Intelligent prognosis evaluation system for stage I-III resected non-small-cell lung cancer patients on CT images: a multi-center study.

Background: Prognosis is crucial for personalized treatment and surveillance suggestion of the resected non-small-cell lung cancer (NSCLC) patients in stage I-III. Although the tumor-node-metastasis (TNM) staging system is a powerful predictor, it is not perfect enough to accurately distinguish all the patients, especially within the same TNM stage. In this study, we developed an intelligent prognosis evaluation system (IPES) using pre-therapy CT images to assist the traditional TNM staging system for more accurate prognosis prediction of resected NSCLC patients. Methods: 20,333 CT images of 6371 patients from June 12, 2009 to March 24, 2022 in West China Hospital of Sichuan University, Mianzhu People's Hospital, Peking University People's Hospital, Chengdu Shangjin Nanfu Hospital and Guangan Peoples' Hospital were included in this retrospective study. We developed the IPES based on self-supervised pre-training and multi-task learning, which aimed to predict an overall survival (OS) risk for each patient. We further evaluated the prognostic accuracy of the IPES and its ability to stratify NSCLC patients with the same TNM stage and with the same EGFR genotype. Findings: The IPES was able to predict OS risk for stage I-III resected NSCLC patients in the training set (C-index 0.806; 95% CI: 0.744-0.846), internal validation set (0.783; 95% CI: 0.744-0.825) and external validation set (0.817; 95% CI: 0.786-0.849). In addition, IPES performed well in early-stage (stage I) and EGFR genotype prediction. Furthermore, by adopting IPES-based survival score (IPES-score), resected NSCLC patients in the same stage or with the same EGFR genotype could be divided into low- and high-risk subgroups with good and poor prognosis, respectively (p < 0.05 for all). Interpretation: The IPES provided a non-invasive way to obtain prognosis-related information from patients. The identification of IPES for resected NSCLC patients with low and high prognostic risk in the same TNM stage or with the same EGFR genotype suggests that IPES have potential to offer more personalized treatment and surveillance suggestion for NSCLC patients. Funding: This study was funded by the National Natural Science Foundation of China (grant 62272055, 92259303, 92059203), New Cornerstone Science Foundation through the XPLORER PRIZE, Young Elite Scientists Sponsorship Program by CAST (2021QNRC001), Clinical Medicine Plus X - Young Scholars Project, Peking University, the Fundamental Research Funds for the Central Universities (K.C.), Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences (2021RU002), BUPT Excellent Ph.D. Students Foundation (CX2022104).

Osimertinib as first-line treatment for recurrent lung cancer patients with EGFR mutation.

Background: Although osimertinib was approved as adjuvant therapy for lung cancer patients with EGFR mutation in various countries, there is still some ongoing debate as osimertinib has been approved based on disease-free survival (DFS) rather than overall survival (OS). We curated a case series in which we documented patterns of recurrence and efficacy and safety of osimertinib after recurrence. Methods: Patients who received osimertinib as first-line treatment for postoperative recurrence between September 2018 and January 2023 were included. Clinicopathological factors, duration of osimertinib treatment (DoT), and adverse events were collected and analyzed. Results: Twenty patients received osimertinib [male, n=6; median age, 75 years (range, 55-85 years)]. The EGFR mutation type was L858R in 11 patients and exon 19 deletion in eight patients. The performance status (PS) was 0 or 1 in all but two patients, who had symptomatic brain metastasis and were therefore PS 3. The first site of postoperative recurrence was locoregional in five patients and distant in 15 patients, including seven with brain metastasis. As of February 2023, 10 patients were still on osimertinib, including three with brain metastasis. Patients with brain metastasis or poor PS had a considerably shorter DoT than their counterparts. Three patients with symptomatic brain metastasis or leptomeningeal metastasis initially responded to osimertinib, but all died of disease progression. Five patients discontinued osimertinib due to serious adverse effects (pneumonitis, drug eruption, and heart failure). Conclusions: Although osimertinib exerts great disease control, even in patients with brain metastasis or poor PS, their presence was associated with a poor prognosis, even with osimertinib treatment. Therefore, adjuvant osimertinib is recommended unless contraindicated.

