Publications by authors named "Hai-Yan Tu"

50 Publications

Clinical outcomes of non-small cell lung cancer patients with leptomeningeal metastases after immune checkpoint inhibitor treatments.

Eur J Cancer 2021 Apr 18;150:23-30. Epub 2021 Apr 18.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China. Electronic address:

Objective: Leptomeningeal metastases (LM) occur in up to 5% of non-small cell lung cancer (NSCLC) patients and often develop after previous systemic treatments. In this article, we explored whether immune checkpoint inhibitors (ICIs) enhanced the dismal survival of patients with LM.

Materials And Methods: Data on NSCLC patients with LM prescribed ICIs were collected at the Guangdong Lung Cancer Institute. Furthermore, relevant literature was reviewed.

Results: A total of 255 NSCLC patients diagnosed with LM were screened from January 2015 to March 2020 at our institute. Cases reported by literature were also included. Finally, 32 NSCLC patients received ICIs after LM diagnosis; their median age was 55 years. Druggable genes were detected in 37.5% of all patients. The ICI regimens included nivolumab (n = 21), pembrolizumab (n = 9), and atezolizumab (n = 2). Ultimately, 62.5% of patients evidenced neurological symptom controlled. Two patients exhibited both intracranial and extracranial complete tumour response; one patient showed both intracranial and extracranial partial response (PR), one patient indicated intracranial PR and a systemic PR, and one patient showed central nervous system PR without extracranial response reported. The median progression-free survival (PFS) in the single-agent subgroup was 2.1 months (95% confidence interval [CI]: 1.4-2.9 months), and the median overall survival (OS) was 4.0 months (95% CI: 0.1-13.3 months). In the combined subgroup, the median PFS and OS were 3.0 months (95% CI: 1.1-4.9 months) and 5.4 months (95% CI: 0.5-10.3 months), respectively. Three patients exhibited remarkable PFS of over 20 months: all patients had ICI single agent, received cranial radiotherapy before ICI prescription, and took ICIs as second-line therapy, and two patients were EGFR/ALK wild type. Multivariate analysis showed that a better Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score was associated with prolonged PFS (P = 0.04). No difference in survival was seen between monotherapy and combination therapy groups.

Conclusion: NSCLC patients with LM may benefit from ICIs of both monotherapy and combination with other therapies, especially those with good ECOG-PS scores. Further work in this regard is required.
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http://dx.doi.org/10.1016/j.ejca.2021.03.037DOI Listing
April 2021

Long-Term Survival of Over 6 Years with Afatinib Sequential Treatment in a Patient with EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Case Report.

Clin Drug Investig 2021 Apr 16. Epub 2021 Apr 16.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan Er Rd, Guangzhou, 510080, China.

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http://dx.doi.org/10.1007/s40261-021-01025-6DOI Listing
April 2021

Effectiveness and Safety of Moxibustion Robots on Primary Dysmenorrhea: A Randomized Controlled Pilot Trial.

Chin J Integr Med 2021 Apr 10. Epub 2021 Apr 10.

Department of Acupuncture and Rehabilitation, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.

Objective: To conduct a pilot trial to explore the effectiveness and safety of moxibustion robots in treating primary dysmenorrhea (PD) and evaluate its feasibility in clinic.

Methods: A total of 70 participants with PD were allocated to either moxibustion robot (MR) group (35 cases) or manual moxibustion (MM) group (35 cases) using computer-generated randomization. One acupoint Guanyuan (CV 4) was selected to receive moxa heat stimulation. Two groups of participants were given 3 menstrual cycles of MM and MR treatment respectively (once a day, 5 days a session) and received another 3 menstrual cycles follow-up. The degree of pain was evaluated by short-form McGill pain questionnaire (SF-MPQ) and the symptoms of dysmenorrhea were evaluated by Cox Menstrual Symptom Scale (CMSS). The safety was measured by the occurrence rate of adverse events (AEs), including burns (blisters, red and swollen), itching, bowel changes, menstrual cycle disorder, menorrhagia and fatigue, etc. RESULTS: A total of 62 patients completed the trial, 32 in MR group and 30 in MM group. Compared with baseline, scores of SF-MPQ and CMSS significantly decreased in both groups (P<0.05), and no significant difference was observed between the two groups in the 3rd and 6th menstrual cycles (P>0.05). The total occurrence rate of AEs in MR group was 2.1%, which was significantly lower than MM group (7.2%, P<0.05).

Conclusions: MR has the same effect as MM at SF-MPQ and CMSS in patients with PD. However, MR is safer than MM (Trial registration No. ChiCTR1800018236).
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http://dx.doi.org/10.1007/s11655-021-3287-8DOI Listing
April 2021

[Development and application of a moxibustion instrument with multi-jointed manipulator].

Zhongguo Zhen Jiu 2021 Feb;41(2):221-4

College of Electrical Engineering, Sichuan University, Chengdu 610065, China.

In view of the limitations of the existing moxibustion instruments, i.e. possible accidental injury when using moxibustion instruments, the negative effects of products from moxibustion instruments on treatment efficacy and health of medical staff and patients, a moxibustion instrument with multi-jointed manipulator is designed. This moxibustion instrument could accurately control the temperature, maintain a safe moxibustion distance, automatically process the burning ashes of moxa and selectively handle moxa smoke. The experimental results shows that this instrument could maintain the constant temperature of target acupoint, reduce the risk of empyrosis, and reasonably deal with the products of moxibustion. The purification rate of moxa smoke is 44.9%, which not only ensures the therapeutic effect of moxa smoke, but also reduces the negative effects of high-concentration moxa smoke on the health of medical staff and patients.
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http://dx.doi.org/10.13703/j.0255-2930.20191123-k0003DOI Listing
February 2021

Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer.

Front Oncol 2020 11;10:596937. Epub 2020 Dec 11.

Division of Pulmonary Oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

Background: Echinoderm microtubule-associated protein-like 4 () is the canonical anaplastic lymphoma kinase () fusion partner in non-small cell lung cancer (NSCLC), and -positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different fusion patterns are still lacking.

