Consensus Statements on Precision Oncology in the China Greater Bay Area.

BACKGROUND: Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA. METHODS: Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0. RESULTS: The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice. CONCLUSION: POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

Real-World Perspectives From Surgeons and Oncologists on Resectability Definition and Multidisciplinary Team Discussion of Stage III NSCLC in People's Republic of China, Hong Kong, and Macau: A Physician Survey.

Introduction: Decision-making in diagnosis and management of stage III NSCLC remains complex owing to disease heterogeneity and diverse treatment options, and often warrants multidisciplinary team discussion. Specifically, the selection of patients for multimodality approaches involving surgical resection presents notable challenges owing to heterogeneity in guideline definitions and the subjective, case-specific nature of evaluating resectability on the basis of preoperative assessments. Methods: An internet- and paper-based survey was conducted in 2020 among lung cancer specialists in the People's Republic of China, Hong Kong, and Macau. This survey captured perspectives on stage III NSCLC on real-world diagnosis/staging practice, definition and evaluation of resectability using case scenarios, and preferred treatment paradigms. Results: A total of 60 completed responses were obtained (60.0% surgeons; 40.0% oncologists). The surgeons' and oncologists' responses differed most in the assessment of resectability in specific case scenarios despite overall agreement on top factors determining resectability (T stage, lymph node size, and lymph node location). Of the 17 scenarios, specialists agreed (≥80%) on four "resectable" and six "unresectable" scenarios; of the seven scenarios with less than 80% agreement, surgeons and oncologists had diverging responses for six scenarios. Multidisciplinary team discussions were available in most of the respondents' institutions but usually covered only selected (<50%) stage III cases. Conclusions: This survey used a comprehensive set of stage III NSCLC case scenarios to understand how working definitions of resectability may differ between surgeons and oncologists, and thus, identify types of cases to prioritize for multidisciplinary discussions to maximize limited resources. In parallel, the development of a multidisciplinary expert consensus on treatment approaches could complement local institutional expertise as a reference for decision-making.

EGFR mutation-guided use of afatinib, erlotinib and gefitinib for advanced non-small-cell lung cancer in Hong Kong - A cost-effectiveness analysis.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) therapy targets at epidermal growth factor receptor (EGFR) gene mutations in non-small-cell lung cancer (NSCLC). We aimed to compare the EGFR mutation-guided target therapy versus empirical chemotherapy for first-line treatment of advanced NSCLC in the public healthcare setting of Hong Kong. METHODS: A Markov model was designed to simulate outcomes of a hypothetical cohort of advanced (stage IIIB/IV) NSCLC adult patients with un-tested EGFR-sensitizing mutation status. Four treatment strategies were evaluated: Empirical first-line chemotherapy with cisplatin-pemetrexed (empirical chemotherapy group), and EGFR mutation-guided use of a TKI (afatinib, erlotinib, and gefitinib). Model outcome measures were direct medical cost, progression-free survival, overall survival, and quality-adjusted life-years (QALYs). Incremental cost per QALY gained (ICER) was estimated. Sensitivity analyses were performed to examine robustness of model results. RESULTS: Empirical chemotherapy and EGFR mutation-guided gefitinib gained lower QALYs at higher costs than the erlotinib group. Comparing with EGFR mutation-guided erlotinib, the afatinib strategy gained additional QALYs with ICER (540,633 USD/QALY). In 10,000 Monte Carlo simulations for probabilistic sensitivity analysis, EGFR mutation-guided afatinib, erlotinib, gefitinib and empirical chemotherapy were preferred strategy in 0%, 98%, 0% and 2% of time at willingness-to-pay (WTP) 47,812 USD/QALY (1x gross domestic product (GDP) per capita), and in 30%, 68%, 2% and 0% of time at WTP 143,436 USD/QALY (3x GDP per capita), respectively. CONCLUSIONS: EGFR mutation-guided erlotinib appears to be the cost-effective strategy from the perspective of Hong Kong public healthcare provider over a broad range of WTP.

Psychometric testing of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) subscale in a longitudinal study of cancer patients treated with chemotherapy.

