Ribosomal Protein L9 Maintains Stemness of Colorectal Cancer via an ID-1 Dependent Mechanism.

The identification of therapeutic target genes that are functionally involved in stemness is crucial to effectively cure patients with metastatic carcinoma. We have previously reported that inhibition of ribosomal protein L9 (RPL9) expression suppresses the growth of colorectal cancer (CRC) cells by inactivating the inhibitor of DNA-binding 1 (ID-1) signaling axis, which is functionally associated with cancer cell survival. In addition to cell proliferation, ID-1 is also involved in the maintenance of cancer stemness. Thus, we aimed in this study to investigate whether the function of RPL9 could correlate with CRC stem cell-like properties. Here, we demonstrated that siRNA silencing of RPL9 reduced the invasiveness and migrative capabilities of HT29 and HCT116 parental cell populations and the capacity for sphere formation in the HT29 parental cell population. CD133+ cancer stem cells (CSCs) were then separated from CD133- cancer cells of the HT29 parental cell culture and treated with RPL9-specific siRNAs to verify the effects of RPL9 targeting on stemness. As a result, knockdown of RPL9 significantly suppressed the proliferative potential of CD133+ colorectal CSCs, accompanied by a reduction in CD133, ID-1, and p-IκBα levels. In line with these molecular alterations, targeting RPL9 inhibited the invasion, migration, and sphere-forming capacity of CD133+ HT29 CSCs. Taken together, these findings suggest that RPL9 promotes CRC stemness via ID-1 and that RPL9 could be a potential therapeutic target for both primary CRC treatment and the prevention of metastasis and/or recurrence.

Efficacy and safety of biosimilar trastuzumab (CT-P6) in routine clinical practice in the Republic of Korea: a real-world post-marketing surveillance study.

BACKGROUND: The trastuzumab biosimilar CT-P6 is approved for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), metastatic breast cancer (MBC), and metastatic gastric cancer (MGC). The objective of this post-marketing surveillance (PMS) study was to evaluate the real-world safety and effectiveness of CT-P6 in patients with HER2-positive cancers. RESEARCH DESIGN AND METHODS: This open-label, observational, prospective, PMS study collected data via investigator surveys from 35 centers in the Republic of Korea (5 October 2018-4 October 2022). Eligible patients with HER2-positive EBC, MBC, or MGC started CT-P6 treatment during routine clinical practice, followed by 1-year observation. Evaluations included adverse events (AEs), adverse drug reactions (ADRs), and effectiveness. RESULTS: Safety was analyzed in 642 patients (494 EBC, 94 MBC, 54 MGC). Overall, 325 (50.6%) patients experienced 1316 AEs, and 550 ADRs occurred in 199 (31.0%) patients. Unexpected ADRs occurred in 62 (9.7%) patients. Unexpected ADRs and ADRs of special interest did not raise any new safety signals. Among trastuzumab-naïve patients, 34/106 (32.1%) with EBC achieved pathological complete response; 30/74 (40.5%) MBC and 24/49 (49.0%) MGC patients achieved complete or partial response. CONCLUSIONS: In a real-world setting, CT-P6 demonstrated safety and efficacy findings consistent with previous CT-P6 studies.

Impact of PIK3CA and cell cycle pathway genetic alterations on durvalumab efficacy in patients with head and neck squamous cell carcinoma: Post hoc analysis of TRIUMPH study.

OBJECTIVES: This study aimed to investigate whether genetic alterations in PI3KCA and the cell cycle pathways influence the efficacy of durvalumab, an immune checkpoint inhibitor, in patients with head and neck squamous cell carcinoma (HNSCC) who had previously failed platinum-based treatment. MATERIALS AND METHODS: We obtained data from a phase II umbrella trial of patients with HNSCC who failed platinum-based treatment (TRIUMPH, NCT03292250). Patients receiving durvalumab treatment comprised those with PIK3CA alterations (Group A), those with cell cycle pathway alterations such as CDKN2A (Group B), and those with no druggable genetic alterations (Group C). We analyzed the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in each group and evaluated the potential predictive factors for durvalumab. RESULTS: We analyzed the data of 87 patients: 18, 12, and 57 in groups A, B, and C, respectively. The ORRs were 27.8 %, 8.3 %, and 15.8 % in Groups A, B, and C, respectively (P = 0.329), and the median PFS for each group was 2.3, 1.6, and 1.7 months, respectively, with no significant differences between the groups (P = 0.24). Notably, patients with lower neutrophil-lymphocyte ratio (NLR) (≤5.8) had longer PFS (median, 2.8 vs 1.6 months, P < 0.001), while those with lower platelet-lymphocyte ratio (PLR) (≤491.2) exhibited longer PFS (median, 1.8 vs 1.2 months, P < 0.001). CONCLUSION: Durvalumab's efficacy was similar, irrespective of the presence of PIK3CA or cell cycle pathway genetic alterations in patients with platinum-resistant HNSCC. The NLR and PLR may be promising predictive biomarkers.

