Advanced Adenocarcinoma Patients Research Articles

The Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Predicting Treatment Response Before EGFR TKI Treatment in Patients with Advanced Lung Adenocarcinoma.

Objectives:This study makes a retrospective examination of exploring the prognostic value of 18fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) related metabolic-volumetric variables, nutritional status, and immune and inflammatory markers on progression-free survival (PFS) and overall survival (OS) in advanced adenocarcinoma patients with positive epidermal growth factor receptor (EGFR) mutations undergoing EGFR tyrosine kinase inhibitor (TKI) therapy.Methods:A retrospective examination was made of patients diagnosed with lung adenocarcinoma who underwent 18F-FDG PET/CT imaging for staging maximum four weeks before starting treatment, between January 2015 and July 2020. Included in the study were 68 patients identified histopathologically to have locally advanced/metastatic EGFR mutation-positive adenocarcinoma, and who underwent EGFR TKI therapy. The laboratory data of the patients, obtained 15 days before imaging performed for PET/CT staging, were evaluated.Results:Metabolic tumor volume, modified Glasgow prognostic score and locally advanced disease were identified as independent prognostic parameters for PFS (p=0.004, p=0.029, p=0.016, respectively). A univariate Cox regression analysis revealed albumin/alkaline phosphatase and tumor size to be significant parameters for prognosis (p=0.033, p=0.043, respectively). A multivariate Cox regression analysis revealed that none of the parameters were predictive or OS.Conclusion:The parameters of 18F-FDG PET/CT, especially the volumetric parameters, were found to be strong prognostic factors with statistical significance for predicting PFS. We believe that these parameters are important prognostic markers that should be evaluated together in the management and follow-up of patients with EGFR mutation-positive adenocarcinoma.

Frequency and clinical features of BRAF mutations among patients with stage III/IV lung adenocarcinoma without EGFR/ALK aberrations.

PurposeBRAF mutations are found in 1–5% of non-small cell lung cancers, particularly adenocarcinomas. However, information regarding this mutation is limited in patients without EGFR/ALK aberrations, who have limited treatment options.Patients and methodsThe medical records of 224 stage III/IV adenocarcinoma patients without EGFR/ALK aberrations and with available pathologic tissue, were retrospectively reviewed. BRAF mutations were evaluated using a PNAClampTM BRAF mutation detection kit (Panagene, Daejeon, Korea). The outcomes in the study population were compared with stage III/IV adenocarcinoma patients harboring an EGFR mutation. A case report of targeted therapy against BRAF mutations was also presented.ResultsA cohort of 222 adenocarcinoma patients with adequate pathologic tissue samples was analyzed. The median patient age was 63 years, 68.8% of the patients were male and 68.7% were ever-smokers. The V600E BRAF mutation was detected in 4 patients (1.8%). The 222 study patients had a poorer survival outcome compared to stage III/IV adenocarcinoma patients with an EGFR mutation (median, 12 vs 67 months, P<0.001) from a recent previous study. Moreover, a 47-year-old female with a recurrent adenocarcinoma and a BRAF V600E mutation exhibited tumor regression after a fourth line therapy with dabrafenib and trametinib, targeting agents against BRAF mutations.ConclusionAlthough BRAF mutations are found in 1.8% of advanced adenocarcinoma patients without EGFR/ALK aberration, they may be able to serve as a treatment target in those patients.

Caspase 8 polymorphisms contribute to the prognosis of advanced lung adenocarcinoma patients after platinum-based chemotherapy

ABSTRACTLung cancer is the leading cause of cancer deaths in China, and about 60% of the cases are diagnosed with histological adenocarcinoma. The caspase 8 (CASP8) gene is a critical initiator of the extrinsic apoptosis pathway. To explore the relationship between tagSNPs or haplotypes of CASP8 and the efficacy of platinum-based chemotherapy in advanced lung adenocarcinoma patients of China, we recruited 555 advanced adenocarcinoma patients. We extracted the genomic DNA from patients' peripheral blood samples and sequenced tagSNPs of CASP8. We calculated the individual haplotype of CASP8 frequencies using the PHASE 2.0 program. The association between CASP8 tagSNPs and overall survival (OS) was calculated by univariate and multivariate Cox regression analysis. A univariate logistic regression analysis was done to analyze the CASP8 tagSNPs and the toxicity of platinum-based chemotherapy. The same statistical methods were used for exploring haplotypes of CASP8. Rs3769821 and rs1045494 of CASP8 were independent prognosis factors for overall survival (OS) using multivariate Cox's regression models. For the haplotype of the 7 tagSNPs, haplotype AGGAAAGA was correlated with the efficacy of platinum-based chemotherapy. The polymorphisms of CASP8, rs7608692, and haplotype AGAACAG correlated with neutropenia toxicity. The haplotype GGGGAAA was associated with thrombocytopenia toxicity. We conclude that the polymorphisms of CASP8 contribute to the prognosis of advanced lung adenocarcinoma and influence the quality of life and survival.