BACKGROUND: The aim of this study was to evaluate the psychometric properties of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) subscale in a longitudinal study of cancer patients treated with chemotherapy. METHODS: Patients were assessed with the FACT/GOG-Ntx subscale, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy Scale 20 (EORTC QLQ-CIPN20), National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE), and light touch test using 10 g monofilament for up to ten assessment points from baseline (prior to initiation of first chemotherapy), after the end of each cycle (up to 6 cycles, 3 weeks per cycle), and at 6, 9, and 12 months after starting chemotherapy. Psychometric analyses included internal consistency reliability, convergent validity, factorial validity, sensitivity to change and responsiveness (minimal clinically important difference, MCID). RESULTS: Cronbach's alpha coefficients of the FACT/GOG-Ntx subscale were 0.82-0.89 across assessment points. The subscale strongly correlated with the EORTC QLQ-CIPN20 (r = 0.79-0.93) but low-to-moderately correlated with the NCI-CTCAE sensory (rs = 0.23-0.45) and motor items (rs = 0.15-0.50) as well as the monofilament test (rs = 0.23-0.47). The hypothesized 4-factor structure of the FACT/GOG-Ntx subscale was not confirmed at assessment points (χ2/df = 2.26-8.50; all P < 0.001). The subscale exhibited small-to-moderate sensitivity to change (r = 0.17-0.37). The MCIDs were between 1.38 and 3.68. CONCLUSION: The FACT/GOG-Ntx subscale has satisfactory reliability, validity, sensitivity to change and responsiveness to evaluate CIPN in cancer patients. Future research is needed to explore the factorial structure of the FACT/GOG-Ntx subscale as the published four-factor structure was not supported in this study.

Risk factors for chemotherapy-induced peripheral neuropathy in patients receiving taxane- and platinum-based chemotherapy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant and difficult to manage side effect of neurotoxic chemotherapies. Several risk factors for CIPN have been identified to date, but inconsistencies and methodological limitations exist in past research. Also, a limited number of potential risk factors has been investigated in the past. AIM: The objective of this study was to assess the relative contribution of a wider range of risk factors in the development of CIPN. METHODS: This analysis used the 6-month data after starting chemotherapy from a larger prospective observational study on CIPN risk, prevalence, and quality of life. Patients were assessed at recruitment for possible CIPN risk factors, including prior history of neuropathies, current/past infectious diseases; neurotoxic medication history; personal and treatment characteristics; smoking history, alcohol use, and vegetable/fruit intake. Neuropathy was assessed at 6-months after starting chemotherapy with the neuropathy (motor/sensory) items of the NCI-CTCAE scale and the WHO criterion for neuropathy. Data on symptom burden were also collected. RESULTS: Data were available from 255 patients from three cancer centers in Hong Kong, Singapore, and UK. The use of different scales did not always identify the same predictor variables. Key risk factors in multivariate regression models included older age (highest OR = 1.08, p < 0.01 with the WHO scale), chemotherapy (platinum-based chemotherapy had OR = 0.20-0.27 in developing CIPN compared to taxane-based chemotherapy), history of neuropathy (for motor CIPN only, OR = 8.36, p < 0.01), symptom burden (OR = 1.06, p < 0.05), number of chemotherapy cycles received (OR = 1.19-1.24, p < 0.01), and alcohol intake (OR = 0.32, p < 0.05). In univariate analysis, the use of statins was implicated with CIPN (p = 0.03-0.04 with different assessments) and diabetes showed a trend (p = 0.09) in the development of CIPN. CONCLUSION: This study confirmed the CIPN risk related to certain variables and identified new ones. This knowledge can assist with treatment decisions and patient education.

Occupational risk factors for nasopharyngeal carcinoma in Hong Kong Chinese: a case-referent study.

