Resected Pathological Stage Research Articles

Late recurrence of completely resected stage I to IIIA lung adenocarcinoma

ObjectiveResearch into the risk factors associated with late recurrence (>2 years after surgery) of lung adenocarcinoma is limited. We investigated the incidence of and clinicopathologic and genomic features associated with late recurrence of resected stage I-IIIA lung adenocarcinoma. MethodsWe performed a retrospective analysis of patients with completely resected pathologic stage I-IIIA lung adenocarcinoma (2010-2019). Patients with a history of lung cancer, neoadjuvant therapy, or mucinous or noninvasive lung adenocarcinoma, or with follow-up of less than 2 years were excluded. Cox and logistic regression modeling were used to compare clinicopathologic variables among patients with no, early (≤2 years), and late recurrence. Comparisons of genomic mutations were corrected for multiple testing. ResultsOf the 2349 patients included, 537 developed a recurrence during follow-up. Most recurrences (55% [297/537]) occurred early; 45% (240/537) occurred late. A larger proportion of late recurrences than early recurrences were locoregional (37% vs 29%; P = .047). Patients with late recurrence had more aggressive pathologic features (International Association for the Study of Lung Cancer grade 2 and 3, lymphovascular invasion, visceral pleural invasion) and higher stage than patients without recurrence. Pathologic features were similar between patients with early and late recurrence, except stage IIIA disease was more common in the early cohort. No genomic mutations were associated with late recurrence. ConclusionsLate recurrence of lung adenocarcinoma after resection is more common than previously reported. Patients without disease more than 2 years after surgery who had aggressive pathologic features at the time of resection have an elevated risk of recurrence and may benefit from more aggressive follow-up.

Tumor Location Is an Independent Prognostic Factor in Completely Resected Pathological Stage I Non-Small Cell Lung Cancer: A Multicenter Retrospective Study.

Previous studies suggested that the location of the primary tumor in non-small cell lung cancer (NSCLC) is associated with clinical features and prognosis, but results are conflicting. The purpose of this study was to explore tumor location as an independent risk factor of survival for patients with completely resected pathological stage I NSCLC. This was a multicenter retrospective study conducted in Taiwan. Included patients were diagnosed with stage I NSCLC and had undergone primary tumor resection. Variables including tumor location, pathological stage, histological differentiation, and International Association for the Study of Lung Cancer (IASLC) grade were evaluated for predictive ability for disease-free survival (DFS) and overall survival (OS). A total of 208 patients were included, with 123 (59.1%) patients having a primary tumor in the upper and middle lobes. The median duration of follow-up for survivors was 60.5 months. Compared to patients with IASLC Grade 3 disease, patients with Grade 1 disease had significantly longer DFS. Tumor location and IASLC grade were independent predictors for OS in multivariate analysis. Specifically, patients with NSCLC in the lower lobe and patients who are histologically classified as IASLC Grade 3 may have poorer prognosis and require greater attention to improve outcomes.

Prognostic significance of ground-glass areas within tumours in non-small-cell lung cancer.

To validate or refute the hypothesis that non-small-cell lung cancers (NSCLC) with ground-glass areas (GGA+) within the tumour on high-resolution computed tomography are associated with a more favourable prognosis than those without GGA (GGA-). We analysed data from a multicentre observational cohort study in Japan including 5005 patients with completely resected pathological stage I NSCLC, who were excluded from the Japan Clinical Oncology Group (JCOG) 0707 trial on oral adjuvant treatment during the enrolment period. The patients' medical and pathological records were assessed retrospectively by physicians and re-staged according to the 8th tumour, node, metastasis edition. Of the 5005 patients, 2388 (48%) were ineligible for the JCOG0707 trial and 2617 (52%) were eligible but were not enrolled. A total of 958 patients (19.1%) died. Patients with GGA+ NSCLC and pathological invasion ≤3 cm showed significantly better overall survival than others. In patients with tumours with an invasive portion ≤4 cm, GGA+ was associated with better survival. The prognoses of patients with GGA+ T2a and GGA- T1c tumours were similar (5-year overall survival: 84.6% vs 83.1%, respectively). The survival with T2b or more tumours appeared unaffected by GGA, and GGA was not prognostic in these larger tumours. Patients with GGA+ NSCLC on high-resolution computed tomography and ≤4 cm invasion size may have a better prognosis than patients with solid GGA- tumours of the same T-stage. However, the presence or absence of radiological GGA has little impact on the prognosis of patients with NSCLC with greater (>4 cm) pathological invasion.