Methods: Ninety-eight -positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their fusion patterns. Non-canonical fusions were validated using RNA-sequencing.

Results: 54.1% of patients had pure canonical fusions, 19.4% carried only non-canonical fusions, and 26.5% harbored complex fusions with coexisting canonical and non-canonical fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex fusion group. Notably, patients with complex fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical fusion group (p = 0.010). The complex fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical fusions were likely to be expressed in tumors, and some of them formed canonical transcripts during mRNA maturation.

Conclusion: Our results suggest NSCLC patients with complex fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel fusions and predict prognosis.
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http://dx.doi.org/10.3389/fonc.2020.596937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759679PMC
December 2020

Effect of Dose Adjustments on the Safety and Efficacy of Afatinib in Chinese Patients with Mutated Non-Small Cell Lung Cancer Who Participated in the LUX-Lung Clinical Trial Program.

Onco Targets Ther 2020 7;13:12539-12547. Epub 2020 Dec 7.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, People's Republic of China.

Background: Post hoc analysis of the LUX-Lung 3 and 6 (LL3/6) Phase III trials showed that tolerability-guided dose-adjustments of afatinib reduced treatment-related adverse events (TRAEs) without affecting progression-free survival (PFS) in patients with epidermal growth factor receptor () mutation-positive non-small-cell lung cancer (NSCLC). The current post hoc analysis evaluated outcomes of tolerability-guided dose adjustments of afatinib in patients enrolled in the LL3/6/7 trials in Chinese centers.

Patients And Methods: Patients enrolled in LL3/6/7 had advanced mutation-positive NSCLC. LL3 and LL7 recruited patients globally (including China) and LL6 enrolled Asian patients from China, Thailand, and South Korea. In LL3 and LL6, patients were randomized to afatinib 40 mg/day or cisplatin-based chemotherapy. In the Phase IIb LL7 trial, patients were randomized to afatinib 40 mg/day or gefitinib. Tolerability-guided dose adjustments were permitted for TRAEs, and PFS was the primary endpoint. This post hoc analysis pooled data from patients enrolled in Chinese centers in LL3/6/7 and analyzed the frequency and severity of TRAEs before and after afatinib dose reductions during the first 6 months. PFS and overall survival (OS) were compared for patients who had a dose reduction in the first 6 months and those who did not.

Results: Overall, 299 patients were enrolled in Chinese centers; 68 (23%) had afatinib dose reductions to <40 mg/day in the first 6 months. Prior to dose reduction, 55/68 patients (81%) experienced grade ≥3 TRAE versus 13/68 (19%) after dose reduction. Grade ≥3 TRAEs were much more common in patients with than in those without dose reduction. Median PFS was 11.0 months in both groups, and median OS did not differ significantly: 23.1 months in patients with a dose reduction and 26.9 months in those without a dose reduction.

Conclusion: Tolerability-guided afatinib dose adjustment is an effective strategy to reduce TRAEs without affecting efficacy in Chinese patients.
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http://dx.doi.org/10.2147/OTT.S273866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733053PMC
December 2020

Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer: 2-year follow-up from a randomized, open-label, phase 3 study (CheckMate 078).

Lung Cancer 2021 02 24;152:7-14. Epub 2020 Nov 24.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, 106 Zhongshan Second Road, Guangzhou 510080, China. Electronic address:

Background: In the phase 3 CheckMate 078 study, nivolumab showed significant overall survival (OS) benefit and superior tolerability versus docetaxel in a predominantly Chinese patient population with non-small cell lung cancer (NSCLC). However, data on long-term outcomes with immunotherapy in Asian patients are limited. We report 2-year efficacy and safety data.

Methods: Patients with advanced/metastatic NSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks; n = 338) or docetaxel (75 mg/m every 3 weeks; n = 166) until progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was OS; secondary endpoints included progression-free survival, objective response rate, and safety.

Results: After 25.9 months minimum follow-up, 21 patients (6 %) remained on nivolumab versus 0 on docetaxel. Median OS was 11.9 months with nivolumab versus 9.5 months with docetaxel (HR: 0.75; 95 % CI: 0.61-0.93); 2-year OS rates were 28 % versus 18 %, respectively. Survival benefits were observed across a variety of predefined subgroups. At 2 years, 39 % and 0 % of responders had ongoing responses with nivolumab and docetaxel, respectively. Grade 3-4 treatment-related adverse events occurred in 12 % of patients with nivolumab versus 47 % with docetaxel, leading to discontinuation in 4 % and 5 % of patients, respectively. No new treatment-related deaths occurred.

Conclusion: At 2 years, nivolumab maintained a favorable safety profile and continued to demonstrate superior OS versus docetaxel in this predominantly Chinese patient population with previously treated NSCLC. These data are consistent with long-term outcomes from the global CheckMate 017/057 studies.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.013DOI Listing
February 2021

Predictive and Prognostic Potential of TP53 in Patients With Advanced Non-Small-Cell Lung Cancer Treated With EGFR-TKI: Analysis of a Phase III Randomized Clinical Trial (CTONG 0901).

Clin Lung Cancer 2021 Mar 17;22(2):100-109.e3. Epub 2020 Nov 17.

Cancer Center, Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China. Electronic address:

Background: Mutations in TP53 are commonly found in patients with epidermal growth factor receptor (EGFR) mutant advanced non-small-cell lung cancer (NSCLC). In this study, we determined the predictive and prognostic potential of different subtypes of TP53 using data from a phase III randomized trial (CTONG 0901).

Patients And Methods: The trial enrolled 195 patients who had undergone next-generation sequencing of 168 genes before treatment with EGFR tyrosine kinase inhibitors. Mutations in TP53 (exon 4 or 7, other mutations, and wild-type) were analyzed based on the therapeutic response and survival. A Cox proportional hazards model was used to determine the potential of the predictive and prognostic factors.

