PFS was 62% in the entire cohort. The corresponding 12-months OS and 12-month PFS for those receiving SD-ICIs (n=29) was 69% and 62%, while it was 72% and 64%, respectively for the LD-ICIs cohort (n=22). The ORR was 61%, with 10 patients (20%) achieving complete response (CR) and 21 (41%) achieving partial response (PR). The most common IRAEs (all grades) were fatigue (62%), thyroid disturbances (37%), and pruritus (23%).
Conclusions:
The current study from India highlights the importance of treating non-colorectal dMMR/MSI-H cancers with ICIs and shows outcomes commensurate with published trial data. Within the confines of a small retrospective study with a short follow-up, low dose ICIs should be explored in these patients in scenarios where standard dosing schedules are not feasible due to logistic reasons. Key Words – Low dose immunotherapy; non-colorectal dMMR/MSI-H cancers; Overall survival.
Focusing on clinical trial ineligibility: Nivolumab plus chemotherapy for patients with advanced gastric cancer.
Authors: Motoo Iori , Ando Takayuki , Nakayama Yurika , Ueda Yuko , Kajiura Shinya , Ogawa Kohei , Takagi Hiroaki , Tsukada Kenichiro , Tabata Kazuhisa , Ohya Yuno , Tamura Hotaka , Hosokawa Ayumu , Yasuda Ichiro
Published: January 2025

355

Background:
Nivolumab demonstrates promising efficacy when combined with chemotherapy as first-line treatment in patients with advanced gastric cancer (AGC). However, a large proportion of patients are perceived as ineligible for clinical trials in clinical practice. The aim of this study is to analyze the treatment outcomes and safety among patients deemed ineligible in clinical trials for AGC.
Methods:
A retrospective examination was conducted involving 187 patients who received treatment for HER2-negative unresectable or recurrent AGC between December 2014 and October 2023 at six institutions. Eleven patients were excluded due to massive ascites or poor performance status (PS). Ineligible patients were defined as meeting any of the seven criteria: age 75 years or over, PS 2, bone marrow dysfunction, hepatic dysfunction, renal dysfunction, serious complications, and extended bone metastasis. Of the 104 patients meeting these criteria, individuals were divided into the ICI group (nivolumab plus chemotherapy) and the non-ICI group (chemotherapy only). A comparative assessment of survival outcomes and tumor responses between the two groups was performed. Additionally, the incidence of immune-related adverse events (irAE) in the ICI group was assessed.
Results:
The ICI group comprised 57 patients, while the non-ICI group comprised 47 patients. The median follow-up for survival analysis was 11.6 months. In the ICI group, response rate (RR), median progression-free survival (mPFS), and median overall survival (mOS) were 48.7% among patients with measurable lesions, 7.4 months (95%CI, 5.3-10.0), and 15.1 months (95%CI, 13.1-21.0). In the non-ICI group, RR, mPFS, and mOS were 33.3%, 6.4 months (95%CI, 4.1-7.8), and 11.8 months (95%CI, 10.1-14.6). The OS in the ICI group was significantly better than those in the non-ICI group (log-rank
p
= 0.0436). Furthermore, irAEs were observed in eight patients (14.0%), including hypothyroidism (n=3), arthritis (n=2), hypopituitarism (n=2), and dermatitis (n=1). No patients discontinued treatment due to intolerable irAEs.
Conclusions:
The combination of nivolumab and chemotherapy showed a favorable outcome even in AGC patients with ineligible group.
Prognosis of signet ring cell (SRC) gastric carcinoma (GC) compared with other histological subtypes.
Authors: Torosian Rafael , Nered Sergey , Kozlov Nikolay , Sun Henian , Kononets Pavel , Stilidi Ivan
Published: January 2025

