tbuckley/cabot-search huggingface dataset:
Impact of PD-L1 expression on survival in patients with unresectable/recurrent gastric cancer receiving first-line chemotherapy without immune checkpoint inhibitors.
Authors: Hidekazu Hirano, Yasuhide Yamada, Kengo Nagashima, Nobuyoshi Hiraoka, Shigeki Sekine, Naoki Takahashi, Mizutomo Azuma, Satoru Iwasa, Keisuke Kanato, Nozomu Machida, Takahiro Kinoshita, Hiroaki Hata, Hisato Kawakami, Daisuke Takahari, Toshiyasu Ojima, Shigenori Kadowaki, Narikazu Boku, Yukinori Kurokawa, Masanori Terashima, Takaki Yoshikawa
Journal: Journal of Clinical Oncology (2024)

391 Background: Although high PD-L1 expression predicts a favorable response of advanced solid tumors to immune checkpoint inhibitors (ICIs), its impact on survival in patients with unresectable/recurrent gastric cancer (GC) has remained unclear. We investigated the prognostic value of PD-L1 expression for survival in unresectable/recurrent GC patients receiving first-line chemotherapy without ICIs. Methods: JCOG1013, a phase 3 randomized trial, demonstrated the addition of docetaxel to cisplatin and S-1 as first-line chemotherapy was of no benefit to patients with unresectable/recurrent GC (N=741) either for overall survival (OS) or progression-free survival (PFS). Tumor specimens prior to chemotherapy were collected for assessing PD-L1 expression for this ancillary study. PD-L1 expression was determined using immunohistochemistry (Dako, 28-8 pharmDx) and used to derive the PD-L1 combined positive score (CPS) and PD-L1 tumor proportion score (TPS). As with the CheckMate 649 study, the cutoff values for PD-L1 CPS and PD-L1 TPS were set at 5 and 1%, respectively. Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of PD-L1 CPS and PD-L1 TPS as predictors of OS and PFS. All p values were 2-sided; values &lt;0.05 were considered statistically significant. Results: We analyzed 427 patients with unresectable/recurrent GC. The prevalence of PD-L1 CPS≥5, and PD-L1 TPS≥1% was 33% and 24%, respectively. There was no significant difference in OS and PFS between the PD-L1 CPS ≥5 group and the PD-L1 CPS &lt;5 group (Table). The PD-L1 TPS ≥1% group had superior OS and PFS compared to the PD-L1 TPS &lt;1% group (Table). In multivariable analyses for OS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (hazard ratio (HR) = 0.64 [95% CI: 0.50–0.83], p&lt;0.001), but PD-L1 CPS≥5 was not (HR = 0.82 [95% CI: 0.65–1.02], p = 0.073). In multivariable analyses for PFS, PD-L1 TPS ≥1% was a significant favorable prognostic factor (HR = 0.67 [95% CI: 0.52–0.84], p&lt;0.001), but PD-L1 CPS≥5 was not (HR = 0.83 [95% CI: 0.67–1.03], p = 0.090). Conclusions: PD-L1 TPS≥1% is significantly correlated with longer OS and PFS in patients with unresectable/recurrent GC receiving first-line chemotherapy without ICIs. PD-L1 TPS should be considered as a stratification factor in randomized clinical trials for unresectable/recurrent GC. Clinical trial information: UMIN000007652 . [Table: see text]
Correlation between postoperative systemic inflammatory response and prognosis in patients with advanced gastric cancer.
Authors: Kenji Kuroda, Takahiro Toyokawa, Yuichiro Miki, Mami Yoshii, Hiroaki Kasashima, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Shigeru Lee, Masakazu Yashiro, Kiyoshi Maeda
Journal: Journal of Clinical Oncology (2024)

411 Background: Several studies have shown that postoperative infectious complications correlate with poor prognosis in various malignancies, but the prognostic significance of the postoperative inflammatory response in patients with gastric cancer remains unclear. The aim of study was to examine whether the systemic inflammatory response present in the early phase of the postoperative state correlates with long-term outcomes and to identify markers in patients with advanced gastric cancer. We evaluated C-reactive protein (CRP) and white blood cell (WBC) count as simple and versatile markers of postoperative systemic inflammation in clinical practice that may be suitable for detecting the magnitude of inflammatory reaction. Methods: This study retrospectively reviewed 444 patients who underwent radical gastrectomy for stage II/III gastric cancer. We evaluated maximum serum C-reactive protein (CRPmax) and white blood cell count (WBCmax), defined as the maximum serum CRP level and maximum WBC count during the interval from surgery until discharge, as systemic inflammation markers. Results: In univariate analyses, CRPmax, WBCmax and infectious complications were significantly associated with both overall survival (OS) (p&lt;0.001, p&lt;0.001 and p=0.011, respectively) and relapse-free survival (RFS) (p&lt;0.001, p=0.001 and p&lt;0.001, respectively). Multivariate analysis revealed that high CRPmax (&gt;9.2 mg/dL) was an independent prognostic factor for OS (hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.18–2.42, p=0.004) and RFS (HR 1.42, 95%CI 1.02–1.98, p=0.038), while WBCmax and infectious complications were not. Regarding the pattern of recurrence, hematogenous recurrence was significantly more frequent in the high-CRPmax group (16.7%) than in the low-CRPmax group (3.8%, p&lt;0.001). Conclusions: CRPmax, which reflects the magnitude of systemic inflammation induced by surgical stress and postoperative complications in the early phase after surgery, may be a promising prognostic indicator in patients with stage II/III gastric cancer who undergo curative resection.
