Primary tumor consolidative therapy improves the outcomes of patients with advanced EGFR-mutant lung adenocarcinoma treated with first-line osimertinib.

Background: Patients with advanced epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LAD) inevitably experience drug resistance following treatment with EGFR-tyrosine kinase inhibitors (TKIs). Objectives: We aimed to analyze the effect of primary tumor consolidative therapy (PTCT) on patients treated with first-line osimertinib. Design and methods: This retrospective cohort study was conducted in patients with advanced stage III or stage IV LAD with EGFR-sensitizing mutations (exon 19 deletion or L858R mutation) with disease control after first-line osimertinib. A curative dose of primary tumor radiotherapy or primary tumor resection was classified as PTCT. We compared the progression-free survival (PFS) and overall survival (OS) of patients with and without PTCT. Results: This study included 106 patients with a median age of 61.0 years, and of those, 42% were male and 73.6% were never-smokers. Exon 19 deletion was observed in 67.9%, 30.2% had a programmed cell death ligand 1 (PD-L1) tumor proportion score <1%, 33.0% had brain metastasis, and 40.6% had oligometastasis. In all, 53 (50%) patients underwent PTCT. Patients who underwent PTCT demonstrated significantly better PFS [30.3 (95% confidence interval (CI), 24.1-36.4) versus 18.2 (95% CI, 16.1-20.2) months; p = 0.005] and OS [not reached versus 36.7 (95% CI, 32.5-40.9) months; p = 0.005] than patients who did not. A multivariate analysis showed that PTCT was an independent factor associated with better PFS [hazard ratio (HR), 0.22; 95% CI, 0.10-0.49; p < 0.001] and OS [HR, 0.10; 95% CI, 0.01-0.82; p = 0.032]. The PFS benefits of PTCT were consistent across subgroups, and the HR tended to be lower in patients aged <65 years, males, smokers, stage IVB disease, L858R, PD-L1 expression ⩾1%, non-oligometastasis, and brain metastasis. Conclusion: Of the patients with advanced EGFR-mutant LAD, those who underwent PTCT had a significantly better survival outcome than those who did not. The survival benefits were consistent across different subgroups.

Attenuation of PI3K-Akt-mTOR Pathway to Reduce Cancer Stemness on Chemoresistant Lung Cancer Cells by Shikonin and Synergy with BEZ235 Inhibitor.

Lung cancer is considered the number one cause of cancer-related deaths worldwide. Although current treatments initially reduce the lung cancer burden, relapse occurs in most cases; the major causes of mortality are drug resistance and cancer stemness. Recent investigations have provided evidence that shikonin generates various bioactivities related to the treatment of cancer. We used shikonin to treat multi-resistant non-small lung cancer cells (DOC-resistant A549/D16, VCR-resistant A549/V16 cells) and defined the anti-cancer efficacy of shikonin. Our results showed shikonin induces apoptosis in these ABCB1-dependent and independent chemoresistance cancer sublines. Furthermore, we found that low doses of shikonin inhibit the proliferation of lung cancer stem-like cells by inhibiting spheroid formation. Concomitantly, the mRNA level and protein of stemness genes (Nanog and Oct4) were repressed significantly on both sublines. Shikonin reduces the phosphorylated Akt and p70s6k levels, indicating that the PI3K/Akt/mTOR signaling pathway is downregulated by shikonin. We further applied several signaling pathway inhibitors that have been used in anti-cancer clinical trials to test whether shikonin is suitable as a sensitizer for various signaling pathway inhibitors. In these experiments, we found that low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines. Inhibiting the proliferation of lung cancer stem cells is believed to reduce the recurrence of lung cancer; therefore, shikonin's anti-drug resistance and anti-cancer stem cell activities make it a highly interesting molecule for future combined lung cancer therapy.

Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.

Outcome of Thromboembolic Events and Its Influence on Survival Time of Advanced NSCLC Patients Treated with Antiangiogenic Therapy.