357

Background:
Signet ring cell (SRC) gastric cancer (GC) has its unique clinicopathological features with poor tissue differentiation, high invasiveness, diffuse growth pattern and poor prognosis. Survival rates and clinicopathological characteristics of patients with SRC GC regardless of the stage of the disease has not been well studied.
Methods:
The retrospective analysis was undertaken of 993 patients with diagnosed gastric cancer. These patients received surgical resection in period from January 2013 to December 2018 in N.N. Blokhin National Medical Research Center of Oncology. We compared clinical and pathological features as well as prognostic factors between these groups.
Results:
For early SRC carcinoma, the median survival rates weren’t reached; 3- and 5-year survival rates were 100% and 89.0 %; for non-SRC carcinoma 91.4 and 85.3 % (HR=0.73; 95 % CI 0.22–2.42,
р
= 0.6) respectively. For locally advanced/metastatic SRC carcinoma, the median survival rates, 3- and 5-year survival rates were 38 months, 53.0 and 38.4 %; for non-SRC carcinoma 51.1 months, 59.2 and 48.0 % (HR=1.2; 95 % CI 0.91–1.54,
р
= 0.2). At univariate analysis SRC morphology was found as independent risk factor for overall survival (HR=1.19; CI 95% 0.94 – 1.50; p<0.0001). Multivariate analysis did not reveal SRC morphology to be significant and independent risk factor for overall survival (HR=1.00; CI 95% 0.72 – 1.38; p=0.98).
Conclusions:
Overall survival rates in patients with early (mucosal and submucosal tumor regardless of lymph nodes status) SRC gastric cancer did not show any significant differences in comparison with other histological types of GC. Thus, the prognosis of early SRC GC is equivalent or better than that of other histological subtypes of GC. Overall survival rates of locally advanced/metastatic SRC gastric cancer are worse than non-SRC cancer, but the differences are not statistically significant.
Incidence of mediastinal lymph node positivity in patients undergoing robotic transthoracic esophagectomy.
Authors: Meredith Kenneth Lee , Huston Jamie , Shridhar Ravi
Published: January 2025

379

Background:
Esophageal cancer is increasing in incidence worldwide. Robotic approaches have quickly become mainstream due to the improved visualization and possible increase in nodal harvest. There remains significant debate on the utility of mediastinal lymph node dissection in esophageal cancer patients. We sought to analyze the incidence of mediastinal lymph node positivity and to evaluate its impact on survival in patients with esophageal cancer undergoing robotic assisted trans-thoracic esophagectomy (RATE).
Methods:
Utilizing a prospectively maintained esophageal database, we identified patients who were diagnosed with EC and underwent RATE between 2009-2024. We then identified patients with positive lymph nodes and stratified by location (celiac or mediastinal). Baseline univariate comparisons were made for continuous variables using both the Mann-Whitney U and Kruskal Wallis tests. Pearson’s Chi-square test was used to compare categorical variables. Survival analysis was performed via Kaplain-Meier method.
Results:
We identified 201 patients who underwent RATE with a median age of 70 (41-91). There were 160 (79.6%) males and 41 (20.4%) females. The mean BMI was 26.5 ± 5.5 and mean ASA score was 3.1 ± 0.6. Adenocarcinoma was the predominate histology at 162(80.6%). Locally advanced T3/T4 tumors were identified in 53 (26.4%) patients and 63(31.3%) had clinical node + disease. Neoadjuvant therapy was utilized in 159(79.1%) patients. The median lymph nodes resected 18 (14 – 22), and length of hospitalization 8 (7 – 11) days. The 30 and 90-day mortality were 2.2% and 2.6% respectively. R0 resections was performed in 200 (99.5%) of patients and the pathologic complete response rates were 42.1%. The incidence of mediastinal lymph node positivewas 6.3% vs 76.3% abdominal. There were 17.6% of patients that had both mediastinal and abdominal lymph nodes positive. The median survival was 23 months for abdominal LN+, 19.5 months for mediastinal LN+ p=0.23. Multivariate analysis revealed that age, neoadjuvant radiation, nodal positivity were predictors of survival.
Conclusions:
The incidence of mediastinal positive lymph nodes are much higher than previously reported. Perhaps the improved visualization and manipulation of tissue with robotic approaches have enhanced our ability to resect these nodes. Mediastinal lymph node positivity is a poor prognostic factor for survival in patients undergoing robotic esophagectomy. Given these findings, we would continue to support aggressive nodal resection in patients diagnosed with esophageal cancer.
Phase II preoperative pembrolizumab for MSI high or MSS/PD-L1 gastric cancer followed by surgery and adjuvant therapy with pembrolizumab (NCT03257163): Results of a multicenter study.
Authors: Kennedy Timothy , Shah Mihir Maheshkumar , Kabarriti Rafi , Boland Patrick M , In Haejin , Chen Chunxia , Szabo Stephen M. , Hochster Howard S , Moore Dirk F. , Jabbour Salma K.
Published: January 2025