The International Association for the Study of Lung Cancer (IASLC) Staging Project for Lung Cancer: Recommendation to Introduce Spread Through Air Spaces as a Histologic Descriptor in the Ninth Edition of the TNM Classification of Lung Cancer. Analysis of 4061 Pathologic Stage I NSCLC

IntroductionSpread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established. MethodsTo assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI). ResultsSTAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses. ConclusionsThese data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification.

Beneficial implications of adjuvant chemotherapy for stage IB lung adenocarcinoma exhibiting elevated SUVmax in FDG-PET/CT: a retrospective study from a single center.

Controversy surrounds the efficacy of adjuvant chemotherapy (ACT) in the treatment of stage I lung adenocarcinoma (LUAD). The objective of this study was to examine the impact of the maximum standardized uptake value (SUVmax) as measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) on the efficacy of ACT in patients diagnosed with stage I LUAD. We scrutinized the medical records of 928 consecutive patients who underwent complete surgical resection for pathological stage I LUAD at our institution. The ideal cut-off value for primary tumor SUVmax in terms of disease-free survival (DFS) and overall survival (OS) was determined using the X-tile software. The Kaplan-Meier method and Cox regression analysis were used for survival analysis. Based on the SUVmax algorithm, the ideal cutoff values were determined to be 4.9 for DFS and 5.0 for OS. We selected 5.0 as the threshold because OS is the more widely accepted predictive endpoint. In a multivariate Cox regression analysis, SUVmax ≥ 5.0, problematic IB stage, and sublobectomy were identified as independent risk factors for poor DFS and OS. It is noteworthy that patients who were administered ACT had significantly longer DFS and OS than what was observed in the subgroup of patients with pathological stage IB LUAD and SUVmax ≥ 5.0 (p < 0.035 and p ≤ 0.046, respectively). However, there was no observed survival advantage for patients in stages IA or IB who had an SUVmax < 5.0. The preoperative SUVmax of tumors served as an indicator of the impact of ACT in the context of completely resected pathological stage I LUAD. Notably, patients within the Stage IB category exhibiting elevated SUVmax levels emerged as a subgroup experiencing substantial benefits from postoperative ACT.

Intrinsic impacts of the expression of PD-L1 on postoperative recurrence in EGFR-mutated lung adenocarcinoma.

This study aimed to assess the intrinsic impacts of the expression of PD-L1 on postoperative recurrence and the prognosis in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas. Data from 221 surgically resected pathological stage IA-IIIA lung adenocarcinomas, collected between 2017 and 2019, were analyzed. This included measurements of EGFR mutations and the PD-L1 expression. Recurrence-free survival (RFS) and overall survival (OS) were estimated using a Kaplan-Meier analysis and log-rank test. The independent risk factors for RFS were assessed using univariate and multivariate analyses. Among the patients, 140 were PD-L1-negative (<1%), while 81 were PD-L1-positive (≥1%). PD-L1 positivity was significantly associated with male sex (p=0.038), smoking habit (p=0.005), ND2 lymph node dissection (p=0.013), higher malignant subtype (p=0.003), higher histological grade (p=0.001), and advanced pathological stage (p=0.004). Conversely, EGFR mutations were more common in the PD-L1-negative group than in the PD-L1-positive group (p=0.006). Patients were categorized into four groups based on their EGFR mutation status and PD-L1 expression status: PD-L1-positive (≥1%) with or without EGFR mutations (EGFR(+)/PD-L1≥1% or EGFR (-)/PD-L1≥1%), and PD-L1-negative (<1%) with or without EGFR mutations (EGFR(+)/PD-L1<1% or EGFR (-)/PD-L1<1%). Among these groups, EGFR(+)/PD-L1≥1% cases exhibited the worst 5-year RFS (log-rank, p=0.010), while there was no significant difference in 5-year OS (log-rank, p=0.122). Furthermore, a multivariate analysis revealed that PD-L1 positivity was an independent significant factor for RFS in EGFR-mutated lung adenocarcinoma (p=0.013). PD-L1 positivity emerged as an independent risk factor for RFS in patients with EGFR-mutant resected lung adenocarcinoma. These findings may provide valuable insights into the prognostic impact of PD-L1 expression and guide the implementation of postoperative adjuvant therapy in this patient population.