Lazertinib versus Gefitinib as First-Line Treatment for EGFR-mutated Locally Advanced or Metastatic NSCLC: LASER301 Korean Subset.

PURPOSE: This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment-related AEs occurred with lazertinib than gefitinib. CONCLUSION: Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC. METHODS: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment. RESULTS: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths. CONCLUSION: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

Genomic analysis of plasma circulating tumor DNA in patients with heavily pretreated HER2 + metastatic breast cancer.

We explored accumulated genomic alterations in patients with heavily treated HER2 + metastatic breast cancer enrolled in the KCSG BR18-14/KM10B trial. Targeted sequencing was performed with circulating tumor DNAs (ctDNAs) collected before the treatment of 92 patients. ctDNAs collected at the time of disease progression from seven patients who had a durable response for > 12 months were also analyzed. Sixty-five genes were identified as pathogenic alterations in 99 samples. The most frequently altered genes were TP53 (n = 48), PIKCA (n = 21) and ERBB3 (n = 19). TP53 and PIK3CA mutations were significantly related with shorter progression free survival (PFS), and patients with a higher ctDNA fraction showed a worse PFS. The frequency of homologous recombination deficiency (HRD)-related gene mutations was higher than that in matched tumor tissues, and these mutations tended to be associated with shorter PFS. New pathogenic variants were found at the end of treatment in all seven patients, including BRCA2, VHL, RAD50, RB1, BRIP1, ATM, FANCA, and PIK3CA mutations. In conclusion, TP53 and PIK3CA mutations, as well as a higher ctDNA fraction, were associated with worse PFS with trastuzumab and cytotoxic chemotherapy. The enrichment of HRD-related gene mutations and newly detected variants in ctDNA may be related to resistance to treatment.

Dual Biomarker Combining DNA Damage Repair Gene Mutations and PD-L1 Expression for Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) improve long-term survival in advanced non-small cell lung cancer (NSCLC) and require robust predictive biomarkers for the selection of responders. This study investigated the optimal implementation of DNA damage repair (DDR) gene mutations to predict response to ICIs in real-world NSCLC patients. PATIENTS AND METHODS: We retrospectively reviewed 55 advanced NSCLC patients who had undergone targeted high-throughput sequencing and received ICIs. Patients with two or more DDR gene mutations were defined as DDR2 positive. RESULTS: The patients' median age was 68 (range=44-82) years, and 48 (87.3%) were men. Seventeen patients (30.9%) showed ≥50% high programmed death-ligand 1 (PD-L1) expression. Ten patients (18.2%) received an ICI-chemotherapy combination as first-line therapy, and 38 (69.1%) received ICI monotherapy as more than second-line therapy. Fourteen patients (25.5%) were DDR2-positive. The objective response rate of patients with DDR2-positive or PD-L1 ≥50% was 45.5%, and that of patients with DDR2-negative and PD-L1 <50% was 11.1% (p=0.007). In the PD-L1 low expression subgroup (<50%), patients with DDR2-positive had improved progression-free survival (PFS) and overall survival (OS) after ICIs compared to those with DDR2-negative (PFS: 5.8 vs. 1.9 months, p=0.026, OS: 14.4 vs. 7.2 months, p=0.078). DDR2-positive patients or those with PD-L1 ≥50% (24, 43.6%) had statistically significant improvement in PFS and OS after ICIs compared to DDR2-negative and those with PD-L1 <50% (PFS: 4.4 vs. 1.9 months, p=0.006, OS: 11.6 vs. 7.2 months, p=0.037). CONCLUSION: A dual biomarker combining DDR gene mutations and PD-L1 expression improves the prediction of response to ICIs in advanced NSCLC.