Results: All 195 patients harbored activating EGFR mutations: the most common concomitant mutations were TP53 (134/195, 68.7%), CTNNB1 (20/195, 10.3%), and RB1 (16/195, 8.2%). The genetic profiles between patient subgroups administered first-line (132, 67.7%) or later-line (63, 32.3%) treatments did not significantly differ. The median progression-free survival in patients with mutations in exon 4 or 7 of TP53, other TP53 mutations, and wild-type TP53 were 9.4, 11.0, and 14.5 months (P = .009), respectively. Overall survival times were 15.8, 20.0, and 26.1 months (P = .004), respectively. Mutations in exon 4 or 7 of TP53 served as independent prognostic factors for progression-free (P = .001) and overall survival (P = .004) in patients.

Conclusion: Mutations in exon 4 and/or 7 in TP53 are promising predictive and prognostic indicators in EGFR-mutated NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.11.001DOI Listing
March 2021

[Design and application of moxibustion mechanical arm].

Zhen Ci Yan Jiu 2020 Nov;45(11):936-40

School of Acupuncture-moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075.

Traditional moxibustion treatment mainly relies on doctors using specific techniques to stimulate the patient's acupoints with ignited moxa sticks. In view of the poor reproducibility, and different methods of different doctors, difficult to carry out quantitative and qualitative research work in clinical research, a moxibustion mechanical arm was designed. The hardware modules of the mechanical arm are composed of power, micro controller STM32, position servos, moxibustion strip thruster, human-computer interaction panel and sensors; the software parts are composed of main control program and interrupt service program. The use of this moxibustion mechanical arm will enhance the system's multi-task adaptability and could perform a variety of moxibustion methods including circling moxibustion and sparrow-pecking moxibustion. The data collected in real time will be transmitted to PC through bluetooth, displayed on OLED, and the system operation modes could be switched by button. Clinical trials showed that moxibustion mechanical arm had the same treatment effects with traditional moxibustion. Meanwhile, its convenience of ope-ration, repeatability of treatment, doctors and patients's treatment experience are all better than those of traditional moxibustion.
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http://dx.doi.org/10.13702/j.1000-0607.200030DOI Listing
November 2020

Integrated histological and molecular analyses of rebiopsy samples at osimertinib progression improve post-progression survivals: A single-center retrospective study.

Lung Cancer 2020 12 20;150:97-106. Epub 2020 Oct 20.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China; Cancer Center, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. Electronic address:

Background: This single-center retrospective cohort study sought to investigate the impact of rebiopsy analysis after osimertinib progression in improving the survival outcomes.

Methods: Eighty-nine patients with EGFR T790M-positive advanced NSCLC who received second- or further-line osimertinib between January 2017 and July 2019 were included in this study. The co-primary study endpoints were post-progression progression-free survival (pPFS), defined as the time from osimertinib progression until progression from further-line treatment, and post-progression overall survival (pOS), defined as the time from osimertinib progression until death or the last follow-up date.

Results: Pairwise analysis revealed that receiving targeted therapy as further-line treatment after osimertinib progression did not statistically improve the pPFS (P = 0.285) or the pOS (P = 0.903) compared to chemotherapy. However, patients who submitted rebiopsy samples at osimertinib progression for histological and molecular analyses, particularly those who had actionable markers and received highly matched therapy, had significantly longer pPFS and pOS as compared to those who received low-level matched therapy (pPFS = 10.0 m vs. 4.1 m, P = 0.005; pOS = 19.4 m vs. 10.0 m, P = 0.023), unmatched therapy (pPFS = 10.0 m vs. 4.7 m, P = 0.009; pOS = 19.4 m vs. 7.0 m, P = 0.001), and those without rebiopsy data (Rebiopsy vs Non-rebiopsy; pPFS = 6.1 m vs. 3.3 m, P = 0.014; pOS = 11.7 m vs. 6.8 m, P = 0.011).

Conclusion: Our real-world cohort study demonstrates that integrated histological and molecular analyses of rebiopsy specimens after osimertinib progression could provide more opportunities for individualized treatments to improve the post-progression survival of patients with advanced NSCLC. Our findings provide clinical evidence that supports the inclusion of NGS-based analysis of rebiopsy specimens as standard-of-care after osimertinib progression and warrants further prospective evaluation.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.010DOI Listing
December 2020

Genotyping of Cerebrospinal Fluid Associated With Osimertinib Response and Resistance for Leptomeningeal Metastases in EGFR-Mutated NSCLC.

J Thorac Oncol 2021 02 26;16(2):250-258. Epub 2020 Oct 26.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. Electronic address:

Introduction: Patients with NSCLC with leptomeningeal metastases (LM) presented dismal prognosis. Cerebrospinal fluid (CSF) is suggested as a medium of liquid biopsy of LM. However, the clinical implications of CSF genotyping on treatment outcomes remained elusive.

Methods: Patients with EGFR-mutated advanced NSCLC with LM were included: cohort 1, patients with LM who were treated with osimertinib with CSF and plasma genotyping performed before the first dosing of osimertinib (baseline, n = 45); cohort 2, CSF genotyping on progression on osimertinib and development of LM (the progression event on osimertinib is the diagnosis of LM, n = 35). Circulating tumor DNA in CSF underwent next-generation sequencing.

Results: Sensitivity of CSF genotyping for EGFR-sensitizing mutations was 93.3% (42 of 45) and 97.1% (34 of 35) in cohorts 1 and 2, respectively. In cohort 1, patients with EGFR exon 19 deletion had higher median intracranial progression free survival (iPFS) than those with EGFR exon 21 L858R mutation (11.9 versus 2.8 mo; p = 0.02). Median iPFS was significantly longer in patients with T790M-positive CSF genotyping (15.6 mo) than T790M-negative CSF (7.0 mo, p = 0.04). Concurrent CDK4 (2.8 versus 11.6 mo, p = 0.002) and CDKN2A (2.5 versus 9.6 mo, p = 0.04) mutation with EGFR-sensitizing mutations indicated lower median iPFS. Patients with T790M-negative CSF, EGFR exon 21 L858R mutation, concurrent FGF3 alteration, and over first-line osimertinib had shortened iPFS. In cohort 2, possible EGFR-related and EGFR-independent resistance mechanisms were found including C797S mutation, MET dysregulation, and TP53 plus RB1 co-occurrence. Patients with loss of T790M in CSF had a shorter median iPFS (7.4 mo) compared with those with reserved T790M (13.6 mo, p = 0.01).