Prognostic value of predominant subtype in pathological stage II–III lung adenocarcinoma with epidermal growth factor receptor mutation

ObjectivesThis study extracted clinicopathological features associated with recurrence and evaluated the tumor microenvironment in consecutive cases with resected pathological stage II–III epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (EGFR-mt). MethodsBetween January 2008 and November 2018, we retrospectively reviewed 387 consecutive patients with pathological stage II–III lung adenocarcinoma who underwent surgical resection. We examined the EGFR mutation status (wild-type or mutant) and the evaluated clinicopathological features of all patients. In addition, tumor-promoting cancer-associated fibroblasts (CAFs), tumor-associated M2 macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment of EGFR-mt cells were evaluated by immunohistochemical analysis. ResultsEGFR-mt (n = 124, 32 %) had more lymph node and pulmonary metastases than EGFR-wild-type lung adenocarcinoma (EGFR-wt) despite the smaller invasive component size. The disease-free survival (DFS) of patients with EGFR-mt tended to be shorter than that of patients with EGFR-wt. In the analysis according to the predominant subtype, EGFR-mt with papillary-predominant subtype had a significantly shorter 5-year DFS than that of EGFR-wt with papillary-predominant subtype (15.3 % vs. 44.1 %, p < 0.01). We observed no significant differences among the other subtypes. Multivariate analysis of DFS in patients with EGFR-mt revealed that male sex, pathological stage III, lymph node metastasis, pulmonary metastasis in the same lobe and non-acinar and non-lepidic predominant subtypes (papillary, solid, or micropapillary) were independent poor prognostic factors. Immunohistochemical analysis of EGFR-mt revealed that non-acinar- and non-lepidic-predominant subtypes were associated with a higher frequency of podoplanin-positive CAFs (36 % vs. 13 %, p = 0.01) and a higher median number of CD204-positive TAMs (61 vs. 49, p = 0.07) compared to the acinar- or lepidic-predominant subtypes. ConclusionsNon-acinar and non-lepidic predominant subtypes were predictors of recurrence and had an aggressive tumor microenvironment in pathological stage II–III EGFR-mt.

Prognostic factors of resected pathological stage I lung adenocarcinoma: evaluating subtypes and PD-L1/CD155 expression

We aimed to compare the prognostic impacts of adenocarcinoma subtypes, programmed death-ligand I (PD-L1), and CD155 expression on patients with resected pathological stage (p-stage) I lung adenocarcinoma. In total, 353 patients with completely resected p-stage I lung adenocarcinomas were retrospectively reviewed. The expression levels of PD-L1 and CD155 in tumour cells from each adenocarcinoma subtype were evaluated using several clinicopathological and histological features, such as the presence of a micropapillary pattern. A total of 52 patients (14.7%) had PD-L1-positive tumours, whereas 128 patients (36.3%) had CD155-positive tumours, with a tumour proportion score of 5% for both PD-L1 and CD155 expression. Compared with patients with other adenocarcinoma subtypes, those with solid-predominant adenocarcinomas were significantly more positive for PD-L1 and CD155. Multivariate analysis showed that PD-L1 expression status was significantly associated with progression-free survival and overall survival, whereas CD155 expression and the presence of a micropapillary pattern were not significantly associated with either parameter. Patients with PD-L1-positive tumours had poorer prognoses than those with CD155-positive tumours. Moreover, PD-L1 and CD155 were significantly expressed in solid-predominant adenocarcinomas. The results of this study suggest that immune checkpoint inhibitors can be used as adjuvants in the treatment of patients with p-stage I adenocarcinoma.

Relative Efficacies of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors for Treatment of Recurrent Non-Small Cell Lung Cancer after Surgery