Comparison of Treatment Patterns and Clinical Outcomes by Gender in Locally Advanced Head and Neck Squamous Cell Carcinoma (KCSG HN13-01).

We aimed to compare treatment modalities and outcomes by gender in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). We characterized the sex-specific differences and compared the overall survival (OS) between male and female patients in a multicenter cohort of LA-HNSCC. To minimize the observed confounding, propensity score matching was utilized. The study included 445 patients; 385 (86.5%) were men and 60 (13.5%) were women. In terms of age, smoking habits, drinking habits, and primary tumor locations, there was a significant imbalance in sex before the matching. Propensity score matching yielded 60 patient pairs, with no statistical difference between the sexes in terms of their characteristics. As for the treatment strategies, there were no significant differences between the sexes before (p = 0.260) and after (p = 0.585) the propensity score matching. When comparing the survival probabilities between the sexes, OS was not significantly different in the overall (HR 1.02; 95% CI 0.59-1.76; p = 0.938) and propensity-score-matched population (HR 1.46; 95% CI 0.68-3.17; p = 0.331). These results suggest that there was no difference in prognosis by gender in the treatment modalities and outcomes of LA-HNSCC in real-world practice.

A randomized Phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation.

BACKGROUND: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: This is an open-label, multicenter, randomized Phase 2 study in South Korea. Chemonaïve patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. RESULTS: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty-nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression-free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51-1.08; p = .119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31-0.95; p = .032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. CONCLUSIONS: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. PLAIN LANGUAGE SUMMARY: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression-free survival compared with the erlotinib alone. However, the progression-free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects.

A Phase 2 Study of Palbociclib for Recurrent or Refractory Advanced Thymic Epithelial Tumors (KCSG LU17-21).

INTRODUCTION: Thymic epithelial tumors (TETs) are rare but are the most common tumors of the anterior mediastinum. Platinum-based combination chemotherapy is the standard of care for such tumors and is associated with a 50% to 90% objective response rate (ORR) in metastatic disease. Nevertheless, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with the cell cycle, including pRB, p16INK4A, and cyclin D1, are most often observed in TETs. On the basis of these results, we conducted a phase 2 trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. METHODS: This is a phase 2, multicenter, open-label, single-arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapies. The patients received 125 mg of oral palbociclib daily for 21 days, followed by a 7-day break. The primary end point was progression-free survival (PFS). The secondary end points were ORR, duration of response, overall survival, and safety. RESULTS: Between August 2017 and October 2019, a total of 48 patients were enrolled. The median number of previous chemotherapies was one (range: one to four), and 21 (43.7%) of 48 patients received thymectomy. By the WHO classification, the patients were type A (n = 1), type B1 (n = 2), type B2 (n = 8), type B3 (n = 13), thymic carcinoma (n = 23), and unknown (n = 1). With a median follow-up of 14.5 months (range: 0.8-38.2), the median number of cycles of palbociclib monotherapy was 10 (range: 1-40). The ORR was 12.5% (four partial responses in thymoma and two partial responses in thymic carcinoma). The PFS at 6 months was 60.2%, and the median PFS was 11.0 months (95% confidence interval: 4.6-17.4). The median overall survival was 26.4 months (95% confidence interval: 17.4-35.4). The most common treatment-related adverse events of any grade were neutropenia (62.5%), anemia (37.5%), and thrombocytopenia (29.1%), and the most common grade 3/4 treatment-related hematologic adverse event was neutropenia (41.7%). Neutropenia above grade 3 was reversible, and there were no cases with neutropenic fever. CONCLUSIONS: Palbociclib monotherapy was well tolerated and had encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy.

Clinical Implications of BRCA Mutations in Advanced Biliary Tract Cancer.

