While traditionally informed by tumor tissue origin and histopathology, advancements in next-generation sequencing (NGS) technology have catalyzed tumor-agnostic approaches which prioritize molecular alterations for personalized treatment. Here, we demonstrate the clinical utility of molecularly guided tumor-agnostic precision medicine in an Asian cohort, leveraging an Asian-centric NGS panel tailored to address the unique genetic landscape of the region. 1,167 formalin-fixed paraffin-embedded tissue samples from 1,150 Asian cancer patients across >70 centers in 7 countries underwent real-world NGS testing using an Asian-centric pan-cancer hybrid-capture NGS panel (UNITED), profiling 572 cancer-related genes and 91 RNA fusion partners. Biomarkers were classified as actionable if therapeutic indications were FDA-approved, guideline-recommended, or supported by robust phase III clinical trials. The cohort encompassed 23 cancer types, with lung (17.7%), colorectal (12.8%), prostate (11.1%), and breast (8.6%) cancers accounting for 50.1% of the clinical volume. Actionable biomarkers were identified in 62.2% of samples, with KRAS, EGFR, and PIK3CA among the most frequently mutated genes. The likelihood of identifying ≥1 actionable mutation was highest in CNS tumors (83.6%), followed by lung cancer (81.2%), breast cancer (79%), and others. Among 27,552 somatic variants detected, 1,291 (4.7%) were potentially targetable by regulatory-approved therapies. Notably, ≥1 tumor-agnostic biomarker (including TMB-H, dMMR/MSI-H, NTRK/RET fusions, and BRAF V600E) was identified in every cancer type, detected in 98 samples (8.4%). This includes in 16.9% of lung tumors, 12.2% of tumors of unknown primary origin, 11.8% of endometrial tumors, and others. As expected, TMB was significantly associated with MSI (p<0.0001). ERBB2 amplification, a potential surrogate marker for HER2 overexpression, was identified in 42 samples (3.6%) and was most frequently detected in breast tumors (15%), followed by endometrial tumors (11.8%), ovarian tumors (8.9%), and others. Homologous recombination deficiency (HRD) was observed in 407 samples (34.9%) and were present in about half of the tumors of the breast (50%), colon (49%), urothelium (47.1%), endometrium (47.1%) and lung (44%). Notably, HRD-positive tumors exhibited significantly higher TMB compared to HRD-negative tumors (median TMB 5.58 vs. 5.15, p=0.0001). Leveraging an Asian-centric NGS panel, actionable molecular alterations were detected in 62.2% of Asian cancer patients. The high prevalence of actionable biomarkers, coupled with the detection of regulatory-approved tumor-agnostic markers, underscores the significance of comprehensive NGS testing in facilitating tumor-agnostic precision medicine in an Asian setting, thereby improving treatment strategies and patient outcomes. Jing Yi Lee, Aya E. Helali, Zi Yi Wan, Donald Y. Poon, Jens Samol, Tsz Him So, Su Pin Choo, Ravindran Kanesvaran, Cheng-Vai Hui, Joseph S. Au, Timothy Yip, Ross Soo, Michelle Pek, Ruifen Weng, Bin Tean Teh, Min-Han Tan, Jonathan Poh, Jason Y. Chan. Clinical actionability of an Asian pan-cancer tissue-based next generation sequencing (NGS) assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 720.