Conclusions: Genotyping of CSF indicated heterogeneous response to osimertinib and revealed the genetic characteristic of LM on osimertinib failure in patients with EGFR-mutated NSCLC diagnosed with LM.
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http://dx.doi.org/10.1016/j.jtho.2020.10.008DOI Listing
February 2021

Afatinib for the first-line treatment of mutation-positive NSCLC in China: a review of clinical data.

Future Oncol 2020 Nov 15;16(31):2569-2586. Epub 2020 Sep 15.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, 510080, PR China.

Mutations in the  gene are particularly prevalent among Chinese patients with non-small-cell lung carcinoma. Six EGFR tyrosine kinase inhibitors are approved for the first-line treatment of mutation-positive non-small-cell lung carcinoma in China, which poses questions about which agent is most suitable for a particular patient. In this article, we review available clinical trial and real-world data with afatinib in Chinese patients. We assess its efficacy and safety in key patient subgroups such as those with uncommon mutations or brain metastases. We also consider possible subsequent therapies following afatinib. Encouragingly, available data suggest that sequential afatinib and osimertinib confer prolonged overall time to failure of almost 4 years in Asian patients, and represents a viable option in this setting.
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http://dx.doi.org/10.2217/fon-2020-0320DOI Listing
November 2020

Association of Cerebrospinal Fluid Tumor DNA Genotyping With Survival Among Patients With Lung Adenocarcinoma and Central Nervous System Metastases.

JAMA Netw Open 2020 08 3;3(8):e209077. Epub 2020 Aug 3.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

Importance: Owing to the improvement of systemic therapies for lung cancer, patients live longer, but the incidence of central nervous system (CNS) metastases also increases. Cerebrospinal fluid (CSF) has been proven better than plasma to reveal unique genetic profiling of intracranial metastases. How genetic alterations in CSF are associated with the prognosis of this heterogeneous patient group remains elusive.

Objective: To examine the association of molecular alterations in CSF with the survival of patients with a diagnosis of lung adenocarcinoma and CNS metastases.

Design, Setting, And Participants: This retrospective cohort analysis of 94 patients with advanced lung adenocarcinoma and CNS metastases was conducted from July 1, 2016, to July 31, 2018. Patients' CSF samples were collected, and next-generation sequencing of CSF circulating tumor DNA was performed.

Main Outcome And Measures: The main outcome was survival after diagnosis with CNS metastases. Genotyping of CSF circulating tumor DNA was studied to examine its association with the clinical outcomes of patients with CNS metastases.

Results: Of the 94 patients (49 male; mean [SD] age, 53 [1] years) with lung adenocarcinoma and CNS metastases evaluated, 79 harbored an EGFR variant. The most common genes seen in CSF were EGFR (79 [84.0%]), TP53 (57 [60.6%]), MET (23 [24.5%]), CDKN2A (22 [23.4%]), MYC (20 [21.3%]), NTRK1 (19 [20.2%]), and CDK6 (15 [16.0%]). Cluster analysis identified 5 molecular subtypes of CNS metastases. Patients in cluster I had the shortest median survival after diagnosis of CNS metastases compared with each of the other clusters (cluster I, 7.5 months; cluster II, 55.7 months; cluster III, 17.9 months; cluster IV, 27.9 months; cluster V, 21.0 months) and significantly increased risk of death compared with patients in the other clusters (cluster II: hazard ratio [HR], 4.95; 95% CI, 1.50-16.41; P = .009; cluster III: HR, 4.75; 95% CI, 1.49-15.12; P = .008; cluster IV: HR, 6.38; 95% CI, 1.76-23.09; P = .005; cluster V: HR, 5.42; 95% CI, 1.63-17.98; P = .006). The genetic profiles of cluster I were characterized by a high detection rate of CDK4 (9 of 9 [100%]), TP53 (8 of 9 [88.9%]), MET (7 of 9 [77.8%]), and CDKN2A (7 of 9 [77.8%]). For those with EGFR variants, coalterations with CDK4 (HR, 2.02; 95% CI, 1.03-3.96; P = .04), CDK6 (HR, 2.52; 95% CI, 1.32-4.83; P = .005), and MYC (HR, 2.24; 95% CI, 1.21-4.15; P = .01) were associated with poor outcomes.

Conclusions And Relevance: Patients with a diagnosis of lung adenocarcinoma and CNS metastases experienced heterogeneous survival outcomes based on genetic profiling in CSF. These data suggest that CSF might facilitate risk stratifying CNS metastases into appropriate outcomes and provide reference for further clinical study.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.9077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403922PMC
August 2020

Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study.

J Hematol Oncol 2020 04 15;13(1):37. Epub 2020 Apr 15.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.

Background: Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared.

Methods: Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs).

Results: Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6-39.1] vs 24.8 months [95% CI, 11.7-52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9-19.9] vs 4.8 months [95% CI, 4.5-5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10).

Conclusions: RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.
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http://dx.doi.org/10.1186/s13045-020-00866-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160902PMC
April 2020

HER2-Mediated Internalization of Cytotoxic Agents in Amplified or Mutant Lung Cancers.

Cancer Discov 2020 May 25;10(5):674-687. Epub 2020 Mar 25.

mProbe Inc., Rockville, Maryland.

Amplification of and oncogenic mutations in , the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with -amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in . This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196485PMC
May 2020

Retrospective study on bevacizumab in the treatment of non-small cell lung cancer with brain metastases.

Int J Clin Oncol 2020 Feb 5;25(2):267-273. Epub 2019 Oct 5.

Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangdong Lung Cancer Institute, 106 Zhongshan 2nd Road, Guangzhou, 510080, People's Republic of China.

