Disease-free Survival In Stage Research Articles

Impact of chemotherapy delay on long-term prognosis of laparoscopic radical surgery for locally advanced gastric cancer: a pooled analysis of four randomized controlled trials.

Adjuvant chemotherapy following curative surgery for locally advanced gastric cancer (AGC) significantly improves long-term patient prognosis. However, delayed chemotherapy (DC), in which patients are unable to receive timely treatment, is a common phenomenon in clinical practice for various reasons. This study aimed to investigate the impact of DC on the prognosis of patients with stage II-III locally AGC and explore the associated risk factors. Data from four prospective studies were included in the pooled analysis. The planned chemotherapy (PC) group was defined as the time interval between surgery and the first chemotherapy ≤ 49 d, while the DC group was defined as the time interval between surgery and chemotherapy > 49 d. The prognosis, recurrence, and risk factors were compared, and a nomogram for predicting DC was established. In total, 596 patients were included, of whom 531 (89.1%) had PC and 65 (10.9%) had DC. Survival analysis revealed that the 5-year overall survival (OS) and disease-free survival (DFS) were significantly lower in the DC group than those in the PC group (log-rank P < 0.001). Cox univariable and multivariable analyses showed that DC was an independent risk factor for OS and DFS in stage II-III patients (P < 0.05). Based on the significant factors for DC, a prediction model was established that had a good fit, high accuracy (AUC = 0.780), and clinical applicability in both the training and validation sets. Delayed chemotherapy after gastrectomy is associated with poor long-term prognosis in patients with locally advanced stage II-III GC disease. But standardized, full-cycle adjuvant chemotherapy after surgery may play a remedial role, and can to a certain extent compensate the poor effects caused by delayed chemotherapy.

Adjuvant Osimertinib in Patients With Stage IB to IIIA EGFR Mutation-Positive NSCLC After Complete Tumor Resection: ADAURA China Subgroup Analysis

IntroductionIn Chinese patients with NSCLC, prevalence of EGFR-mutated (EGFRm) disease is high. In the global phase 3 ADAURA study (NCT02511106), adjuvant osimertinib was found to have a statistically significant and clinically meaningful improvement in disease-free survival (DFS) versus placebo in resected stage IB to IIIA EGFRm NSCLC. We present efficacy and safety data from a subgroup analysis of 159 Chinese patients enrolled in the People’s Republic of China from ADAURA. MethodsIn ADAURA, patients with completely resected stage IB to IIIA EGFRm (exon 19 deletion/exon 21 L858R) NSCLC were randomized 1:1 to receive osimertinib (80 mg once daily) or placebo for 3 years or until disease recurrence/discontinuation. Adjuvant chemotherapy was permitted before randomization, per physician/patient choice. Primary end point was investigator-assessed DFS in stage II to IIIA disease; secondary end points included DFS in stage IB to IIIA (overall population), overall survival, health-related quality of life (HRQoL), and safety. ResultsOf 682 patients enrolled globally, 159 patients in the People’s Republic of China were included in this subgroup analysis (osimertinib n = 77; placebo n = 82). Baseline characteristics were balanced across the treatment arms. At data cutoff, stage II to IIIA DFS hazard ratio (HR) was 0.23 (95% confidence interval [CI]: 0.13–0.42; maturity 59%); stage IB to IIIA DFS HR was 0.29 (95% CI: 0.17–0.48; maturity 42%). At 13% maturity (21 deaths), HR for overall survival in the stage IB to IIIA population was 0.51 (95% CI: 0.21–1.20). HRQoL was maintained from baseline, and safety was consistent with the global population. ConclusionsIn this population of Chinese patients from ADAURA, adjuvant osimertinib was found to have a clinically meaningful improvement in DFS versus placebo, with maintained HRQoL and a safety profile consistent with the global study population.

Long-Term Oncologic Outcomes in Robot-Assisted and Video-Assisted Lobectomies for Non-Small Cell Lung Cancer.