INTRODUCTION: Current standard chemotherapy for biliary tract cancer (BTC) has limited survival benefits, and the need for targeted therapies is increasing. This study investigated the genetic profiles and clinical implications of BRCA mutations in patients with advanced BTC. METHODS: Targeted high-throughput sequencing was performed on samples obtained from 25 patients with advanced BTC who had received palliative first-line platinum-based chemotherapy. RESULTS: Of the 25 patients, 16 (64.0%) were younger than 65 years of age and 16 (64.0%) were male. The BTC cases consisted of intrahepatic cholangiocarcinoma (9, 36.0%), extrahepatic cholangiocarcinoma (5, 20.0%), and gallbladder cancer (11, 44.0%). The median overall survival (OS) and progression-free survival (PFS) of all patients were 11.9 months (95% confidence interval [CI]: 9.2-14.6) and 5.6 months (95% CI: 3.8-7.3), respectively. Genomic alterations in TP53 (52.0%), BRCA (36.0%), ATM (32.0%), ERBB2 (24.0%), NOTCH1 (20.0%), and FGFR3 (20.0%) were frequently reported. TP53 and ATM mutations were associated with OS (TP53: hazard ratio [HR] 2.719, 95% CI: 1.074-6.881, p = 0.035; ATM: HR 2.780, 95% CI: 1.091-7.082, p = 0.032). Patients with BRCA mutations had a slightly improved PFS compared to those with intact BRCA (6.7 months [range, 2.7-10.7 months] vs. 5.3 months [range, 3.6-7.0 months], p = 0.090). However, there was no significant difference in OS between groups (BRCA mutant vs. intact: 10.6 months [range, 3.6-17.6 months] vs. 11.9 months [range, 7.5-16.3 months], p = 0.252). BRCA mutations were significantly associated with PFS in the multivariate analysis (HR 0.150, 95% CI: 0.034-0.655, p = 0.012). CONCLUSION: This study demonstrated that BRCA mutations might have a role as predictive biomarkers for palliative first-line platinum-based chemotherapy in patients with advanced BTC.

Totality outcome of afatinib sequential treatment in patients with EGFR mutation-positive non-small cell lung cancer in South Korea (TOAST): Korean Cancer Study Group (KCSG) LU-19-22.

Background: Irrespective of the first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor chosen, acquired resistance to therapy is inevitable. Therefore, a key consideration when assessing therapeutic choices is the availability of subsequent treatment options following disease progression. We assessed clinical outcomes in patients who received first-line afatinib treatment with various second-line treatments including osimertinib for patients acquiring the T790M mutation. Methods: A total of 737 EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) patients receiving first-line afatinib treatment were categorized by second-line treatment: T790M+ sequentially treated with osimertinib (cohort A, n=116); T790M- given chemotherapy or others (cohort B, n=143); patients with unknown T790M status (cohort C, n=111); and patients who were undergoing afatinib treatment at the time of data collection, were dead, had discontinued afatinib treatment due to serious adverse events or were lost to follow-up (cohort D, n=367). The primary outcomes were total time on treatment (TOT) and TOT for first-line (TOT-1) and second-line treatments (TOT-2). Secondary outcomes were objective response rates (ORR), overall survival (OS), and central nervous system (CNS) efficacy. Results: Median total TOT in cohorts A, B, C, and D were 35.10 months [95% confidence interval (CI): 30.09-43.53 months], 18.80 months (95% CI: 16.92-20.20 months), 12.00 months (95% CI: 10.22-14.98 months), and 42.60 months (95% CI: 30.95-59.23 months), respectively. The ORR of patients given afatinib was 75.7%. In patients with initial brain metastasis without local treatment, the CNS response rate was 67.0% and CNS progression-free survival was 24.70 months (95% CI: 19.84-33.15 months). Conclusions: This study showed that sequential approach of afatinib followed by second line treatment is an effective therapeutic strategy for EGFR M+ NSCLC patients.

Phase II study to investigate the efficacy of trastuzumab biosimilar (Herzuma®) plus treatment of physician's choice (TPC) in patients with heavily pretreated HER-2+ metastatic breast cancer (KCSG BR 18-14/KM10B).

We investigated the efficacy and safety of a trastuzumab biosimilar, Herzuma®, in combination with treatment of physician's choice (TPC) in patients with HER2+ metastatic breast cancer (MBC) who had failed at least two HER2 directed chemotherapies.