Clinical significance of DNA damage response mutations in stage I and stage IIIa NSCLC.

BACKGROUND: DNA damage response (DDR) pathways are essential to sustain genomic stability and play a critical role in cancer development and progression. Here, we investigated the profile of DDR gene mutations in early-stage non-small cell lung cancer (NSCLC) and their prognostic values. METHODS: We first examined 74 DDR genes involved in seven DDR pathways and then focused on six specific genes: ATM, BRCA1, BRCA2, CHEK1, BARD1, and BRIP1. A total of 179 stage I and IIIa NSCLC patients who received curative resection in Peking Union Medical College Hospital and their corresponding samples were collected for DNA sequencing, immunohistochemistry and survival analysis. RESULTS: A total of 167 eligible patients were finally analyzed. Mutation frequencies were 82% and 26.3% for the selected 74 genes and six genes, respectively. Mismatch repair (MMR) and nucleotide excision repair (NER) alterations were observed more frequently in lung squamous cell carcinoma (LUSC) and smokers were more likely to develop the selected six DDR gene mutations than those who never smoked. Deleterious mutations in the six genes were independent prognostic indicators of significantly longer disease-free survival and overall survival. No association was found between DDR gene status and PD-L1 expression, CD8 positive lymphocyte and tumor-associated macrophage infiltration in tumor area. However, numbers of mutations were significantly increased among patients with DDR alterations. CONCLUSIONS: Deleterious mutations of these six genes were common in resected NSCLC and could serve as prognostic biomarkers.

Pre-existing tumor host immunity characterization in resected non-small cell lung cancer.

INTRODUCTION: Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery. METHODS: A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103+) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes. RESULTS: We found increased levels of T cell markers (CD3+, CD4+, CD8+ cells), functional immune markers (FOXP3+ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68+ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3+, CD8+ cells), regulatory T cells (FOXP3+ cells) and macrophages (CD68+ cells) was observed in the CD103+/PD-L1+ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103+ immune cells was associated with improved OS (p = 0.009). CONCLUSIONS: TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.

Deconstructing ADAURA: It is Time to Forgo Adjuvant Platinum-Based Chemotherapy in Resected IB-IIIA EGFR+ NSCLC (Except with RB Alterations?) When Adopting Adjuvant Osimertinib.

Adjuvant cisplatin-based chemotherapy is considered the standard of care for resected stage IB (tumor ≥ 4m)-IIIA non-small cell lung cancer (NSCLC). The ADAURA trial is a randomized placebo-controlled Phase III trial that demonstrated statistically significant improved disease-free survival (DFS) with the use of 3-years of adjuvant osimertinib in resected stage IB-IIIA NSCLC harboring epidermal growth factor receptor (EGFR) del 19 or L858R mutations. Subgroup analysis revealed that the DFS improvement with adjuvant osimertinib is independent of adjuvant chemotherapy in the primary analysis. A recent follow-up report suggested that adjuvant cisplatin-based chemotherapy provided no additional 2-year DFS improvement on top of adjuvant osimertinib regardless of stage (IB, II, or IIIA) and minimal numerical DFS benefit in stage II or IIIA resected EGFR+ NSCLC for those patients who did not receive adjuvant osimertinib. Here, we argue that if clinicians adopt the use of 3 years of adjuvant osimertinib in resected early-stage EGFR+ NSCLC, there is no role for adjuvant platinum-based chemotherapy. The use of adjuvant chemotherapy was balanced between the osimertinib and the placebo arms by stage even though adjuvant chemotherapy was not one of the three stratification factors (del 19 vs L858R; Stage IA vs II vs III; Asians versus non-Asian) in ADAURA. There may be a potential role of adjuvant cisplatin/vinorelbine in a small subgroup of EGFR+ NSCLC patients whose tumor harbors retinoblastoma (RB) gene alterations but requires further investigation.