441

Background:
Data suggest that patients with tumors with microsatellite instability (MSI-H), EBV expression, or positive PD-L1 expression can benefit from immunotherapy. This trial evaluated PD-1 immunotherapy in this subset of patients with operable gastric cancer.
Methods:
We present results of a phase 2 multi-institutional clinical trial (NCT03257163). Patients with cT2-T4, N0-N3, M0 gastric adenocarcinoma with MSI-H, PDL1 CPS > 1%, or EBV+ were included. Patients received 2 cycles preop pembrolizumab 200 mg IV q3 weeks followed by surgery. Pembrolizumab was given for 16 additional cycles postoperatively, concurrently with adjuvant chemoradiation (45 Gy) and 5 cycles of capecitabine (825 mg/m2 days 1-14 during cycles 3, 6 and 7; 625 mg/m2 BID days 1-14 during cycles 4 and 5 with radiation). Patients were defined as evaluable if they received > one cycle of postop pembrolizumab. Primary endpoint is DFS, powered to detect 3-yr DFS of 70% with 89% power.
Results:
All enrolled patients received two cycles of pembrolizumab preoperatively (n=45). Eight patients did not undergo surgery (1 due to frailty, 2 with distant progression on preoperative imaging, 2 with peritoneal disease on surgical exploration and 3 with locally advanced, unresectable tumors). Six patients did not receive adjuvant therapy (2 due to surgical complications, 2 for failure to thrive, 1 refusal and 1 pending adjuvant therapy). 31 patients received adjuvant therapy and are included in the predetermined, evaluable analytic cohort. These 31 patients had a median age of 67 years (range 44 – 85) with 22.6% Hispanic, 29.0% Asian, 25.8% Black and 25.8% White. Median follow-up was 31.1 months (range 3.45-63.8). In these patients, 14 (45.2%) had MSI-H, 2 (6.5%) EBV+, and 29 (93.5%) had PDL1 expression >1% tumors. Most tumors were advanced stage with 81% ≥ cT3 and 58% cN+. In the 31 evaluable patients, the 3-year DFS was 79.4%; 3-year OS was 78.9%. For MSI-H patients, 3-year DFS was 81.8%. For patients with MSS/PD-L1+ tumors, 3-year DFS was 77.8%. For the 45-patient cohort, 3-year DFS was 70%; 3-year OS was 65%. Three patients had pCR, two with MSI-H tumors and one with PD-L1 CPS of 4%. Downstaging occurred in 62.2% of patients, and 40% of surgical specimens had pT0/T1 tumors consistent with significant pathologic responses.
Conclusions:
A biomarker-driven preoperative treatment strategy for MSI-H, EBV+, and MSS/PDL1+ operable gastric adenocarcinoma patients is promising and warrants additional evaluation. This treatment strategy is novel and effective, and it incorporates immune checkpoint immunotherapy, low dose chemotherapy, and radiation thus avoiding more intensive combination chemotherapy regimens for patients with these biomarkers.
Clinical trial information: NCT03257163
.
Preliminary results of benmelstobart plus anlotinib combined with SOX in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma with low PD-L1 expression: A single-arm, multicenter phase II clinical trial.
Authors: Jia Yong-Xu , Chang Zhiwei , Zhong Ya-Li , Cui Donghai , Han Hui-Qiong , Gao Ya-Ping , He Jian , Liu Xiao-Lei , Yan Jie , Qin Yanru
Published: January 2025