Genome-wide DNA methylation status to predict the efficacy of modified (m)-FOLFOXIRI plus cetuximab as initial treatment for <i>RAS</i> wild-type metastatic colorectal cancer: A biomarker study of the DEEPER trial (JACCRO CC-13AR).
Authors: Kota Ouchi, Akihito Tsuji, Manabu Shiozawa, Takashi Kawai, Hisateru Yasui, Hirofumi Ota, Mitsugu Kochi, Dai Manaka, Hisatsugu Ohori, Toru Miyake, Tatsuro Yamaguchi, Masato Matsuura, Tamotsu Sagawa, Akitaka Makiyama, Kunihiko Wakamura, Masahiro Takeuchi, Wataru Ichikawa, Masashi Fujii, Chikashi Ishioka, Yu Sunakawa
Journal: Journal of Clinical Oncology (2024)

152 Background: Genome-wide DNA methylation status (GWMS) has been shown to be a predictor of therapeutic response to anti-EGFR antibody therapies. This study investigated the association between GWMS and clinical outcomes of first-line chemotherapy with anti-EGFR or anti-VEGF antibody agents for metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the JACCRO CC-13AR (clinical trial number: UMIN000018412) were analyzed for GWMS and were classified into low-methylated colorectal cancer (LMCC) and high-methylated colorectal cancer (HMCC). Clinical data were obtained from the randomized phase II trial, DEEPER trial (JACCRO CC-13) [NCT02515734], in which patients were randomly assigned to m-FOLFOXIRI plus cetuximab (CET) arm and m-FOLFOXIRI plus bevacizumab (BEV) arm for treatment. Progression-free survival (PFS), overall survival (OS), depth of response (DpR), and response rate (RR) were analyzed according to GWMS for each treatment arm. Results: One hundred thirty-seven out of 227 patients enrolled in the JACCRO CC-13AR were analyzed. Of these, 122 (89.1%) and 15 (10.9%) were classified in the LMCC and HMCC, respectively; 66 were assigned to the CET arm including 7 HMCCs, and 54 were assigned to the BEV arm including 8 HMCCs. In the CET arm, PFS and OS of the LMCC were significantly longer than those of the HMCC (median PFS 14.3 vs. 4.0 months, hazard ratio [HR] 0.11, 95% CI: 0.05–0.29, P&lt;0.01; median OS 42.7 vs. 13.6 months, HR 0.04, 95% CI: 0.01–0.13, P&lt;0.01). There were no differences in DpR and RR between the LMCC and the HMCC (median DpR 58.1% vs. 46.7%, P=0.45), although RR of the LMCC was numerically higher than that of the HMCC (71.2% vs. 42.9%, P=0.13). In contrast, in the BEV arm, there were no differences in PFS, DpR, and RR between the two groups (median PFS 16.1 vs. 12.2 months, P=0.08; median DpR 48.3% vs. 53.9%, P=0.99; RR 73.0% vs. 75.0%, P=0.91). However, OS of the LMCC was significantly longer than that of the HMCC (median OS 48.9 vs. 24.2 months, HR 0.39, 95% CI: 0.16–0.95, P=0.03). Conclusions: This study showed that GWMS may be a prognostic marker for initial treatment in RAS wild-type mCRC. Also, GWMS correlates to the survival outcomes of m-FOLFOXIRI plus CET as initial treatment for RAS wild-type mCRC. Clinical trial information: 000018412 .