Background: Antiangiogenetic therapy and lung cancer, per se, are associated with an increased risk of thromboembolic events (TE). We aim to evaluate the pattern and outcome of TE as well as its influence on survival time of advanced non-small cell lung cancer (NSCLC) patients receiving antiangiogenic therapy. Methods: This was a retrospective cohort study, which included advanced NSCLC patients receiving antiangiogenic therapy. All TE were confirmed by objective image studies. We disclosed the presentation and risk factors of TE and evaluated its influence on outcome. Results: A total of 427 patients were included. TE occurred in 43 patients (10.1%). Deep vein thrombosis (DVT) was the most common TE (n = 20). Up to 46.2% of DVT did not occur in the typical lower extremities. Two patients died of TE. Among patients with continuous use or reuse of antiangiogenetic therapy, 18.2% had recurrent TE events. At the occurrence of TE, 28 patients experienced progressive disease (TE with PD), while tumor status remained stable in another 15 patients (TE without PD). The post-TE survival of patients without and with PD were 8.9 months (95% CI 3.9-13.9) vs 2.2 months (95% CI 0.1-4.3), P = 0.012. As compared with patients without TE (31.4 months [95% CI 27.1-35.7]), TE with PD patients experienced a significantly shorter overall survival (20.1 months [95% CI 15.5-24.6]), but TE without PD patients had comparable survival time (32.7 months [95% CI 7.4-28.1]) (P = 0006). The use of hormone analogue and proteinuria predicted the events among TE with PD group (aOR 2.79 [95% CI 1.13=6.92]; P = 0.027) and TE without PD group (aOR 4.30 [95% CI 1.13-16.42]; P = 0.033), respectively. Conclusion: Owing to the different risk factors and influences on the survival time, TE with and without PD may be two different disease entities.

Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer.

INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.

The Role of Neutrophil-to-Lymphocyte Ratio in Advanced EGFR-Mutant NSCLC Patients Treated with First-Line Osimertinib.

Purpose: Although serum neutrophil-to-lymphocyte ratio (NLR) is correlated with the outcome of various cancer types, its role in treatment-naïve, advanced, epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients treated with osimertinib remains uncertain. We have the intention to use this biomarker to evaluate the outcomes in NSCLC. Patients and Methods: Advanced EGFR-mutant NSCLC patients receiving osimertinib as the first-line treatment were included. We evaluated the prognostic role of baseline NLR and explored its association with patients' characteristics. A high NLR was defined as pretreatment serum NLR ≥ 5. Results: A total of 112 eligible patients were included. The objective response rate was 83.7%. The median progression-free survival (PFS) and overall survival (OS) were 20.5 months (95% CI 14.5-26.5) and 47.3 months (95% CI 36.7-58.2), respectively. A high NLR predicted an inferior PFS (HR 1.90 [95% CI 1.02-3.51], P = 0.042) and OS (HR 3.85 [95% CI 1.39-10.66], P = 0.009). Patients with stage IVB disease were more likely to have a high baseline NLR than those with stage IIIB-IVA (33.9% vs 15.1%, P = 0.029). Other patients' characteristics did not correlate with the baseline NLR significantly. Patients with a high NLR had significantly more metastatic organs than those with a low NLR (2.5 ± 1.3 vs 1.8 ± 0.9, P = 0.012), particularly brain, liver, and bone metastasis. There was no significant association between NLR and intrathoracic metastasis. Conclusion: Baseline serum NLR could act as an important prognostic marker for EGFR-mutant NSCLC patients receiving first-line osimertinib. A high NLR was associated with higher metastatic burden, more extrathoracic metastases, and therefore, a worse outcome.

Adjuvant chemotherapy compared with observation in patients with T2aN0 stage IB lung adenocarcinoma.