PURPOSE: This study aimed to investigate the occupational risk factors for nasopharyngeal carcinoma (NPC) in Hong Kong Chinese. METHODS: We conducted a case-referent study with 352 incident cases and 410 referents recruited between June 2010 and December 2012. Full occupational histories were obtained via face-to-face interviews. Unconditional logistic regressions were performed to estimate the odds ratios (ORs) for NPC associated with occupational risk factors. RESULTS: Workers of craft related trades and elementary occupations were at elevated NPC risk with the adjusted ORs of 2.09 [95% confidence interval (CI) 1.09, 4.01] and 2.14 (95% CI 1.04, 4.41), respectively, compared with those clerical support workers as the reference group. Occupational exposures to cotton dust, chemical fumes, and welding fumes were significantly associated with increased NPC risk after adjustment for confounders [adjusted ORs (95% CIs) 1.93 (1.13, 3.28), 13.11 (1.53, 112.17), and 9.18 (1.05, 80.35), respectively]. We also observed significant exposure-response relationship for the duration of exposure to cotton dust (P for trend = 0.0175). Those with occupational exposure to cotton dust for 15 years or more were at significantly increased risk of NPC (adjusted OR 2.08, 95% CI 1.01, 4.28). CONCLUSIONS: This study indicates that employment in craft related trades and elementary occupations, as well as occupational exposures to chemical fumes, welding fumes, and cotton dust may be associated with an increased risk of NPC. Further epidemiological studies remain warranted to clarify the roles of specific occupational risk factors on NPC development.

Tobacco smoking, family history, and the risk of nasopharyngeal carcinoma: a case-referent study in Hong Kong Chinese.

PURPOSE: This study aimed to investigate the associations of tobacco smoking and family history of nasopharyngeal carcinoma (NPC) with the risk of NPC in Hong Kong Chinese. METHODS: Between June 2010 and December 2012, we conducted a case-referent study with 352 incident cases and 410 referents in Hong Kong. We collected information on tobacco smoking and family history of NPC via face-to-face interviews. RESULTS: There were 174 (49.4%) and 131 (32.0%) ever-smokers among cases and referents, respectively. The adjusted odds ratio (OR) for NPC related to current smoking was 1.67 [95% confidence interval (CI) 1.06, 2.61]. Exposure-response relationships were observed between years and total pack-years of smoking, and NPC risk (p = 0.001 and p = 0.018, respectively). History of NPC in first-degree relatives was associated with an increased NPC risk (adjusted OR = 4.52, 95% CI 2.39, 8.55). The increased NPC risk associated with sibling history (adjusted OR = 6.80, 95% CI 2.63, 17.56) was higher than that for parental history (adjusted OR = 3.04, 95% CI 1.27, 7.25). The adjusted OR for ever-smokers with family history using never-smokers without family history as the reference was 4.54 (95% CI 1.67, 12.34). CONCLUSIONS: This study verified the important roles of tobacco smoking and family history on NPC risk among Hong Kong Chinese. The provided evidence supported the knowledge that both environmental exposures and inherited susceptibility contributed to the risk of NPC.

Domestic incense burning and nasopharyngeal carcinoma: a case-control study in Hong Kong Chinese.

Incense burning is a powerful producer of carcinogens and has been considered as a risk factor for nasopharyngeal carcinoma (NPC). We conducted a case-control study and case-only analyses to investigate the effect of incense burning and its interaction with genetic background on NPC risk among Hong Kong Chinese. Between June 2010 and December 2012, we recruited 352 incident cases of NPC and 410 controls. We collected information on lifelong practice of domestic incense burning via interviews and genotyped 80 single nucleotide polymorphisms (SNPs) in DNA repair genes. We observed an increased NPC risk associated with daily burning in women [Adjusted OR = 2.49, 95% confidence interval (CI): 1.33, 4.66] but not in men. The adjusted OR for daily burning with poor ventilation was 2.08 (95% CI: 1.02, 4.24), while that with good ventilation was 1.35 (95% CI: 0.92, 1.98). Interactions between 2 SNPs (rs2074517 and rs4771436) and incense burning were significantly associated with NPC risk and tended to have a SNP exposure-response effect. Evidence for gene-environment interactions supported the knowledge that NPC is a multi-factorial disease resulting from the joint effects of environmental exposures and inherited susceptibility.

Joint effects of environmental exposures and familial susceptibility to lung cancer in Chinese never smoking men and women.