Prevalence and predictors of aspirin/NSAID use among patients with Lynch syndrome (LS).
Authors: Sachi Singhal, Yana Chertok, Nadine Osorio, Juan Pablo Chavez, Emma D. Riggs, Mary Beryl Daly, Michael J. Hall
Journal: Journal of Clinical Oncology (2024)

19 Background: LS is among the most common hereditary cancer (CA) syndromes, underlying 3% cases of colorectal CA (CRC) and 8% CRC &lt;50 yrs. LS patients have a high lifetime risk of CRC which is lowered by intensive colonoscopy surveillance. However, interval CRC can still develop, and adjunctive therapies like ASA and NSAIDs have been recognized for their CP benefits, with 35% risk reduction associated with sustained (&gt;2 yrs) ASA use. Existing data are scarce on uptake of CP in LS pts, as well as patient-level factors that may impact uptake. Methods: PREVENTLynch recruited LS participants in the FoxChase Cancer Center (FCCC) Risk Registry, who were invited to complete a one-time e-survey after providing informed consent (1/2020-6/2020; IRB 20-8014). This survey was additionally provided online (PREVENTLynch-II) to US and international patients through 2 patient advocacy websites (10/2022-7/2023). Demographic/personal/familial CA history were collected. Perceived inconvenience, side effects, reassurance, and likelihood of recommending available and emerging CA prevention modalities were measured on 9-point scales (low=1; high=9). Results: 296 patients with LS completed the survey. Median age was 53 yrs [IQR 44-62], and overall CP use was 37.5%. No significant variation in CP uptake was seen based on race, age, marital status or geographic region (nationally and internationally). Personal history of cancer was reported by 56.4%, but was not associated with CP (p=0.6). Gene mutated (MLH1, MSH2, MSH6, PMS2) was not associated with CP (p=0.5).CP users vs non-users perceived greater convenience (mean 1.32 vs 1.90 respectively, p=0.02), lower concern for side effects (2.30 vs 3.61, p=0.0008), and higher perceived preventive reassurance from CP use (5.68 vs 3.93 p&lt;0.0001). CP users were more likely to recommend CP to others (7.57 vs 4.49, p&lt;0.0001). Conclusions: CP uptake is low among patients with LS. Patient perceptions of CP convenience, side effects and preventive benefits predicted CP uptake whereas factors such as age, sex, geographical location, gene affected and personal history of malignancy did not. This suggests a critical need for education addressing negative perceptions of CP among LS patients to improve CP uptake. [Table: see text]
The efficacy of chemotherapy for colorectal cancer with early recurrence after adjuvant chemotherapy.
Authors: Dai Okemoto, Toshifumi Yamaguchi, Kanako Sugino, Nanako Matsuo, Makoto Sanomura, Shin Kameishi, Toru Kadono, Hiroki Yukami, Masahiro Goto, Hiroki Nishikawa
Journal: Journal of Clinical Oncology (2024)

43 Background: Adjuvant chemotherapy is the standard treatment for patients with stage III colorectal cancer (CRC) underwent surgery.However, the efficacy of chemotherapy for early recurrence after adjuvant chemotherapy remains unclear. This study aimed to assess the efficacy of chemotherapy for CRC with early recurrence during or after adjuvant chemotherapy. Methods: We retrospectively reviewed CRC patients who underwent surgery at 3 institutions between 2016 and 2021. The inclusion criteria were as follows: ECOG performance status was 0 or 1, histology was adenocarcinoma, patients who received adjuvant chemotherapy following surgical resection, early recurrence during or within 12 months after adjuvant chemotherapy and no prior treatment for CRC after early recurrence. The interval from the last administration of adjuvant chemotherapy to recurrence was defined as the recurrence-free interval (RFI). Overall survival (OS), progression-free survival (PFS), objective response rates (ORR), and disease control rate (DCR) were assessed according to the RFI. Results: Of 448 patients, 32 patients were eligible. Median age was 57 years (range 26–79), 14 patients (44%) were male and ECOG performance status 0 / 1 was 29 (91%) / 3 (9%). RAS wild-type / mutant was 12 (38%) / 20 (62%) and right / left as sidedness was 21 (66%) / 11 (34%). Regarding adjuvant chemotherapy, 4 patients (12%) received single-agent therapy, while 28 patients (88%) received combination therapy with two agents. Palliative chemotherapy after early recurrence included Oxaliplatin-based regimens in 13 patients (41%), irinotecan-based regimens in another 13 patients (41%), and other regimens in 6 patients (18%). For all patients, the median PFS and OS were 10.4 months and 43.0 months, respectively. The ORR and DCR were 34.4% and 75.0%, respectively. When patients were divided into RFI &lt; 6 months and RFI ≥ 6 months, the ORR was superior in the RFI ≥ 6 months group to RFI &lt; 6 months group (56 % vs. 26%). The PFS (median 10.4 months vs. 17.8 months, HR 0.92; 95% Cl 0.36-2.38, p = 0.87) and OS (median 31.3 months vs. 43.0 months, HR 0.97; 95% Cl 0.31-3.08, p = 0.97) did not differ between the RFI &lt; 6 months group and the RFI ≥ 6 months group. Multivariate analysis for OS indicated a trend toward a poor prognosis in the RFI &lt; 6 months group compared to the RFI ≥ 6 months group (HR 1.78; 95% CI 0.35-8.98, p = 0.48). Conclusions: In patients with CRC experienced early recurrence, the RFI &lt; 6 months group had a trend of poor efficacy compared to the RFI of ≥ 6 months group.