Introduction: The relative efficacies of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) for the treatment of recurrent non-small cell lung cancer (NSCLC) after surgery remain unclear. Methods: Among 801 patients with NSCLC who underwent pulmonary resection at Kanazawa Medical University between 2017 and 2021, sixty-four patients had recurrence. We retrospectively compared the efficacies of EGFR-TKIs and ICIs in these patients with recurrent NSCLC who underwent pulmonary resection. Results: The 3-year overall survival rates after recurrence were 79.3% in patients who received EGFR-TKIs, 69.5% in patients who received ICIs, and 43.7% in patients who received cytotoxic agents. There was no significant difference in overall survival between patients treated with EGFR-TKIs and ICIs (p = 0.14) or between patients treated with ICIs and cytotoxic agents (p = 0.23), but overall survival was significantly higher in patients treated with EGFR-TKIs compared with cytotoxic agents (p < 0.01). The probabilities of a 2-year response were 88.5%, 61.6%, and 25.9% in patients treated with EGFR-TKIs, ICIs, and cytotoxic agents, respectively. There was no significant difference in response periods between patients treated with EGFR-TKIs and ICIs (p = 0.18), but the response period was significantly better in patients treated with EGFR-TKIs (p < 0.01) or ICIs (p = 0.03) compared with cytotoxic agents. Percent-predicted vital capacity (p = 0.03) and epidermal growth factor receptor gene mutation (p < 0.01) were significant factors affecting the overall response to chemotherapy in multivariate analysis. Conclusion: EGFR-TKIs and ICIs are effective for treating recurrent NSCLC after surgery. Although adjuvant chemotherapy for completely resected pathological stage II to IIIA NSCLC, atezolizumab or osimertinib, has also been recently approved as adjuvant chemotherapy, there is a risk that patients who relapse after adjuvant chemotherapy will have less choice.

Clinical implication of the 2020 International Association for the Study of Lung Cancer histologic grading in surgically resected pathologic stage 1 lung adenocarcinomas: Prognostic value and association with computed tomography characteristics

ObjectivesTo investigate the incremental prognostic value of the 2020 International Association for the Study of Lung Cancer (IASLC) histologic grading system over traditional prognosticators in surgically resected pathologic stage 1 lung adenocarcinomas and to identify the clinical and radiologic characteristics of lung adenocarcinomas reclassified by the 2020 histologic grading system. Materials and methodsWe retrospectively enrolled 356 patients who underwent surgery for pathologic stage 1 adenocarcinoma between January 2016 and December 2017. The histologic grading was classified according to the predominant histologic subtype (conventional system) and the updated 2020 IASLC grading system. The clinical and computed tomography (CT) characteristics were compared according to the reclassification of the updated system. The performance of prognostic models for recurrence-free survival based on the combination of pathologic tumor size, histologic grade, and CT-based information was compared using the c-index. ResultsPostoperative recurrence occurred in 6.7% of patients during the follow-up period (mean, 1589.2 ± 406.7 days). Fifty-nine of 244 (24.2%) tumors with intermediate grades in the conventional system were reclassified as grade 3 with the updated grading system. They showed significantly larger solid proportions and higher percentages of pure solid nodules on CT compared to tumors without reclassification (n = 185) (P < 0.05). Prognostic prediction models based on pathology tumor size and histologic grades had significantly higher c-indices (0.754–0.803) compared to the model based on pathologic tumor size only (c-index:0.723, P < 0.05). ConclusionThe 2020 IASLC histologic grading system has significant incremental prognostic value over the pathologic stage in surgically resected pathologic stage 1 lung adenocarcinoma. Reclassified lung adenocarcinomas using the updated grading system have a larger solid proportion and a higher percentage of pure solid nodules on CT.

Phase II trial of adjuvant de-escalated radiation + adjuvant nivolumab for intermediate-high risk P16+ oropharynx cancer.

6014 Background: Treatment de-intensification for resected, human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is an area of active investigation, with a goal of providing a less toxic adjuvant regimen compared to the current standard of care 66 Gy of radiation (RT) combined with concurrent cisplatin defined in recently reported as Arm D of the ECOG3311 trial. Here, the programmed death 1 (PD-1) antibody nivolumab was added to de-intensified RT in high risk, resected HPV+ OPC. Methods: Eligible patients included transorally resected pathologic stage III or IVA HPV+ OPSCC using p16 immunohistochemistry, featuring high-risk neck disease factors (gross extracapsular extension &gt;1mm or ≥5 positive lymph nodes) to mirror ECOG3311 Arm D patients accrued. Positive margin status was excluded except by PI approval. Postoperative treatment consisted of accelerated fractionation RT (50 Gy over 4 weeks) concurrent with nivolumab at 240 mg every 2 weeks, followed by 6 months of adjuvant nivolumab biweekly or monthly. The primary endpoint was progression-free survival (PFS). Swallowing and quality of life patient reported outcome (PRO) measures were collected at baseline and defined intervals after treatment. Results: Forty-one patients (n=41) were accrued and were analyzed. Forty of 41 patients remain alive with a median follow-up of 30 months (range 1 – 49 months). The probability of 3-year overall survival is 97% (95% CI = 90% - 100%) and the probability of 3-year PFS is 86% (95% CI = 68% - 100%). Two patients developed recurrent disease, one of whom died. One patient developed isolated metastasis while a second developed local, regional, and distant metastasis. The most common adverse grade ≥3 adverse events were lymphocytopenia (n=24), dysphagia (n=2) and oral mucositis (n=2). One grade 4 sepsis/multi-organ failure was reported. Comparison of PRO results with those observed in ECOG3311 trial are underway and will be reported. Conclusions: De-intensification of adjuvant treatment adding nivolumab to RT is tolerable and demonstrates favorable clinical outcome for high-risk, resected, HPV+ HNSCC patients. Further targeted immunotherapy combinations are warranted. Clinical trial information: NCT03715946 .