4535 Background: NIVO IV has improved outcomes in multiple tumor types. Evolving treatment paradigms have created a need for administration options that address treatment burden and improve efficiencies of healthcare systems. In a phase 1/2 study (CheckMate 8KX), pts were highly satisfied with NIVO SC and preferred it over NIVO IV [Lonardi et al, ESMO 2022; Lonardi et al, SITC 2023]. CheckMate 67T (NCT04810078) is a multicenter, randomized, open-label, phase 3 study that demonstrated pharmacokinetic and objective response rate noninferiority of NIVO SC vs IV in pts with locally advanced or metastatic ccRCC [George et al, ASCO-GU 2024]. This exploratory analysis assessed non-inferiority of HRQoL between pts randomized to NIVO SC (n=248) vs NIVO IV (n=247) in CheckMate 67T. Methods: HRQoL was measured using patient-reported outcomes (PROs), FKSI-19 (kidney cancer-related HRQoL) and the EQ-5D-5L (pt’s health status). FKSI-19 total score (range 0-76, higher score better HRQoL)and EQ-5D-5L visual analogue scale (VAS) (range 0-100, higher score better health HRQoL) scores were evaluated longitudinally on-treatment visits with ≥10 pts per arm included in model [week 57]) using linear mixed models (constrained longitudinal data analysis), with least squares (LS) mean changes from baseline and differences in the LS mean between NIVO SC and NIVO IV assessed; non-inferiority of NIVO SC vs NIVO IV was evaluated by examining overall treatment differences for on-treatment visits relative to prespecified thresholds. Results: PRO data were available for 247 pts (99.6%) for NIVO SC and 245 pts (99.2%) for NIVO IV, with completion rates >87% across instruments up to week 57 for both treatment arms. HRQoL was maintained over time for both NIVO arms for FKSI-19 total score and subscales and EQ-5D-5L VAS. NIVO SC was non-inferior to NIVO IV across FKSI-19 total score and subscales and EQ-5D-5L VAS (Table). Conclusions: These results demonstrate maintenance of HRQoL for pts with advanced or metastatic ccRCC while on treatment with NIVO, regardless of the mode of administration (SC or IV), supporting the use of NIVO SC as a new option to align with patient preferences. Clinical trial information: NCT04810078 . [Table: see text]

Triplet regimens containing immunomodulatory drugs and proteasome inhibitors (PIs) have improved outcomes and extended survival for patients with relapsed/refractory multiple myeloma (RRMM). We evaluated updated health-related quality of life (HRQoL) findings from the phase 2 ELOQUENT-3 clinical trial (NCT02654132) after 4 years of treatment with elotuzumab plus pomalidomide and dexamethasone (EPd) and assessed the impact of the addition of elotuzumab on patients' HRQoL. HRQoL was assessed as an exploratory endpoint using the MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM), which evaluates symptom severity, symptom interference, and HRQoL, and the 3-level EQ-5D, a patient-reported measure of health utility and general health. Statistical analyses included descriptive responder, longitudinal mixed-model, and time-to-first-deterioration (TTD) analyses using prespecified minimally important differences and responder definitions. Of 117 randomized patients, 106 (EPd, n = 55; pomalidomide and dexamethasone [Pd], n = 51) were eligible for inclusion in HRQoL analyses. Completion rates at almost all on-treatment visits were ≥80%. The proportion of patients treated with EPd who improved or maintained stable HRQoL until cycle 13 ranged from 82% to 96% for MDASI-MM total symptom score and 64% to 85% for MDASI-MM symptom interference. Across measurements, there were no clinically meaningful differences in changes from baseline between treatment arms, and TTD was not significantly different for EPd versus Pd. In conclusion, HRQoL was not impacted by the addition of elotuzumab to Pd and did not significantly deteriorate in patients with RRMM previously treated with lenalidomide and a PI in ELOQUENT-3.

262 Background: This analysis evaluated HRQoL as exploratory endpoints in CheckMate 648, a randomized, open-label, global Phase 3 study, evaluating treatment with N+I, N+CT and CT alone in inoperable advanced, recurrent, or metastatic ESCC. Methods: The effects of N+I vs N+CT vs CT on HRQoL were assessed using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) (including the GP5 item to assess impact of side effects) and EQ-5D-3L. A mixed model for repeated measures was used to evaluate longitudinal changes from baseline (BL) and differences between treatment groups. Comparison of the risk of being bothered by the side effects of treatment was estimated for the GP5 using generalized estimating equation (GEE). Time to confirmed deterioration (TTCD) was assessed using Kaplan-Meier plots along with Cox proportional hazard models. Analyses were conducted on both the all-randomized population and the subset of patients with PD-L1 expression ≥1%. Results: 970 pts were randomized 1:1:1 to N+I (n=325), N+CT (n=321), or CT (n=324). 90% of pts completed both a BL and at least one on-treatment assessment and were included in the PRO analysis population. FACT-E (all randomized pts). Study showed similar BL scores across all 3 treatment groups. Changes from BL showed a trend towards better HRQoL for pts treated with N+I and N+CT compared to CT alone, however these results were not statistically significant. Patients treated with N+I had significantly decreased risk of experiencing bother associated with the side effects of treatment than patients treated with either N+CT or CT. TTCD analysis demonstrated delayed deterioration for pts treated with N+CT vs CT. Findings for PD-L1 ≥1% subpopulation were similar to all randomized pts. Conclusions: In pts with inoperable advanced, recurrent, or metastatic ESCC, HRQoL is maintained throughout treatment with N+I and N+CT. Trends towards better HRQoL and decreased risk of deterioration were observed with N+I and N+CT compared to CT alone. Clinical trial information: NCT03143153. [Table: see text]