Introduction: For patients with T2aN0 stage IB lung adenocarcinoma, benefits of adjuvant chemotherapy remain controversial. Here, we aimed to evaluate such benefits. Methods: This retrospective cohort study was conducted on the database of the National Taiwan Cancer Registry. We analyzed patients with T2aN0 stage IB lung adenocarcinoma (re-classified by AJCC 8th edition) diagnosed during the period from January 2011 to December 2017. They were divided into two groups: (1) group 1: tumor <=3 cm with visceral pleural invasion (VPI); (2) group 2: tumor >3 cm, but <=4 cm. Overall survival (OS) and cancer specific survival (CSS) were evaluated. Risk factors for survival were determined. Results: A total of 2,100 patients with T2aN0 stage IB lung adenocarcinoma (1,265 in group 1 and 835 in group 2) were enrolled for study. The proportions of patients receiving adjuvant chemotherapy in group 1 and 2 were 39.1% and 68.6%, respectively. Amongst group 1 patients, adjuvant chemotherapy was not an independent risk factor for OS and CSS. Amongst group 2 patients, high-grade histologic findings and receiving sublobar resection were two risk factors for poorer survival. Adjuvant chemotherapy was also associated with an OS (adjusted hazard ratio (aHR), 0.52; 95% confidence interval (CI), 0.38-0.72; P<0.001) and CSS (aHR, 0.54; 95% CI, 0.37-0.78; p=0.001) benefit regardless of the presence or absence of risk factors. Conclusion: For patients with T2aN0 stage IB lung adenocarcinoma, adjuvant chemotherapy improved OS and CSS in those with tumors >3 cm, but <=4 cm.For patients with tumors <=3 cm with VPI, adjuvant chemotherapy had no survival benefit.

Rice OsHsp16.9A interacts with OsHsp101 to confer thermotolerance.

Class I small heat shock proteins (CI sHSPs), OsHsp16.9A and OsHsp18.0, share 74% identity in amino acid sequences and accumulate in response to heat shock treatments. Individual rice transformants overexpressing OsHsp16.9A and OsHsp18.0 exhibit distinct thermoprotection/thermotolerance modes. Under high temperature stress, OsHsp16.9A-overexpressing lines showed higher seed germination rate, seedling survival, and pollen germination than wild-type controls, while OsHsp18.0 overexpression provided higher thermoprotection/thermotolerance for seedling survival. To elucidate the functional roles of OsHsp16.9A, mass spectrometry was used to identify OsHsp16.9A-interacting proteins. OsHsp101 was consistently identified in the OsHsp16.9A protein complex in several mass spectrometry analyses of seed proteins from OsHsp16.9A-overexpressing lines. Both OsHsp16.9A and OsHsp101 proteins accumulated during similar developmental stages of rice seeds and formed a heat-stable complex under high temperature treatments in in vitro assays. Co-localization of OsHsp16.9A and OsHsp101 was observed via ratiometric bimolecular fluorescence complementation analyses. Amino acid mutation studies revealed that OsHsp16.9A glutamate residue 74 and amino acid residues 23-36 were essential for OsHsp16.9A-OsHsp101 interaction. Moreover, overexpressing OsHsp16.9A in OsHsp101 knockdown mutants did not increase the seed germination rate under heat stress, which further confirmed the functional roles of OsHsp16.9A-OsHsp101 interaction in conferring thermotolerance to rice plants.

Thoracic radiotherapy may improve the outcome of extensive stage small cell lung carcinoma patients treated with first-line immunotherapy plus chemotherapy.

OBJECTIVE: Immunotherapy plus etoposide and platinum (EP)-based chemotherapy is the standard of care for patients with extensive stage-small cell lung carcinoma (ES-SCLC). In the era of immunotherapy, the role of thoracic radiotherapy for ES-SCLC remains unclear. METHODS: We retrospectively included ES-SCLC patients treated with first-line EP-based chemotherapy plus atezolizumab or durvalumab at Taichung Veterans General Hospital to evaluate the prognostic role and safety of thoracic radiotherapy. RESULTS: A total of 22 patients were included. The median age was 64 years and most of them were male and smokers. Sixteen patients (72.7%) received durvalumab, while the other 6 patients (27.3%) underwent atezolizumab treatment. Among these patients, 11 (50.0%) had a history of thoracic radiotherapy. There was no significant difference in baseline characteristics between patients with and without thoracic radiotherapy. In the overall population, the objective response rate to immunotherapy plus chemotherapy was 73.7%. The progression-free survival and overall survival were 6.0 months (95% CI: 4.0-7.9) and 13.8 months (95% CI: 8.0-19.6), respectively. The overall survival was significantly longer in patients with thoracic radiotherapy (not-reached [NR] [95% CI NR-NR] vs. 9.6 months [95% CI 2.5-16.6]), respectively ( P value by log-rank test <0.001). Both multivariate analysis and subgroup analysis specifically comparing patients with consolidative thoracic radiotherapy and patients with clinical benefits to systemic therapy who did not undergo thoracic radiotherapy indicated that thoracic radiotherapy improved survival. CONCLUSION: The real-world efficacy of EP-based chemotherapy plus atezolizumab or durvalumab was comparable with that of clinical trials. Thoracic radiotherapy may improve the outcome of ES-SCLC.