Randomized phase II study of daily versus alternate-day administrations of S-1 for the elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm)-IIIA of non-small cell lung cancer: Setouchi Lung Cancer Group Study 1201.

It is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC. Elderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. We enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11). Although several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC. Unique ID issued by UMIN: UMIN000007819 (Date of registration: Apr 25, 2012) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009128. Trial ID issued by jRCT: jRCTs061180089 (Date of registration: Mar 22, 2019, for a shift toward a "specified clinical trial" based on Clinical Trials Act in Japan) https://jrct.niph.go.jp/en-latest-detail/jRCTs061180089.

Prognostic impact of noninvasive areas in resected pathological stage IA lung adenocarcinoma.

In non-small-cell lung cancer, ground-glass opacity on computed tomography imaging reflects pathological noninvasiveness and is a favorable prognostic factor. However, the significance of pathological noninvasive areas (NIAs) has not been fully revealed. In this study, we aimed to elucidate the prognostic impact of NIAs on lung adenocarcinoma. We analyzed 402 patients with pathological stage (p-Stage) IA lung adenocarcinoma who underwent surgery in 2013-2016 at two institutions and examined the association of the presence of NIAs with clinicopathological factors and prognosis. Furthermore, after using propensity-score matching to adjust for clinicopathological factors, such as age, sex, smoking history, pathological invasive area size, pathological T factor (p-T), p-Stage, and histological subtype (lepidic predominant adenocarcinoma [LPA] or non-LPA), the prognostic impact of NIAs was evaluated. Patients were divided into NIA-present (N = 231) and NIA-absent (N = 171) groups. Multivariable analysis showed that NIA-present was strongly associated with earlier p-T, earlier p-Stage, LPA, and epidermal growth factor receptor mutation. Kaplan-Meier survival analysis showed that the NIA-present group displayed a better prognosis than the NIA-absent group in disease-free survival (DFS) and overall survival (OS) (5-year DFS 94.6% vs. 87.2%, 5-year OS 97.2% vs. 91.1%). However, after adjusting for clinicopathological factors by propensity score matching, no significant differences in prognosis were identified between the NIA-present and NIA-absent groups (5-year DFS 92.4% vs 89.6%, 5-year OS 95.6% vs 94.3%). Our current study suggests that the prognostic impact of the presence of NIAs on lung adenocarcinoma is due to differences in clinicopathological factors.

Abstract 4535: Clinical outcomes and molecular features of different histopathologic patterns in patients with stage IB non-squamous non-small-cell lung cancer