P2.03b-052 XRCC1 Arg399Gln and Rad51 G135C Gene Polymorphisms in Advanced Lung Adenocarcinoma in Serbia: Topic: Biomarkers

XRCC1 and Rad51 are proteins involved in DNA base excision repair and DNA homologous recombination/double-stranded-break repair mechanisms respectively. In non-small cell lung cancer, XRCC1 Arg399Gln polymorphism (disrupts protein-protein interactions), and Rad51 G135C polymorphism (enhances Rad51 promoter activity), have been proposed as factors that influence the overall and progression-free survival (OS and PFS) of patients treated with platinum-based chemotherapy. This study aimed to evaluate the influence of XRCC1 Arg399Gln and Rad51 G135C polymorphisms on the toxicity of chemotherapy and clinical outcome (OS, PFS) of advanced adenocarcinoma patients in Serbia. The study included 94 advanced lung adenocarcinoma patients, EGFR wild type, stage IIIB or IV (TNM7), performance status 0, 1 or 2, of Caucasian descent, who received standard platinum-based chemotherapy. XRCC1 and Rad51 genotyping was done by PCR-RFLP. Statistical analysis was performed using Chi-square, Fisher’s exact, Wilcoxon rank sum test, Breslow-Day test. Survival methodology was used for OS and PFS (Kaplan-Meier product limit method and Log-Rank test, Cox regression for HR). Statistical significance was considered for p<0.05. The group consisted of 62 males (66%) and 32 females (34%), median age at diagnosis 61 years (range 37-84), with 77 (82 %) of current or ex-smokers, and 65 (66%) of which presented with metastases at diagnosis. Follow up period was 1-55 months (median 11 months), during which 76 patients (81%) progressed, and 24 (19%) experienced chemotherapy-related toxicity of grade 3 and 4. Median (95%CI) PFS was 8,1 months (7.1-9.1), and median OS was 10 months (8.2-11.7). Genotype frequencies for XRCC1 Arg399Gln were 39.4% for Arg/Arg, 25.5% for Arg/Gln and 3.2% for Gln/Gln genotype. For Rad51 G135C frequencies were 61.7% for G/G, 26.6% for G/C and 1.1% for C/C genotype. Carriers of the XRCC1 Gln allele had a significantly shorter PFS (7.2m vs 9.5m, Breslow p=0.023) and OS (6.4m vs 15.7m, Breslow p=0.04), and were more susceptible to progression during chemotherapy. Although Rad51 genotypes alone had no statistically significant effect on PFS and OS, carriers of both XRCC1 Gln allele and Rad51 C allele had a 4 months shorter OS, the difference was not statistically significant. There were no statistically significant differences in the occurrence of high grade chemotherapy-induced toxicity according to the patients' XRCC1 and Rad51 genotypes. These results suggest that in the Serbian population XRCC1 and Rad51 genotyping could be a useful tool for predicting the clinical outcome with platinum-based chemotherapy in advanced EGFR wild-type adenocarcinoma patients.

Quantification of mutant alleles in circulating tumor DNA can predict survival in lung cancer.

PurposeWe aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the quantitative and dynamic detection of EGFR mutations and next generation sequencing (NGS) for screening EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance-relevant mutations in circulating tumor DNA (ctDNA) from advanced lung adenocarcinoma (ADC) patients.ResultsDetection limit of EGFR mutation in ctDNA by ddPCR was 0.04%. Taking the EGFR mutation in tumor tissue as the golden standard, the concordance of EGFR mutations detected in ctDNA was 74% (54/73). Patients with EGFR mutation in ctDNA (n = 54) superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P < 0.001) and overall survival (OS, median, 35.6 vs. 23.8 months, P = 0.028) compared to those with EGFR wild type in ctDNA (n = 19). Patients with high EGFR-mutated abundance in ctDNA (> 5.15%) showed better PFS compared to those with low EGFR mutated abundance (≤ 5.15%) (PFS, median, 15.4 vs. 11.1 months, P = 0.021). NGS results showed that 66.6% (8/12) total mutational copy number were elevated and 76.5% (26/34) mutual mutation frequency increased after disease progression.MethodsSeventy-three advanced ADC patients with tumor tissues carrying EGFR mutations and their matched pre- and post-EGFR-TKIs plasma samples were enrolled in this study. Absolute quantities of plasma EGFR mutant and wild-type alleles were measured by ddPCR. Multi-genes testing was performed using NGS in 12 patients.ConclusionsDynamic and quantitative analysis of EGFR mutation in ctDNA could guide personalized therapy for advanced ADC. NGS shows good performance in multiple genes testing especially novel and uncommon genes.