Various impacts of driver mutations on the PD-L1 expression of NSCLC.

We aimed to evaluate whether different driver mutations have varying impacts on the programmed cell death-ligand 1 (PD-L1) expression of non-small cell lung cancer (NSCLC), and whether the prognostic roles of PD-L1 amongst our patients were divergent. This was a single-institute study that included patients with NSCLC. Six driver mutations, PD-L1 status, and the outcomes of treatment were assessed. A total of 1,001 NSCLC patients were included for analysis. Overall, the PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rates were 52.2% and 17.3%, respectively. As compared with wild type lung adenocarcinoma, EGFR-mutant and HER2-mutant patients had similarly low PD-L1 and strong PD-L1 positive rates. BRAF-mutant patients had numerically higher PD-L1 and strong PD-L1 positive rates. Patients with fusion mutation (ALK and ROS1) (aOR 2.32 [95% CI 1.10-4.88], P = 0.027 and 2.33 [95% CI 1.11-4.89], P = 0.026), KRAS mutation (aOR 2.58 [95% CI 1.16-5.75], P = 0.020 and 2.44 [95% CI 1.11-5.35], P = 0.026), and non-adenocarcinoma histology (aOR 2.73 [95% CI 1.72-4.34], P < 0.001 and 1.93 [95% CI 1.13-3.30], P = 0.016) all had significantly higher PD-L1 and strong PD-L1 positive rates. A trend towards longer survival was noted in ROS-1 rearranged and KRAS-mutant patients with strong PD-L1 expression who had received crizotinib and chemotherapy, respectively. In conclusion, individual driver mutations had various impacts on the PD-L1 expression of NSCLC patients. The prognostic role of PD-L1 may also be divergent amongst patients harboring different driver mutations.

Histological Transformation after Acquired Resistance to the Third-Generation EGFR-TKI in Patients with Advanced EGFR-Mutant Lung Adenocarcinoma.

Background and Objectives: Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is one of the standard-of-care therapies in patients with EGFR-mutant lung adenocarcinoma; however, acquired resistance inevitably developed. Despite the proposition of histological transformation being one of the resistance mechanisms, its incidence and influence on outcome remain unclear. Materials and Methods: This was a retrospective study conducted at Taichung Veterans General Hospital on patients with advanced EGFR-mutant lung adenocarcinoma receiving the third-generation EGFR-TKI. Only patients receiving rebiopsy were included in the analysis. Results: A total of 55 patients were studied. Eight patients (14.5%) showed histological transformation, including three small cell carcinoma, three squamous cell carcinoma, one large cell neuroendocrine carcinoma, and one with a mixture of adenocarcinoma and squamous cell carcinoma components. The median treatment duration of the third-generation EGFR-TKI before rebiopsy was numerically longer in patients with histological transformation than those without (16.0 vs. 10.9 months). Both the overall survival time from the start of third-generation EGFR-TKI initiation (30.8 vs. 41.2 months) and from rebiopsy (6.6 vs. 12.9 months) to mortality were numerically shorter amongst the transformed population. All patients in the transformed group did not respond to the next line of systemic treatment. One patient with histological transformation receiving local treatment for the metastatic site had a longer overall survival. Conclusions: Repeating biopsy to identify histological transformation should be considered in patients with progression to the third-generation EGFR-TKI. Histological transformations could contribute to the acquired resistance with the implication of a worse prognosis. Further studies are needed to determine the optimal therapy for these patients.