This study compares long-term outcomes in patients undergoing video-assisted thoracic surgery (VATS) and robotic-assisted thoracic surgery (RATS) lobectomy for non-small cell lung cancer (NSCLC); all consecutive patients who underwent RATS or VATS lobectomy for NSCLC between July 2015 and December 2021 in our center were enrolled in a single-center prospective study. The primary outcomes were overall survival (OS), disease-free survival (DFS), and recurrence rate. The secondary outcomes were complication rate, length of hospitalization (LOS), duration of chest tubes (LOD), and number of lymph node stations harvested. A total of 619 patients treated with RATS (n = 403) or VATS (n = 216) were included in the study. There was no significant difference in OS between the RATS and VATS groups (3-year OS: 75.9% vs. 82.3%; 5-year OS: 70.5% vs. 68.5%; p = 0.637). There was a statistically significant difference in DFS between the RATS and VATS groups (3-year DFS: 92.4% vs. 81.2%; 5-year DFS: 90.3% vs. 77.6%; p < 0.001). Subgroup analysis according to the pathological stage also demonstrated a significant difference between RATS and VATS groups in DFS in stage I (3-year DFS: 94.4% vs. 88.9%; 5-year DFS: 91.8% vs. 85.2%; p = 0.037) and stage III disease (3-year DFS: 82.4% vs. 51.1%; 5-year DFS: 82.4% vs. 37.7%; p = 0.024). Moreover, in multivariable Cox regression analysis, the surgical approach was significantly associated with DFS, with an HR of 0.46 (95% CI 0.27-0.78, p = 0.004) for RATS compared to VATS. VATS lobectomy was associated with a significantly higher recurrence rate compared to RATS (21.8% vs. 6.2%; p < 0.001). LOS and LOD, as well as complication rate and in-hospital and 30-day mortality, were similar among the groups. RATS lobectomy was associated with a higher number of lymph node stations harvested compared to VATS (7 [IQR:2] vs. 5 [IQR:2]; p < 0.001). In conclusion, in our series, RATS lobectomy for lung cancer led to a significantly higher DFS and significantly lower recurrence rate compared to the VATS approach. RATS may allow more extensive nodal dissection, and this could translate into reduced recurrence.

Combining perineural invasion with staging improve the prognostic accuracy in colorectal cancer: a retrospective cohort study

BackgroundCurrent guidelines only propose the importance of perineural invasion(PNI) on prognosis in stage II colon cancer. However, the prognostic value of PNI in other stages of colorectal cancer (CRC) is ambiguous.MethodsThis single-center retrospective cohort study included 3485 CRC patients who underwent primary colorectal resection between January 2013 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University. Associations of PNI with overall survival (OS) and disease-free survival (DFS) were evaluated using multivariable Cox proportional hazards regression models. In addition, interaction analyses were performed to explore the prognostic effects of PNI in different clinical subgroups.ResultsAfter median follow-up of 61.9 months, we found PNI was associated with poorer OS (adjusted hazard ratio [aHR], 1.290; 95% CI, 1.087–1.531) and DFS (aHR, 1.397; 95% CI, 1.207–1.617), irrespective of tumor stage. Interestingly, the weight of PNI was found second only to incomplete resection in the nomogram for risk factors of OS and DFS in stage II CRC patients. Moreover, OS and DFS were insignificantly different between stage II patients with PNI and stage III patients (both P > 0.05). PNI was found to be an independent prognostic factor of DFS in stage III CRC (aHR: 1.514; 95% CI, 1.211–1.892) as well. Finally, the adverse effect of PNI on OS was more significant in female, early-onset, and diabetes-negative patients than in their counterparts (interaction P = 0.0213, 0.0280, and 0.0186, respectively).ConclusionPNI was an important prognostic factor in CRC, more than in stage II. The survival of patients with stage II combined with perineural invasion is similar with those with stage III. PNI in stage III CRC also suggests a worse survival.

Development and validation of prognostic nomograms based on De Ritis ratio and clinicopathological features for patients with stage II/III colorectal cancer

BackgroundMetabolic derangements and systemic inflammation are related to the progression of colorectal cancer (CRC) and the prognoses of these patients. The survival of stage II and III CRC patients existed considerable heterogeneity highlighting the urgent need for new prediction models. This study aimed to develop and validate prognostic nomograms based on preoperative serum liver enzyme as well as evaluate the clinical utility.MethodsA total of 4014 stage II/III primary CRC patients pathologically diagnosed from January 2007 to December 2013 were included in this study. These patients were randomly divided into a training set (n = 2409) and a testing set (n = 1605). Univariate and multivariate Cox analyses were used to select the independent factors for predicting overall survival (OS) and disease-free survival (DFS) of stage II/III CRC patients. Next, nomograms were constructed and validated to predict the OS and DFS of individual CRC patients. The clinical utility of nomograms, tumor-node-metastasis (TNM), and the American Joint Committee on Cancer (AJCC) system was evaluated using time-dependent ROC and decision curve analyses.ResultsAmong seven preoperative serum liver enzyme markers, aspartate aminotransferase-to-alanine aminotransferase ratio (De Ritis ratio) was identified as an independent factor for predicting both OS and DFS of stage II/III CRC patients. The nomograms incorporated De Ritis ratio and significant clinicopathological features achieved good accuracy in terms of OS and DFS prediction, with C-index of 0.715 and 0.692, respectively. The calibration curve showed good agreement between prediction by nomogram and actual observation. The results of time-dependent ROC and decision curve analyses suggested that the nomograms had improved discrimination and greater clinical benefits compared with TNM and AJCC staging.ConclusionsDe Ritis ratio was an independent predictor in predicting both the OS and DFS of patients with stage II/III CRC. Nomograms based on De Ritis ratio and clinicopathological features showed better clinical utility, which is expected to help clinicians develop appropriate individual treatment strategies for patients with stage II /III CRC.

Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

LBA3 Background: Osimertinib is a third-generation, central nervous system (CNS) active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. In the primary analysis from the Phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a clinically meaningful, statistically significant, and practice-changing disease-free survival (DFS) benefit vs placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC ± adjuvant chemotherapy. In an updated DFS analysis, with 2 years additional follow-up, DFS and CNS DFS benefit with adjuvant osimertinib were sustained (stage II–IIIA DFS hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.18, 0.30; stage IB–IIIA DFS HR 0.27; 95% CI 0.21, 0.34; stage II–IIIA CNS DFS HR 0.24; 95% CI 0.14, 0.42), with a tolerable safety profile observed over the extended treatment duration. Here, we report the planned final overall survival (OS) analysis from ADAURA. Methods: Eligible patients (aged ≥18 years [≥20 in Japan and Taiwan], WHO PS 0/1 with completely resected EGFRm (ex19del/L858R) stage IB, II or IIIA [AJCC/UICC 7th edition] NSCLC; adjuvant chemotherapy allowed) were randomized 1:1 to osimertinib 80 mg once daily or placebo until disease recurrence, treatment completion (3 years), or a discontinuation criterion was met. The primary endpoint was investigator-assessed DFS in stage II–IIIA. Key secondary endpoints: DFS in stage IB–IIIA, OS and safety. Data cut-off: January 27, 2023. Results: Globally, 682 patients were randomized; osimertinib n=339, placebo n=343. Adjuvant osimertinib significantly improved OS vs placebo. In patients with stage II–IIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p=0.0004; 100/470 events, 21% maturity); 5-year OS rate was 85% with osimertinib vs 73% with placebo. Median follow-up for OS in stage II–IIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IB–IIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p&lt;0.0001; 124/682 events, 18% maturity); 5-year OS rate was 88% with osimertinib vs 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). Median OS was not reached in either population or treatment group. Conclusions: Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC. Clinical trial information: NCT02511106 .

O127 Application of machine learning approaches in the diagnosis and management of colorectal cancer

Abstract Introduction Colorectal cancer (CRC) is one of the most common cancers worldwide. In recent years, Artificial Intelligence (AI) and Machine Learning (ML) algorithms have gained traction in CRC research for their ability to efficiently analyse large volumes of variables and offer objective data driven models to optimise clinical decision making. The present review provides a contemporary summary of the current application of these approaches in CRC. Methods A literature search was performed on AI models and ML learning in CRC and relevant articles were scrutinized. Results AI aided detection systems were successful in identifying CRC, and able to outperform endoscopists in detecting adenomas (detection rate 0.29 vs. 0.20, p &amp;lt; 0.001). ML models based on radiomics showed promise in identifying CRC metastasis and even outperforming national guideline-based models (AUC 0.83 vs. 0.73, p&amp;lt;0.01) in predicting risk of T1 CRC metastasis to lymph nodes. ML models were also able to identify novel genomic targets, predict response to oncological therapy, and predict 5-year disease free survival in stage II and III CRC (AUC of 0.698). In the operative context, AI can be trained to identify surgical steps and operative actions with accuracy scores of over 80% as well as. Conclusion AI modelling takes advantage of increasing digital medical data keeping to allow rapid high-volume data analysis which has found application in the diagnosis, staging, treatment, and prognosis of CRC and may be useful in the development of intra-operative guidance systems to optimize surgical approaches and training.

Abstract 2049: Clinically and biologically distinct molecular subtypes of lung squamous cell carcinoma (LUSC)

Abstract Background: Lung cancer is the leading cause of cancer death worldwide, with LUSC accounting for a third of cases. Stage I and II LUSC is typically treated with resection, and decisions related to adjuvant chemotherapy are related to recurrence risk, which is a function of stage. However, disease stage does not fully capture tumor biology, which may be a more important determinant of recurrence risk. Our objective was to identify biologically significant molecular subgroups of LUSC that more accurately reflect recurrence risk. Methods: Transcriptomic data for resected stage I/II LUSC were obtained from The Cancer Genome Atlas (TCGA). A training set consisting of patients who underwent resection without adjuvant chemotherapy or radiotherapy was used for discovery (N=161). A proprietary machine learning algorithm (HighLifeR™) was used to identify the genes most associated with disease-free survival (DFS). Molecular subgroups were identified by unsupervised clustering of prognostic genes. Functional differences between molecular subgroups were identified by gene set enrichment analysis (GSEA) and Ingenuity Pathway Analysis (IPA). Results: HighLifeR™ identified 60 highly prognostic genes. Two molecular subgroups were identified with significantly different median DFS: a high-risk group with 59.300 months and hazard ratio of 11.551, and a low-risk group that did not reach 50% DFS (log-rank p = 1.96 x 10-5). These subgroups did not differ in age, sex, race, smoking status, or overall stage (p &amp;gt; 0.05). Importantly, univariate and multivariate Cox regression analysis showed that the molecular subgroups outperformed clinical stage in predicting DFS. The molecular subgroups were biologically distinct. On GSEA, the high-risk group was significantly enriched in genes involved in mitotic spindle assembly (NES=1.94, p&amp;lt;0.001); TGFα signaling and PI3K/AKT/mTOR signaling were modestly enriched. IPA pathway analysis demonstrated significant enrichment of numerous pathways linked to neuronal growth and signaling (eg: CREB signaling, S100 signaling, pathways in myelination and synaptogenesis), as well as TGFα signaling and AMPK signaling (all p&amp;lt;0.001). Conclusions: Our prognostic transcriptomic signature identified two biologically distinct molecular subgroups of LUSC. Molecular subgroup classification was more predictive of DFS in stage I and II LUSC than any other clinical or pathological variable. If further validation confirms this, then this biomarker may form the basis of a diagnostic test that helps inform which patients could be considered for adjuvant chemotherapy. Citation Format: Ashar Siddiqui, Cynthia Stretch, Farshad Farshidfar, Oliver F. Bathe. Clinically and biologically distinct molecular subtypes of lung squamous cell carcinoma (LUSC) [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 2049.

