A phase 2 multicenter study of docetaxel-PM and trastuzumab-pkrb combination therapy in recurrent or metastatic salivary gland carcinomas.

BACKGROUND: Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. The high positivity rate for human epidermal growth factor receptor 2 (HER2) led to an investigation of the efficacy of HER2-targeted agents. Docetaxel-PM (polymeric micelle) is a low-molecular-weight, nontoxic, biodegradable, and docetaxel-loaded micellar formulation. Trastuzumab-pkrb is a biosimilar to trastuzumab. METHODS: This was a multicenter, single-arm, open-label phase 2 study. Patients with HER2-positive (immunohistochemistry [IHC] score of ≥2+ and/or HER2/chromosome enumeration probe 17 [CEP17] ratio of ≥2.0) advanced SDCs were enrolled. Patients received docetaxel-PM (75 mg/m2 ) and trastuzumab-pkrb (8 mg/kg in the first cycle and 6 mg/kg in subsequent cycles) every 3 weeks. Primary end point was objective response rate (ORR). RESULTS: A total of 43 patients were enrolled. The best objective responses were partial response in 30 (69.8%) patients and stable disease in 10 (23.3%) patients, leading to an ORR of 69.8% (95% confidence interval [CI], 53.9-82.8) and a disease control rate of 93.0% (80.9-98.5). Median progression-free survival, duration of response, and overall survival were 7.9 (6.3-9.5), 6.7 (5.1-8.4), and 23.3 (19.9-26.7) months, respectively. Patients with HER2 IHC score of 3+ or HER2/CEP17 ratio ≥2.0 demonstrated better efficacies compared to those with HER2 IHC score of 2+. Thirty-eight (88.4%) patients experienced treatment-related adverse events (TRAE). Because of TRAE, nine (20.9%), 14 (32.6%), and 19 (44.2%) patients required temporary discontinuation, permanent discontinuation, or dose reduction, respectively. CONCLUSIONS: The combination of docetaxel-PM and trastuzumab-pkrb demonstrated promising antitumor activity with a manageable toxicity profile in HER2-positive advanced SDC. PLAIN LANGUAGE SUMMARY: Salivary duct carcinoma (SDC) is uncommon but is the most aggressive subtype of salivary gland carcinomas. SDC shares morphological and histological similarities with invasive ductal carcinoma of breast, which led to an investigation of hormonal receptor and human epidermal growth factor receptor 2 (HER2)/neu expression status in SDC. In this study, patients with HER2-positive SDC were enrolled and treated with combination of docetaxel-polymeric micelle and trastuzumab-pkrb. Promising antitumor activities were shown with objective response rate of 69.8%, disease control rate of 93.0%, median progression-free survival of 7.9 months, median duration of response of 6.7 months, and median overall survival of 23.3 months.

Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients.

BACKGROUND: KEYNOTE-063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second-line therapy in Asian patients with advanced programmed death ligand 1 (PD-L1)-positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer. METHODS: This randomized, open-label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety. RESULTS: Between February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE-061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4-10 months) with pembrolizumab versus 8 months (95% CI, 5-11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63-1.54). Median PFS was 2 months (95% CI, 1-3 months) with pembrolizumab versus 4 months (95% CI, 3-6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04-2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any-grade treatment-related adverse events occurred in 28 pembrolizumab-treated patients (60%) and 42 paclitaxel-treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively. CONCLUSIONS: Definitive conclusions about the efficacy of second-line pembrolizumab in Asian patients with advanced PD-L1-positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE-061 trial.

Intermuscular fat density as a novel prognostic factor in breast cancer patients treated with adjuvant chemotherapy.