Background: Bevacizumab was demonstrated to have efficacy in patients with non-small cell lung cancer (NSCLC) and brain metastases. However, cerebral toxicities were a major concern. This study aims to investigate the efficacy and risk factors of toxicity of bevacizumab in brain metastases.

Methods: All patients with advanced NSCLC hospitalized in our institute were screened and only those, who underwent bevacizumab administration after the diagnosis of brain metastases, were included.

Results: Fifty-one patients, who were treatment naïve or pretreated prior to bevacizumab regimens, were enrolled. Regardless of treatment lines, the objective response rate (ORR) was 62.7% (32/51), progression free survival (PFS) and overall survival were 6.2 months (95%CI, 5.0-7.4) and 14.0 months (95%CI, 9.6-18.4), respectively, and intracranial PFS was 7.8 months (95%CI, 7.1-8.5). For 41 patients with measurable brain metastatic lesions, the intracranial ORR was 46.3% (19/41). Ten patients (19.6%, 10/51) experienced cerebral toxicities (seven cases of grade 1 and three cases of grade 3), including cerebral or intratumoral hemorrhage and ischemic stroke. Cardiovascular disease was the risk factor contributing to cerebral toxicities (OR 16.645; 95%CI, 2.443-113.430; P = 0.004).

Conclusions: This retrospective study shows that bevacizumab has efficacy and favorable toxicity in patients with NSCLC and brain metastases and cardiovascular disease might be a risk factor for cerebral toxicity.
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http://dx.doi.org/10.1007/s10147-019-01552-5DOI Listing
February 2020

Plasma extracellular vesicle microRNAs for pulmonary ground-glass nodules.

J Extracell Vesicles 2019 18;8(1):1663666. Epub 2019 Sep 18.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangdong Key Laboratory of Lung Cancer Translational Medicine, Guangzhou, China.

In this study, we evaluated the diagnostic value and molecular characteristics of plasma extracellular vesicles (EVs)-derived miRNAs for patients with solitary pulmonary nodules (SPNs), particularly ground-glass nodules (GGNs). This study was registered at www.clinicaltrials.gov under registration number NCT03230019. Small RNA sequencing was performed to assess plasma EVs miRNAs in 59 patients, including 12 patients with benign nodules (2017, training set). MiRNA profiles of 40 an additional individuals were sequenced (2018, validation set). Overall, 16 pure GGNs, 21 mixed GGNs, and 42 solid nodules were included, with paired post-operative plasma samples available for 20 patients. The target miRNA/reference miRNA ratio was used to construct a support vector machine (SVM) model. The SVM model with the best specificity showed 100% specificity in both the training and validation sets independently. The model with the best sensitivity showed 100% and 96.9% sensitivity in the training and validation sets, respectively. Principal component analysis revealed that pure GGN distributions were distinct from those of solid nodules, and mixed GGNs had a diffuse distribution. Among differentially expressed miRNAs, , and were upregulated in tumor tissues and enhanced overall survival. The SVM classifier accurately distinguished malignant GGNs and benign nodules. The distinct profile characteristics of miRNAs provided insights into the feasibility of EVs miRNAs as prognostic factors in lung cancer.
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http://dx.doi.org/10.1080/20013078.2019.1663666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758624PMC
September 2019

A molecular graded prognostic assessment (molGPA) model specific for estimating survival in lung cancer patients with leptomeningeal metastases.

Lung Cancer 2019 05 18;131:134-138. Epub 2019 Mar 18.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Medical Research Center, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China. Electronic address:

Objectives: Leptomeningeal metastases (LM) had increased in advanced non-small-cell lung cancer (NSCLC) over the last 10 years. The survival outcome remained overall poor, heterogeneous and was reported in association with genotypes in lung cancer patients with LM. Graded prognostic assessment model integrated with molecular alterations (molGPA) might be accurate for outcome prediction of LM patients, but needs to be established.

Materials And Methods: We retrospectively screened 8921 consecutive lung cancer patients from January 2011 to March 2018. A total of 301 patients diagnosed as LM were enrolled, and randomly divided into training and validation sets after stratified by gender and age. A molGPA score for each patient was calculated based on the weighted significant parameters including gene mutations.

Result: The median OS for the 301 patients was 9.2 months (95%CI: 7.9-10.5). In the training set, EGFR/ALK positivity, Karnofsky performance score (KPS) score≥60 and absence of extracranial metastasis (ECM) independently predicted better OS. We developed a molGPA model based on above significant prognostic factors. This molGPA model classified LM patients into three prognosis groups of high, intermediate and low risk (molGPA score of 0, 0.5-1.0 and 1.5-2.0, respectively. The median OS of high, intermediate and low risk LM patients in the training set was 0.3, 3.5 and 15.9 months, respectively (p < 0.001). In the validation set, the median OS was 0.9, 5.8 and 17.7 months in the three molGPA subgroups, accordingly (p < 0.001). The C-index of this model in training and validation sets was 0.70 (95%CI: 0.66-0.73) and 0.64 (95%CI: 0.58-0.70) respectively.

Conclusion: The LM molGPA model with integration of gene status, KPS and ECM can accurately classify lung cancer patients with LM into diverse prognosis.
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http://dx.doi.org/10.1016/j.lungcan.2019.03.015DOI Listing
May 2019

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC.

J Thorac Oncol 2019 05 17;14(5):924-932. Epub 2019 Jan 17.

Guangdong General Hospital, School of Medicine, South China University of Technology, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. Electronic address:

Introduction: Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene-mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce.

Methods: Patients with lung cancer with ALK rearrangement were screened from September 2011 to February 2018 at our institute. CSF and paired plasma were tested by next-generation sequencing.