A Phase II Study of Nivolumab plus Gemcitabine in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (KCSG HN17-11).

PURPOSE: Although programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are promising agents for recurrent or metastatic nasopharyngeal carcinoma (NPC), PD-1/PD-L1 inhibitor monotherapy has shown modest efficacy. This study evaluated the efficacy and safety of nivolumab plus gemcitabine in patients with NPC who failed prior platinum-based chemotherapy. PATIENTS AND METHODS: This is a phase II, multicenter, open-label, single-arm study. Patients with recurrent or metastatic NPC received nivolumab 3 mg/kg and gemcitabine 1,250 mg/m2 every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. To identify potential biomarkers, whole-exome sequencing, whole-transcriptome sequencing, and immune phenotype analysis based on Lunit SCOPE IO, an artificial intelligence-powered spatial tumor-infiltrating lymphocyte analyzer, were performed. RESULTS: Thirty-six patients were enrolled between June 2018 and June 2019. The ORR was 36.1% and disease control rate was 97.2%. With median follow-up of 22.0 months, median PFS was 13.8 months [95% confidence interval (CI), 8.6-16.8 months]. Median OS was not reached, and OS rate at 6 months was 97.0% (95% CI, 80.4%-99.6%). The grade ≥3 treatment-related adverse events were hypertension (2.8%) and anemia (2.8%). In multivariate analysis of mutation of chromatin modifier gene, tumor mutational burden (≥ 2.1 mut/Mb), and somatic copy-number alteration (SCNA) level, the group with high SCNA (> 3 points; HR, 7.0; 95% CI, 1.3-37.9; P = 0.02) had independently associated with poor PFS. Immune phenotype analysis showed that tumors with high proportion of immune-excluded immune phenotype was significantly correlated with poor PFS (HR, 4.4; 95% CI, 1.2-16.2; P = 0.018). CONCLUSIONS: Nivolumab plus gemcitabine showed promising efficacy with favorable toxicity profiles in patients with advanced NPC in whom platinum-based combination chemotherapy failed.

RPL17 Promotes Colorectal Cancer Proliferation and Stemness through ERK and NEK2/ß-catenin Signaling Pathways.

Aims: Ribosomal protein L17 (RPL17), a 60S subunit component, is up-regulated in colorectal cancer (CRC). However, its oncogenic role in CRC progression remains unexplored. Thus, we aimed to investigate the effect of RPL17 targeting on CRC in vitro and in vivo and whether RPL17 gained an extra-ribosomal function during CRC development. Methods: RPL17-specific siRNAs complexed with cationic lipids were transfected to CRC cells to silence target gene expression and then real-time RT-PCR and western blotting were applied to observe the change of expression or activity of genes or proteins of interest. Cell proliferation assay, clonogenic assay and cell cycle analysis were used to determine the in vitro effects of RPL17siRNAs on CRC cell growth, and a subcutaneous xenograft assay was applied to test the effect of RPL17siRNAs on in vivo tumor growth. RNA sequencing and western blotting were used to investigate the underlying mechanisms. Sphere-forming assay, invasion assay and migration assay were used to evaluate the effects of RPL17siRNAs on CRC stemness. Results: siRNA-mediated inhibition of RPL17 expression suppressed CRC cell growth and long-term colony formation by inducing apoptotic cell death. Similarly, targeting RPL17 effectively suppressed tumor formation in a mouse xenograft model. RNA sequencing of RPL17-silenced CRC cells revealed the same directional regulation of 159 (93 down- and 66 up-regulated) genes. Notably, NIMA-related kinase 2 (NEK2), which functionally cooperates with extracellular-regulated protein kinase (ERK) and plays a pivotal role in mitotic progression and stemness maintenance, was down-regulated. RPL17 silencing reduced NEK2, ß-catenin, and p-ERK protein levels. These molecular alterations reflected the reduction in sphere-forming capacity, expression of stem cell marker genes, migration, and invasion. Reversely, RPL17 overexpression increased the ability of long-term colony formation, migration, and invasion. Conclusion: Our findings indicate that RPL17 promotes CRC proliferation and stemness via the ERK and NEK2/ß-catenin signaling axis, and targeting RPL17 could be the next molecular strategy for both primary CRC treatment and prevention of secondary tumor formation.