444

Background:
First-line chemotherapy for advanced HER2-negative gastric/gastroesophageal (G/GEJ) adenocarcinoma has limited efficacy. PD-1 inhibitors plus chemotherapy show promise but need improvement, especially for patients (pts) with low PD-L1 expression. Anlotinib, a multi-targeted TKI for tumor angiogenesis/proliferation, is approved in China. This study aims to evaluate the efficacy and safety of benmelstobart a PD-L1 blockade) in combination with anlotinib and SOX (S-1 plus oxaliplatin) as a first-line regimen for advanced G/GEJ adenocarcinoma in patients with low PD-L1 expression, Preliminary findings will be reported promptly.
Methods:
Pts with HER2-negative, unresectable, locally advanced, or metastatic G/GEJ adenocarcinomas and a PD-L1 Combined Positive Score (CPS) < 5, who had not received prior systemic therapy were included. They received benmelstobart (1200mg, iv, d1, q3w) combined with anlotinib (10mg, po, d1~14, q3w), oxaliplatin (130mg/m
2
, d1, iv, q3w) and S-1 (40mg, po, bid, d1~14, q3w) for 6 cycles as initial therapy. Maintenance therapy with benmelstobart (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) followed for non-progressive diseaseuntil PD or unacceptable toxicity occurred. Tumor responses were evaluated by RECIST 1.1 criteria. The target sample size was 37, with ORR as the primary endpoint, and safety, DCR, DoR, PFS, and 1-year OS rate as secondary endpoints.
Results:
From Jun 2023 to Sep 2024, 28 pts were enrolled and 27 were available for efficacy and safety evaluation. The patients’ characteristics were as follows; median age (range): 59 (38-77) years, Male/Female: 19 (70%)/8 (30%), ECOG PS 0/1: 2 (7%)/25 (93%), Surgical history yes/no: 6 (22%)/21 (78%), CPS: ＜1/ ≥1: 4 (15%)/23 (85%), respectively. In the response assessment, 19 PR (70.4%), 6 SD (22.2%), and 2 NE (7.4%) were observed, yielding an ORR of 70.4% (95% CI: 49.8-86.2) and DCR of 92.6% (95% CI: 75.7-99.1). As of September 17, 2024, 6 of 27 patients discontinued (3 due to PD, 3 voluntary), leaving 21 ongoing. The longest DoT was 15.08 months, and the median PFS was not reached. Common TEAEs ≥10% included thrombocytopenia (37%), anemia (33%), leukopenia (22%), HFS (19%), fatigue (15%), liver function abnormalities (15%), and appetite loss (11%). Grade ≥3 TEAEs were thrombocytopenia (4%) and anemia (4%).
Conclusions:
Preliminary findings indicate that the combination of benmelstobart and anlotinib with the SOX regimen as a first-line treatment for advanced G/GEJ adenocarcinoma with low PD-L1 expression demonstrates promising therapeutic efficacy and tolerable adverse events. Further validation of these results in a larger, consecutive patient population is warranted. Clinical trial information: ChiCTR2400085396.
Fruquintinib plus camrelizumab combined with paclitaxel liposome and nedaplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, phase II clinical trial.
Authors: Gu Yanhong , Qiu Tianzhu , Mingjie Lu , Dong Yuwen
Published: January 2025