Results: LMs were diagnosed in 30 (10.3%) of 291 patients with ALK-rearranged lung cancer. A total of 11 paired CSF and plasma samples tested by next-generation sequencing were analyzed. Driver genes were detected in 81.8% of the CSF samples (9 of 11) and 45.5% of the plasma samples (5 of 11) (p = 0.183). The maximum allelic fractions were all higher in CSF than in plasma (p = 0.009). ALK and tumor protein p53 gene (TP53) were the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutations were identified in CSF after resistance to alectinib. Multiple copy number variants were mainly found in CSF, including in EGFR, cyclin D1 gene (CCND1), fibroblast growth factor 3 gene (FGF3), and fibroblast growth factor 4 gene (FGF4). Also found were v-myc avian myelocytomatosis viral oncogene homolog gene (MYC) copy number gains and TP53 and cyclin dependent kinase inhibitor 2A gene (CDKN2A) copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF could be used to monitor disease development of LM and longitudinally monitor tumor response.

Conclusion: Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM.
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http://dx.doi.org/10.1016/j.jtho.2019.01.007DOI Listing
May 2019

Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced NSCLC: CheckMate 078 Randomized Phase III Clinical Trial.

J Thorac Oncol 2019 05 17;14(5):867-875. Epub 2019 Jan 17.

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Introduction: Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated NSCLC.

Methods: CheckMate 078 was a randomized, open-label, phase III clinical trial in patients from China, Russia, and Singapore with squamous or nonsquamous NSCLC that had progressed during/after platinum-based doublet chemotherapy (ClinicalTrials.gov: NCT02613507). Patients with EGFR/ALK alterations were excluded. Patients (N = 504) were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m every 3 weeks), stratified by performance status, tumor histology, and tumor programmed death ligand 1 expression. The primary endpoint was overall survival (OS); secondary endpoints included objective response rate, progression-free survival, and safety.

Results: OS was significantly improved with nivolumab (n = 338) versus docetaxel (n = 166); median OS (95% confidence interval): 12.0 (10.4-14.0) versus 9.6 (7.6-11.2) months, respectively; hazard ratio (97.7% confidence interval): 0.68 (0.52-0.90); p = 0.0006. Objective response rate was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5.3 months. Minimum follow-up was 8.8 months. The frequency of grade 3 or greater treatment-related adverse events was 10% with nivolumab and 48% with docetaxel.

Conclusions: This is the first phase III study in a predominantly Chinese population reporting results with a programmed death 1 inhibitor. In this population with previously treated advanced NSCLC, nivolumab improved OS versus docetaxel. Results were consistent with global CheckMate 017 and 057 studies.
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http://dx.doi.org/10.1016/j.jtho.2019.01.006DOI Listing
May 2019

Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression.

BMC Cancer 2018 Nov 26;18(1):1171. Epub 2018 Nov 26.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080, China.

Objective: Crizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi-targeted tyrosine kinase inhibitor (TKI). The objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression.

Methods: Totally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression.

Results: Sixteen patients were identified with c-Met overexpression in 160 ALK-rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK-rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK-rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2.

Conclusions: C-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients.
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http://dx.doi.org/10.1186/s12885-018-5078-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258481PMC
November 2018

Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer.

Lung Cancer 2018 11 14;125:86-92. Epub 2018 Sep 14.

School of Medicine, South China University of Technology, Guangzhou, 510006, China; Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. Electronic address:

Objectives: EGFR-mutated or ALK-rearranged non-small cell lung cancer (NSCLC) often showed unfavorable clinical benefit to checkpoint inhibitors (CPIs). However, few reports exist with integrated analysis, to interpret the underlying mechanism of poor response to PD-1/PD-L1 inhibitors. We have retrospectively analyzed the tumor microenvironment (TME) based on tumor PD-L1 expression and CD8+ T cells infiltration in patients with EGFR mutations and ALK rearrangements, and the prognostic value of TME subtypes on overall survival (OS).

Materials And Methods: Tumor samples from 715 patients with lung cancer were retrospectively collected at Guangdong Lung Cancer Institute. Tumoral PD-L1 expression (N = 715) and CD8+ T cells infiltration (N = 658) was determined by immunohistochemistry (IHC), based on which TME was categorized into four different subtypes: PD-L1+/CD8+, PD-L1-/CD8+, PD-L1+/CD8-, PD-L1-/CD8-. Proportion of four TME subtypes was determined, and overall survival with PD-L1 expression and TME was analyzed.

Results: In patients with EGFR mutations or ALK rearrangements, proportion of PD-L1+/CD8+ tumors was the lowest (5.0%, 17/342), and that of PD-L1-/CD8- tumors was the highest (63.5%, 217/342). In patients with wild-type EGFR and ALK, 14.2% (45/316) tumors were PD-L1+/CD8+ and 50.3% (159/316) tumors were PD-L1-/CD8- (P < 0.001). Median OS of EGFR-mutated or ALK-rearranged lung cancer was 78.6 months in PD-L1 positive group and 93.4 months in PD-L1 negative group (HR 0.47, 95%CI 0.23-0.76, P = 0.005). PD-L1+/CD8+ group exhibited the shortest OS, with 44.3 months, but is likely to respond to CPIs. The PD-L1-/CD8+ group exhibited the longest OS but is unlikely to respond to CPIs.

Conclusion: Patients with EGFR mutations or ALK rearrangements exhibited lower PD-L1 and CD8 co-expression level in TME, which could be responsible for poor response to CPIs. PD-L1 and CD8 co-expression in EGFR-mutated or ALK-rearranged lung cancer is a biomarker for poor prognosis with shorter OS.
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http://dx.doi.org/10.1016/j.lungcan.2018.09.010DOI Listing
November 2018

Impact of menopausal status and HER-2/neu protein on efficacy of EGFR-TKI in mutant patients with non-small cell lung cancer.

J Cancer 2018 30;9(17):2987-2993. Epub 2018 Jul 30.