Correlation Analysis of Ki67 Expression and EGFR Mutation on the Risk of Recurrence and Metastasis in Postoperative Patients with Stage I Lung Adenocarcinoma

The prognosis of stage I non-small cell lung cancer (NSCLC) is generally good. However, some of the stage I NSCLC patients still may have early recurrence and metastasis, and there is no standard method to screen this part of the population. The aim of this study is to investigate the relationship between Ki67 expression as well as epidermal growth factor receptor (EGFR) mutation and the risk of recurrence in postoperative patients with stage I lung adenocarcinoma. We retrospectively enrolled 118 postoperative patients with stage I lung adenocarcinoma. EGFR mutation was tested using amplification refractory mutation system polymerase chain reaction (ARMS-PCR) , and Ki67 level was detected by immunohistochemistry (IHC), followed by the collection of the patients' clinical characteristics. Kaplan-Meier method, Log-rank test, and Cox proportional hazards regression model were used for the prognostic statistical analysis. Among the 118 patients, the rate of high Ki67 expression was 43.22% (51/118), which is related to gender, smoking status, surgical method, differentiation degree, and postoperative stage (P<0.05). Meanwhile, EGFR mutation rate was 61.02% (72/118), of which EGFR exon 19 deletion mutation rate was 19.49% (23/118), and the EGFR exon 21 L858R mutation rate was 41.53% (49/118). However, Ki67 expression was not associated with EGFR mutation status (χ2=1.412, P=0.235). Survival analysis showed that high Ki67 expression was inversely associated with disease-free survival (DFS) and overall survival (OS) in stage I lung adenocarcinoma (P<0.05), but EGFR mutation status was not significantly associated with DFS and OS (P>0.05). In the subgroup analysis, the DFS of the EGFR exon 19 deletion group was significantly decreased compared with the EGFR exon 21 L858R mutation group (P=0.031), but there was no significant difference in OS (P=0.308). Multivariate analysis showed that there was statistical significance between Ki67 expression (P=0.001) and DFS in stage I lung adenocarcinoma; Ki67 expression (P=0.03) and gender (P=0.015) were associated with OS in stage I lung adenocarcinoma. Ki67 expression is an independent influencing factor for postoperative recurrence and OS of stage I lung adenocarcinoma and it is not significantly associated with EGFR mutation. There is no significant difference between EGFR mutation status and the prognostis of stage I lung adenocarcinoma. However, the prognosis differed in EGFR mutation types; the patients with EGFR exon 19 deletion are at higher risk of recurrence than EGFR exon 21 L858R mutation.

A novel prognostic model to predict OS and DFS of stage II/III gastric adenocarcinoma patients in China

BackgroundThe prognosis of advanced gastric adenocarcinoma (GAC) after radical gastrectomy varies greatly. We aimed to build and validate a novel individualized nomogram based on inflammation index and tumor markers for patients with stage II/III GAC. MethodsA total of 755 individuals with stage II/III GAC who had undergone radical gastrectomy at the First Affiliated Hospital of Zhengzhou University between 2012 and 2017 were included in this retrospective study. The patients were randomly divided into a training cohort (n ​= ​503) and a validation cohort (n ​= ​252). Univariate and multivariate analyses were used to determine independent prognostic factors of overall survival (OS) and disease-free survival (DFS). A nomogram was developed based on these independent factors. The concordance index (C-index) and calibration curves were used to evaluate the predictive accuracy of the nomogram. ResultsUnivariate and multivariate analyses demonstrated that older age, poor differentiation, advanced stage, elevated neutrophil-to-lymphocyte ratio (NLR), lower hemoglobin, and high carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were significantly associated with lower OS and DFS and were independent prognostic factors in stage II/III GAC. The nomogram developed based on these factors in the training cohort showed excellent calibration and discrimination (OS: C-index ​= ​0.739, 95% CI ​= ​0.706–0.772; DFS: C-index ​= ​0.735, 95% CI ​= ​0.702–0.769). In the internal validation cohort, the nomogram was also well-calibrated for the prediction of OS and DFS; it was superior to the 8th edition UICC/AJCC TNM staging system (for OS: C-index ​= ​0.746 vs. 0.679, respectively; for DFS: C-index ​= ​0.736 vs. 0.675, respectively; P ​< ​0.001). ConclusionThe nomogram model could reliably predict OS and DFS in stage II/III gastric cancer patients with radical gastrectomy. It may help physicians make better treatment decisions.