Dose Modification of Etoposide plus Platinum in Elderly Patients with Extensive-Disease Small-Cell Lung Cancer.

BACKGROUND: Elderly patients with extensive-disease small-cell lung cancer (ED-SCLC) have a high risk of chemotherapy toxicity due to multiple comorbidities and poor performance status. Although dose modification is often used to avoid toxicity in elderly patients with ED-SCLC, there is little data on the effect of initial dose-reduced chemotherapy on survival outcomes. METHODS AND PATIENTS: We retrospectively reviewed 100 elderly patients (≥70 years) with ED-SCLC who received first-line etoposide plus platinum chemotherapy between January 2006 and December 2020. RESULTS: The median age was 74 years. Eighty-nine patients (89%) had a history of smoking, and 38 (38%) had chronic lung disease. Thirty-four patients (34%) received dose-reduced etoposide plus platinum in the first cycle. The dose-reduced group had significantly higher age, lower body mass index, and poor Eastern Cooperative Oncology Group Performance Score. There were no significant differences in survival outcomes between the dose-reduced and full-dose chemotherapy (median overall survival [OS], 4.9 vs. 6.5 months, p = 0.440; median progression-free survival [PFS], 3.7 vs. 4.6 months, p = 0.272). In multivariate analyses, DR in the first cycle (hazard ratio 0.519, 95% CI: 0.269-1.000, p = 0.050) was significantly associated with OS. Following a subgroup analysis of 59 patients who received minimum four cycles, no significant differences in survival outcomes between the two groups (median OS, 10.9 vs. 9.4 months, p = 0.817; median PFS, 6.3 vs. 6.5 months, p = 0.902) were noted. CONCLUSIONS: The dose-reduced chemotherapy with first-line etoposide plus platinum had non-inferior survival outcomes compared to the full-dose chemotherapy in elderly patients with ED-SCLC.

Induction Chemotherapy as a Prognostication Index and Guidance for Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: The Concept of Chemo-Selection (KCSG HN13-01).

PURPOSE: Certain patient subgroups who do not respond to induction chemotherapy (IC) show inherent chemoresistance in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). This study aimed to assess the prognostic value of IC, and role of IC in guiding the selection of a definitive locoregional therapy. MATERIALS AND METHODS: Out of the 445 patients in multi-institutional LA-HNSCC cohort, 158 (36%) receiving IC were enrolled. The study outcome was to assess overall survival (OS) through IC responsiveness and its role to select subsequent treatments. RESULTS: Among 135 patients who completed subsequent treatment following IC, 74% responded to IC (complete response in 17% and partial response in 58%). IC-non-responders showed 4.5 times higher risk of mortality than IC-responders (hazard ratio, 4.52; 95% confidence interval, 2.32 to 8.81; p < 0.001). Among IC-responders, 84% subsequently received definitive concurrent chemoradiotherapy (CCRT) and OS was not differed by surgery or CCRT (p=0.960). Regarding IC-non-responders, 54% received CCRT and 46% underwent surgery, and OS was poor in CCRT (24-month survival rate of 38%) or surgery (24-month survival rate of 63%). CONCLUSION: Response to IC is a favorable prognostic factor. For IC-responders, either surgery or CCRT achieved similar survival probabilities. For IC-non-responder, multidisciplinary approach was warranted reflecting patients' preference, morbidity, and prognosis.

Characteristics and treatment patterns in older patients with locally advanced head and neck cancer (KCSG HN13-01).