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Clinical studies have confirmed epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) used in lung cancer patients with mutations can obtain a better result, but still part of the patients with poor efficacy. mutation is highly related to female, nonsmoking and adenocarcinoma. Thus, we hypothesize that estrogen and circulating HER-2/neu protein might influence the efficacy of EGFR-TKIs in mutant patients with non-small cell lung cancer. HER-2/neu expression level of 357 eligible patients in its peripheral serum was determined using ELISA. The median progression-free survival (PFS) in five groups (premenopausal group, perimenopause group, peri to postmenopausal group, postmenopausal group and control group) was statistically difference ( = 0.025). Premenopausal group could predict the efficacy of EGFR-TKI ( = 2.45, 95% CI = 1.42-4.23, = 0.001). No statistical significance was found in median overall survival (OS) among five groups. Optimal diagnostic cut off value of HER-2/neu was set at 47.5 ng/ml, with = 0.0607. As the cutoff value to 47.5 ng/ml division, concentrations and menopausal status was of no significant difference ( = 0.874). PFS of the group below 47.5 ng/ml was significantly longer than that of the group over 47.5 ng/ml ( = 0.000). HER-2/neu concentration was positively correlated with optimal efficacy ( = 0.042). HER-2/neu concentration over than 47.5 ng/ml was a risk factor of EGFR-TKI prognosis. Premenopausal status is an independent predictor of EGFR-TKI curative effect and circulating HER-2/neu protein is an independent prognostic factor in patients with advanced NSCLC.
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http://dx.doi.org/10.7150/jca.25679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134809PMC
July 2018

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation.

J Thorac Oncol 2018 11 26;13(11):1668-1675. Epub 2018 Jul 26.

Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address:

Introduction: This study evaluated whether tumor expression of programmed death ligand 1 (PD-L1) could predict the response of EGFR-mutated NSCLC to EGFR tyrosine kinase inhibitor (TKI) therapy.

Methods: We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC at the Guangdong Lung Cancer Institute between April 2016 and September 2017 and were not enrolled in clinical studies. The patients' EGFR and PD-L1 statuses were simultaneously evaluated.

Results: Among the 101 eligible patients, strong PD-L1 expression significantly decreased objective response rate, compared with weak or negative PD-L1 expression (35.7% versus 63.2% versus 67.3%, p = 0.002), and shortened progression-free survival (3.8 versus 6.0 versus 9.5 months, p < 0.001), regardless of EGFR mutation type (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% versus 30.2%, p = 0.009). Notably, we found a high proportion of PD-L1 and cluster of differentiation 8 (CD8) dual-positive cases among patients with de novo resistance (46.7%, 7 of 15). Finally, one patient with de novo resistance to EGFR-TKIs and PD-L1 and CD8 dual positivity experienced a favorable response to anti-programmed death 1 therapy.

Conclusions: This study revealed the adverse effects of PD-L1 expression on EGFR-TKI efficacy, especially in NSCLC patients with de novo resistance. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1 and CD8 dual positivity and suggest potential therapeutic sensitivity to programmed death 1 blockade.
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http://dx.doi.org/10.1016/j.jtho.2018.07.016DOI Listing
November 2018

Heterogeneous responses and resistant mechanisms to crizotinib in ALK-positive advanced non-small cell lung cancer.

Thorac Cancer 2018 09 6;9(9):1093-1103. Epub 2018 Jul 6.

Guangdong Cardiovascular Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Background: ALK-tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK-positive non-small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis.

Methods: Targeted next-generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment.

Results: ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK -positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post-treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK-TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib.

Conclusions: Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes.
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http://dx.doi.org/10.1111/1759-7714.12791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119621PMC
September 2018

EGFR L792H and G796R: Two Novel Mutations Mediating Resistance to the Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib.

J Thorac Oncol 2018 09 30;13(9):1415-1421. Epub 2018 May 30.

Southern Medical University, Guangzhou, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. Electronic address:

Background: The third-generation EGFR tyrosine kinase inhibitor osimertinib has been approved in many countries to treat advanced NSCLC in patients with the EGFR T790M mutation. As the development of acquired resistance is inevitable, it is urgent that the mechanisms of such resistance be clarified.

Methods: DNA samples from a cohort of 340 patients with lung adenocarcinoma who were taking osimertinib were subjected to next-generation sequencing and screened in terms of the frequencies of the L792H and G796R mutations. Ba/F3 cells stably expressing the EGFR L858R/T790M mutations (in cis) with either the L792H or G796R mutation were created to investigate the impact of the two novel mutations on EGFR tyrosine kinase inhibitors and other potential drug combinations in vitro. Structural analyses were performed by using Schrödinger/Maestro software (version 11.1.012, Schrödinger LLC, Cambridge, MA).

Results: L792H and G796R were detected in 1.76% (six of 340) and 0.56% (two of 340) patients with lung adenocarcinoma treated with osimertinib, respectively. The introduction of L792H or G796R mutations against an L858R/T790M background caused dramatic reductions in osimertinib sensitivity. Structural modeling showed that mutations in cis with T790M either forced the ligand (osimertinib) to rotate out (breaking the binding) or pulled the hinge loop (breaking the hinge). Various other drug combinations. including cetuximab with EAI045, failed to inhibit either cis mutant effectively.

Conclusions: The EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations conferred resistance to osimertinib both in vitro and in silico. For patients in whom the two resistance mutations occur at low frequency, more precise treatment strategies and additional combinational approaches are required.
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http://dx.doi.org/10.1016/j.jtho.2018.05.024DOI Listing
September 2018

Optimal pembrolizumab dosing for non-small cell lung cancer: further studies still needed.

J Thorac Dis 2017 Dec;9(12):4821-4824

Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510515, China.

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http://dx.doi.org/10.21037/jtd.2017.10.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757035PMC
December 2017

Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells Define the Response of Different Subsets of Non-Small Cell Lung Cancer to PD-1/PD-L1 Blockade Immunotherapy.

J Thorac Oncol 2018 04 18;13(4):521-532. Epub 2017 Dec 18.

Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. Electronic address:

Introduction: Inhibition of programmed cell death-1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) by using an immune checkpoint inhibitor has emerged as a promising immunotherapy for NSCLC. The correlation of PD-L1 expression in tumor cells with treatment outcomes has been reported in many pivotal trials; however, the relationship remains unclear. Here, we demonstrate that those patients with both high density of PD-1-positive CD8 and PD-L1-positive CD4-positive CD25-positive (PD-1 PD-L1) regulatory T cells (Tregs) have a better response to PD1/PD-L1 blockade.