OBJECTIVES: Previous epidemiological studies had limited power to investigate the joint effects of individual environmental risk factors and familial susceptibility to lung cancer. This study aimed to address this shortcoming. METHODS: We recruited 345 never smoking lung cancer cases and 828 community referents. We developed a collective environmental exposure index by assigning a value of 1 to subjects at high risks regarding environmental risk factors and 0 otherwise, and then summed over using weights equivalent to the excess odds ratio. Potential additive and multiplicative interactions between environmental exposure index and family cancer history were examined. RESULTS: Compared with "low environmental exposure and without family cancer history", the odds ratio was 6.80 (95% confidence interval = 3.31-13.98) for males who had high environmental exposures but without family cancer history, whereas it increased to 30.61 (95% confidence interval = 9.38-99.87) if they also had a positive family history. The corresponding associations became weaker in never smoking females. No multiplicative interaction was observed for both genders and an additive interaction was restricted among males. CONCLUSIONS: This study developed a novel environmental exposure index that offers sufficient interest deserving further studies on the interactions between environmental exposures and familial susceptibility to lung cancer risk.

A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER).

INTRODUCTION: PIONEER (NCT01185314) was a prospective, multinational, epidemiological study of epidermal growth factor receptor (EGFR) mutations in patients from Asia with newly diagnosed advanced lung adenocarcinoma. METHODS: Eligible patients (aged ≥20 years) had untreated stage IIIB/IV adenocarcinoma. The EGFR mutation status (primary end point: positive, negative, or undetermined) of tumor samples (biopsy, surgical specimen, or cytology) was determined (Scorpion amplification refractory mutation system). EGFR mutation frequency was calculated and compared between demographic and clinical subgroups. RESULTS: Of 1482 patients from seven Asian regions, 43.4% of patients were female, median age was 60 years (range, 17-94), and 52.6% of patients were never-smokers. EGFR mutation status was evaluable in tumors from 1450 patients (97.8%) (746 [51.4%] positive; 704 [48.6%] negative). Country, sex, ethnicity, smoking status, pack-years (all p < 0.001), disease stage (p = 0.009), and histology type (p = 0.016) correlated significantly with EGFR mutation frequency. Mutation frequency was 61.1% in females, 44.0% in males; lower in patients from India (22.2%) compared with other areas (47.2%-64.2%); highest among never-smokers (60.7%); and decreased as pack-year number increased (>0-10 pack-years, 57.9%; >50 pack-years, 31.4%) (similar trend by sex). Ethnic group (p < 0.001) and pack-years (p < 0.001) had statistically significant associations with mutation frequency (multivariate analysis); sex was not significant when adjusted for smoking status. CONCLUSION: PIONEER is the first prospective study to confirm high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma. The observed high mutation frequency in demographic/clinical subgroups compared with white populations suggests that mutation testing should be considered for all patients with stage IIIB/IV adenocarcinoma, even males and regular smokers, among Asian populations.

Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis.

BACKGROUND: The epidermal growth factor receptor (EGFR) signaling pathway is crucial for regulating tumorigenesis and cell survival and may be important in the development and progression of non-small cell lung cancer (NSCLC). We examined the impact of EGFR-tyrosine kinase inhibitors (TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with and without EGFR mutations. METHODS: Randomized trials that compared EGFR-TKIs monotherapy or combination EGFR-TKIs-chemotherapy with chemotherapy or placebo were included. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs for the EGFR mutation-positive (EGFRmut(+)) and EGFR mutation-negative (EGFRmut(-)) subgroups were calculated with the fixed-effects inverse variance weighted method. All statistical tests were two-sided. RESULTS: We included 23 eligible trials (13 front-line, 7 second-line, 3 maintenance; n = 14570). EGFR mutation status was known in 31% of patients. EGFR-TKIs treatment prolonged PFS in EGFRmut(+) patients, and EGFR mutation was predictive of PFS in all settings: The front-line hazard ratio for EGFRmut(+) was 0.43 (95% confidence interval [CI] = 0.38 to 0.49; P < .001), and the front-line hazard ratio for EGFRmut(-) was 1.06 (95% CI = 0.94 to 1.19; P = .35; P interaction < .001). The second-line hazard ratio for EGFRmut(+) was 0.34 (95% CI = 0.20 to 0.60; P < .001), and the second-line hazard ratio for EGFRmut(-) was 1.23 (95% CI = 1.05 to 1.46; P = .01; P interaction < .001). The maintenance hazard ratio for EGFRmut(+) was 0.15 (95% CI = 0.08 to 0.27; P < .001), and the maintenance hazard ratio for EGFRmut(-) was 0.81 (95% CI = 0.68 to 0.97; P = .02; P interaction < .001). EGFR-TKIs treatment had no impact on OS for EGFRmut(+) and EGFRmut(-) patients. CONCLUSIONS: EGFR-TKIs therapy statistically significantly delays disease progression in EGFRmut(+) patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut(+) advanced NSCLC patients.