LBA47 Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA

Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. It has efficacy in EGFRm NSCLC, including in central nervous system (CNS) metastases. In the Phase III ADAURA (NCT02511106) primary analysis adjuvant osimertinib showed a significant and clinically meaningful disease-free survival (DFS) benefit vs placebo (PBO) in pts with completely resected EGFRm (ex19del/L858R) NSCLC, ± adjuvant chemotherapy (CT): stage IIꟷIIIA DFS HR, 0.17; 99.06% CI, 0.11, 0.26; p<0.0001; stage IBꟷIIIA DFS HR, 0.20; 99.12% CI 0.14, 0.30; p<0.0001. We report updated exploratory analyses of DFS and recurrence patterns after 2 yrs added follow up. Eligible pts (aged ≥18 yrs [≥20 in Japan/Taiwan], WHO PS 0/1, completely resected EGFRm stage IBꟷIIIA [AJCC 7th edition] NSCLC; adjuvant CT allowed) were randomised 1:1 to osimertinib 80 mg once daily or PBO for up to 3 yrs. Primary endpoint: investigator-assessed DFS in stage IIꟷIIIA. Secondary endpoints: DFS in stage IBꟷIIIA, overall survival and safety. Patterns of recurrence and CNS DFS were pre-specified exploratory endpoints. Data cut-off: 11 April 2022. Globally, 682 pts were randomised; osimertinib n=339, PBO n=343. In this updated analysis, in pts with stage IIꟷIIIA disease DFS HR was 0.23 (95% CI 0.18, 0.30; 242/470 events; 51% maturity); 3-yr DFS rate was 84% with osimertinib vs 34% with PBO. In the overall population (stage IBꟷIIIA) DFS HR was 0.27 (95% CI 0.21, 0.34; 305/682 events); 3-yr DFS rate was 85% with osimertinib vs 44% with PBO. In the osimertinib arm, fewer pts experienced local/regional and distant recurrence vs PBO. CNS DFS HR was 0.24 (95% CI 0.14, 0.42; 63/470 events) in stage IIꟷIIIA. The long-term safety profile remains consistent with the known profile of osimertinib. With 2 yrs further follow-up, a continued DFS benefit was sustained with osimertinib vs PBO, consistent with the primary analysis. These mature data reinforce adjuvant osimertinib as standard of care for pts with EGFRm stage IB–‍IIIA NSCLC after complete tumour resection and adjuvant CT, when indicated.

High expression of secretory leukocyte protease inhibitor (SLPI) in stage III micro-satellite stable colorectal cancer is associated with reduced disease recurrence

Secretory leukocyte protease inhibitor (SLPI) is a pleiotropic protein produced by healthy intestinal epithelial cells. SLPI regulates NF-κB activation, inhibits neutrophil proteases and has broad antimicrobial activity. Recently, increased SLPI expression was found in various types of carcinomas and was suggested to increase their metastatic potential. Indeed, we demonstrated that SLPI protein expression in colorectal cancer (CRC) liver metastases and matched primary tumors is associated with worse outcome, suggesting that SLPI promotes metastasis in human CRC. However, whether SLPI plays a role in CRC before distant metastases have formed is unclear. Therefore, we examined whether SLPI expression is associated with prognosis in CRC patients with localized disease. Using a cohort of 226 stage II and 160 stage III CRC patients we demonstrate that high SLPI protein expression is associated with reduced disease recurrence in patients with stage III micro-satellite stable tumors treated with adjuvant chemotherapy, independently of established clinical risk factors (hazard rate ratio 0.54, P-value 0.03). SLPI protein expression was not associated with disease-free survival in stage II CRC patients. Our data suggest that the role of SLPI in CRC may be different depending on the stage of disease. In stage III CRC, SLPI expression may be unfavorable for tumors, whereas SLPI expression may be beneficial for tumors once distant metastases have established.