BACKGROUND: Body composition, including sarcopenia and fat parameters, has received much attention as a prognostic factor in breast cancer. METHODS: A total of 479 breast cancer patients who underwent surgery and received adjuvant chemotherapy were enrolled in this study. Body composition, including the index and density of skeletal muscle, visceral fat, subcutaneous fat, and intermuscular fat calculated by CT scan, was used as a prognostic factor. The endpoints were breast cancer-specific survival (BCSS) and overall survival (OS). RESULTS: The number of patients with stages I, II, and III was 146 (30.5%), 237 (49.5%), and 96 (20%), respectively. Sarcopenia and muscle density were not significant prognostic factors for BCSS and OS. A high visceral fat index (VFI) was an independent prognostic factor for BCSS (HR, 2.55; 95% CI 1.10-5.95, p = 0.03) and OS (HR 2.55, 95% CI 1.26-5.16, p = 0.01). In addition, high intermuscular fat density (IMFD) was also a significant prognostic factor for BCSS (HR, 2.95; 95% CI 1.34-6.46, p = 0.007) and OS (HR 2.28, 95% CI 1.22-4.26, p = 0.01) in multivariate analysis. CONCLUSION: VFI and IMFD were significant prognostic factors for BCSS and OS in breast cancer patients treated with adjuvant chemotherapy.

The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy.

BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Loss of Von Hippel-Lindau (VHL) Tumor Suppressor Gene Function: VHL-HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC).

Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel-Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL-HIF-VEGF/VEGFR pathway, which involves the von Hippel-Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL-HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL-HIF pathway.

Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG).

BACKGROUND: Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). METHODS: Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. RESULTS: Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. CONCLUSION: In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.

Multicenter, cross-sectional observational study of the impact of neuropathic pain on quality of life in cancer patients.

PURPOSE: Neuropathic cancer pain (NCP) is a common and potentially debilitating symptom in cancer patients. We investigated the prevalence of NCP, as well as its management and association with QOL. METHODS: Cancer patients with pain ≥1 on the visual analogue scale (VAS) were surveyed with the Douleur Neuropathique (DN4) questionnaire, the Brief Pain Inventory-Short Form (BPI-SF), and the EuroQOL five dimensions (EQ-5D) questionnaire. The associations between NCP and pain severity or NCP and QOL, while controlling for variables relevant to QOL, were then analyzed. RESULTS: A total of 2003 patients were enrolled in this survey; the prevalence of NCP was 36.0% (n = 722, 95% CI, 32.5-39.5). We found that NCP in cancer patients was closely correlated to a higher pain severity (BPI-SF; 4.96 ± 1.94 versus 4.24 ± 2.02, p < 0.001), and in patients with NCP, pain more severely interfered with daily living, as compared to those without NCP (BPI-SF; 4.86 ± 2.71 versus 4.41 ± 2.87, p < 0.001). Patients with NCP also had worse QOL than those without NCP, as measured by EQ-5D index score (0.47 ± 0.30 vs. 0.51 ± 0.30, p = 0.005), and this was confirmed using multivariate analysis (p < 0.001), even after controlling for other variables such as age, sex, disease stage, cancer duration, radiotherapy, chemotherapy, and comorbidities. Importantly, adjuvant analgesics were used in less than half of patients with NCP (n = 358, 46.4%). CONCLUSIONS: We found that NCP in cancer patients was significantly associated with a worsened QOL, and current management is inadequate. Therefore, future research aimed at developing improved strategies for management of NCP is required.

Role of autophagy-related protein expression in patients with rectal cancer treated with neoadjuvant chemoradiotherapy.

BACKGROUND: Autophagy, a cellular degradation process, has complex roles in tumourigenesis and resistance to cancer treatment in humans. The aim of this study was to explore the expression levels of autophagy-related proteins in patients with rectal cancer and evaluate their clinical role in the neoadjuvant chemoradiotherapy setting. METHODS: All specimens evaluated were obtained from 101 patients with colorectal cancer who had undergone neoadjuvant chemoradiotherapy and curative surgery. The primary outcomes measured were the expression levels of two autophagy-related proteins (microtubule-associated protein 1 light chain 3 beta (LC3ß) and beclin-1) by immunohistochemistry and their association with clinicopathological parameters and patient survival. RESULTS: Among the 101 patients, the frequency of high expression of beclin-1 was 31.7% (32/101) and that of LC3ß was 46.5% (47/101). A pathologic complete response was inversely associated with LC3ß expression (P = 0.003) and alterations in the expression of autophagy-related proteins (P = 0.046). In the multivariate analysis, however, autophagy-related protein expression did not show prognostic significance for relapse-free survival or overall survival. CONCLUSIONS: High expression of autophagy-related proteins shows a strong negative association with the efficacy of neoadjuvant chemoradiotherapy in patients with rectal cancer. Autophagy has clear implications as a therapeutic target with which to improve the efficacy of neoadjuvant chemoradiotherapy.