Abstract Background: About 15% to 20% of patients with stage IB non-small-cell lung cancer (NSCLC) may develop recurrence within 5 years. However, the use of adjuvant therapy for resected stage IB patients remains controversial. This study investigated the differences in prognosis and molecular features between different histopathologic patterns of stage IB non-squamous NSCLC (nsNSCLC) and tried to identify patients who most in need of adjuvant therapy. Methods: A total of 215 patients with completely resected pathologic stage IB (tumor size 3-4 cm) nsNSCLC from Tianjin Medical University Cancer Institute &amp; Hospital between 2014 and 2018 were included in the study. For 130 patients, genomic profiling of tumor tissues was sequenced by a panel of 9 driver genes (OncoScreen® Focus CDx Tissue Kit, Burning Rock Biotech) and the molecular risk stratification was assessed by 14-gene quantitative PCR (qPCR) assay (DetermaRxTM, Burning Rock Biotech). Results: Among the 215 patients, 67.9% were solid/micropapillary-predominant pattern (S/MP), 40.5% had received platinum-based doublet adjuvant chemotherapy, and 5.1% had received adjuvant targeted therapy with or without chemotherapy. Patients with S/MP pattern had significantly worse DFS than those with lepidic/acinar/papillary-predominant (L/A/P) pattern (hazard ratio [HR]: 2.16, 95% confidence interval (CI): 1.28 to 3.67; P = 0.013). However, neither pattern could benefit from adjuvant therapy. EGFR mutation was successfully detected in 75 out of 126 patients (59.5%), and the positive rate in S/MP pattern was significantly lower than that in L/A/P pattern (50.6% vs 79.5%, P = 0.002). However, EGFR mutation status was not a prognostic factor for DFS in neither overall population nor different histopathologic patterns. EGFR-mutant patients showed the trend to benefit from adjuvant targeted-based therapy in the limited samples. Molecular risk stratification was successfully assessed in 99 patients, of which 37.4%, 26.3%, and 36.4% were predicted as molecularly high-risk, intermediate-risk, and low-risk patients, respectively. There were significant differences in the proportion of high- and low-risk patients between S/MP and L/A/P patterns (for high-risk: 46.2% vs 20.6%; for low-risk: 26.2% vs 55.9%; P = 0.009). The high-risk patients had significantly shorter DFS than the low-risk patients (HR, 2.93, 95% CI: 1.31-6.54; P = 0.012), especially those in S/MP pattern (HR, 3.45, 95% CI: 1.46-8.15; P = 0.017). Conclusion: Our study confirms that S/MP pattern is a significantly worse prognostic factor for DFS in nsNSCLC and that there are significant differences in molecular features between these two different histopathologic patterns. qPCR-based assay could reliably identify patients with a worse prognosis in S/MP pattern, suggesting that such patients are most likely to benefit from personalized adjuvant therapy. Citation Format: Dongsheng Yue, Bin Zhang, Chen Chen, Qiang Zhang, Xinyi Wu, Jiping Xie, Changli Wang, Zhenfa Zhang. Clinical outcomes and molecular features of different histopathologic patterns in patients with stage IB non-squamous non-small-cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4535.

Efficacy of Adjuvant Chemotherapy for Stage II/III Nonsmall Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations.

Adjuvant cisplatin-based chemotherapy improves the survival of patients with resected pathological stage II/III nonsmall cell lung cancer (NSCLC). However, the efficacy in patients with epidermal growth factor receptor (EGFR) mutations remains controversial. This retrospective study included 353 patients with resected pathological N1/N2 stage II/III NSCLC between 2010 and 2016. Mutant EGFR (mEGFR) was detected in 76 patients. Adjuvant chemotherapy (AC) was administered to 151 patients. We compared cancer-specific survival (CSS) and recurrence-free survival (RFS) between AC and surgery-alone (SA) groups, including patients with wild-type EGFR (wEGFR) and mEGFR. Using multivariate analysis, we evaluated the prognostic factors in patients with wEGFR and mEGFR. The median follow-up time was 4.7 years. In patients with wEGFR, the differences in CSS and RFS between the AC (n = 114) and SA (n = 163) groups were significant (CSS: 66.8% [5 years] vs. 49.4% [5 years], p = 0.001; RFS: 54.2% [5 years] vs. 39.2% [5 years], p = 0.013). The significant prognostic factors were AC (vs. SA; p < 0.0001), diffusing capacity of the lung for carbon monoxide > 60% (p = 0.028), tumor size (p < 0.001), lymphatic permeation (p = 0.041), and pN1 (vs. pN2; p < 0.001). However, the differences in CSS and RFS between the AC (n = 37) and SA (n = 39) groups were not significant (CSS: 64.0% [5 years] vs. 58.1% [5 years], p = 0.065; RFS: 45.0% [5 years] vs. 33.8% [5 years], p = 0.302). Multivariate analysis identified no significant prognostic factors in patients with mEGFR. We demonstrated the efficacy of AC in patients with mEGFR and wEGFR. The efficacy of AC may be lower in patients with mEGFR than in those with wEGFR.