9574 Background: In CheckMate 238, NIVO 3 mg/kg vs ipilimumab 10 mg/kg showed significantly longer recurrence-free survival and a lower rate of grade 3–4 treatment-related adverse events (TRAEs) in pts with completely resected stage IIIB/C or IV melanoma. This analysis assessed the association of long-term HRQoL and TRAEs in NIVO-treated pts in this trial. Methods: HRQoL was assessed using EORTC QLQ-C30 (global health status [GHS] and physical/emotional functioning) and EQ-5D-3L visual analogue scale (VAS) questionnaires administered after randomization, during 1 y of treatment (wk 5, 7, 11, 17, 25, 37, and 49), at posttreatment FU visits 1 and 2 (FU1 and FU2; 30 and 114 days after last dose), and at survival FU visits up to 4 y after last dose (EQ-5D-3L only). NIVO-treated pts were grouped based on whether they had experienced a grade 3–4 TRAE, any-grade TRAE leading to NIVO discontinuation, or any-grade select (immune-related) TRAE on treatment or up to 100 days after last dose. Longitudinal change from baseline (BL) in scores was assessed for pts with and without TRAEs having patient-reported outcome data at BL and ≥1 post-BL assessment (HRQoL population) using descriptive statistics. QLQ-C30 subscale and VAS changes of 10 and 7, respectively, were considered clinically meaningful. Results: The HRQoL population comprised 446 of 453 pts randomized to NIVO. EQ-5D-3L assessments were completed by 81% of survivors (263/324) after 4 y post-randomization. Grade 3–4 TRAEs occurred in 17% of NIVO-treated pts (77/446). A slight trend toward deterioration of GHS from BL on treatment was noted, with clinically meaningful deterioration at posttreatment FU1 (mean [SD], −13.8 [25.0]) and FU2 (−10.3 [22.0]; last available time point). For the VAS, a similar trend on treatment was noted (−6.9 [28.3] at wk 11), with a clinically meaningful deterioration after NIVO discontinuation (−9.9 [27.0] at FU1) and a return to BL level by the start of survival FU. For pts without grade 3–4 TRAEs, mean change from BL scores remained stable (ie, no clinically meaningful deterioration on treatment or during FU). Any-grade TRAEs led to NIVO discontinuation in 9% of pts (42/446); HRQoL findings were similar to those for pts with grade 3–4 TRAEs. The most common any-grade TRAE was fatigue (35%). No clinically meaningful deterioration in VAS was noted for any select TRAE during FU except for hyperthyroidism (8%), with which deterioration occurred at FU1. EORTC QLQ-C30 physical and emotional functioning results will be presented. Conclusions: In CheckMate 238, pts with TRAEs showed early HRQoL deterioration after NIVO discontinuation, but HRQoL returned to BL levels with no sustained deterioration during survival FU. Overall, HRQoL was maintained on treatment and over a long-term FU period in pts with resected melanoma receiving adjuvant NIVO. Clinical trial information: NCT02388906.