Reduced luminal circumference of tumors plays a key role in anorectal function during the early period after neoadjuvant chemoradiation therapy in rectal cancer patients.

PURPOSE: The deterioration of anorectal function after neoadjuvant chemoradiation therapy (nCRT) combined with surgery for rectal cancer has not been well defined. The aim of this study was to evaluate the relationship between the tumor response to nCRT and changes in anorectal function during a short-term period after nCRT. METHODS: We analyzed 100 consecutive patients with available preoperative anorectal manometry data, both before and after nCRT, from 2010 to 2013. RESULTS: Comparing the manometric data before and after nCRT, the values reflecting rectal sensory function after nCRT was significantly lower than those before nCRT. However, in patients who experienced changed tumor morphology and a reduction in luminal circumferential ratio (LCIR) of tumor after nCRT, the values reflecting rectal sensory function were significantly less decreased after nCRT. On multivariate analysis, the reduction of LCIR after nCRT was a very important factor preventing the impairment of anorectal function during the short-term period in terms of the first rectal sensory threshold (RST) (P = 0.002), the RST of "desire to defecate" (P = 0.006), and rectal compliance (P = 0.003). Additionally, in linear regression analysis, the RST for the desire to defecate was positively affected by tumor morphology (P = 0.015) and the reduced LCIR (P = 0.025), and rectal compliance was positively affected by the reduced LCIR (P = 0.001). CONCLUSION: The nCRT impaired significantly rectal sensory function during the short-term period after nCRT and before a radical operation. However, this reduced LCIR of tumors after nCRT may prevent or minimize impediments to anorectal function during the short-term period after nCRT.

New insights into ATR inhibition in muscle invasive bladder cancer: The role of apolipoprotein B mRNA editing catalytic subunit 3B.

Background: Apolipoprotein B mRNA editing catalytic polypeptide (APOBEC), an endogenous mutator, induces DNA damage and activates the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) pathway. Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer (MIBC), it has a poor survival rate. Therefore, this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B (APOBEC3B) expressing MIBC. Methods: Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC. The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis. Western blot analysis was performed to confirm differences in phosphorylated Chk1 (pChk1) expression according to the APOBEC3B expression. Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin. Conclusion: There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC. Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels. Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression. Compared to cisplatin single treatment, combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression. Conclusion: Our study shows that APOBEC3B's higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition. This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.

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.

Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04).

PURPOSE: In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. MATERIALS AND METHODS: We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). RESULTS: A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. CONCLUSION: To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.

Glucose transporter 1 (GLUT1) of anaerobic glycolysis as predictive and prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer.

PURPOSE: We investigated the relationships between biomarkers related to anaerobic glycolytic metabolism (GLUT1, LDH5, PDK1, and HIF-1α proteins), pathologic response, and prognosis. METHODS: All stage II and stage III rectal cancer patients had 50.4 Gy (1.8 Gy/day in 28 fractions) over 5.5 weeks, plus 5-fluorouracil (425 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GLUT1, LDH5, PDK1, and HIF-1α proteins was determined by immunohistochemistry and was assessed in 104 patients with rectal cancer treated with neoadjuvant chemoradiotherapy. RESULTS: This study included stage II and III rectal cancer patients, and each stage accounted for each 50 % of the total cases. A high expression of GLUT1 protein was associated with a significantly lower rate of ypCR compared with low expression of GLUT1 protein (4.0 % vs. 27.8 %, respectively; p = 0.012). GLUT1 expression was also significantly higher in the poor response group (Grade 0, 1) than in the good response group (Grade 2, 3) (34.0 % vs. 14.8 %, respectively; p = 0.022). In recurrence analysis, the expression of GLUT1 protein demonstrated a significant correlation with time to recurrence, based on a log-rank method (p = 0.016). When analyzed by multiple Cox regression, the positive expression of GLUT1 was the most significant and independent unfavorable prognostic factor (p = 0.004). CONCLUSIONS: GLUT1 expression is a predictive and prognostic factor for pathologic complete response and recurrence in rectal cancer patients treated with 5-flurouracil and leucovorin neo-adjuvant chemoradiotherapy.