Symptom burden in patients with early-onset colorectal cancer: A subgroup analysis of the enhanced, EHR-facilitated cancer symptom control (E2C2) trial.
Authors: Michael H. Storandt, Oudom Kour, Kathryn Jean Ruddy, Andrea L. Cheville, Deirdre R. Pachman, Parvez Rahman, Ashley Wilder Smith, Sandra A. Mitchell, Qian Shi, Zhaohui Jin
Journal: Journal of Clinical Oncology (2024)

31 Background: Incidence of early-onset colorectal cancer (eoCRC, &lt;50 years of age at diagnosis) is increasing globally. However, little is known regarding symptom burden in this sub-population. We compared symptoms in patients with eoCRC to those of patients with average-onset CRC (aoCRC, diagnosed at age ≥ 50). Methods: E2C2 is a stepped-wedge, cluster-randomized pragmatic trial evaluating a collaborative care model for the assessment and management of six symptoms [Sleep disturbance, Pain, Physical function impairment, Anxiety, emotional Distress, and Energy deficit (SPPADE)]. Patients were asked to complete assessments rating each of these symptoms on an 11-point numerical rating scale. Symptom severity was classified as mild (0-3), moderate (4-6), or severe (7-10). We conducted a subgroup analysis of patients with CRC, comparing SPPADE symptoms on an initial survey, regardless of timing in treatment course, between patients with eoCRC and aoCRC. Results: Patients with CRC (n=4281) completed a survey between March 2019 and December 2022. Patient demographics and SPPADE symptoms are reported in the table. Patients with eoCRC were more likely to report severe sleep disturbance ( p&lt;0.0001), pain ( p=0.03485), anxiety ( p&lt;0.0001), emotional distress ( p&lt;0.0001), and fatigue ( p=0.01083). In patients with eoCRC, women were more likely to report severe pain (12.6% vs 6.9%, p=0.0069), anxiety (16.1% vs 10.0%, p=0.012), emotional distress (12.1% vs 5.4%, p=0.00066), fatigue (18.9% vs 13.4%, p=0.038), and physical function impairment (10.1% vs 5.8%, p=0.026) compared to men. Conclusions: Patients with eoCRC reported higher symptom severity than patients with aoCRC. This suggests unique needs for symptom management in patients with eoCRC. Additional research is needed to evaluate how time since diagnosis, disease characteristics, cancer-directed treatment patterns, and co-occurring symptoms are associated with specific symptoms in this population. [Table: see text]
CEACAM6 and IFITM3 as potential biomarkers for pelareorep in pancreatic adenocarcinoma (PDAC).