BACKGROUND:Although the majority of nasopharyngeal carcinoma (NPC) patients demonstrate favorable outcomes after radiotherapy and/or chemotherapy, about 8-10% of patients will develop recurrent disease, and genomic alterations (GAs) associated with the recurrence are unclear. METHODS:This study investigated the GAs in the paired primary tumors and recurrent tumors of 7 NPC patients with relapse, as well as the primary tumors of 15 NPC patients without relapse by deep targeted next-generation sequencing on 440 cancer-related genes. RESULTS:BRCA1 and TP53 mutations were significantly enriched in patients with relapse (P = 0.021 and P = 0.023, respectively). Survival analysis revealed that the GAs of TP53, ZNF217, VEGFB, CDKN1B, GNAS, PRDM1, and MEN1 were associated with significantly shorter overall survival. The GAs of the tumor also altered after treatment in the relapsed group, and five genes (CDK4, FGFR3, ALK, BRCA1, and CHEK2) in the recurrent tumors were potentially druggable. CONCLUSIONS:The discovery of GAs associated with recurrence or survival in NPC may serve as potential prognostic gene signatures of high-risk patients. Targeted therapies are available in some of the clinically relevant GAs and may be considered in future clinical trials. Given the limitation of the sample size, validation by a larger cohort is warranted.

483 Background: SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to help improve or maintain HRQoL. This phase 3 study compared HRQoL of NIVO vs SOR as 1L therapy in pts with aHCC as an exploratory endpoint. Methods: FACT-Hep was administered cycle 1, day 1 and every other cycle. The effect of NIVO vs SOR on HRQoL using FACT-Hep was assessed via repeated measures mixed models (MMRM). Kaplan–Meier curves and Cox proportional-hazards models determined between-treatment differences in time to first and time until definitive deterioration (TTD/TUDD) based on prespecified thresholds for minimally important differences. The GP5 item from FACT-Hep was used to assess the burden associated with treatment side effects. Results: 743 pts with aHCC were randomized to NIVO (n = 371) or SOR (n = 372). Median OS was 16.4 mo for NIVO, 14.7 mo for SOR (HR 0.85 [95% CI 0.72–1.02]; P = 0.0752). ORR was 15% for NIVO, 7% for SOR (OR 2.41 [95% CI 1.48–3.92]). HRQoL scores were completed at baseline by 94.6% and 92.5% of participants, respectively, and were similar (FACT-Hep total: NIVO 140.7 [SD 21.5] and SOR 140. 6 [SD 19.1]. Questionnaire compliance rates exceeded 70% at most visits. MMRM analyses yielded clinically meaningful and statistically significant least squares means differences favoring NIVO on FACT-Hep total (10.1 [95% CI 7.3–13.0]), physical well-being (PWB; 2.0 [95% CI 1.4–2.6]), and functional well-being (FWB; 2.5 [95% CI 1.7–3.2]) scores. No sub-scales favored sorafenib. TTD was significantly delayed in NIVO for FACT-Hep total (HR 0.62 [95% CI 0.51–0.74]), PWB (HR 0.62 [95% CI 0.52–0.74]), FWB (HR 0.73 [95% CI 0.61–0.88]), and hepatobiliary cancer subscale (HR 0.57 [95% CI 0.48–0.69]). TUDD results were consistent with TTD. A greater proportion of NIVO pts did not experience increased burden of side effects (50%–67.7%) compared with SOR (26.8%–45%) based on the GP5 item. Conclusions: These patient-reported findings demonstrate that pts taking NIVO had superior HRQoL and reduced side effect burden, further supporting clinical data showing a treatment benefit for 1L NIVO in aHCC. Clinical trial information: NCT02576509.

Excellent locoregional control can now be achieved in patients with nasopharyngeal cancer (NPC) after chemoradiotherapy delivered by intensity-modulated radiotherapy (IMRT). Distant failure occurs in up to 25%–30% of all patients, and has become the main cause of cancer mortality. As prognosis of patients with metastatic NPC can be variable, assigning patients to different prognostic groups using different prognostic models can facilitate personalized cancer treatment. While gemcitabine-cisplatin doublet emerges as the standard first-line chemotherapy, both nonplatinum and platinum-containing chemotherapy regimens and various targeted therapies can serve as second or later lines of systemic therapy. Apart from standard radiological assessments, Epstein–Barr virus DNA is also an important and unrivalled blood biomarker, which can provide longitudinal monitoring of therapeutic outcome as well as potentially predicting early chemotherapy response. With advent of image-guided high-precision IMRT, there has been a paradigm shift in recent years to offer more ablative local radiotherapy for patients with oligometastasis, and also high dose radiotherapy to the primary tumor in patients with de novo metastasis when appropriate. It is envisaged that intensifying both systemic and local therapy may help confer durable control of the distant, with a view to improving symptom control, quality of life, and even survival.