Relationship between Systemic Inflammatory Markers, GLUT1 Expression, and Maximum 18F-Fluorodeoxyglucose Uptake in Non-Small Cell Lung Carcinoma and Their Prognostic Significance.

BACKGROUND: Factors involved in inflammation and cancer interact in various ways with each other, and biomarkers of systemic inflammation may have a prognostic value in cancer. Glucose transporter 1 (GLUT1) plays a pivotal role in glucose transport and metabolism and it is aberrantly expressed in various cancer types. We evaluated the differential expression of GLUT1, along with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in non-small-cell lung cancer (NSCLC), and then analyzed their prognostic significance. METHODS: A total of 163 patients with resectable NSCLC were included in this study. Tumor sections were immunohistochemically stained for GLUT1 and GLUT3. Maximum standardized uptake value (SUVmax) was measured by preoperative FDG-PET, and neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were derived from pretreatment blood count. RESULTS: GLUT1 and GLUT3 was positively expressed in 74.8% and 6.1% of the NSCLC tissues, respectively. GLUT1 expression was significantly correlated with squamous cell carcinoma histology, poor differentiation, high pathologic stage, old age, male, smoking, and high SUVmax (>7) (all p < 0.05). The squamous cell carcinoma and smoker group also showed significantly higher SUVmax (both p < 0.001). Systemic inflammation markers, including NLR, PLR, and LMR, were positively correlated with high SUVmax (all p < 0.05). High GLUT1 expression, high SUVmax, high NLR, and low LMR, were significantly associated with poor overall survival in patients with NSCLC. However, in the multivariate survival analysis, LMR was an independent prognostic factor overall (HR 1.86, 95% CI 1.05-3.3) and for the stage I/II cohort (HR 2.3, 95% CI 1.24-4.3) (all p < 0.05). CONCLUSIONS: Systemic inflammatory markers-NLR, PLR, and LMR are strongly correlated with the SUVmax and are indicators of aggressive tumor behavior. Specifically, LMR is a promising prognostic biomarker in NSCLC patients.

A Randomized Phase III Study of Patients With Advanced Gastric Adenocarcinoma Without Progression After Six Cycles of XELOX (Capecitabine Plus Oxaliplatin) Followed by Capecitabine Maintenance or Clinical Observation.

PURPOSE: Oxaliplatin, a component of the capecitabine plus oxaliplatin (XELOX) regimen, has a more favorable toxicity profile than cisplatin in patients with advanced gastric cancer (GC). However, oxaliplatin can induce sensory neuropathy and cumulative, dose-related toxicities. Thus, the capecitabine maintenance regimen may achieve the maximum treatment effect while reducing the cumulative neurotoxicity of oxaliplatin. This study aimed to compare the survival of patients with advanced GC between capecitabine maintenance and observation after 1st line XELOX chemotherapy. MATERIALS AND METHODS: Sixty-three patients treated with six cycles of XELOX for advanced GC in six hospitals of the Catholic University of Korea were randomized 1:1 to receive capecitabine maintenance or observation. The primary endpoint was progression-free survival (PFS), analyzed using a two-sided log-rank test stratified at a 5% significance level. RESULTS: Between 2015 and 2020, 32 and 31 patients were randomized into the maintenance and observation groups, respectively. After randomization, the median number of capecitabine maintenance cycles was 6. The PFS was significantly higher in the maintenance group than the observation group (6.3 vs. 4.1 months, P=0.010). Overall survival was not significantly different between the 2 groups (18.2 vs. 16.5 months, P=0.624). Toxicities, such as hand-foot syndrome, were reported in some maintenance group patients. Maintenance treatment was a significant factor associated with PFS in multivariate analysis (hazard ratio, 0.472; 95% confidence interval, 0.250-0.890; P=0.020). CONCLUSIONS: After 6 cycles of XELOX chemotherapy, capecitabine maintenance significantly prolonged PFS compared with observation, and toxicity was manageable. Maintenance treatment was a significant prognostic factor associated with PFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02289547.