Authors: Anne M. Noonan, Jason David, John L. Hays, James Lin Chen
Journal: Journal of Clinical Oncology (2024)

684 Background: Pelareorep (P) is a proprietary formulation of live, replication-competent, naturally occurring Reovirus Type 3 Dearing strain. We previously performed a phase II trial of P with carboplatin (C) and paclitaxel (Pxl) vs C and Pxl alone in metastatic PDAC (NCT01280058). Although P did not improve progression-free survival compared to C and Pxl alone, some exceptional durable responses were seen in the P arm. Low levels of carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) mRNA expression were associated with prolonged PFS in P-treated pts (p=0.05) and there was a 3.3 times higher fold change in Interferon-inducible transmembrane protein 3 (IFITM3) expression in the pts doing poorly versus responders (nominal p&lt;0.05) in P arm. Here we investigate mechanisms of resistance to P infection mediated through CEACAM6 and IFITM3 in a panel of pancreatic ductal adenocarcinoma cell lines. Methods: Prior studies noted CEACAM6 and IFITM3 may restrict cell entry of certain enveloped viruses. CEACAM6 and IFITM3 protein levels were measured in PDAC cell lines using Western blot. Flow cytometry was used to assess P infectivity. We have generated multiple knockdowns of CEACAM6 and IFITM3 in PDAC cell lines to determine changes in P infectivity and other inflammatory signalling pathways. Live cell imaging was used to assess cell viability. Results: Basal expression of CEACAM6 was measured in a panel of 4 PDAC cells (PANC10.5, HPAFII, BxPC3, CFPAC1). Panc10.05 had low basal expression nor could expression be induced by 24hr P infection. All other cell lines showed moderate to high basal expression that was inducible. P infectivity at 24hrs was significantly higher in Panc10.05 cells compared to high CEACAM6 expressing cell lines. There was varying basal expression of IFITM3, however all cell lines showed IFITM3 induction when exposed to P. Of the 3 cell lines that also expressed high levels of CEACAM6 (HPAFII, CFPAC1, BxPC3), low basal expression of IFITM3 was strongly associated with increased sensitivity to P infection and decreased viability at 72hrs, which could be induced by knockdown of IFITM3 in high expressing cell lines. Neither C or Pxl altered levels of CEACAM6 or IFITM3 in any of the four cell lines. Conclusions: High CEACAM6 and IFITM3 play a role in P viral infectivity across multiple pancreatic cell lines, confirming results obtained in translational datasets. Further analysis is ongoing to elucidate mechanism and identify pathways to alter expression of CEACAM6 and IFITM3 and enhance P infectivity in future trials.
Zanzalintinib (XL092) plus atezolizumab versus regorafenib in previously treated MSS/MSI-low metastatic colorectal cancer (mCRC): The randomized phase 3 STELLAR-303 study.
Authors: Anwaar Saeed, Josep Tabernero, Guan Wang, Xia Ma, Robina Smith, J. Randolph Hecht
Journal: Journal of Clinical Oncology (2024)

TPS229 Background: Patients with microsatellite stable/microsatellite instability-low (MSS/MSI-low) mCRC account for ~95% of mCRC cases, and there is a significant unmet need in patients with treatment-refractory MSS/MSI-low mCRC. Although immune checkpoint inhibitors (ICIs) have shown limited activity in this patient population, the addition of tyrosine kinase inhibitors (TKIs) may increase sensitivity to ICIs by promoting an immune-permissive tumor microenvironment. Furthermore, TKI-ICI combinations have demonstrated encouraging clinical activity in patients with mCRC, particularly in subgroups of patients without liver metastases (LM). Most recently, in the phase 3 LEAP-017 study of patients with non–MSI-high/mismatch repair deficient (dMMR) mCRC, although pembrolizumab + lenvatinib did not improve overall survival (OS) vs standard of care, subgroup analysis suggested the potential for clinical benefit in patients without LM (Kawazoe et al, ESMO-WCGI 2023). Zanzalintinib is a novel multi-kinase inhibitor targeting VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). In a phase 1 study, zanzalintinib alone and in combination with atezolizumab (an anti–PD-L1 ICI) showed preliminary anti-tumor activity and a manageable safety profile across multiple tumor types (Sharma et al, ESMO 2022). Methods: STELLAR-303 (NCT05425940) is a global, randomized, open-label phase 3 study to assess the efficacy and safety of zanzalintinib + atezolizumab versus regorafenib in adult patients with MSS/MSI-low mCRC. Patients must have documented MSI/MMR status (non–MSI-high/dMMR) and RAS status by tissue-based analysis, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and radiographic progression during/after or intolerance to standard of care treatments for mCRC. Prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed. Patients with or without active LM at baseline are eligible; those with definitively treated LM (includes surgical resection, microwave/radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) are considered to have non-active LM if treated ≥6 months before enrollment with no evidence of radiologic progression on subsequent imaging. Patients are randomized 1:1 to receive zanzalintinib + atezolizumab or regorafenib. Planned enrollment is 874 patients; number of patients with LM will be capped to ensure results of the study are relevant to the real-world mCRC population. Primary endpoint is OS in patients without LM. The key secondary efficacy endpoint is OS in all randomized patients. A hierarchical testing strategy will be employed for primary and key secondary endpoints. Safety will also be assessed. Enrollment is ongoing in the US, Europe, and Asia-Pacific region. Clinical trial information: NCT05425940 .