BackgroundSulforaphane (SFN), a natural compound present in cruciferous vegetable, has been shown to possess anti-cancer activities. Cancer stem cell (CSC) in bulk tumor is generally considered as treatment resistant cell and involved in cancer recurrence. The effects of SFN on nasopharyngeal carcinoma (NPC) CSCs have not yet been explored.PurposeThe present study aims to examine the anti-tumor activities of SFN on NPC cells with CSC-like properties and the underlying mechanisms.MethodsNPC cells growing in monolayer culture, CSCs-enriched NPC tumor spheres, and also the NPC nude mice xenograft were used to study the anti-tumor activities of SFN on NPC. The population of cells expressing CSC-associated markers was evaluated using flow cytometry and aldehyde dehydrogenase (ALDH) activity assay. The effect of DNA methyltransferase 1 (DNMT1) on the growth of NPC cells was analyzed by using small interfering RNA (siRNA)-mediated silencing method.ResultsSFN was found to inhibit the formation of CSC-enriched NPC tumor spheres and reduce the population of cells with CSC-associated properties (SRY (Sex determining Region Y)-box 2 (SOX2) and ALDH). In the functional study, SFN was found to restore the expression of Wnt inhibitory factor 1 (WIF1) and the effect was accompanied with the downregulation of DNMT1. The functional activities of WIF1 and DNMT1 were confirmed using exogenously added recombinant WIF1 and siRNA knockdown of DNMT1. Moreover, SFN was found to inhibit the in vivo growth of C666-1 cells and enhance the anti-tumor effects of cisplatin.ConclusionTaken together, we demonstrated that SFN could suppress the growth of NPC cells via the DNMT1/WIF1 axis.

PURPOSE:The identification of genomic alterations related to recurrence in early-stage non-small cell lung cancer (NSCLC) patients may help better stratify high-risk individuals and guide treatment strategies. This study aimed to identify the molecular biomarkers of recurrence in early-stage NSCLC.RESULTS:Of the 42 tumors evaluable for genomic alterations, TP53 and EGFR were the most frequent alterations with population frequency 52.4% and 50.0%, respectively. Fusion genes were detected in four patients, which had lower mutational burden and relatively better genomic stability. EGFR mutation and fusion gene were mutually exclusive in this study. CDKN2A, FAS, SUFU and SMARCA4 genomic alterations were only observed in the relapsed patients. Increased copy number alteration index was observed in early relapsed patients. Among these genomic alterations, early-stage NSCLCs harboring CDKN2A, FAS, SUFU and SMARCA4 genomic alterations were found to be significantly associated with recurrence. Some of these new findings were validated using The Cancer Genome Atlas (TCGA) dataset.CONCLUSIONS:The genomic alterations of CDKN2A, FAS, SUFU and SMARCA4 in early-stage NSCLC are found to be associated with recurrence, but confirmation in a larger independent cohort is required to define the clinical impact.MATERIALS AND METHODS:Paired primary tumor and normal lung tissue samples were collected for targeted next-generation sequencing analysis. A panel targets exons for 440 genes was used to assess the mutational and copy number status of selected genes in three clinically relevant groups of stage I/II NSCLC patients: 1) Early relapse; 2) Late relapse; and 3) No relapse.

During tumor development, cancer cells constantly confront different types of extracellular barriers. However, fundamental questions like whether tumor cells will continue to grow against confinement or away from it and what key factors govern this process remain poorly understood. To address these issues, here we examined the growth dynamics of human lung epithelial carcinoma A549 cells partially confined in micrometer-sized cylindrical pores with precisely controlled wall stiffness. It was found that, after reaching confluency, the cell monolayer enclosed by a compliant wall was able to keep growing and pushing the boundary, eventually leading to a markedly enlarged pore. In contrast, a much reduced in-plane growth and elevated strain level among cells were observed when the confining wall becomes stiff. Furthermore, under such circumstance, cells switched their growth from within the monolayer to along the out-of-plane direction, resulting in cell stacking. We showed that these observations can be well explained by a simple model taking into account the deformability of the wall and the threshold stress for inhibiting cell growth. Interestingly, cadherins were found to play an important role in the proliferation and stress buildup within the cell monolayer by aggregating at cell cell junctions. The stiff confinement led to an elevated expression level of cadherins. Furthermore, inhibition of N-cadherin resulted in a significantly suppressed cell growth under the same confining conditions.

