Development and validation of a predictive model for estimating EGFR mutation probabilities in patients with non-squamous non-small cell lung cancer in New Zealand.

BACKGROUND: Targeted treatment with Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) is superior to systemic chemotherapy in non-small cell lung cancer (NSCLC) patients with EGFR gene mutations. Detection of EGFR mutations is a challenge in many patients due to the lack of suitable tumour specimens for molecular testing or for other reasons. EGFR mutations are more common in female, Asian and never smoking NSCLC patients. METHODS: Patients were from a population-based retrospective cohort of 3556 patients diagnosed with non-squamous non-small cell lung cancer in northern New Zealand between 1 Feb 2010 and 31 July 2017. A total of 1694 patients were tested for EGFR mutations, of which information on 1665 patients was available for model development and validation. A multivariable logistic regression model was developed based on 1176 tested patients, and validated in 489 tested patients. Among 1862 patients not tested for EGFR mutations, 129 patients were treated with EGFR-TKIs. Their EGFR mutation probabilities were calculated using the model, and their duration of benefit and overall survival from the start of EGFR-TKI were compared among the three predicted probability groups: < 0.2, 0.2-0.6, and > 0.6. RESULTS: The model has three predictors: sex, ethnicity and smoking status, and is presented as a nomogram to calculate EGFR mutation probabilities. The model performed well in the validation group (AUC = 0.75). The probability cut-point of 0.2 corresponds 68% sensitivity and 78% specificity. The model predictions were related to outcome in a group of TKI-treated patients with no biopsy testing available (n = 129); in subgroups with predicted probabilities of < 0.2, 0.2-0.6, and > 0.6, median overall survival times from starting EGFR-TKI were 4.0, 5.5 and 18.3 months (p = 0.02); and median times remaining on EGFR-TKI treatment were 2.0, 4.2, and 14.0 months, respectively (p < 0.001). CONCLUSION: Our model may assist clinical decision making for patients in whom tissue-based mutation testing is difficult or as a supplement to mutation testing.

Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Cancer of the nasopharynx in Aotearoa New Zealand from 1994 to 2018: Incidence and survival in a population-based, national registry cohort study.

Background: Cancer of the nasopharynx has remarkable geographic and ethnic variation in incidence and outcomes globally. Recent advances in diagnostic and therapeutic technologies provide new opportunities for early detection and improved outcomes. This study aimed to determine the incidence, demographics, outcomes and time trends of cancer of the nasopharynx in Aotearoa New Zealand over the last 25 years. Methods: In a population-based, national registry cohort study of notifications of malignant neoplasms of the nasopharynx made to the New Zealand Cancer Registry between 1994 and 2018, age-specific and age-standardised incidence rates and survival outcomes were evaluated. Findings: 577 registrations of nasopharyngeal cancer from between 1994 and 2018 were analysed; median age at diagnosis 54 years; 72.4% male; 37.4% Asian, 24.3% New Zealand European, 25.3% Pacific peoples, 13.0% Maori. Age-standardised annual incidence remained low (<1/100,000 person-years) and stable from 1994 to 2018. Age-standardised incidence rates in Pacific peoples, Asian and Maori were 21 (95% CI 12.07-35.21)-, 17 (10.95-25.33)- and 4 (2.79-7.07)-fold higher, respectively, than New Zealand Europeans. Epstein-Barr virus-related morphologies predominated keratinising squamous cell carcinoma and not-otherwise-specified morphological subtypes. Ten-year overall survival rate for the cohort was 49.2% (95% CI 44.7-53.5). Older age at diagnosis (65-94 years), Maori or Pacific ethnicity, keratinising squamous cell carcinoma and distant disease were associated with shorter overall survival, whereas younger age at diagnosis (10-29 years), and Asian ethnicity were associated with longer survival. Interpretation: Aotearoa New Zealand has a distinct profile of nasopharyngeal cancer, with age, ethnicity and morphology among the main determinants of incidence and survival. Funding: None.

