Somatic mutations introduced into the epidermal growth factor receptor (EGFR) gene in non‐small‐cell lung cancer (NSCLC) are important factors to determine therapeutic responses to gefitinib. The ...current diagnostic test measures the overall EGFR mutation status of the cancer tissue, and may ignore the presence of non‐mutated, gefitinib‐unresponsive cancer cells. Twenty‐one NSCLC patients with EGFR mutations were recruited for the study. All patients were treated with gefitinib after surgical treatment. Fifty to sixty areas of NSCLC tumors were sampled from each tissue, and their EGFR mutation states were determined by a primer extension assay. This assay discriminates between EGFR mutation‐positive and ‐negative cancer cells within a single tumor tissue. Fifteen tissues consisted only of cells with EGFR mutations, but the remaining six tissues contained both mutated and non‐mutated cells. Time to disease progression and overall survival after gefitinib treatment were significantly shorter in those patients with EGFR heterogeneity (P = 0.009 and P = 0.003, respectively). A considerable proportion of NSCLC contains a heterogeneous population of both EGFR mutated and non‐mutated cancer cells, resulting in a reduced response to gefitinib. The intratumor genetic heterogeneity of a target molecule such as EGFR would be an important factor to consider when treating patients with molecular target agents. (Cancer Sci 2008; 99: 929–935)
We retrospectively compared the oncologic outcome after segmentectomy versus lobectomy in patients with clinical (c-) T1a N0 M0 non-small cell lung cancer (NSCLC) detected as a part-solid ...ground-glass nodule or purely solid nodule on thin-section computed tomography.
From 1997 to 2010, 312 patients with c-T1a N0 M0 NSCLC were determined to require a surgical approach categorized as segmentectomy or lobectomy. Preoperatively available data were collected using logistic regression analysis, and propensity matching was performed. Factors affecting local-regional recurrence were assessed by Cox proportional hazards regression analysis and Kaplan-Meier estimates.
The 5-year and 10-year overall survival rates for the 80 patients who underwent segmentectomy were 97.5% and 83.5%, respectively, compared with 87.75% and 75.0%, respectively, for the 232 patients who underwent lobectomy (p = 0.019). Local-regional recurrence as the first relapse site was found in 3 the 80 segmentectomies (3.8%) of and in 15 of the 232 lobectomies (6.5%). The difference in local-regional recurrence-free survival in patients undergoing segmentectomy compared with lobectomy was not significant (p = 0.304). In 69 propensity score-matched pairs, there was no significant difference in the overall survival (p = 0.442) or local-regional recurrence-free survival (p = 0.717) between the two groups. Multivariate analysis using the Cox proportional hazards regression model identified lymphatic invasion as the only independent factor predicting local-regional recurrence (relative risk, 10.764; 95% confidence interval, 2.98 to 57.68).
Our results suggest that the oncologic outcome of segmentectomy vs lobectomy is similar in this cohort of c-T1a N0 M0 NSCLC patients. These results will be validated by large-scale, prospective, randomized trials.
The Japanese Joint Committee of Lung Cancer Registry performed the fourth nationwide registry study of surgical cases. Demographics, safety and quality, prognostic information, and correlations ...between the seventh and the eighth editions of the TNM classification were investigated. The principal results were compared with those of previous Japanese Joint Committee of Lung Cancer Registry studies.
The clinicopathologic profiles, staging, and prognosis of patients who had an operation for primary lung cancer in 2010 were retrospectively collected in 2016 and analyzed.
The cohort consisted of 18,973 patients from 297 hospitals (11,771 males, mean age 68.3 years). Tumor smaller than 2.0 cm was seen in 39.0% of patients, and limited resection was performed in 22.7%. The 30- and 90-day mortality rates were 0.43 and 1.26%, respectively. The overall and disease-free survival rates at 5 years were 74.7 and 67.8%, respectively. The respective 5-year survival rates by pathological stage in the seventh edition in the present study (2010) and in the previous study (2004) were 88.9% and 86.8% for stage IA, 76.7% and 73.9% for stage IB, 64.1% and 61.6% for stage IIA, 56.1% and 49.8% for stage IIB, 47.9% and 40.9% for stage IIIA, 30.2% and 27.8% for stage IIIB, and 36.1% and 27.9% for stage IV. The 5-year survival rates by clinical stage in the eighth edition in the present study were 97.0% for stage 0, 91.6% for stage IA1, 81.4% for stage IA2, 74.8% for stage IA3, 71.5% for stage IB, 60.2% for stage IIA, 58.1% for stage IIB, 50.6% for stage IIIA, 40.5% for stage IIIB, 37.5% for stage IIIC, and 36.0% for IVA/B. With restaging, the overall survival rates of clinical stage IA and IB in the seventh edition were stratified into stages 0 to IA3 and stages IA1 to IIA in the eighth edition, respectively.