An electroporation device was developed to introduce transient membrane pores and, consequently, enhance membrane permeability in living cells in a controllable manner. The validity of this platform was assessed on six non-small cell lung cancer (NSCLC) cell lines using different fluorescent dyes. Interestingly, it was found that the electroporation efficiency of these cells, i.e. the percentage of cells with membrane pores created, decreases significantly (from similar to 60% to 30%) as their resistivity against Erlotinib increases, demonstrating the potential of such approach as a screening tool for assessing drug resistance in tumours in the future. Furthermore, we showed that the inverse relationship between the electroporation efficiency and Erlotinib resistance is likely due to the fact that NSCLC cell lines with higher drug resistivity appear to have lower cortical tensions and hence make it harder for membrane pores to be created, consistent with existing electroporation theories.

Recent advances in the development of anti-inflammatory agents have improved their therapeutic outcome in inflammatory bowel disease (IBD), however, the presence of side effects and limited effectiveness hinder their widespread use. Therefore, novel compounds with strong anti-inflammatory efficacy are still required. In this study, we investigated the anti-inflammatory effect and potential mechanisms of Gynostemma pentaphyllum (Thunb.) Makino saponins (GpS), a major component of the herbal medicine widely used in Asian countries. In in vitro studies, we demonstrated that GpS dose dependently suppressed activation of macrophages, one of the main effectors in IBD. GpS also suppressed cytokine production and the activation of NF-κB and STAT3 signaling in lipopolysaccharide-induced macrophages, without affecting their viability. Further in vivo studies demonstrated that GpS could ameliorate the weight loss, increased disease activity index, colon shortening and histological damage associated with dextran sulfate sodium (DSS)-induced colitis in mice. In agreement with results from our in vitro experiments, GpS suppressed cytokine production and activation of NF-κB and STAT3 signaling in the colons of DSS-induced mice. In this study, we present for the first time, evidence of the therapeutic effect of GpS in IBD, highlighting its potential as an effective therapeutic against the disease.

Abstract Background Multiple subpopulations of cells with different phenotypes and genotypes coexist within malignant tumours. Different subpopulations seem to maintain themselves in an equilibrium position via stochastic interconversion. Such plasticity plays an important role in cancer progression, such as transition from epithelial states to mesenchymal state during metastasis, dedifferentiation of non-CSCs to CSCs and rapid transition to MDR cells during drug exposure. We attempt to explore this interconversion plasticity at both population and single cell levels to better understand the dynamics of phenotypic transition. Methods: We isolated CD90+ and CD90- cells from A549 lung adenocarcinoma cell line by flow cytometry and then characterized their phenotypic behaviors and interconversion dynamics at both population and single cells level. Single cells were cultured in 96 well plate for 13 days. Viable cells were then transferred into 6 well plate for further expansion until enough cells were collected for measurement of CD90 expression in flow cytometry. Results: A549 maintains a stable expression of CD90 (~50%) which is bimodal distributed. The sorted subpopulations eventually achieved a new equilibrium (CD90+ à 60% , CD90 - à 30%) and did not converge during the bulk cell interconversion. Individual single cell clones showed large variation of CD90 expression. The distribution of CD90 expression was significantly different between CD90+ and CD90- single cell clones, while both groups of clones achieved a similar average equilibrium as compared with the bulk cells. We noted two types of clones defined as transition clones and committed clones with differential interconversion capacities. The later one showed no sign of interconversion and was committed to the original CD90+/- expression level. Further experiments showed that the committed CD90+ cells were more mesenchymal with higher migration ability, while the committed CD90- cells were more epithelial and tumorigenic. Conclusions: Interconversion plasticity varied from cell to cell and the committed cells prohibited the return of sorted cell subpopulations returned back to the original equilibrium. Phenotypic studies of CD90+ and CD90- revealed that the interconversion between them was EMT related. Citation Format: Yuen San Chan, Edwin-Wai Kin Yu, William Weimao Wang, Chi-Chun Fong, Timothy Tak-Chun Yip, Joseph Siu-Kie Au, Mengsu Yang. Dynamic interconversion of cancer cells: single-cell analysis of population-based equilibrium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3938. doi:10.1158/1538-7445.AM2017-3938