Abstract 2172: Tumor break load is a biologically relevant characteristic of genomic instability with prognostic value for patients with localized colorectal cancer

Abstract Background: Genomic instability is a common feature of colorectal cancer (CRC). More than 80% of CRCs exhibit chromosomal instability (CIN) and 15-20% microsatellite instability (MSI). MSI results in a high ‘tumor mutational burden’ (TMB) and is associated with relatively good prognosis in localized CRC. However, for the large group of CIN CRC patients with localized disease it remains unclear who has a relatively good prognosis and who is at high risk of disease recurrence. CIN is characterized by excessive somatic copy number aberrations (SCNAs), which is often summarized as the ‘fraction genome altered’ (FGA). In addition, CIN is also characterized by excessive chromosomal rearrangement structural variants (SVs). We quantitated the chromosomal breaks as the ‘Tumor Break Load’ (TBL) to investigate the biological impact and clinical relevance of chromosomal breakage in colorectal cancer. Aim: To investigate the biological impact and clinical relevance of TBL in CRC. Data and Methods: We used SCNA, RNA-Seq, and Disease-Free Survival (DFS) data from 633 CRC samples from The Cancer Genome Atlas project. For validation purposes, we used SCNA and DFS data from an independent series of 72 CRC samples. TBL was calculated as the sum of SCNA-associated chromosomal breaks. We used the 25% and 75% quantiles of the TBL distribution as predefined high and low TBL groups to train an RNA expression-based classifier that identifies TBL-associated expression phenotypes as an indicator of biological impact. Results: Within the group of microsatellite stable (MSS) CRC samples there was a large variety in TBL (median TBL of 54 [1-308]). TBL was poorly correlated with TMB (R2: 0.06) and FGA (R2: 0.07). Using RNA expression data as a phenotypic representation of genomic instability, MSI and MSS CRC samples could be classified with high accuracy (AUC: 0.99, p &amp;lt; 0.01), confirming the well-known impact of MSI on tumor biology. Using the same methodology within the group of MSS samples, the TBL could also be classified with high accuracy (AUC: 0.88; p &amp;lt; 0.01). Moreover, high TBL was associated with poor DFS in stage II-III localized MSS CRC (HR: 6.1; p = 0.007). This result was validated in an independent data series of 72 untreated stage II-III localized MSS CRC patients (HR: 3.0; p &amp;lt; 0.02). Conclusion: TBL is a characteristic of chromosomal instability that is largely independent from TMB and FGA, with significant impact on tumor biology. Our data indicate that the TBL may be used as a valuable prognostic biomarker for DFS in patients with localized colorectal cancer. Citation Format: Soufyan Lakbir, Jaap Heringa, Gerrit A. Meijer, Sanne Abeln, Remond J. Fijneman. Tumor break load is a biologically relevant characteristic of genomic instability with prognostic value for patients with localized colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2172.

Prognostic significance of PD-L1 expression and CD8+ TILs density for disease-free survival in surgically resected lung squamous cell carcinoma: a retrospective study.

BackgroundThis study sought to depict the genomic landscape of patients with surgically resected lung squamous cell carcinoma (LUSC) and its relationship with clinical outcome indicators.MethodsWe retrospectively collected the clinical data of 180 patients from the electronic medical records and applied targeted sequencing and immunohistochemistry (IHC) to depict the genomic landscape, including the tumor mutation burden (TMB), programmed cell death-ligand 1 (PD-L1), and cluster of differentiation CD8+ tumor-infiltrating lymphocytes (CD8+ TILs). And comparative analysis and survival analysis of these parameters were conducted to find prognostic factors for clinical outcome.ResultsPD-L1+ tumor cells were observed in 75 (41.7%) of the patients, the median rate of CD8+ TILs was 11.5 [4, 24], and the median TMB was 9.4 (7.5–13.7) mutations per megabase (mut/Mb). Patched receptor 1 (PTCH1) gene mutation frequency was significantly associated with CD8+ TILs density (12% vs. 1%; P=0.024). High PD-L1 expression and CD8+ TILs+ were significantly associated with longer disease-free survival (DFS), and a further subgroup analysis revealed that both were significantly correlated with the DFS of stage I/II patients but not stage III patients.ConclusionsThe results suggest that only PTCH1 gene mutation frequency was correlated with CD8+ TILs density. Additionally, intense CD8+ TILs density and high PD-L1 expression were found to be associated with longer DFS. Our findings provide insights into the precise treatment strategy for surgically resected LUSC patients.

Identifying biomarkers associated with disease-free survival in stage I non–small cell lung cancer.