Methods: In our study between April 1, 2014, and May 30, 2017, a total of 73 NSCLC peripheral blood samples and fresh tumor specimens were collected for study. Of these, 42 large (10-mm) fresh tumor specimens were obtained from surgical procedures and checked for expression of immunology biomarkers, including PD-L1, PD-1, CD8, CD4, and CD25, in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry, immunohistochemistry, and immunofluorescence (IF). Moreover, 31 small biopsy specimens from patients who received immunotherapy (pembrolizumab or nivolumab) were analyzed by immunohistochemistry and IF. The correlation between flow cytometry and IF detected for TILs' density was evaluated by Spearman's rank correlation test; the primary end point was progression-free survival. For the PD-1/PD-L1 blockade assay, the TILs and peripheral blood mononuclear CD8 T cells were cultured (1×10 per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by anti-PD-1 and anti-PD-L1 was measured by a conventional Cr release assay.

Results: We first identified a population of high-PD-L1-expressing CD25-positive CD4-positive T cells (PD-L1 Tregs) in the tumor microenvironment. The frequency of PD-L1 Tregs was higher in tumor tissue (mean 48.6 ± 14.3% in CD25-positive CD3-positive CD4-positive T cells) than in blood (mean 35.4 ± 10.2% in CD25-positive CD3-positive CD4-positive T cells) and normal tissue (mean 38.6 ± 9.7% in CD25-positive CD3-positive CD4-positive T cells) (p < 0.05), as determined by flow cytometry. The frequency of PD-L1 Tregs was positively correlated with PD-1-positive CD8 in Tregs. In addition, the TILs from these patients (PD-1 PD-L1) showed PD-1/PD-L1 pathway dependence and could induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The patients with PD-L1-positive NSCLC with PD-1 PD-L1 TILs showed a better clinical outcome than those with a low frequency of PD-1 CD8 or PD-L1 Tregs (median progression-free survival not reached versus 2 months).

Conclusions: Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2017.11.132DOI Listing
April 2018

A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer.

Lung Cancer 2017 12 7;114:96-102. Epub 2017 Nov 7.

Southern Medical University, Guangzhou, 510080, People's Republic of China; Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou, 510080, People's Republic of China. Electronic address:

Introduction: Patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations are a heterogeneous group exhibiting differential responses to EGFR inhibitors. This retrospective study reviews the prevalence of uncommon EGFR mutations in a Chinese NSCLC cohort and the clinical characteristics and efficacy of EGFR tyrosine kinase inhibitors (TKIs) associated with these patients.

Materials Andmethods: A total of 5363 lung cancer patients were screened and underwent EGFR genotyping at the Guangdong Lung Cancer Institute. Of those with uncommon EGFR mutations, the clinical characteristics and responses to EGFR-TKIs were reviewed retrospectively.

Results: Uncommon EGFR mutations were observed in 218 patients, comprising 11.9% of all patients with documented EGFR mutations. More smokers (30.7% vs. 24.3%, P=0.039) and males (54.1% vs. 44.4%, P=0.007) were among the patients with uncommon mutations compared with common mutations. The most frequent uncommon mutations were exon 20 insertions (30.7%, n=67), followed by G719X mutations (21.1%, n=46) and compound L858R mutations (17.0%, n=37). Favorable efficacy was observed in patients harboring compound L858R or G719X mutations, with a median progression-free survival (PFS) of 15.2 (95% CI: 8.7-21.7) or 11.6 (95% CI: 3.6-19.6) months, respectively. The median PFS of those with the T790M mutation or an exon 20 insertion was 1.0 (95% CI: 0.0-2.2) and 3.0 (95% CI: 1.3-4.7) months, respectively.

Conclusion: This study reviewed the prevalence of uncommon EGFR mutations and their sensitivity to EGFR-TKIs. Favorable responses were observed in patients with G719X and compound L858R mutations, indicating that they may benefit from EGFR-TKIs as a first-line therapy.
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http://dx.doi.org/10.1016/j.lungcan.2017.11.005DOI Listing
December 2017

EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer.

Oncoimmunology 2017;6(11):e1356145. Epub 2017 Jul 26.

Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Patients with mutations showed unfavorable response to programmed cell death-1 (PD-1) blockade immunotherapy in non-small cell lung cancer (NSCLC). Yet the underlying association between mutation and immune resistance remains largely unclear. We performed an integrated analysis of PD-ligand 1(PD-L1)/CD8 expression and mutation profile based on the repository database and resected early-stage NSCLC in Guangdong Lung Cancer Institute (GLCI). Meanwhile, 2 pool-analyses were set to clarify the correlation between mutation and PD-L1 expression, and the association of status with response to anti-PD-1/L1 therapy. Pool-analysis of 15 public studies suggested that patients with mutations had decreased PD-L1 expression (odds ratio: 1.79, 95% CI: 1.10-2.93; P = 0.02). Analysis of The Cancer Genome Atlas (TCGA) and the GCLI cohort confirmed the inverse correlation between mutation and PD-L1 expression. Furthermore, patients with mutation showed a lack of T-cell infiltration and shrinking proportion of PD-L1/CD8 TIL (P = 0.034). Importantly, patients with mutations, especially the sensitive subtype, showed a significantly decreased mutation burden, based on analysis of the discovery and validation sets. Finally, a pool-analysis of 4 randomized control trials confirmed that patients with mutation did not benefit from PD-1/L1 inhibitors (Hazard ratio [HR] = 1.09, P = 0.51) while patients with wild-type did (HR = 0.73, P < 0.00001). This study provided evidence of a correlation between mutations and an uninflamed tumor microenvironment with immunological tolerance and weak immunogenicity, which caused an inferior response to PD-1 blockade in NSCLCs.
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http://dx.doi.org/10.1080/2162402X.2017.1356145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674946PMC
July 2017