Updated Prognostic Factors in Localized NSCLC.

Lung cancer is the most common cause of cancer mortality worldwide, and non-small cell lung cancer (NSCLC) represents 80% of lung cancer subtypes. Patients with localized non-small cell lung cancer may be considered for upfront surgical treatment. However, the overall 5-year survival rate is 59%. To improve survival, adjuvant chemotherapy (ACT) was largely explored and showed an overall benefit of survival at 5 years < 7%. The evaluation of recurrence risk and subsequent need for ACT is only based on tumor stage (TNM classification); however, more than 25% of patients with stage IA/B tumors will relapse. Recently, adjuvant targeted therapy has been approved for EGFR-mutated resected NSCLC and trials are evaluating other targeted therapies and immunotherapies in adjuvant settings. Costs, treatment duration, emergence of resistant clones and side effects stress the need for a better selection of patients. The identification and validation of prognostic and theranostic markers to better stratify patients who could benefit from adjuvant therapies are needed. In this review, we report current validated clinical, pathological and molecular prognosis biomarkers that influence outcome in resected NSCLC, and we also describe molecular biomarkers under evaluation that could be available in daily practice to drive ACT in resected NSCLC.

Potential utility of longitudinal somatic mutation and methylation profiling for predicting molecular residual disease in postoperative non-small cell lung cancer patients.

GROWING EFFORTS ARE BEING INVESTED IN INVESTIGATING VARIOUS MOLECULAR APPROACHES TO DETECT MINIMAL RESIDUAL DISEASE (MRD) AND PREDICT DISEASE RECURRENCE. IN OUR STUDY, WE INVESTIGATED THE UTILITY OF PARALLEL LONGITUDINAL ANALYSIS OF MUTATION AND DNA METHYLATION PROFILES FOR PREDICTING MRD IN POSTOPERATIVE NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS. TUMOR TISSUES AND LONGITUDINAL BLOOD SAMPLES WERE OBTAINED FROM 65 PATIENTS WITH RESECTED STAGE IA-IIIB NSCLC. SOMATIC MUTATION AND DNA METHYLATION PROFILING WERE PERFORMED USING ULTRA-DEEP TARGETED SEQUENCING AND TARGETED BISULFITE SEQUENCING, RESPECTIVELY. DYNAMIC CHANGES IN PLASMA-BASED MUTATION AND TUMOR-INFORMED METHYLATION PROFILES, REFLECTED AS MRD SCORE, WERE OBSERVED FROM BEFORE SURGERY (BASELINE) TO POSTOPERATIVE FOLLOW-UP, REFLECTING THE DECREASE IN TUMOR BURDEN OF THE PATIENTS WITH RESECTED NSCLC. MUTATIONS WERE DETECTED FROM PLASMA SAMPLES IN 63% OF THE PATIENTS AT BASELINE, WHICH SIGNIFICANTLY REDUCED TO 23-25% DURING POST-OPERATIVE FOLLOW-UPS. MRD SCORE POSITIVE RATE WAS 95.7% AT BASELINE, WHICH REDUCED TO 74% AT THE FIRST AND 70% AT THE SECOND FOLLOW-UP. AMONG THE 5 RELAPSED PATIENTS WITH PARALLEL LONGITUDINAL ANALYSIS OF MUTATION AND METHYLATION PROFILE, ELEVATED MRD SCORE WAS OBSERVED AT FOLLOW-UP BETWEEN 0.5-7 MONTHS PRIOR TO RADIOLOGIC RECURRENCE FOR ALL 5 PATIENTS. OF THEM, 4 PATIENTS ALSO HAD CONCOMITANT INCREASE IN ALLELIC FRACTION OF MUTATIONS IN AT LEAST 1 FOLLOW-UP TIME POINT, BUT ONE PATIENT HAD NO MUTATION DETECTED THROUGHOUT ALL FOLLOW-UPS. OUR RESULTS DEMONSTRATE THAT LONGITUDINAL PROFILING OF MUTATION AND DNA METHYLATION MAY HAVE POTENTIAL FOR DETECTING MRD AND PREDICTING RECURRENCE IN POSTOPERATIVE NSCLC PATIENTS.