Population-based incidence rates and increased risk of EGFR mutated non-small cell lung cancer in Maori and Pacifica in New Zealand.

BACKGROUND: Non-squamous non-small cell lung cancer (NSCLC) patients with Epidermal Growth Factor Receptor (EGFR) mutation benefit from targeted treatments. Previous studies reported EGFR mutation-positive proportions among tested non-squamous NSCLC patients. However, incidence rates and population risk of EGFR mutation-positive and EGFR mutation-negative non-squamous NSCLC have not been assessed. This study therefore aimed to estimate the population-based incidence rates of EGFR mutation-positive and EGFR mutation-negative non-squamous NSCLC in different population groups defined by sex, ethnic group and smoking status. METHODS: This study included data from all non-squamous NSCLC patients diagnosed in northern New Zealand between 1/02/2010 and 31/07/2017 (N = 3815), obtained from a population-based cancer registry. Age-specific incidence rates, WHO age-standardised rates (ASRs) and rates adjusted for incomplete testing were calculated for EGFR mutation-positive and EGFR mutation-negative diseases for the study cohort as a whole and subgroups of patients. RESULTS: Among 3815 patients, 45% were tested for EGFR mutations; 22.5% of those tested were EGFR mutation-positive. The ASR of EGFR mutation-positive NSCLC was 5.05 (95%CI 4.71-5.39) per 100,000 person-years. ASRs for EGFR mutation-positive NSCLC were higher for females than males: standardised incidence ratio (SIR) 1.50 (1.31-1.73); higher for Pacifica, Asians and Maori compared with New Zealand Europeans: SIRs 3.47 (2.48-4.85), 3.35 (2.62-4.28), and 2.02 (1.43-2.87), respectively; and, only slightly increased in ever-smokers compared with never-smokers: SIR 1.25 (1.02-1.53). In contrast, the ASR of EGFR mutation-negative NSCLC was 17.39 (16.75-18.02) per 100,000 person-years, showing a strong association with smoking; was higher for men; highest for Maori, followed by Pacifica and then New Zealand Europeans, and lowest for Asians. When corrected for incomplete testing, SIRs by sex, ethnicity and smoking, for both diseases, remained similar to those based on tested patients. CONCLUSION: The population risk of EGFR mutation-positive NSCLC was significantly higher for Maori and Pacifica compared with New Zealand Europeans.

Factors associated with overall survival in a population-based cohort of non- squamous NSCLC patients from northern New Zealand: A comparative analysis by EGFR mutation status.

BACKGROUND: Previous studies have reported inconsistent results regarding the effect of epidermal growth factor receptor (EGFR) mutations on overall survival in patients with non-squamous non-small-cell lung cancer (NSCLC). This study assesses the effect of EGFR mutation on overall survival, and how the effects of other survival predictors differ by EGFR mutation status. METHODS: The study used a population- based cohort of 1534 non-squamous NSCLC patients diagnosed in northern New Zealand between 1st February 2010 and 31st July 2017. Cox regression survival analyses were used to explore the associations between clinicopathological factors and overall survival by EGFR mutation status. The factors included were age at diagnosis, sex, ethnicity, smoking status, performance status, metastasis status and tumour site. RESULTS: In this cohort, 20% had anEGFR mutation. The median overall survival times were 0.8 years and 2.79 years in EGFR-mutation-negative and -positive groups, respectively (p < 0.0001). Metastasis at diagnosis showed large effects on overall survival in both EGFR-mutation- negative (hazard ratio (HR) = 3.6) and mutation-positive (HR = 3.3) groups. In subgroup analyses by mutation status and metastasis, females had lower survival only if they were mutation-positive; Maori had lower survival (than European New Zealanders) only if the disease was metastatic, and tumour site had significant effects only in patients without metastasis. Age, performance status and smoking status showed consistent effects in all subgroups. CONCLUSION: EGFR mutation status and metastasis are the main predictors for overall survival in non-squamous NSCLC patients. The effects of sex, ethnicity and tumour site vary depending on EGFR mutation and metastasis status.