Synergistic effect between alcohol consumption and familial susceptibility on lung cancer risk among Chinese men.

We aimed to examine the effect of alcohol consumption on lung cancer risk stratified by smoking, and to explore whether the impact of alcohol was modified by familial susceptibility to cancer. We recruited 1208 male lung cancer incident cases and 1069 community referents during 2004-2006 and collected their lifetime history of alcohol consumption, cigarette smoking, and family cancer history. Unconditional multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (OR). We tested multiplicative-scale interaction between exposures of interest and examined the additive-scale interaction using synergy index. A moderate association between frequent alcohol consumption and lung cancer was observed among men who had family cancer history (OR = 4.22, 95%CI: 2.46-7.23) after adjustment of smoking and other confounders, while the alcohol effect among men without family history was weak (OR = 1.24, 95%CI: 0.95-1.63) and it became no excess in the never smokers. We observed a consistent synergistic effect between alcohol drinking and family cancer history for all lung cancers and the adenocarcinoma, while there was no multiplicative-scale interaction between the exposures of interest (likelihood ratio test for interaction, p>0.05). Our study revealed a possible synergistic effect between alcohol consumption and familial susceptibility for lung cancer risk; however, this observed possible association needs to be confirmed by future larger analytic studies with more never smoking cases.

Efficacy and safety of first-line erlotinib in elderly patients with advanced non-small cell lung cancer.

TaRceva LUng cancer Survival Treatment (TRUST) was an open-label, phase IV study of advanced non-small cell lung cancer (NSCLC). Patients failing or unsuitable for chemotherapy or radiotherapy received erlotinib 150 mg/day until progression. We examined a subpopulation of elderly patients (≥70 years) receiving first-line erlotinib (n=485) in TRUST. In this subpopulation, disease control rate (n=356 with best response data available) was 79% (vs. 69% for the overall TRUST population; p<0.0001); median progression-free survival (PFS) was 4.57 months [95% confidence interval (CI), 3.68-5.22]; median overall survival (OS) was 7.29 months (95% CI, 6.27-8.67); and one-year survival, was 36.6%. PFS and OS were significantly longer in patients developing rash, compared to those without, and in those with good performance status (PS; 0/1), compared to poor PS (≥2). Eighty-seven subpopulation patients (18%) had an erlotinib-related AE; other than the protocol-defined frequent adverse events (AEs); 4% had a grade ≥3 erlotinib-related AE, 7% had an erlotinib-related serious AE. In the subpopulation, dose reductions were required in 27%, most (97%) were reductions to 100 mg/day; treatment was discontinued in 10%, and one death was associated with treatment-related toxicity (<1%). Erlotinib was effective and well-tolerated and may be considered for elderly patients with advanced NSCLC who are unsuitable for standard first-line chemotherapy or radiotherapy.

Clinical and testing protocols for the analysis of epidermal growth factor receptor mutations in East Asian patients with non-small cell lung cancer: a combined clinical-molecular pathological approach.

BACKGROUND: Several randomized phase III studies in advanced stage non-small cell lung cancer (NSCLC) confirmed the superior response rate and progression-free survival of using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor as first-line therapy compared with chemotherapy in patients with activating EGFR mutations. Despite the need for EGFR mutation tests to guide first-line therapy in East Asian NSCLC, there are no current standard clinical and testing protocols. METHODS: A consensus meeting was held involving expert oncologists, pulmonologists, and pathologists to discuss the current status and variations in EGFR mutation testing of NSCLC across Asia and to recommend a standard clinical and laboratory testing approach for future use. RESULTS: Currently, EGFR mutation tests are only routinely performed in some East Asian countries and medical centers. The consensus recommendation was to perform the test in all newly diagnosed patients with advanced stage nonsquamous lung cancer and some squamous patients with clinical features associated with higher prevalence of EGFR mutations. To increase the sensitivity and specificity of the EGFR mutation tests, tissue acquisition and pretest sample evaluation are important steps in addition to standardization of the EGFR mutation test methodology. CONCLUSION: A standardized EGFR mutation testing protocol is an essential step toward realization of personalized medicine in East Asian NSCLC treatment.