PD-L1 strong expressions affect the clinical outcomes of osimertinib in treatment naïve advanced EGFR-mutant non-small cell lung cancer patients.

The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.

Influence of the Timing of Leptomeningeal Metastasis on the Outcome of EGFR-Mutant Lung Adenocarcinoma Patients and Predictors of Detectable EGFR Mutations in Cerebrospinal Fluid.

BACKGROUND: We aim to evaluate the influence of the timing of leptomeningeal metastasis (LM) occurrence on the outcome of EGFR-mutant lung adenocarcinoma and to explore the predictors of detectable EGFR mutation in the cerebrospinal fluid (CSF). METHODS: EGFR-mutant lung adenocarcinoma patients with cytologically confirmed LM were included for analysis. EGFR mutation in CSF was detected by MALDI-TOF MS plus PNA. RESULTS: A total of 43 patients was analyzed. Of them, 8 (18.6%) were diagnosed with LM prior to first-line EGFR-TKI treatment (early onset), while 35 patients (81.4%) developed LM after first-line EGFR-TKI treatment (late onset). Multivariate analysis suggested that both late-onset LM (aHR 0.31 (95% CI 0.10-0.94), p = 0.038) and a history of third-generation EGFR-TKI treatment (aHR 0.24 (95% CI 0.09-0.67), p = 0.006) independently predicted a favorable outcome. EGFR mutation detection sensitivity in CSF was 81.4%. The radiological burden of LM significantly correlated with CSF tumor cell counts (p = 0.013) with higher CSF tumor cell counts predicting a higher detection sensitivity of EGFR mutation (p = 0.042). CONCLUSIONS: Early onset LM was an independently poor prognostic factor. A higher radiological severity score of LM could predict higher tumor cell counts in CSF, which in turn were associated with a higher detection rate of EGFR mutation.

Characteristics and immune checkpoint inhibitor effects on non-smoking non-small cell lung cancer with KRAS mutation: A single center cohort (STROBE-compliant).

ABSTRACT: Kirsten rat sarcoma (KRAS) mutation (KRASm) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. We have aimed to survey NSCLC patients harboring KRASm in Taiwan, where never-smoking lung adenocarcinoma predominates, and analyze the immune checkpoint inhibitor effect on NSCLC harboring KRASm.NSCLC patients with KRASm were enrolled and tested on programmed death-ligand 1 (PD-L1) expression using available tissue. We analyzed their clinical features, PD-L1 status, responses to ICIs, and overall survival (OS).We studied 93 patients with a median age 66.0 years, 23.7% of whom were women, and 22.6% were never-smokers. The results showed that G12C (36.6%) was the most common KRASm. In 47 patients with available tissue for PD-L1 testing, PD-L1 expression was positive in 66.0% of patients, while PD-L1 ≥50% was higher in ever-smokers (P = .038). Among 23 patients receiving ICI treatment, those with PD-L1 ≥50% experience a 45.5% response rate to ICI. There were benefits from ICI treatment on OS compared with no ICI treatment (median OS 35.6 vs 9.8 months, P = .002) for all of our patients, and for patients with PD-L1 ≥50% (median OS not-reached vs 8.4 months, P = .008). There were no differences in survival across different KRAS subtypes (P = .666).Never-smokers composed more than one-fifth of KRASm in NSCLC in Taiwan. A high PD-L1 expression was related to smoking history and responded well to ICI. ICI treatment improved the OS in NSCLC patients with KRASm, particularly those with PD-L1 ≥50%.

