A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Cancer in Victorian prisoners: a description of cancer diagnoses, demographics, risk factors and barriers to optimal care.

BACKGROUND: The Victorian prison population is growing and ageing. Little has been documented about this group's cancer incidence, presentation or treatment. AIMS: To conduct a retrospective review of Victorian prisoners with cancer, including assessment of change over 15 years and adequacy of treatment delivery. METHODS: Detailed demographic, cancer and treatment data were collected for all prisoners with malignancy treated at St Vincent's Hospital Melbourne from 2002 to 2017. Detailed analysis of adherence to Optimal Care Guidelines was undertaken for a subset. Descriptive statistics were used. RESULTS: We identified 200 cancers in 191 prisoners. The population was predominantly male (185 of 191, 93%), with a median age of 54 years. Rates of cigarette smoking (118 of 191, 59%), mental illness (92 of 191, 46%) and intravenous drug use (59 of 191, 29.5%) were high. Exposure-related cancers predominated (nonmelanoma skin cancer, lung cancer and hepatoma). Most were symptomatic (154 of 191, 77%) and almost one-third had incurable disease at diagnosis (64 of 191, 32%). The number of prisoners with cancer increased over time (2002-2006 [T1], n = 31 vs 2012-2016 [T3], n = 101), as did the median age (45 years in T1 vs 55 years in T3) and rates of mental illness (10 of 31 [32%] in T1 vs 55 of 101 [54%] in T3). Delayed treatment initiation occurred in eight of 12 (66%) assessable patients, largely because of nonattendance. CONCLUSIONS: Victorian prisoners with cancer are at risk of poor outcomes because of late presentation, delayed treatment initiation and medical comorbidities. Tailored interventions are urgently required to improve the provision of timely, comprehensive cancer care to this vulnerable and growing population.

Pilot Study of Patients' Preferences for Immediate Resection Versus a Watch and Wait Approach After Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer.

PURPOSE: In patients with rectal cancer who achieve a clinical complete response to neoadjuvant chemoradiation, it may be reasonable to adopt a watch-and-wait (W&W) strategy rather than proceed to immediate resection of the rectum. Patient preferences for this strategy are unknown. The primary aim of the current study was to determine the feasibility of assessing hypothetical recurrence and survival differences that relevant patients would tolerate to avoid immediate resection of the rectum. A secondary aim included estimating patients' tolerance thresholds and the factors that might predict them. METHODS: We developed a study-specific written questionnaire based on a previously validated instrument. Hypothetical time tradeoff tasks were used to determine the recurrence rate patients would accept to adopt a W&W strategy and the survival benefit that would be needed to justify choosing immediate resection over W&W. Feasibility was measured on the basis of response rate, the stated ease of completion and the satisfaction of task, and time used. RESULTS: Twenty of 31 potentially eligible patients completed the study-specific questionnaire. The majority of respondents felt that questions were clear (70%) and not hard to understand (65%). The median acceptable recurrence risk to adopt a W&W strategy was 20% (interquartile range [IQR], 10%-35%). Patients required a median of 2.0 extra years of survival (IQR, 1.0-3.0 years) over a baseline 7.0 years, and they required a median extra 10% (IQR, 4%-19%) over baseline 70% survival rates to justify immediate resection. CONCLUSION: Measuring the preferences of patients with rectal cancer using time tradeoff methods seemed to be feasible. Larger studies are needed to confirm how acceptable a W&W strategy would be for relevant patients.

A retrospective cohort study of metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy, with an exploratory analysis of changing serum carcinoembryonic antigen levels.

AIM: To examine the relationship between changes in serum carcinoembryonic antigen (CEA) levels and survival during oxaliplatin-based chemotherapy for metastatic colorectal cancer (mCRC). METHODS: A retrospective review of 142 patients with mCRC who were treated with oxaliplatin-based chemotherapies (mostly FOLFOX 6 or XELOX) by St Vincent's Hospital, from October 1999 until 30 November 2007. Survival analysis was used to determine median overall survival (OS) from commencement of chemotherapy. A CEA response was defined by ≥50% decline compared with baseline, maintained on two consecutive occasions at least 4 weeks apart. The Cox proportional hazard model and a landmark analysis at 3 months were used to evaluate survival differences between CEA responders (rCEA) and non-responders (non-rCEA). RESULTS: The median OS was 14.7 months. Using an intention-to-treat analysis, 76 (53.5%) patients achieved a CEA response, while 66 (46.5%) did not. Using the landmark analysis at 3 months, rCEA had a longer survival than non-rCEA (median 16.0 vs 7.8 months, P < 0.0001). The hazard ratio for patients dying of mCRC in non-rCEA was 2.2 (P < 0.0001). In multivariate analysis, CEA response and better baseline Eastern Cooperative Oncology Group (ECOG) predicted for survival (P < 0.0001 for both), while age, gender and histology grade did not. CONCLUSION: The median OS of our patients is similar to published randomized trials. A CEA response of ≥50% at 3 months and good ECOG were independent predictors of OS of patients with mCRC treated with oxaliplatin-based chemotherapies.

Maintenance Chemotherapy Use for Advanced Non-Small Cell Lung Cancer in an Australian Cancer Centre.