This study demonstrates improved surgical results for lung cancer in Japan. The TNM revision for the eighth edition was supported by the assessment of stage migration from the previous edition and the prognostic stratification.
We performed a validation study to confirm the prognostic importance of the presence of a ground-glass opacity component based on data of the Japan Clinical Oncology Group study, JCOG0201, which was ...a prospective observational study to predict the pathological noninvasiveness of clinical stage IA lung cancer in Japan.
Among the 811 patients registered in JCOG0201, 671 were confirmed eligible by study monitoring and a central review of computed tomography. Registered c-stage IA lung cancer was less than 30 mm in maximum tumor size, which was classified into a with ground-glass opacity group (pure ground-glass opacity and part-solid tumor) or solid group based on the status of a ground-glass opacity component. T staging was reassigned in accordance with the 8th edition of the TNM staging system. To validate the prognostic impact, overall survival was estimated.
Of the cases, 432 (64%) were in the with ground-glass opacity group and 239 (36%) were in the solid group with a median follow-up time of 10.1 years. The 5-year overall survival was significantly different between the with ground-glass opacity group and solid group (95.1% vs 81.1%). The 5-year overall survival was excellent regardless of the solid component size in the with ground-glass opacity group (c-T1a or less: 97.2%, c-T1b: 93.4%, c-T1c: 91.7%). In contrast, prognostic impact of the tumor size was definitive in the solid group (c-T1a: 87.5%, c-T1b: 85.9%, c-T1c: 73.7%).
Favorable prognostic impact of the presence of a ground-glass opacity component was demonstrated in JCOG0201. The presence or absence of a ground-glass opacity should be considered as an important parameter in the next clinical T classification.
This supplemental analysis aimed to confirm the prognostic importance of the presence of a GGO component based on data of the JCOG study, JCOG0201. Among the 671 eligible patients, 432 (64%) were classified in the with GGO group and 239 (36%) were classified in the solid group according to the radiological central review board. The 5-year OS was excellent regardless of the solid component size in the with GGO group, whereas prognostic impact of the tumor size was definitive in the solid group. The presence or absence of a GGO would be considered as an important parameter in the next clinical T classification. GGO, Ground-glass opacity. Display omitted
Examination of somatic epidermal growth factor receptor (EGFR) mutations is now a diagnostic routine for treatment of cancer using EGFR tyrosine kinase inhibitors (EGFR-TKI). Circulating tumor DNA is ...a promising target for noninvasive diagnostics. We evaluated its utility by quantitatively detecting activating and resistant mutations, which were measured with BEAMing (beads, emulsion, amplification, and magnetics).
Twenty-three patients with lung cancer with progressive disease after EGFR-TKI treatment and 21 patients who had never been treated with EGFR-TKIs were studied. Their primary tumors were confirmed to have activating mutations. In the plasma DNA of each patient, the activating mutation found in the corresponding primary tumor and the T790M resistance mutation were quantified by BEAMing.
In 32 of 44 patients, activating mutations were detected in the plasma DNA 72.7%; 95% confidence interval (CI), 58.0%-83.6%. The T790M mutation was detected in 10 of 23 patients in the first group (43.5%; 95% CI, 25.6%-53.4%). The ratio of T790M to activating mutations ranged from 13.3% to 94.0%. The peak of the distribution of the mutation allele fraction in the plasma DNA was in the 0.1% to 1% range.
The major advantage of BEAMing is its ability to calculate the fraction of T790M-positive alleles from the alleles with activating mutations. This feature enables the detection of increases and decreases in the number of T790M mutations in cancer cells, regardless of normal cell DNA contamination, which may be useful for monitoring disease progression. Circulating tumor DNA could potentially be used as an alternative method for EGFR mutation detection.
The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs).
Eight facilities participated in this study. A total of 795 patients with 1229 ...SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground-glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part-solid nodules.