The Difference in Clinical Outcomes Between Osimertinib and Afatinib for First-Line Treatment in Patients with Advanced and Recurrent EGFR-Mutant Non-Small Cell Lung Cancer in Taiwan.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small cell lung cancer. OBJECTIVE: The main objective of the present study was to compare the clinical efficacies between osimertinib and afatinib as first-line treatment in patients with EGFR-mutant non-small cell lung cancer. METHODS: We retrospectively analyzed patients with advanced and recurrent non-small cell lung cancer who harbored an exon 19 deletion or an exon 21 L858R mutation and were being given either osimertinib or afatinib as first-line treatment from January 2018 to December 2020. RESULTS: A total of 128 patients were selected for this study. The osimertinib group included 47 patients, while 81 patients received afatinib. The median follow-up time was 20.1 months in the osimertinib group and 22.7 months in the afatinib group. The median progression-free survival was 18.8 months and 13.1 months in the osimertinib and afatinib groups, respectively (hazard ratio 0.75 [95% confidence interval 0.48-1.18]). The median overall survival was not reached in the osimertinib group and was 41.7 months in the afatinib group (hazard ratio 0.79 [95% confidence interval 0.36-1.72]). In patients without brain metastasis, the median progression-free survival was 17.9 months and 17.2 months in the osimertinib and afatinib groups, respectively (hazard ratio 1.02 [95% confidence interval 0.56-1.85]). In patients with brain metastasis at baseline, the median progression-free survival was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted hazard ratio 0.45 [95% confidence interval 0.21-0.96]). CONCLUSIONS: Our research demonstrates that there was no strong evidence showing that patients taking osimertinib as first-line treatment experienced longer median progression-free survival and overall survival than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median progression-free survival than afatinib in patients with brain metastasis at baseline.

Association of Smoking With Patient Characteristics and Outcomes in Small Cell Lung Carcinoma, 2011-2018.

Importance: Small cell lung carcinoma (SCLC) is uncommon in individuals who have never smoked (never-smokers). The related epidemiologic factors and prognosis remain unclear. Objective: To assess the epidemiologic factors, clinical characteristics, and outcomes of SCLC in never-smokers. Design, Setting, and Participants: A retrospective cohort study was conducted using data from the national Taiwan Cancer Registry, which was inaugurated in 1979 and maintains standardized records of patients' characteristics and clinical information for all individuals with cancer. Patients with cytologically or pathologically proven lung cancer were included for analysis. The study obtained data on patients from January 1, 1996, to December 31, 2018; data analysis was conducted from January 1, 1996, to December 31, 2019. Exposures: Clinical characteristics and outcomes of smokers and never-smokers with SCLC. Main Outcomes and Measures: Clinical characteristics for comparison included age at diagnosis, sex, performance status, tumor stage, and treatment. The main outcome parameter was overall survival of patients with SCLC from 2011 to 2018. Results: From 1996 to 2018, a total of 225 788 patients had diagnosed lung cancer; 141 654 patients (62.7%) were men; mean (SD) age was 67.55 (12.58) years. The numbers of both patients with newly diagnosed lung cancer and those with SCLC increased until 2009 by 111.5% for lung cancer and 118.5% for SCLC. Thereafter, lung cancer cases grew in number, but SCLC cases did not; hence, the percentage of patients with SCLC decreased from 9.3% in 2009 to 6.3% in 2018. From 2011 to 2018, the percentage of never-smokers increased significantly among all patients with lung cancers (from 49.9% in 2011 to 60.2% in 2018) and among those with lung adenocarcinomas (from 64.1% in 2011 to 70.9% in 2018) (both P < .001). However, the percentage of never-smokers appeared to vary little in the SCLC population: 15.5% in 2011 and 16.1% in 2018 (P = .28). The median overall survival was significantly longer in patients with adenocarcinoma vs SCLC (adjusted hazard ratio, 0.32; 95% CI, 0.31-0.33; P < .001). Compared with smokers with SCLC, never-smokers with SCLC tended to include more older patients (age ≥70 years: 492 [57.3%] vs 2242 [44.8%]), more women (274 [31.9%] vs 322 [6.4%]), more individuals with a poor performance status (Eastern Cooperative Oncology Group performance status ≥2: 284 [33.1%] vs 1261 [25.2%]) and stage IV cancer (660 [76.9%] vs 3590 [71.8%]), and more patients without treatment (203 [23.7%] vs 626 [12.5%]). Furthermore, never-smokers, particularly men, experienced a shorter survival rate (adjusted hazard ratio, 1.10; 95% CI, 1.00-1.20; P = .04) compared with the other groups. Conclusions and Relevance: The findings of this cohort study suggest that the decrease in the percentage of patients with SCLC was associated with increased lung cancers of other histologic types, with no substantial decrease in the number of those with SCLC.