8543 Background: Patients with early stage, non-small cell lung cancer (NSCLC) with solitary pulmonary lesions ≤4 cm typically have favorable outcomes. However, disease recurrence impacts up to 30% of patients, leading to either additional surgical or systemic interventions. New methods to risk stratify patients based on clinical and molecular parameters may improve our ability to select cases that would benefit from more frequent surveillance or enrollment in clinical trials evaluating systemic therapy. Methods: We retrospectively analyzed data from 179 patients with early stage (T1a-2aN0M0) NSCLC from a single institution. All patients had anatomic resection, negative margins, and systematic nodal sampling. Clinical and demographic data were abstracted from patient charts and tumor samples were molecularly profiled using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage, whole exome-capture RNA-seq). Pathogenic alterations (single nucleotide variants and insertion/deletions) and RNA expression were examined. Bivariate Cox-proportional Hazards models were used to assess the association of individual clinical, demographic, and molecular variables with recurrence-free survival, defined as the time from surgery until recurrence or death. Results: Our dataset included 166 stage IA1-3 patients and 13 stage IB patients, of which 36 patients experienced a recurrence or death event after surgery. Clinical and DNA-seq data was available for all patients, and RNA expression data was available for 172 patients. Across all patients, the most common somatically mutated genes were TP53 (33% of tumors) and KRAS (16% of tumors), consistent with previous studies. Increasing log10-RNA expression for NTRK1 (HR: 5.95; 95% CI, 1.16-30.4; p = 0.027) and CD274 (PD-L1) (HR: 7.88; 95% CI, 1.61-38.6; p = 0.013) and decreasing log10-RNA expression for EGFR (HR: 0.24; 95% CI, 0.05-1.21; p = 0.071) and ERBB2 (Her2) (HR: 0.20; 95% CI, 0.04-0.97; p = 0.042) were associated with increased risk of recurrence or death. Conclusions: Increased expression of NTRK1 and CD274 (PD-L1) and decreased expression of EGFR and ERBB2 (Her2) were associated with a increased risk for recurrence following surgery. This may have mechanistic implications for heightened tumor aggressiveness and/or metastatic potential. Future work will expand our cohort and validate our findings in a broader set of early-stage NSCLC patients.

Impact of Surgery in De Novo Metastatic Breast Cancer after Systemic Disease Control

Background: Systemic chemotherapy is the standard of care for patients with metastatic breast cancer, with an undecided role in surgery. Limited data is available for the role of surgery on the overall survival of stage 4 breast cancer in regards to luminal subtypes of patients. This is a retrospective data analysis comparing overall survival benefit and disease-free survival in stage IV breast cancer after systemic treatment and systemic disease control concerning luminal classification in the last five years. Method: Patients who had surgery and no surgery after systemic treatment and disease control were compared for 5 years overall survival as the primary endpoint and disease-free survival as the secondary endpoint. The survival benefit was also compared in regards to tumor biology (ER/PR, HER2 status) Results: Data included 430 patients, 244 in surgery and 186 in no surgery group. At one year survival for surgery performed and not performed was not significant. Five-year overall survival for surgery performed and not performed was 84.4% and 74.6%. A statistically highly significant difference in survival rates was observed (p&lt;0.0001). The mortality rate was 15.6% in surgery performed and 25.4% in the no-surgery group which showed a significant difference among the two study groups (p=0.011). We found statistically significant differences in luminal B (p=0.01) and triple-negative breast cancer patients (p=0.001) for survival rates in surgery performed and not performed groups. Conclusion: Surgery has a positive impact on overall survival in Stage 4 patients with systemic disease control even in high-risk luminal B, Her 2 Positive, and triple-negative breast cancer patients. There was no significant difference observed in disease-free survival who were operated on or not. However, there was no local recurrence in the operated group. Keywords: Metastatic breast cancer: Neoadjuvant chemotherapy, local breast surgery, Luminal sub-types

Survival after curative resection for stage I colorectal mucinous adenocarcinoma

PurposeThe prognostic value of the mucinous adenocarcinoma histotype on the early stages especially for stage I colorectal cancer (CRC) is still unclear. This study determined the clinicopathologic characteristics and long-term outcome of stage I colorectal mucinous adenocarcinomas (MAC).MethodsAmong the total of 530 patients with stage I CRC (58 having MAC and 472 having non-MAC) who underwent radical resection, the correlation between clinicopathological factors and MAC was analyzed. Multivariate analysis was performed to determine whether mucinous histotype itself was an independent prognostic impact in stage I patients.ResultsMACs were observed more frequently located in the colon than rectum (p = 0.049), more frequently displayed the deficient mismatch repair (dMMR) phenotype (p = 0.001) and had a greater frequency of T2 stage (p = 0.002). The rate of recurrence was 15.3% and the mortality was 9.2% among all stage I CRC patients. There was no difference in disease-free survival and overall survival between MACs and non-MACs. On multivariate analysis, older age (p = 0.009, hazard ratio: 2.22), rectal cancer (p = 0.008, hazard ratio: 3.21), lymphovascular invasion (LVI) (p < 0.001, hazard ratio: 6.28), and deficient mismatch repair (dMMR) phenotypes (p = 0.044, hazard ratio: 2.62) were independently associated to poor survival of stage I CRC. A high carcinoembryonic antigen level (p = 0.034, hazard ratio: 1.86), rectal cancer (p = 0.035, hazard ratio: 1.81), LVI (p = 0.002, hazard ratio: 3.59) and dMMR phenotypes (p = 0.009, hazard ratio: 2.85) were independently related to short disease-free survival of stage I CRC.ConclusionsCompared with non-MAC, MAC patients had more T2 patients and more dMMR phenotypes in stage I CRC at presentation, but the mucinous histology is not a significant predictor of recurrence and prognosis in stage I CRC.