Lung cancer decreased sharply in first 5 years after smoking cessation in Chinese men.

BACKGROUND: The rate of decline in lung cancer risk after smoking cessation among male population and the importance of the magnitude of the early decline were not sufficiently defined in the earlier studies. We evaluated the detailed duration-response relationship between years since smoking cessation and lung cancer risk across major histological types in a population-based case-referent study. METHODS: We recruited 1208 consecutive incident cases of primary lung cancer among Chinese males from the largest oncology center in Hong Kong during 2004-2006, and 1069 male community referents frequency-matched in 5-year age groups. We performed unconditional multiple logistic regression and generalized additive model incorporating smoothing spline to model the potential nonlinear effect of years since cessation on lung cancer. RESULTS: All histological types of lung cancer were strongly associated with current smoking. We observed a rapidly decreasing odds ratio of lung cancer (>50%) across all major histological types of lung cancer (except for the large cell type) within the first 5 years of quitting; the odds ratio continued to decrease but at a slower rate in the subsequent years. CONCLUSION: The substantial benefits obtainable within a short period of 5 years' abstinence should convey an encouraging message to chronic smokers, clinicians, and public health workers.

A novel KIF5B-ALK variant in nonsmall cell lung cancer.

BACKGROUND: The anaplastic lymphoma kinase (ALK) gene is involved frequently in chromosomal translocations, resulting in fusion genes with different partners found in various lymphoproliferative conditions. It was recently reported in nonsmall cell lung cancer (NSCLC) that the fusion protein encoded by echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion gene conferred oncogenic properties. The objective of the current study was to identify other possible ALK fusion genes in NSCLC. METHODS: Immunohistochemical analysis was used to screen for aberrant ALK expression in primary NSCLC. The authors used 5' rapid amplification of complementary DNA ends to screen for potential, novel 5' fusion partners of ALK other than EML4-ALK. Reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization analyses were used to confirm the identity of 5' fusion partners. The genomic breakpoint was verified using genomic sequencing. Overexpression of the novel ALK fusion gene and variants 3a and 3b of EML4-ALK was performed to assess downstream signaling and functional effects. RESULTS: The authors identified a novel gene resulting from the fusion of kinesin family member 5B (KIF5B) exon 15 to ALK exon 20 in a primary lung adenocarcinoma. Western blot analysis of clinical tumor tissues revealed the expression of a protein whose size correlated with that of the predicted KIF5B-ALK. Overexpression of KIF5B-ALK in mammalian cells led to the activation of signal transducer and activator of transcription 3 and protein kinase B and to enhanced cell proliferation, migration, and invasion. CONCLUSIONS: The discovery of the novel KIF5B-ALK variant further consolidated the role of aberrant ALK signaling in lung carcinogenesis.

Safety and efficacy of first-line bevacizumab with chemotherapy in Asian patients with advanced nonsquamous NSCLC: results from the phase IV MO19390 (SAiL) study.

INTRODUCTION: First-line treatment with bevacizumab combined with chemotherapy has been shown to improve outcomes in patients with advanced, nonsquamous non-small cell lung cancer (NSNSCLC) in phase III clinical trials. SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a preplanned subanalysis of Asian patients enrolled in SAiL. METHODS: Patients with untreated, locally advanced, metastatic or recurrent NSNSCLC received bevacizumab 7.5 or 15 mg/kg every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Eligibility criteria for SAiL permitted enrolment of a broad patient population. The primary end point was safety; secondary end points included time to disease progression and overall survival. RESULTS: The Asian intent-to-treat population comprised 314 of the 2212 patients enrolled in the SAiL trial. In the Asian subanalysis, patients received a median of nine cycles of bevacizumab, and the median follow-up was 16.4 months. The incidence of clinically significant adverse events (grade ≥3) of special interest was relatively low in this population (15.6% overall); proteinuria (7.6%), hypertension (4.8%), and bleeding (2.5%) were the most common. A total of five adverse events related to bevacizumab were reported as grade 5. Disease control rate was 94.1%, median time to disease progression was 8.3 months, and median overall survival was 18.9 months. CONCLUSIONS: The safety and efficacy of first-line bevacizumab-based treatment in Asian patients with advanced NSNSCLC is consistent with that demonstrated in phase III studies and in the overall SAiL population. There were no new safety signals.