BACKGROUND/AIMS: Treatment decisions for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are complicated, and multi-modal treatments are usually indicated. However, it is challenging for older patients to complete treatments. Thus, we investigated disease characteristics, real-world treatment, and outcomes in older LA-HNSCC patients. METHODS: Older patients (aged ≥ 70 years) were selected from a large nationwide cohort that included 445 patients with stage III-IVB LA-HNSCC from January 2005 to December 2015. Their data were retrospectively analyzed and compared with those of younger patients. RESULTS: Older patients accounted for 18.7% (83/445) of all patients with median age was 73 years (range, 70 to 89). Proportions of primary tumors in the hypopharynx and larynx were higher in older patients and older patients had a more advanced T stage and worse performance status. Regarding treatment strategies of older patients, 44.5% of patients received concurrent chemoradiotherapy (CCRT), 41.0% underwent surgery, and 14.5% did not complete the planned treatment. Induction chemotherapy (IC) was administered to 27.7% (23/83) of older patients; the preferred regimen for IC was fluorouracil and cisplatin (47.9%). For CCRT, weekly cisplatin was prescribed 3.3 times more often than 3-weekly cisplatin (62.2% vs. 18.9%). Older patients had a 60% higher risk of death than younger patients (hazard ratio, 1.6; p = 0.035). Oral cavity cancer patients had the worst survival probability. CONCLUSION: Older LA-HNSCC patients had aggressive tumor characteristics and received less intensive treatment, resulting in poor survival. Further research focusing on the older population is necessary.

Usefulness of cyclic thermal therapy and red blood cell scintigraphy in patients with chemotherapy-induced peripheral neuropathy.

BACKGROUND: Pharmacological and non-pharmacological therapies have been used to treat patients with chemotherapy-induced peripheral neuropathy (CIPN). However, the effect of therapies in cancer patients has yet to be investigated comprehensively. We hypothesized that cyclic thermal therapy would improve blood flow and microcirculation and improve the symptoms driven by CIPN. METHODS: The criteria of assessment were blood volume in region of interest (ROI) in the images, and European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 questionnaire scores. The blood volume was quantified by using red blood cell (RBC) scintigraphy. All patients were treated 10 times during 10 days. The thermal stimulations, between 15° and 41°, were repeatedly delivered to the patient's hands. RESULTS: The total score of the questionnaires, the score of questions related to the upper limbs, the score of questions closely related to the upper limbs, and the score excluding the upper limbs questions was decreased. The blood volume was decreased, and the variance of blood volume was decreased. During cooling stimulation, the blood volume was decreased, and its variance was decreased. During warming stimulation, the blood volume was decreased, and its variance was decreased. CONCLUSIONS: We suggest that cyclic thermal therapy is useful to alleviate CIPN symptoms by blood circulation improvement. RBC scintigraphy can provide the quantitative information on blood volume under certain conditions such as stress, as well as rest, in peripheral tissue.

Silencing CDCA8 Suppresses Hepatocellular Carcinoma Growth and Stemness via Restoration of ATF3 Tumor Suppressor and Inactivation of AKT/ß-Catenin Signaling.

Big data analysis has revealed the upregulation of cell division cycle associated 8 (CDCA8) in human hepatocellular carcinoma (HCC) and its poorer survival outcome. However, the functions of CDCA8 during HCC development remain unknown. Here, we demonstrate in vitro that CDCA8 silencing inhibits HCC cell growth and long-term colony formation and migration through the accumulation of the G2/M phase cell population. Conversely, CDCA8 overexpression increases the ability to undergo long-term colony formation and migration. RNA sequencing and bioinformatic analysis revealed that CDCA8 knockdown led to the same directional regulation in 50 genes (25 down- and 25 upregulated). It was affirmed based on protein levels that CDCA8 silencing downregulates the levels of cyclin B1 and p-cdc2 and explains how it could induce G2/M arrest. The same condition increased the protein levels of tumor-suppressive ATF3 and GADD34 and inactivated AKT/ß-catenin signaling, which plays an important role in cell growth and stemness, reflecting a reduction in sphere-forming capacity. Importantly, it was demonstrated that the extent of CDCA8 expression is much greater in CD133+ cancer stem cells than in CD133- cancer cells, and that CDCA8 knockdown decreases levels of CD133, p-Akt and ß-catenin and increases levels of ATF3 and GADD34 in the CD133+ cancer stem cell (CSC) population. These molecular changes led to the inhibition of cell growth and sphere formation in the CD133+ cell population. Targeting CDCA8 also effectively suppressed tumor growth in a murine xenograft model, showing consistent molecular alterations in tumors injected with CDCA8siRNA. Taken together, these findings indicate that silencing CDCA8 suppresses HCC growth and stemness via restoring the ATF3 tumor suppressor and inactivating oncogenic AKT/ß-catenin signaling, and that targeting CDCA8 may be the next molecular strategy for both primary HCC treatment and the prevention of metastasis or recurrence.