445

Background:
Camrelizumab in combination with chemotherapy has become a standard of care for the first-line treatment of advanced ESCC. Previous studies have indicated synergistic effect of fruquintinib in combination with chemotherapy or immunotherapy. Hence, we conducted a phase II trial to evaluate the efficacy and safety of fruquintinib plus camrelizumab, paclitaxel liposome, and nedaplatin as a first-line therapy for advanced ESCC.
Methods:
This is a single-arm, phase II study consisting of a dose-finding and a dose-expansion phase. A total of 33~36 patients aged 18~80 years with previously untreated advanced ESCC and an ECOG PS of 0-2 were planned to be enrolled. The dose-finding phase followed a 3+3 approach in order to determine the recommended phase II dose (RP2D) of fruquintinib for dose expansion. Patients received fruquintinib (3 mg, 4 mg, and 5 mg once daily on days 1-14, starting at 4 mg) orally, plus intravenous camrelizumab 200 mg d1, paclitaxel liposome 135 mg/m
2
d1, and nedaplatin 70 mg/m
2
d1, 21 days as one cycle. A maximum of 6 cycles was conducted, followed by maintenance therapy with fruquintinib in combination with camrelizumab. The primary endpoint was objective response rate (ORR, RECIST 1.1). Secondary endpoints included RP2D, disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs).
Results:
As of August 24, 2024, 11 patients (9 males) were enrolled with a median age of 66 years (range 50-76). All patients had distant metastases, and the median number of sites of metastasis was 2 (range 1-5). In the dose-finding phase, 3 patients were treated with 4 mg of fruquintinib, and 6 patients were treated with 5 mg of fruquintinib. No dose-limiting toxicities (DLTs) were observed. Thus, the RP2D of fruquintinib was established as 5 mg once daily on days 1-14, 21 days as one cycle. Of the 7 evaluable patients, 6 achieved partial response, and 1 had stable disease. The ORR was 85.7% (95% CI 42.1%-99.6%), and the DCR was 100.0% (95% CI: 59.0%-100.0%). The median PFS was not reached. The most common treatment-related adverse events (TRAEs) were anemia (7/11), hypercholesterolemia (6/11), hypoalbuminemia (5/11), oral mucositis (5/11), hematuria (4/11), hypertension (4/11), fatigue (4/11), constipation (3/11), and neutropenia (3/11). Grade 3 TRAEs were identified in 2 patients, including oral mucositis (2/11), and anemia (1/11). No treatment-related serious adverse events (SAEs) or deaths occurred.
Conclusions:
The combination of fruquintinib, camrelizumab, paclitaxel liposome, and nedaplatin demonstrated significant efficacy and manageable toxicity profiles as a first-line treatment for advanced ESCC, suggesting a potential new treatment strategy.
Clinical trial information: NCT06010212
.
Tislelizumab (Tisle) combined with POFI (irinotecan, paclitaxel, oxaliplatin and 5-FU/levoleucovorin) as first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC): OS analysis results of the SYLT-023.
Authors: Su Liyu , Ye Zaisheng - , Zhuo Changhua , Wei Shenghong - , Li Zhixiong , Zhao Shen , Lin Rongbo
Published: January 2025

450

Background:
Tisle is an anti-PD-1 antibody. The combination of Tisle + XELOX/FP is a first-line treatment of AGC in China. Both irinotecan and paclitaxel have also shown antitumor activity in AGC. In this phase I/II study, we explore the safety, tolerability, and efficacy of Tisle + POFI as first-line treatment of HER-2 negative, pMMR AGC.
Methods:
In a phase I dose finding study using a standard 3+3 design, subjects received four escalating dose levels (dl) of irinotecan/paclitaxel (mg/m
2
): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tisle 200 mg plus oxaliplatin 85 mg/m
2
, levoleucovorin 200 mg/m
2
, and 5-FU 2400 mg/m
2
for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and RP2D.
Results:
Fifteen subjects with treatment naïve AGC were enrolled (3 each in dl #1, dl #2, and dl #3 and 6 in dl #4). The median age was 65 years (range 36-72); 80% were male. Two subjects (13.3%) were diagnosed with GE junction cancer, 11 (73.3%) had undifferentiated disease, and 5 (33.3%) had liver metastasis. PD-L1 CPS scores were: 5 (n=5); 1 (n=1); and 0 (n=9). All subjects were evaluated for DLT. One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. As of 18th Sep 2024, confirmed objective response rate in 13 subjects with measurable disease was 100% (1 CR, 12 PR) per RECIST 1.1. Of the 2 subjects with non-measurable disease, one was a CR and the other was non-CR/non-PD. The median PFS was 10.51 (95% CI: 7.44, 13.58) months (versus 6.9 [5.7-7.2] months for ITT population for RATIONALE 305, ESMO 2023), the median DOR was 7.39 (95% CI: 5.34, 9.44) months, and the median OS was 14.75 (95% CI: 5.48, 24.02) months. The OS showed no significant differences between CPS ≥ 1 and CPS < 1. All subjects (100%) had AEs. Seven (n=7, 46.67%) of the 15 subjects reported grade ≥3 AEs, including neutropenia (n=7; 46.67%), leukopenia (n=3; 20%), anemia (n=2; 13.33%).
Conclusions:
Tisle+POFI was well tolerated and showed preliminary antitumor activity in AGC. A phase II study is ongoing.
Clinical trial information: NCT05319639
.