EGFR Mutation Impact on Definitive Concurrent Chemoradiation Therapy for Inoperable Stage III Adenocarcinoma

Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of epidermal growth factor receptor (EGFR) mutation on CRT efficacy. From 2006 to 2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting and compared the clinical outcomes and recurrence patterns according to mutation status. Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR-mutant and wild-type patients (72.4% versus 72.0%, p = 0.607). The median progression-free survival in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95% confidence interval, CI: 7.6-19.0] versus 16.5 [95% CI: 11.8-19.9] months, p = 0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR-mutant and wild-type patients, respectively (p = 0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% versus 40%, p = 0.001). The brain was the most often affected site in EGFR-mutant patients (35%). However, locoregional recurrence was less common in EGFR-mutant patients than in the wild-type population (14% versus 35%, p = 0.027). Overall survival was similar between EGFR-mutant and wild-type patients (51.1 [95% CI: 28.2-70.2] versus 42.9 [95% CI: 35.3 to not available] months, p = 0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras-mutant patients had significantly worse overall survival than Kras wild-type patients (21.6 versus 49.8 months, p = 0.024). Concurrent CRT resulted in shorter progression-free survival in EGFR-mutant stage III adenocarcinoma patients than in wild-type patients, mainly because of distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-tyrosine kinase inhibitors for EGFR-mutant locally advanced adenocarcinoma patients receiving definitive CRT may be needed.

Survival and recurrence patterns after neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) for locally advanced esophagogastric adenocarcinoma.

We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a safe, tolerable, and effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophagogastric junction (EGJ). We hypothesized that DCF combined with enhanced surgical control would result in a low rate of local or regional recurrence, and thus reviewed our outcomes with this treatment regimen. A prospectively entered database of all esophageal and EGJ ADC patients resected at a high-volume referral center over 6 years (9/07-9/13) was reviewed for cases treated with curative intent neoadjuvant DCF followed by en bloc resection with extended lymphadenectomy (D2/D3). Recurrences was defined as locoregional (biopsy on endoscopy/regional lymph nodes (LNs)) and distant. Standard statistical techniques were used. Of 279 patients with ADC, 86 (85% male, mean age 63 years (interquartile range 56-70)) underwent preoperative DCF and curative intent resection for locally advanced ADC (cT3 93%; cN+ 69%) of the EGJ (54%) or distal esophagus (46%). After median follow-up of 40 months, the overall 5-year survival was 54% and 43 (52%) had recurred at a median time of 14 months. Sites of recurrence included locoregional only in 2 of 45 (4%), distant only in 40 of 45 (89%), and locoregional and distant in 3 of 45 (7%). The present study demonstrates favourable oncologic outcomes with low local/regional recurrence and an excellent overall 5-year survival after neoadjuvant DCF for esophageal and EGJ ADCs. Because the majority of recurrences were distant, our data support the notion that efforts to improve outcomes in these patients should concentrate on enhancing systemic, rather than local, therapy.

Malignant Pleural Effusion Supernatants Are Substitutes for Metastatic Pleural Tumor Tissues in EGFR Mutation Test in Patients with Advanced Lung Adenocarcinoma