Introduction: Patients with DNA mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) have poor outcomes following conventional therapy and experience impact to functional status and well-being. CheckMate 142, an open-label, nonrandomized, phase II study of nivolumab (3 mg/kg every 2 weeks) demonstrated durable responses and disease control, as well as long-term survival in heavily pre-treated patients with dMMR/MSI-H mCRC. Objective response rate was 31.1% per investigator; 68.9% of patients had disease control (complete/partial response or stable disease) for ≥12 weeks, and the 12-month overall survival rate was 73.8%. The objective of this analysis is to describe the impact of nivolumab on health-related quality of life (HRQoL). Methods: HRQoL was assessed in CheckMate 142 using two patient-reported outcome (PRO) measures: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and three-level EQ-5D (EQ-5D-3L). Questionnaires were completed at baseline and every 6 weeks thereafter while on treatment. Analysis cohort was defined as patients with completed baseline and ≥1 post-baseline assessments. Changes in mean scores over time were analyzed using linear mixed models adjusting for baseline response. Analyses included all on-treatment time points up to and including week 79, after which data were available for <10 patients. Clinically meaningful changes in scores were interpreted using established cutoffs of 10 points for the EORTC QLQ-C30 scales, 7 points for the EQ-5D-3L visual analog scale (VAS), and 0.08 points for the EQ-5D-3L utility index. Results: Of the 74 patients treated with nivolumab, the baseline questionnaire completion rates for the EORTC QLQ-C30 and EQ-5D-3L were 95% (n = 70) and 88% (n = 65), respectively. The analysis cohort included 81% (n = 60) patients for the EORTC QLQ-C30 and 76% (n = 56) patients for EQ-5D-3L. Statistically significant (P < 0.05) and clinically meaningful improvements in least squares mean scores for the EORTC QLQ-C30 were reported in scales measuring pain, insomnia, and social functioning as early as week 13 and were observed at ≥ 1 time points in scales measuring emotional functioning, fatigue, financial difficulties, and global health status (Table 1). There were no clinically meaningful declines in any EORTC QLQ-C30 scale score. Statistically significant and clinically meaningful improvements in EQ-5D-3L VAS and utility index scores were observed as early as week 7 and at all on-treatment time points through week 79 and week 61, respectively. Conclusion: In CheckMate 142, patients with dMMR/MSI-H mCRC exhibited statistically significant and clinically meaningful improvements in functioning, symptoms, and quality of life during nivolumab treatment. These analytic findings are broadly consistent with the results of descriptive analyses of the same trial data presented previously.

Although the volume of living cells has been known to heavily influence their behavior and fate, a method allowing us to control the cell size in a programmable manner is still lacking. Here, we develop a technique in which precise changes in the cellular volume can be conveniently introduced by varying the voltage applied across a Nafion membrane that separates the culture medium from a reservoir. It is found that, unlike sudden osmotic shocks, active ion transport across the membrane of leukemia K562 cells will not be triggered by a gradual change in the extracellular osmolarity. Furthermore, when subjected to the same applied voltage, different lung and nasopharyngeal epithelial cancer cells will undergo larger volumetric changes and have a 5-10% higher death rate compared to their normal counterparts. We show that such distinct response is largely caused by the overexpression of aquaporin-4 in tumor cells, with knockout of this water channel protein resulting in a markedly reduced change in the cellular volume. Finally, by taking into account the exchange of water/ion molecules across the Nafion film and the cell membrane, a theoretical model is also proposed to describe the voltage-induced size changes of cells, which explain our experimental observations very well.

Conference Theme: Global Lessons on Cancer Pathogenesis from Insights into a Geographically Restricted Tumor of the Nasopharynx