The Clinical Outcomes of Different First-Line EGFR-TKIs Plus Bevacizumab in Advanced EGFR-Mutant Lung Adenocarcinoma.

PURPOSE: The aim of this study was to investigate the efficacy of various epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) plus bevacizumab in advanced EGFR-mutant lung adenocarcinoma patients. MATERIALS AND METHODS: From August 2016 to October 2020, we enrolled advanced lung adenocarcinoma patients harboring exon 19 deletion or L858R receiving gefitinib, erlotinib and afatinib plus bevacizumab as the first-line treatment for the purposes of analysis. RESULTS: A total of 36 patients were included in the final analysis. Three patients received gefitinib, 17 received erlotinib, and 16 received afatinib combined with bevacizumab as the first-line treatment. The objective response rate was 77.8%, and disease control rate was 94.4%. The overall median progression-free survival (PFS) was 16.4 months, while the median PFS was 17.1 months in patients with exon 19 deletion, and 16.2 months in patients with L858R mutation (p=0.311). Regarding the use of different EGFR-TKIs, the median PFS was 17.1 months in the erlotinib group and 21.6 months in the afatinib group (p=0.617). In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (p=0.747). Amongst patients harboring exon 19 deletion, the median PFS was 16.2 months in the erlotinib group and not-reached in the afatinib group (p=0.141). In patients with L858R mutation, the median PFS was 18.9 months in the erlotinib group and 16.2 months in the afatinib group (p=0.481). CONCLUSION: Our research demonstrates that not only erlotinib combined with bevacizumab, but also afatinib plus bevacizumab as first-line treatment, provides solid clinical efficacy in advanced EGFR-mutant lung adenocarcinoma patients.

Reactivation of Hepatitis B Virus in Lung Cancer Patients Receiving Tyrosine Kinase Inhibitor Treatment.

(1) Background: We aimed to evaluate the risk of hepatitis B virus (HBV) reactivation in lung cancer patients treated with tyrosine kinase inhibitor (TKI), particularly in those with resolved HBV infection. (2) Methods: In this retrospective hospital-based cohort study, we screened all lung cancer patients with positive hepatitis B core antibodies (anti-HBc) receiving systemic antineoplastic treatment during the period from January 2011 to December 2020. Cumulative incidences of HBV reactivation, and their hazard ratios (HRs), were evaluated after adjusting patient mortality as a competing risk. (3) Results: Among 1960 anti-HBc-positive patients receiving systemic therapy, 366 were HBsAg-positive and 1594 were HBsAg-negative. In HBsAg-positive patients without prophylactic NUC, 3-year cumulative incidences of HBV reactivation were similar between patients receiving chemotherapy and patients receiving TKI (15.0%, 95% confidence interval (CI): 0−31.2% vs. 21.2%, 95% CI: 10.8−31.7%; p = 0.680). Likewise, 3-year cumulative incidences of HBV-related hepatitis were similar between the two groups (chemotherapy vs. TKI: 15.0%, 95% CI: 0−31.2% vs. 9.3%, 95% CI: 2.8−15.7%; p = 0.441). In 521 HBsAg-negative TKI users, the 3-year cumulative incidence of HBV reactivation was only 0.6% (95% CI: 0.0−1.9%). From multivariable regression analysis, we found that the only independent risk factor for HBV reactivation in TKI users was HBsAg positivity (HR 53.8, 95% CI: 7.0−412.9; p < 0.001). (4) Conclusion: Due to high risks of HBV reactivation in HBsAg-positive TKI users, NUC prophylaxis can be considered. However, in patients with resolved HBV infection, such risks are lower, and therefore regular monitoring is recommended.