Distribution of EML4-ALK fusion variants and clinical outcomes in patients with resected non-small cell lung cancer.

OBJECTIVES: The molecular profiles and prognosis of anaplastic lymphoma kinase (ALK) fusion and resectable non-small cell lung cancer (NSCLC) remain unclear. This study aimed to explore the distribution of ALK fusion variants and prognostic factors in patients with surgically resected NSCLC. MATERIAL AND METHODS: Among the 93 ALK positive surgical patients screened by immunohistochemistry (IHC) or real-time polymerase chain reaction (RT-PCR), 63 patients were confirmed as ALK rearrangement by next-generation sequencing (NGS), including 55 cases of stage I-III and 8 cases of stage IV. Medical records were retrospectively reviewed, the distribution of ALK fusion variants and prognostic factors were analyzed. RESULTS: All of the 55 early stage patients were histological adenocarcinoma. No other fusion types were found except for echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase (EML4-ALK). EML4-ALK variant 1 (E13:A20; 25/55, 45.5 %) was the predominant variant type, followed by EML4-ALK variant 3 (E6:A20; 19/55, 34.5 %) and variant 2 (E20:A20; 8/55, 14.5 %). Concomitant mutations occurred in 22 patients (22/55, 40.0 %), which involved in 32 co-mutations from 12 kinds of mutated genes. TP53 mutations were most common in coexisting mutations (13/32, 40.6 %). TP53 mutations were less frequently occurred in variant 1 group (3/25, 12.0 %) than in non-variant 1 group (10/30, 33.3 %, P = 0.064). The median disease-free survival (DFS) of the 55 patients was 22.1 months, and the median overall survival (OS) was not mature at the time of analysis. Multivariable analysis showed that stage T3 and EML4-ALK variant 3 were independent prognostic factors for shorter DFS. Neither TP53 mutations nor any coexisting mutations were related to prognosis. CONCLUSIONS: This study illustrated the patterns of EML4-ALK fusion variants and gene profiles in patients with resected NSCLC. Advanced T stage and EML4-ALK variant 3 were associated with worse prognosis. The role of TP53 mutations in prognosis is worthy of further study.

Adherence to surveillance guidelines in resected NSCLC: Physician compliance and impact on outcomes.

BACKGROUND: Resected NSCLC guidelines have varying recommendations on appropriate post-operative surveillance. There is general consensus that patients require follow-up with clinic visits and/or CT scans every 6 months for the first 2 years. This study evaluated compliance with surveillance guidelines and the impact on outcomes. METHODS: The BC Cancer Agency (BCCA) provides cancer control for 4.6 million individuals. Inclusion criteria included referred patients from 2005 to 2010, resected stage Ib/II NSCLC, minimum 2 years follow-up at the BCCA, no prior cancer within 5 years. Retrospective chart review collected baseline parameters, follow up visits, CT imaging, recurrence and death. RESULTS: 479 were referred and 263 were eligible. Baseline characteristics: median age 68, male 52%, current/former/never smoker 38/52/10%, stage Ib/II 51/49%, squamous/non 30%/70%. Adherence to visits and/or CT scans every 6 months in 2 years: clinic visits 77%, CT scans 35%, visit and/or CT 80%. Recurrence rate was 46% at 2 years. Surveillance below vs per/above guidelines; metastatic recurrence 57% vs 79% (p=0.28), curative intent treatment at recurrence 14% vs 9% (p=0.50), palliative systemic treatment given 14% vs 34% (p=0.42), DFS 66.6m vs 37.6m (p<0.001), OS 76.5m vs 37.7m (p<0.001). CONCLUSIONS: Compliance with follow up recommendations for resected NSCLC was 80%. Guideline conformity did not increase the rate of curative treatment at recurrence nor did it increase the proportion of patients treated with palliative chemotherapy. Better adjuvant treatment and surveillance options are needed for resected NSCLC.