BackgroundThough the possibility of using malignant pleural effusions (MPEs) as alternatives for metastatic pleural tumor tissues (MPTTs) in epidermal growth factor receptor (EGFR) mutation test has been examined, due to the lack of studies comparing the results in matching MPEs and MPTTs, the clinical value of MPEs for advanced adenocarcinoma patients with pleural effusions is not confirmed.MethodsEGFR mutation statuses in matching MPTTs, MPE supernatants and cell blocks, of 41 patients with advanced lung adenocarcinoma as diagnosed by thoracoscopy were analyzed using amplification refractory mutation system (ARMS).ResultsEGFR mutations were detected in 46.3% (19/41) of MPTTs, 43.9% (18/41) of MPE supernatants and 56.3% (18/32) of MPE cell blocks by ARMS analysis. Generally, the same EGFR statuses were identified in both MPTTs and matching MPE cell blocks of 81.3% patients (26/32), whereas MPTTs and matching MPE supernatants of 87.8% (36/41) patients shared the same EGFR status. Compared with EGFR mutation detection in MPTTs, the sensitivity of EGFR mutation detection in MPE-cell blocks was 87.5% (14/16), specificity was 75.0% (12/16), while the sensitivity of EGFR mutation detection in MPE-supernatants was 84.2% (16/19), specificity was 90.9% (20/22).ConclusionsThe high concordance of EGFR mutation statuses between MPEs and MPTTs in lung adenocarcinoma patients with pleural metastasis as determined by ARMS analysis suggests that MPEs, particularly MPE supernatants, may be substitutes for MPTTs in EGFR mutation test.

A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1).

CRA8007 Background: Heat shock protein 90 chaperone function is critical for the biological effects of several oncoproteins. Ganetespib (G) is a highly potent 2nd-generation Hsp90 inhibitor with a favorable safety profile and single-agent clinical activity. Methods: Based on synergistic preclinical interactions between docetaxel (D) and G, we conducted a randomized (1:1), international open-label study of D with or without G. Patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1 were included. D was given at 75 mg/m2 on day 1 of a three-week cycle. In the experimental arm, D was given on day 1 and G at 150 mg/m2 on days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutations. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma, 120 eLDH, and 80 mKRAS patients. Statistical tests are 1-sided. Results: Enrollment of 255 adenocarcinoma patients completed in November 2012; results are reported for this population. Patient characteristics were balanced (median age 60 years, males ~60%, PS 0 ~40% and never-smoker ~25%). For D+G vs. D the median number of cycles delivered was 5 vs. 4; the grade 3/4 adverse events were neutropenia 38% vs. 37%; fatigue 4% vs. 3%; anemia 7% vs. 6%; diarrhea 3% vs. 0; fever with neutropenia 8% vs. 2%. At the time of abstract submission OS HR was 0.69 (90% CI 0.48 to 0.99, p=0.093), the PFS HR was 0.70 (90% CI 0.53 to 0.94, p=0.012), and the ORR was 15% vs 11%, favoring D+G. For patients that were enrolled &gt;6 months after diagnosis of advanced NSCLC (N=175; 69%), a prespecified stratification factor, the OS HR was 0.41 (90% CI 0.25 to 0.67, p=0.0009), the PFS HR was 0.47 (90% CI 0.32 to 0.69, p=0.0005), and the ORR was 16% vs 12%. Updated results for both populations above, as well as for the eLDH and mKRAS subsets, will be presented. Conclusions: D+G demonstrated improvement in OS, PFS, and ORR over D alone for second-line therapy of lung adenocarcinoma. A phase III study in second-line advanced adenocarcinoma patients (&gt; 6 months from diagnosis) is ongoing (GALAXY-2). Clinical trial information: NCT01348126.

Gefitinib frequently induces liver damage in patients with lung adenocarcinoma previously treated by chemotherapy.

Gefitinib is known as one of the agents for treating patients with both advanced lung cancer and an epidermal growth-factor receptor mutation. In the epidermal growth-factor receptor-mutant advanced non-small-cell lung cancer population, gefitinib therapy has been associated with increased response rate, longer progression-free survival, and better quality of life compared to other anticancer drugs. However, gefitinib has to be discontinued for patients in whom adverse events occur, even if it is still effective. Here, we retrospectively assessed the clinical course of patients receiving gefitinib therapy, with a particular focus on liver damage. Of 24 Asian patients treated with 250 mg gefitinib daily at Kanagawa National Hospital, Japan, between January 2008 and June 2012, grade 3 liver damage (Common Terminology Criteria for Adverse Events, version 4.0) occurred in nine and were eligible for our assessment. The regimen was subsequently changed to alternate-day administration. The relationships between liver damage and each clinical factor were retrospectively examined using Fisher's exact test. Of the nine patients with liver damage, seven had previous exposure to another anticancer drug. There was a significant relationship between the incidence of liver damage and previous chemotherapy (P = 0.009). The objective response rates of patients treated with daily gefitinib 250 mg and alternate-day gefitinib following liver damage were 66.7% and 46.7%, respectively; these were not significantly different (P = 0.597). Gefitinib for advanced adenocarcinoma patients who have previously undergone chemotherapy should be used cautiously and liver function monitored closely, because it frequently induces significant liver damage. The alternate-day administration of gefitinib may be a suitable option for patients in whom daily gefitinib therapy induces liver damage.

