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The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.The authors of this Review present the current considerations in the treatment of patients with early-stage lung cancer, discussing the critical determination of resectability by thoracic surgical oncologists and the management of both resectable and unresectable disease with a focus on systemic therapy selection. They also address innovations in drug development, trial design and efforts to identify early-stage cancers.

Improvements in outcomes for patients with resectable lung cancers have plateaued. Clinical trials of resectable non-small-cell lung cancers with overall survival as the primary endpoint require a decade or longer to complete, are expensive, and limit innovation. A surrogate for survival, such as pathological response to neoadjuvant chemotherapy, has the potential to improve the efficiency of trials and expedite advances. 10% or less residual viable tumour after neoadjuvant chemotherapy, termed here major pathological response, meets criteria for a surrogate; major pathological response strongly associates with improved survival, is reflective of treatment effect, and captures the magnitude of the treatment benefit on survival. We support the incorporation of major pathological response as a surrogate endpoint for survival in future neoadjuvant trials of resectable lung cancers. Additional prospective studies are needed to confirm the validity and reproducibility of major pathological response within individual histological and molecular subgroups and with new drugs.

RET rearrangements are found in 1–2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease. Patients were given 60 mg of cabozantinib orally per day. The primary objective was to determine the overall response (Response Criteria Evaluation in Solid Tumors version 1.1) in assessable patients; those who received at least one dose of cabozantinib, and had been given CT imaging at baseline and at least one protocol-specified follow-up timepoint. We did safety analyses in the modified intention-to-treat population who received at least one dose of cabozantinib. The accrual of patients with RET-rearranged lung cancer to this protocol has been completed but the trial is still ongoing because several patients remain on active treatment. This study was registered with ClinicalTrials.gov, number NCT01639508. Between July 13, 2012, and April 30, 2016, 26 patients with RET-rearranged lung adenocarcinomas were enrolled and given cabozantinib; 25 patients were assessable for a response. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint, with confirmed partial responses seen in seven of 25 response-assessable patients (overall response 28%, 95% CI 12–49). Of the 26 patients given cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation in four (15%) patients, increased alanine aminotransferase in two (8%) patients, increased aspartate aminotransferase in two (8%) patients, decreased platelet count in two (8%) patients, and hypophosphataemia in two (8%) patients. No drug-related deaths were recorded but 16 (62%) patients died during the course of follow-up. 19 (73%) patients required dose reductions due to drug-related adverse events. The reported activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment. Exelixis, National Institutes of Health and National Cancer Institute Cancer Center Support Grant P30 CA008748.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (for example,. the cell spatial distribution, morphology, proximity, and interactions) derived from pathology images. Ceograph identifies key cell spatial organization features by accurately predicting their influence on patient clinical outcomes. In patients with oral potentially malignant disorders, our model highlights reduced structural concordance and increased closeness in epithelial substrata as driving features for an elevated risk of malignant transformation. In lung cancer patients, Ceograph detects elongated tumor nuclei and diminished stroma-stroma closeness as biomarkers for insensitivity to EGFR tyrosine kinase inhibitors. With its potential to predict various clinical outcomes, Ceograph offers a deeper understanding of biological processes and supports the development of personalized therapeutic strategies. Cell spatial organization in tissue provides essential insights into diseases. Here, the authors show Ceograph, a graph convolutional network, for the analysis of pathology images to predict patient outcomes, highlighting cellular markers to guide personalized treatments and enhance biological understanding.

A new lung adenocarcinoma classification is being proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS). This proposal has not yet been tested in clinical datasets to determine whether it defines prognostically significant subgroups of lung adenocarcinoma. In all, 514 patients who had pathological stage I adenocarcinoma of the lung classified according to the Union for International Cancer Control/American Joint Committee on Cancer 7th Edition, and who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan–Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33–89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ ( n =1) and minimally invasive adenocarcinoma ( n =8) had 100% 5-year disease-free survival; intermediate grade: non-mucinous lepidic predominant ( n =29), papillary predominant ( n =143) and acinar predominant ( n =232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma ( n =13), colloid predominant ( n =9), solid predominant ( n =67) and micropapillary predominant ( n =12), with 75, 7170 and 67%, 5-year disease-free survival, respectively ( P <0.001). Among the clinicopathological factors, stage 1B versus 1A ( P <0.001), male sex ( P <0.008), high histological grade ( P <0.001), vascular invasion ( P =0.002) and necrosis ( P <0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size ( P =0.04) and invasive tumor size adjusted by the percentage of lepidic growth ( P <0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification ( P =0.038), male gender ( P =0.007), tumor invasive size ( P =0.026) and necrosis ( P =0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in identifying candidates for adjunctive therapy. The slightly stronger association with survival for invasive size versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor size could impact TNM staging for small adenocarcinomas.

BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-X L or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-X L inhibitor, prevented BCL-X L from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-X L -addicted cells with low activator BH3s and BCL-X L overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1 . As doxorubicin and dinaciclib also reduced BCL-X L , the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells. Small cell lung cancer cells (SCLC) are differentially sensitive to inhibitors of the BCL-2 family. Here the authors analyse the response to BH3 mimetics in SCLC, delineate patterns of expression of apoptotic proteins correlated with differential sensitivities and demonstrate a synergistic anti-tumour activity between ABT-199 and anthracyclines or CDK9 inhibitors.

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR -mutant lung cancers. Here, we modeled disease progression using EGFR -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS / RAF / MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS , KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of \"acquired\" resistance. We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec). In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.

The Common Terminology Criteria for Adverse Events (CTCAE) are used as standard practice in trials of cancer treatments by clinicians to elicit and report toxic effects. Alternatively, patients could report this information directly as patient-reported outcomes, but the accuracy of these reports compared with clinician reports remains unclear. We aimed to compare the reporting of symptom severity reported by patients and clinicians. Between March and May, 2005, a questionnaire with 11 common CTCAE symptoms was given to consecutive outpatients and their clinicians (physicians and nurses) in lung and genitourinary cancer clinics in the Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Patients completed a version that used language adapted from the CTCAE for patient self-reporting. The results from the questionnaire were compared with clinician reporting of the same symptoms. Of 435 patients and their clinicians asked to take part in the study, 400 paired surveys were completed. For most symptoms, agreement between patient and clinician was high, and most discrepancies were within a grade difference of one point. Agreement was higher for symptoms that could be observable directly, such as vomiting and diarrhoea, than for more subjective symptoms, such as fatigue and dyspnoea. Differences in symptom reporting rarely would have changed treatment decisions or dosing, and patients assigned greater severity to symptoms more than did clinicians. No significant differences were recorded between the results when the questionnaire was completed by the patient before or after the clinician. Patient reporting of symptoms could add to the current approach to symptom monitoring in cancer treatment trials. Future research should assess the effect of self reporting on clinical outcomes and efficiency, and the use of real-time collection of patient-reported outcomes for early detection of potentially serious adverse events.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.