BACKGROUND: To investigate the rates of maintenance therapy in advanced non-small cell cancer, the reasons for not progressing to second line therapy at disease progression at our cancer centre and to use this data as a way to institute it into clinical practice in our cancer centre. METHOD: This study was approved by the ethics committee. The data was collected from a purpose built cancer unit database, patient and pharmacy records for all patients diagnosed with Stage 3 and 4 non-small cell lung cancer between 2005 - 2011. Demographic information was collected and subgroup analysis of mean overall survival was obtained. Reasons for not progressing to second line therapy were also analysed. RESULTS: Of the 105 patients available for analysis, 44 achieved stable disease/partial response (SD/PR) post first cycle of which 42 were eligible for maintenance chemotherapy, 7 went onto receive maintenance with a mean overall survival (OS) of 18.26 months, 23 received second line with the highest OS of 28.19 months and 12 didn't receive either with the lowest OS of 11.52 months. The majority of these patients did not receive second line at disease progression because of being too unwell. CONCLUSION: Similar data on the progression to second line chemotherapy in this patient group was seen. Those that received second line chemotherapy had higher overall survival and thus maintenance therapy could be a means to allow patients to be fit enough to receive second line when they need it.

Integrated mutation, copy number and expression profiling in resectable non-small cell lung cancer.

BACKGROUND: The aim of this study was to identify critical genes involved in non-small cell lung cancer (NSCLC) pathogenesis that may lead to a more complete understanding of this disease and identify novel molecular targets for use in the development of more effective therapies. METHODS: Both transcriptional and genomic profiling were performed on 69 resected NSCLC specimens and results correlated with mutational analyses and clinical data to identify genetic alterations associated with groups of interest. RESULTS: Combined analyses identified specific patterns of genetic alteration associated with adenocarcinoma vs. squamous differentiation; KRAS mutation; TP53 mutation, metastatic potential and disease recurrence and survival. Amplification of 3q was associated with mutations in TP53 in adenocarcinoma. A prognostic signature for disease recurrence, reflecting KRAS pathway activation, was validated in an independent test set. CONCLUSIONS: These results may provide the first steps in identifying new predictive biomarkers and targets for novel therapies, thus improving outcomes for patients with this deadly disease.

Molecular profiling of non-small cell lung cancer: of what value in clinical practice?

Future improvements in lung cancer survival are likely to come from delineating its putative oncogenic pathways. The development of microarray technology to perform thousands of simultaneous genetic experiments and the linking of this to clinical information is an imperative for refining our current treatments and developing new ones. This paper reviews the state of this research, describes a typical microarray experiment and the implications for diagnosis and treatment of non-small cell lung cancer.

High resolution melting analysis for the rapid and sensitive detection of mutations in clinical samples: KRAS codon 12 and 13 mutations in non-small cell lung cancer.

BACKGROUND: The development of targeted therapies has created a pressing clinical need for the rapid and robust molecular characterisation of cancers. We describe here the application of high-resolution melting analysis (HRM) to screen for KRAS mutations in clinical cancer samples. In non-small cell lung cancer, KRAS mutations have been shown to identify a group of patients that do not respond to EGFR targeted therapies and the identification of these mutations is thus clinically important. METHODS: We developed a high-resolution melting (HRM) assay to detect somatic mutations in exon 2, notably codons 12 and 13 of the KRAS gene using the intercalating dye SYTO 9. We tested 3 different cell lines with known KRAS mutations and then examined the sensitivity of mutation detection with the cell lines using 189 bp and 92 bp amplicons spanning codons 12 and 13. We then screened for KRAS mutations in 30 non-small cell lung cancer biopsies that had been previously sequenced for mutations in EGFR exons 18-21. RESULTS: Known KRAS mutations in cell lines (A549, HCT116 and RPMI8226) were readily detectable using HRM. The shorter 92 bp amplicon was more sensitive in detecting mutations than the 189 bp amplicon and was able to reliably detect as little as 5-6% of each cell line DNA diluted in normal DNA. Nine of the 30 non-small cell lung cancer biopsies had KRAS mutations detected by HRM analysis. The results were confirmed by standard sequencing. Mutations in KRAS and EGFR were mutually exclusive. CONCLUSION: HRM is a sensitive in-tube methodology to screen for mutations in clinical samples. HRM will enable high-throughput screening of gene mutations to allow appropriate therapeutic choices for patients and accelerate research aimed at identifying novel mutations in human cancer.

Attitudes of oncology health professionals to information from the Internet and other media.

OBJECTIVE: To investigate attitudes of Australian health professionals working in oncology to health-related information in the media and on the Internet and to patients who search for this information. DESIGN: Questionnaire-based survey. SETTING AND PARTICIPANTS: Questionnaires were mailed in January 2003 to all 333 health professionals belonging to the Victorian Cooperative Oncology Group. MAIN OUTCOME MEASURES: 27 items about attitudes to information in the media and the Internet, patient information-seeking and its effects on the doctor-patient relationship. RESULTS: 226 surveys (68%) were returned and assessable. Most respondents took notice of medical information reported on television/radio, in newspapers (80% each) and on the Internet (56%), mainly to be informed when patients ask questions (82%) and to check its accuracy (60%). Most were concerned about this accuracy (64% believed it accurate only sometimes, and 23% rarely), and 91% believed information from the Internet had the potential to cause harm to patients. Nevertheless, they generally supported patients' information-searching, believing it allowed them to be better informed (58%), and did not affect their ability to cope with their illness (49%), or their trust in, and relationship with, their doctor (69% and 67%, respectively). CONCLUSIONS: Oncology health professionals are aware of patients' use of the Internet and other media to obtain medical information. To ensure oncology patients find reliable and relevant information and to minimise the risk of harm, the health professionals treating them should provide guidance in finding information sources, and assistance in interpreting the information obtained.