Spread through air spaces is a powerful prognostic predictor in patients with completely resected pathological stage I lung adenocarcinoma

PurposeTo evaluate the frequency of spread through air spaces (STAS) in patients with early-stage primary lung cancer and to elucidate the association between STAS and various clinicopathological factors. MethodsWe retrospectively reviewed data from a total of 265 consecutive patients who underwent lobectomy and mediastinal lymph node dissection (172 patients) or sublobar resection (93 patients) for completely resected pathological stage I lung adenocarcinoma. We evaluated clinical variables, including the preoperative serum carcinoembryonic antigen (CEA) level, tumour size, consolidation tumour ratio (CTR), maximum standardized uptake value (SUVmax) on FDG-PET, histological results, presence of STAS and vascular and lymphatic invasion. ResultsThe median follow-up time after surgery was 49 months. Eighty-seven patients (32.8 %) had STAS. The overall survival rates of patients in the STAS-positive and STAS-negative groups were 92.7 % and 97.1 % at 3 years, respectively (p = 0.1255), and the recurrence-free survival rates were 82.1 % and 95.9 % at 3 years, respectively (p = 0.0001). STAS was found in 73 patients (42.4 %) in the lobectomy group, which was a significantly higher proportion than the 14 patients (15.1 %) in the sublobar resection group. The STAS-positive group had significantly larger areas of invasion, higher CTRs, preoperative CEA and SUVmax levels, and more lymphatic and vascular invasion. STAS also correlated significantly with large consolidation sizes, larger invasive size, higher CTRs and the presence of a micropapillary pattern. Cox regression analysis after adjustment for important prognostic factors revealed that the presence of STAS was an independent predictor associated with postoperative recurrence, most of which was observed locoregionally. ConclusionsSTAS was an independent factor associated with postoperative recurrence after lung resection for stage I lung adenocarcinoma. Among stage IA patients, the postoperative outcomes of STAS-positive patients were worse than those of STAS-negative patients and were similar to those of stage IB patients.

Development and Validation of a Decision Support Framework to Evaluate the Role of Postoperative Radiotherapy in Patients with Pathological N2 Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Postoperative radiotherapy (PORT) plays a highly controversial role in pN2 NSCLC disease. Recent study revealed that not all patients can benefit from PORT. Further study is needed to identify predictors for PORT. <h3>Materials/Methods</h3> A total of 1044 patients with completely resected pathologic stage T1-3N2M0 NSCLC were analyzed. Risk factors of distant metastasis were identified by the log-rank tests and the multivariable Cox models. The decision support framework (DSF) was built based on the previously published PI model and risk factors of distant metastasis. An independent dataset was used to validate the DSF. <h3>Results</h3> Clinical N2 status (HR=1.227, 95% CI 1.036 to 1.453, P=0.0178) and >4 involved lymph nodes (HR=1.272, 95% CI 1.071 to 1.510, P=0.0058) were identified as independent risk factors of distant metastasis and were also found to be associated with locoregional recurrence (LRR) in our previous work. The high-intermediate-risk histological type (micropapillary or solid positive adenocarcinomas) was found to be associated with distant metastasis (HR=1.207, 95% CI 1.062 to 1.371, P=0.0129), but not associated with LRR. We built an DSF accordingly and stratify patients into four groups: high LRR risk and high-intermediate histological risk (HHR) group, high LRR risk and low histological risk (HLR) group, low LRR risk and high-intermediate histological risk (LHR) group, and low LRR risk and low histological risk (LLR) group. PORT significantly improved OS only in the subgroup with a high risk of LRR and low-risk histological type (3-year OS rates: 66.7% for PORT vs. 50.2% for non-PORT, respectively; P=0.023). In the HHR group, PORT was associated with a not significant increase in OS. In the LLR and the LHR groups, no significant differences in OS were observed between PORT and non-PORT. <h3>Conclusion</h3> This study developed and validated a DSF combining two types of clinicopathological characteristics to predict the outcome of PORT in patients with completely resected pN2 NSCLC individually.