Outcome and prognostic factors of postoperative radiation therapy (PORT) after incomplete resection of non-small cell lung cancer (NSCLC).

PURPOSE: Current guidelines recommend postoperative radiation therapy (PORT) for incompletely resected non-small cell lung cancer (NSCLC). However, there is still a paucity of evidence for this approach. Hence, we analyzed survival in 78 patients following radiotherapy for incompletely resected NSCLC (R1) and investigated prognostic factors. PATIENTS AND METHODS: All 78 patients with incompletely resected NSCLC (R1) received PORT between December 2001 and September 2014. The median total dose for PORT was 60 Gy (range 44-68 Gy). The majority of patients had locally advanced tumor stages (stage IIA (2.6%), stage IIB (19.2%), stage IIIA (57.7%) and stage IIIB (20.5%)). 21 patients (25%) received postoperative chemotherapy. RESULTS: Median follow-up after radiotherapy was 17.7 months. Three-year overall (OS), progression-free (PFS), local (LPFS) and distant progression-free survival (DPFS) rates were 34.1, 29.1, 44.9 and 51.9%, respectively. OS was significantly prolonged at lower nodal status (pN0/1) and following dose-escalated PORT with total radiation doses >54 Gy (p=0.012, p=0.013). Furthermore, radiation doses >54 Gy significantly improved PFS, LPFS and DPFS (p=0.005; p=0.050, p=0.022). Interestingly, survival was neither significantly influenced by R1 localization nor by extent (localized vs. diffuse). Multivariate analyses revealed lower nodal status and radiation doses >54.0 Gy as the only independent prognostic factors for OS (p=0.021, p=0.036). CONCLUSION: For incompletely resected NSCLC, PORT is used for improving local tumor control. Local progression is still the major pattern of failure. Radiation doses >54 Gy seem to support improved local control and were associated with better OS in this retrospective study.

Adjuvant Chemotherapy in Resected Stage II Non-small Cell Lung Cancer: Evaluating the Impact of Dose Intensity and Time to Treatment.

AIMS: Platinum-based adjuvant chemotherapy is the standard of care for resected stage II non-small cell lung cancer (NSCLC). The purpose of this population-based study was to identify factors that predict for receiving adjuvant therapy and to assess the effect of delayed administration and dose reduction on survival. MATERIALS AND METHODS: The British Columbia Cancer Agency provides cancer care to 4.6 million individuals across a large and varied geographical area. A retrospective review was conducted of all referred patients with resected stage II NSCLC between 2005 and 2010. Baseline characteristics, systemic therapy details and outcomes were recorded. RESULTS: Of 258 stage II NSCLC patients, 158 received adjuvant chemotherapy (61%). No-adjuvant versus adjuvant population: men 52%/57%, median age 67/62, Eastern Cooperative Oncology Group (ECOG) ≤ 1 55%/75%, Charlson comorbidity score (CCS) ≤ 1 61%/74%, pneumonectomy 11%/26%. In patients who received chemotherapy, treatment details were: cisplatin/carboplatin based 81%/19%, median cycles delivered 4, median time from surgery to adjuvant chemotherapy 8 weeks, 72% received ≥ 80% (cisplatin < 256 mg/m(2) and carboplatin < AUC 19.2) total planned dose. On multivariate analysis younger age, better ECOG and pneumonectomy were predictive of adjuvant treatment. Overall survival of adjuvant-treated patients was inferior for those with CCS ≥ 2, age ≥ 70 and reduced dose intensity on multivariate analysis. The surgery to chemotherapy interval did not affect overall survival. CONCLUSIONS: Pneumonectomy and factors associated with better functional status predicted for receiving adjuvant chemotherapy. For patients who received adjuvant chemotherapy the total platinum dose given affected survival but time from surgery did not. A higher platinum dose delivery was important in maintaining the efficacy of adjuvant chemotherapy for resected stage II NSCLC in this retrospective population-based study.