Durvalumab in Combination With Olaparib Versus Durvalumab Alone as Maintenance Therapy in Metastatic NSCLC: The Phase 2 ORION Study.

INTRODUCTION: Increased DNA damage triggered through poly (ADP-ribose) polymerase inhibition may modify tumor immunogenicity, sensitizing tumors to immunotherapy. ORION (NCT03775486) evaluated the combination of olaparib with durvalumab as maintenance therapy in patients with metastatic NSCLC. METHODS: ORION is a phase 2, randomized, multicenter, double-blind, international study. Patients with metastatic NSCLC (without activating EGFR or ALK aberrations) and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled to receive initial therapy with durvalumab (1500 mg intravenously; every 3 wk) plus platinum-based chemotherapy for four cycles. Patients without disease progression were then randomized (1:1) to maintenance durvalumab (1500 mg; every 4 wk) plus either olaparib (300 mg orally) or placebo (both twice daily); randomization was stratified by objective response during initial therapy and tumor histologic type. The primary end point was investigator-assessed progression-free survival (PFS) (Response Evaluation Criteria in Solid Tumors version 1.1). RESULTS: Between January 2019 and February 2020, 269 of 401 patients who received initial therapy were randomized. As of January 11, 2021 (median follow-up: 9.6 mo), median PFS was 7.2 months (95% confidence interval: 5.3-7.9) with durvalumab plus olaparib versus 5.3 months (3.7-5.8) with durvalumab plus placebo (hazard ratio = 0.76, 95% confidence interval: 0.57-1.02, p = 0.074). Safety findings were consistent with the known profiles of durvalumab and olaparib. Anemia was the most common adverse event (AE) with durvalumab plus olaparib (26.1% versus 8.2% with durvalumab plus placebo). The incidence of grade 3 or 4 AEs (34.3% versus 17.9%) and AEs leading to treatment discontinuation (10.4% versus 4.5%) was numerically higher with durvalumab plus olaparib versus durvalumab plus placebo. CONCLUSIONS: Maintenance therapy with durvalumab in combination with olaparib was not associated with a statistically significant improvement in PFS versus durvalumab alone, although numerical improvement was observed.

Clinical Outcomes of Upfront Primary Tumor Resection in Synchronous Unresectable Metastatic Colorectal Cancer.

The role of upfront primary tumor resection (PTR) in patients with unresectable metastatic colorectal cancer without severe symptoms remains controversial. We retrospectively analyzed the role of PTR in overall survival (OS) in this population. Among the 205 patients who enrolled, the PTR group (n = 42) showed better performance (p = 0.061), had higher frequencies of right-sided origin (p = 0.058), the T4 stage (p = 0.003), the M1a stage (p = 0.012), and <2 organ metastases (p = 0.002), and received fewer targeted agents (p = 0.011) than the chemotherapy group (n = 163). The PTR group showed a trend for longer OS (20.5 versus 16.0 months, p = 0.064) but was not related to OS in Cox regression multivariate analysis (p = 0.220). The male sex (p = 0.061), a good performance status (p = 0.078), the T3 stage (p = 0.060), the M1a stage (p = 0.042), <2 organ metastases (p = 0.035), an RAS wild tumor (p = 0.054), and the administration of targeted agents (p = 0.037), especially bevacizumab (p = 0.067), seemed to be related to PTR benefits. Upfront PTR could be considered beneficial in some subgroups, but these findings require larger studies to verify.

Lymphovascular invasion is a significant prognosticator in rectal cancer patients who receive preoperative chemoradiotherapy followed by total mesorectal excision.