KCNQ1 and lymphovascular invasion are key features in a prognostic classifier for stage II and III colon cancer

BackgroundThe risk of recurrence after resection of a stage II or III colon cancer, and therefore qualification for adjuvant chemotherapy (ACT), is traditionally based on clinicopathological parameters. However, the parameters used in clinical practice are not able to accurately identify all patients with or without minimal residual disease. Some patients considered ‘low-risk’ do develop recurrence (undertreatment), whilst other patients receiving ACT might not have developed recurrence at all (overtreatment). We previously analysed tumour tissue expression of 28 protein biomarkers that might improve identification of patients at risk of recurrence. In the present study we aimed to build a prognostic classifier based on these 28 biomarkers and clinicopathological parameters.MethodsClassification and regression tree (CART) analysis was used to build a prognostic classifier based on a well described cohort of 386 patients with stage II and III colon cancer. Separate classifiers were built for patients who were or were not treated with ACT. Routine clinicopathological parameters and tumour tissue immunohistochemistry data were included, available for 28 proteins previously published. Classification trees were pruned until lowest misclassification error was obtained. Survival of the identified subgroups was analysed, and robustness of the selected CART variables was assessed by random forest analysis (1000 trees).ResultsIn patients not treated with ACT, prognosis was estimated best based on expression of KCNQ1. Poor disease-free survival (DFS) was observed in those with loss of expression of KCNQ1 (HR = 3.38 (95% CI 2.12 – 5.40); p < 0.001). In patients treated with ACT, key prognostic factors were lymphovascular invasion (LVI) and expression of KCNQ1. Patients with LVI showed poorest DFS, whilst patients without LVI and high expression of KCNQ1 showed most favourable survival (HR = 7.50 (95% CI 3.57—15.74); p < 0.001). Patients without LVI and loss of expression of KCNQ1 had intermediate survival (HR = 3.91 (95% CI 1.76 – 8.72); p = 0.001).ConclusionKCNQ1 and LVI were identified as key features in prognostic classifiers for disease-free survival in stage II and III colon cancer patients.

Comparison of two-stage and three-stage surgery for obstructing left-sided colon cancer.

Whether the timing of stoma reversal after emergency diversion for obstructive left-sided colon cancer affects patient outcomes is unknown. Our study compared the short- and long-term outcomes of two- and three-stage operations for obstructive left-sided colon cancer. Patients with obstructive left-sided colon cancer who underwent staged resection at a referral hospital between January 2002 and December 2015 were retrospectively identified. Patient demographics and outcomes were analysed and compared between the two groups. Statistical significance was set as p < 0.05. A total of 191 patients were reviewed. The overall complication rate was higher for two-stage surgery than for three-stage surgery (57.1% versus 36.0%, p < 0.01). Surgical site infection and/or wound dehiscence were the most common complications. Other complications, including anastomotic leakage, ileus, and bowel obstruction, were not significantly different between the two groups. The five-year overall survival and disease-free survival in stage II and III patients were comparable. Among patients with obstructive left-sided colon cancer who underwent staged resection, two-stage surgery was associated with a higher complication rate, especially for surgical site infection and/or wound dehiscence, which could be managed by local treatment. The timing of stoma reversal was not associated with survival differences in patients with stage II and III disease. However, issues such as the location of the tumour and diverting stoma, along with the need to resect other upper abdominal organs, should all be considered when deciding between two- and three-stage surgeries.

The association between the lymph node ratio, surgical margin, and survival in patients with colon cancer receiving adjuvant chemotherapy.

Objectives:To investigate the prognostic significant of lymph node ratio and surgical margins in patients with colon cancer undergoing surgery.Methods:This observational and retrospective study was conducted at Karadeniz Technical University Medical Faculty, between 1 January, 2010 and 31 November, 2020. A series of 137 patients who had undergone surgical resection of colon carcinoma were included in this study. mLNR, defined as the ratio of the number of mLNs to the number of examined lymph nodes, was calculated in colorectal cancer cases with lymph node metastasis. Patients were divided into three groups; LNR1 (< 0.25), LNR2 (0.25-0.6) and LNR3 (> 0.6).Results:Mean disease-free survival was 79.2 months (95% CI 71.0-87.4). The mean expected survival time was 73.5 months (95% CI: 65.9-81.0). As the metastatic LN ratio increased, the rate of local recurrence or distant metastasis increased statistically significantly (p=0.007). As the metastatic LN ratio increased, the death rate increased statistically significantly (p=0.036). Metastatic lymph node ratio did not have a statistically significant effect on overall survival in patients with stage-3 and more than 12 LNs removed (p=0.069). There was no statistically significant association between the closeness of the surgical margin and disease-free survival in stage 1 (p=0.505) and stage-2 (p=0.161). There was no statistically significant association between the closeness of the surgical margin and overall survival among patients with stage 1 (p=0.494) and stage 2 (p=0.265).Conclusion:A high metastatic LNR is associated with poorer overall and disease-free survival.