Efficacy and safety of erlotinib in 1242 East/South-East Asian patients with advanced non-small cell lung cancer.

INTRODUCTION: Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor that significantly increases survival for patients with previously treated advanced non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be particularly effective in Asian patients and may have a distinct safety profile in this population compared with non-Asian patients. We report safety and efficacy data from a subpopulation of East/South-East (E/SE) Asian patients enrolled in a global, open-label, phase IV trial of erlotinib (Tarceva Lung Cancer Survival Treatment study). METHODS: Patients who had previously failed on chemotherapy or radiotherapy, or were unsuitable for these treatments, were treated with oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity. RESULTS: Best response data were available for 1118 E/SE Asian and 4276 non-E/SE Asian patients. The overall response rates were 27% versus 10%, respectively (p < 0.0001). The disease control rates were 78% versus 66%, respectively (p < 0.0001). Survival data were available for 1242 E/SE Asian and 5338 non-E/SE Asian patients. The median progression-free survival times were 5.78 months versus 2.92 months, respectively (hazard ratio = 0.66, p < 0.0001). The median overall survival times were 14.7 months versus 6.8 months, respectively (hazard ratio = 0.57, p < 0.0001). One-year survival rates were 58.3% and 32.7%, respectively. Safety data were available for 1242 E/SE Asian patients. Seventeen percent of these patients experienced one or more erlotinib-related adverse event (AE) (other than the most frequently occurring AEs prespecified in the protocol) and 2% experienced an erlotinib-related serious AE. Dose reductions were reported for 171 (14%) patients. CONCLUSION: Erlotinib is an effective and well-tolerated treatment for Asian patients with advanced non-small cell lung cancer.

Are current or future mesothelioma epidemics in Hong Kong the tragic legacy of uncontrolled use of asbestos in the past?

Inhaled asbestos fibers may contribute to three-fourths of malignant mesotheliomas diagnosed in men and almost 40% of cases diagnosed in women. Bans on the manufacture and sale of amphibole asbestos fibers are expected to reduce the incidence of mesothelioma, but the long latency period from initial exposure to clinical disease means that people exposed before bans were enacted will continue to develop asbestos-related mesotheliomas as they age. Tse et al. (p. 382) used historical data on asbestos consumption and mesothelioma diagnoses to predict future mesothelioma trends in Hong Kong. Asbestos use peaked during a construction boom in the early 1960s and subsequently declined by > 90% following a ban on the sale and import of crocidolite and amosite asbestos in 1996, whereas mesothelioma diagnoses in men increased from a single case in 1972­1976 to 63 cases in 2002­2006 (corresponding to crude incidence rates of 0.09 and 3.86 cases/million men, respectively). Assuming an average latency of 42 years, the authors predict that incidence rates will peak in 2009 and that diagnoses will peak in 2014. However, they caution that ongoing use of chrysotile asbestos and the release of asbestos fibers from older buildings during demolition or renovation may slow the projected decline. [corrected]

Cigarette smoking and changing trends of lung cancer incidence by histological subtype among Chinese male population.

We analyzed the time trends of lung cancer by histological subtype in Hong Kong during 1991-2005, and examined how the time trends were influenced by the effects of birth cohort and calendar period of diagnosis. Cancer incidence data were obtained from Hong Kong Cancer Registry and population data from Census and Statistics Department. Age-standardized incidence rates were computed by the direct method using WHO 1966 standard population as reference. Period and cohort effects were assessed by using two separate Poisson regression models adjusting for age. From 1991 to 2005, the incidence rates in Hong Kong Chinese males decreased steadily. The decline in overall lung cancer incidence rates was limited primarily to the decrease in squamous cell carcinoma, which could be explained by the decreasing trend of cigarette smoking. Adenocarcinoma had been the most predominant histological subtype all along. The relatively horizontal trend of adenocarcinoma and the lack of cohort effect implied the important roles of gene-environment interaction and/or the use of low-tar and filter tip cigarettes. Our study suggests that different histological subtypes may represent different disease entities with perhaps some distinct risk factors. The hypotheses generated from this ecological study will need confirmation by subsequent analytic studies.