Serum miR-142-3p is associated with early relapse in operable lung adenocarcinoma patients

The outcome of resectable non-small cell lung cancer (NSCLC) is critically determined by metastatic spread: About 30–50% of early-stage NSCLC patients encounter tumour recurrence within 5 years after surgery. A biomarker-driven stratification of early-stage lung cancer with a high risk of recurrence may improve therapy management and patient care. The aim of this study was to identify microRNAs (miRNAs) in serum of patients associated with early relapse in pulmonary adenocarcinoma.Serum samples were collected from 204 patients before surgery. miRNA screening was done using qRT-PCR based low-density arrays (664 miRNAs) comparing adenocarcinoma patients (n=40) with and without recurrence 24 months after surgery. Selected miRNAs associated with disease recurrence were validated in an independent patient cohort (n=114). miRNAs were also measured in advanced adenocarcinoma patients (n=29), and individuals with benign pulmonary diagnosis (n=21).Circulating miR-142-3p (p=0.005) and miR-29b (p=0.01) were identified in the screening and confirmed in the validation cohort to be increased in sera of early-stage adenocarcinoma patients suffering from recurrence within 24 months. Elevated miRNA levels were exclusively observed in the group of high-risk patient diagnosed for operable adenocarcinoma compared with benign diagnosis or advanced tumour disease. The differentiation between pulmonary adenocarcinoma patients with low and high risk for recurrence was improved by accounting for both miR-142-3p levels and tumour stage (p=0.007; AUC=0.78).In conclusion, circulating miR-142-3p was found to be associated with a high risk of recurrence in early-stage lung adenocarcinoma patients, and a putative serum marker for risk assessment.

WS4-2 - Disease Flare after Gefitinib Discontinuation

ABSTRACT Introduction A recent retrospective analysis mentioned that 23% of Non-Small Cell Lung Cancer (NSCLC) patients those who acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) demonstrated ‘disease flare’ after discontinuation of EGFR-TKI. However, two thirds of patients enrolled in the analysis were treated with EGFR-TKI in the adjuvant setting, maintenance therapy, or combined with cytotoxic chemotherapy. Methods To clarify the details of disease flare in the metastatic NSCLC, we reviewed the clinical records of EGFR mutated, advanced adenocarcinoma patients who were treated with gefitinib monotherapy in our hospital between January 2007 and December 2010. Disease flare was defined as unexpected interventions (e.g. radiation therapy, or pleural drainage), hospitalization, or death attributable to disease progression after gefitinib discontinuation. Results Five of 63 patients (8%; 95% CI: 3–17%) experienced disease flare. The flare group demonstrated shorter median progression-free survival with gefitinib than no flare group (231 versus 328 days, P Conclusion Our analysis demonstrated a lower incidence of disease flare after gefitinib discontinuation compared with the previous report. Clinical factors associated with disease flare were almost similar to that.

Comparison of EGFR mutation status in paired pre- and post-chemotherapy serum for advanced pulmonary adenocarcinoma

背景与目的存在表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变的非小细胞肺癌（non-small cell lung cancer, NSCLC）作为NSCLC的一个特殊亚群，对于表皮生长因子酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI）的治疗显示出良好的疗效。本研究旨在检测晚期肺腺癌患者化疗前后血清EGFR基因外显子19和外显子21的突变状态，并分析化疗是否对EGFR基因突变状态产生影响。方法磁珠法提取血清游离DNA后，使用酶切富集巢式PCR分别对血清游离DNA中EGFR外显子19和外显子21进行特异性扩增，应用直接测序法对EGFR基因突变状态进行检测。结果33例肺腺癌患者化疗前EGFR基因突变率为39.4%（13/33），化疗后为54.5%（18/33），化疗前后EGFR基因突变状态的一致率为54.5%（18/33）；在不一致的15例患者中，10例由化疗前EGFR基因突变阴性变为阳性，5例由化疗前阳性变为阴性。结论化疗可能导致血清EGFR基因突变状态的改变。