PURPOSE: This study was designed to identify the significance of lymphovascular invasion as a prognosticator for tumor recurrence and survival in rectal cancer patients treated with preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME). METHODS: Between January 2003 and October 2010, the study included 328 patients with primary rectal cancer who had received preoperative CRT followed by TME. We analyzed the clinicopathologic factors that may be associated with survival, such as age, gender, carcinoembryonic antigen (CEA) value, pathologic T and N stage, tumor response, histologic grade, lymphovascular invasion (LVI), and perineural invasion. RESULTS: Higher pathologic T and N stage, poor tumor response, high-grade histology, and positive LVI were adverse prognostic factors for both disease-free survival (DFS) and overall survival (OS) on the multivariate analysis. Perineural invasion was a significant adverse prognostic factor affecting DFS (P=0.046) but not OS (P=0.08). Increased T and N stage and distant recurrence, but not local recurrence, were significant factors associated with LVI. The LVI-negative group had a higher DFS (71.4 vs. 56.2%, P=0.012) and OS rate (86.7 vs. 63.4%, P=0.020) at 5 years than the LVI-positive group did. CONCLUSIONS: Positive LVI had a negative impact on survival in patients with rectal cancer who received preoperative CRT and TME and is significantly associated with an increased chance of distant recurrence. Based on this finding, more tailored adjuvant chemotherapy is warranted for advanced rectal cancer patients with LVI to reduce the distant dissemination of tumor.

Prognostic significance of breast cancer subtype and p53 overexpression in patients with locally advanced or high-risk breast cancer treated using upfront modified radical mastectomy with or without post-mastectomy radiation therapy.

BACKGROUND: Although post-mastectomy radiation therapy (PMRT) has shown benefits, its effects in patient subpopulations remain uncertain. Therefore, we assessed whether breast cancer subtype and p53 overexpression were associated with outcome after modified radical mastectomy (MRM), with or without PMRT. METHODS: We retrospectively analyzed the records of patients who underwent MRM, with or without PMRT, between January 1991 and December 2008. Patients were considered eligible if they had T3 or T4 stage disease; any T stage with N2 or N3 stage; any T or N stage with positive, close (<1 mm) resection margins; or skin, nipple, or pectoral muscle invasion. We used immunohistochemistry and/or fluorescent in situ hybridization to determine breast cancer subtypes and p53 overexpression status. RESULTS: We found that 104 patients were eligible, including 59 (56.7%) who underwent PMRT and 45 (43.3%) who did not. Median follow-up duration was 61.3 months (range 16.1-232.7). Overall survival (OS) was significantly longer in patients who underwent PMRT (P = 0.029). This trend was evident in the subgroup of luminal type A breast cancer (P = 0.017) and non-p53 overexpression (P = 0.026) patients. However, there was no significant survival benefit from PMRT in the subgroup of triple negative (TN) breast cancer (P = 0.528) and p53 overexpression (P = 0.189) patients. CONCLUSIONS: The benefit of PMRT differed among subgroups with different breast cancer subtype and p53 overexpression. More efficacious systemic treatment strategies are needed, especially in patients at high risk for distant metastasis, to obtain optimal therapeutic gain.

Efficacy of dabrafenib/trametinib in pancreatic ductal adenocarcinoma with BRAF NVTAP deletion: A case report.

Studies have been actively conducted to identify actionable mutations and incorporate them into clinical practice in pancreatic ductal adenocarcinoma (PDAC), which is known to have a poor prognosis with traditional cytotoxic chemotherapy. A BRAF point mutation in V600E is commonly reported in KRAS wild-type PDAC, and targeting BRAF_V600E is already being applied to various carcinomas, including PDAC. Accumulated evidence also shows that not only BRAF_V600E but also short in-frame deletions of BRAF have an oncogenic function. Here, we report that a patient with BRAF N486_P490 deletion initiated on dabrafenib or trametinib, a BRAF inhibitor, and a MEK inhibitor, respectively, after cytotoxic chemotherapy failure. The patient then presented with a partial response.