The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for mid-low rectal cancer: extended follow-up of a randomised controlled trial

PurposeThe impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection.MethodsThis is an extension of a multicentre RCT (NCT01110798). Kaplan–Meier method and the log-rank test were used to estimate and compare the 3-, 5-, and 10-year OS and DFS, and local and distant recurrence in patients with and without AL. Predictors of OS and DFS were evaluated using the Cox regression analysis as secondary aim.ResultsFollow-up was available for 311 patients. Of them, 252 (81.0%) underwent neoadjuvant chemoradiotherapy and 138 (44.3%) adjuvant therapy. AL occurred in 63 (20.3%) patients. At a mean follow-up of 69.5 ± 31.9 months, 23 (7.4%) patients experienced local recurrence and 49 (15.8%) distant recurrence. The 3-, 5-, and 10-year OS and DFS were 89.2%, 85.3%, and 70.2%; and 80.7%, 75.1%, and 63.5% in patients with AL, and 88.9%, 79.8% and 72.3%; and 83.7, 74.2 and 62.8%, respectively in patients without (p = 0.89 and p = 0.84, respectively). At multivariable analysis, AL was not an independent predictor of OS (HR 0.65, 95%CI 0.34–1.28) and DFS (HR 0.70, 95%CI 0.39–1.25), whereas positive circumferential resection margins and pathological stage impaired both.ConclusionsIn the context of modern multimodal rectal cancer treatment, AL does not affect long-term OS, DFS, and local and distant recurrence in patients with mid-low rectal cancer.

Clinical impact of primary tumor sidedness and sex on unresectable post-recurrence survival in resected pathological stage II-III colorectal cancers: a nationwide multicenter retrospective study

BackgroundSeveral studies have demonstrated that right-sided tumors have poorer prognosis than left-sided tumors in patients with unresectable colorectal cancer (CRC). The predictive ability of the tumor sidedness in CRC treated with chemotherapy in each sex is unclear.MethodsSubjects were 964 unresectable recurrent patients treated with chemotherapy with stage II-III CRC after curative resection between 2004 and 2012. Post-recurrence cancer-specific survival (CSS) for each sex was examined.ResultsPatients were 603 males (222 right-side tumors (cecum to transverse colon) and 381 left-sided tumors (descending colon to rectum)), and 361 females (167 right-side tumors and 194 left-sided tumors). Right-sided tumors developed peritoneal recurrences in males and females. Left-sided tumors were associated with locoregional recurrences in males and with lung recurrences in females. Right-sided tumors were associated with shorter post-recurrence CSS in both sexes. In males, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.53, P < 0.0001) together with the presence of regional lymph node metastasis histopathological type of other than differentiated adenocarcinoma, the recurrence of liver only, the recurrence of peritoneal dissemination only, and relapse-free interval less than one-year. In females, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.50, P = 0.0019) together with advanced depth of invasion, the presence of regional lymph node metastasis, and recurrence of liver only.ConclusionsPrimary tumor sidedness in both sexes in unresectable recurrent CRC patients treated with chemotherapy may have prognostic implications for post-recurrence CSS.

CD155 expression and its clinical significance in non-small cell lung cancer.

CD155 serves an important role in tumor progression by promoting cell proliferation and migration. CD155 is also involved in the immune evasion of tumor cells, which may cause the development and progression of tumors. Accordingly, CD155 has emerged as a novel target in cancer immunotherapy; however, its expression in lung cancer remains unclear. To assess CD155 expression and its prognostic significance, 96 patients with completely resected pathologic stage I adenocarcinoma of the lung were retrospectively reviewed. Immunohistochemical staining was performed to evaluate CD155 expression on tumor cells. Expression levels of programmed death-ligand 1 (PD-L1), another molecule participating in immune evasion, were also evaluated immunohistochemically. CD155 expression was positive in 37 patients (38.5%). CD155-positivity was associated with aggressive tumor behavior, such as pleural invasion and vascular invasion. In addition, CD155-positivity was a significant factor to predict a poor prognosis (5-year overall survival (OS) rate, 63.3% for CD155-positive patients vs. 93.1% for CD155-negative patients; P<0.001). Patients harboring tumors with positive CD155 and PD-L1 expression showed the poorest prognosis (5-year OS rate, 44.4% for both-positive patients vs. 85.4% for the other patients; P<0.001). The positive expression status of both CD155 and PD-L1 was a significant and independent unfavorable prognostic factor (hazard ratio, 3.86; 95% confidence interval, 1.51-9.89; P=0.004; in a multivariate analysis). In conclusion, CD155-positivity was associated with aggressive tumor behavior, and was a factor to predict a poor prognosis. Its prognostic impact was enhanced when combined with PD-L1 expression status. These results should be validated in a large-scale study.