The mean prospective follow-up period was 4.3 ± 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part-solid nodules. Thus, the SSNs at the final follow-up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part-solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas MIAs, 21 adenocarcinomas in situ AIS, and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part-solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part-solid nodules was 3.8 ± 2.0 years, whereas the mean period for the HGGNs was 2.1 ± 2.3 years (p = 0.0004).
This study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the part-solid nodules, corresponding to 1% of all 1229 SSNs.
To elucidate the clinical, pathologic, and prognostic impacts of epidermal growth factor receptor (EGFR) mutation and mutation subtypes in early-stage lung cancer, the study investigators conducted a ...retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for patients with surgically resected lung cancer; n = 18,973).
Of 13,951 patients classified as having nonsquamous non-small cell lung cancer in the database, 5780 patients (41.0%) had been tested for an EGFR mutation and were included in this study.
An EGFR mutation was detected in 2410 patients (41.7%), and the presence of an EGFR mutation was significantly correlated with clinicopathologic factors such as the presence of ground-glass opacity (P < .001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without an EGFR mutation, respectively. Of 2410 patients with EGFR mutations, 983 (40.8%) had an exon 19 deletion (Exon 19 Del), 1170 (48.5%) had an L858R mutation, and 257 (10.7%) had other EGFR mutations. A higher smoking rate was found in patients with other EGFR mutations (P = .02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P < .001), a higher rate of pure solid tumors (P < .001), advanced pathologic stage (trend P < .001), and poorer recurrence-free survival (P = .001).
In addition to the clinicopathologic and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and patients have a poorer prognosis than with L858R in early-stage lung cancers.
Patient‐derived cancer organoid culture is an important live material that reflects clinical heterogeneity. However, the limited amount of organoids available for each case as well as the ...considerable amount of time and cost to expand in vitro makes it impractical to perform high‐throughput drug screening using organoid cultures from multiple patients. Here, we report an advanced system for the high‐throughput screening of 2427 drugs using the cancer tissue‐originated spheroid (CTOS) method. In this system, we apply the CTOS method in an ex vivo platform from xenograft tumors, using machines to handle CTOS and reagents, and testing a CTOS reference panel of multiple CTOS lines for the hit drugs. CTOS passages in xenograft tumors resulted in minimal changes of morphological and genomic status, and xenograft tumor generation efficiently expanded the number of CTOS to evaluate multiple drugs. Our panel of colorectal cancer CTOS lines exhibited diverse sensitivities to the hit compounds, demonstrating the usefulness of this system for investigating highly heterogeneous disease.
We report an advanced system for the high‐throughput screening of 2427 drugs using organoids. In this system, we apply the cancer‐tissue originated spheroid (CTOS) method in an ex vivo platform from xenograft tumors, using machines to handle organoids and reagents, and testing a CTOS reference panel of multiple CTOS lines for the hit drugs. Our panel of colorectal cancer CTOS lines exhibited diverse sensitivities to the hit compounds, demonstrating the usefulness of this system for investigating highly heterogeneous disease.
Purpose
We evaluated the impact of omitting mediastinal lymph node dissection (MLND) from the surgical treatment of non-small cell lung cancer (NSCLC) in older patients.
Methods
We collected data ...retrospectively on 2475 patients who underwent pulmonary resection for NSCLC at our hospital between June, 2006 and December 2018. The subjects of this analysis were 209 patients aged ≥ 75 years who underwent lobectomy for cN0–1 NSCLC. The patients were divided into two groups based on whether they underwent MLND (ND2 group) or not (group ND0–1).
Results
There were more patients aged ≥ 80 years in the ND0–1 group than in the ND2 group (
p
< 0.001). Patients in the ND0–1 group had clinically earlier stage lung cancers than those in the ND2 group (
p
= 0.053). We matched patient characteristics in the ND0–1 and ND2 groups by age, tumor diameter, cN, histology, and radiological findings. There were no significant differences in overall survival between the groups (
p
= 0.295). More patients in the ND2 group suffered complications (41.6% vs. 27.3%,
p
= 0.061) and arrhythmia episodes than those in the ND0–1 group (14.3% vs. 3.9%,
p
= 0.021).
Conclusion
MLND in older patients may not extend survival but it could lead to complications. Thus, the omission of MLND may be considered for patients of advanced age.
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