The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants-a multi-site prospective cohort study.

BACKGROUND: Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. METHODS: This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. RESULTS: Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. CONCLUSIONS: These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Is the Blood an Alternative for Programmed Cell Death Ligand 1 Assessment in Non-Small Cell Lung Cancer?

Anti-programmed cell death (PD)-1/PD-ligand 1 (L1) therapies have significantly improved the outcomes for non-small cell lung cancer (NSCLC) patients in recent years. These therapies work by reactivating the immune system and enabling it to target cancer cells once more. There is a general agreement that expression of PD-L1 on tumour cells predicts the therapeutic response to PD-1/PD-L1 inhibitors in NSCLC. Hence, immunohistochemical staining of tumour tissue biopsies from NSCLC patients with PD-L1 antibodies is the current standard used to aid selection of patients for treatment with anti-PD-1 as first line therapy. However, issues of small tissue samples, tissue heterogeneity, the emergence of new metastatic sites, and dynamic changes in the expression of PD-L1 may influence PD-L1 status during disease evolution. Re-biopsy would expose patients to the risk of complications and tardy results. Analysis of PD-L1 expression on circulating tumour cells (CTCs) may provide an accessible and non-invasive means to select patients for anti-PD-1 therapies. Additionally, CTCs could potentially provide a useful biomarker in their own right. Several published studies have assessed PD-L1 expression on CTCs from NSCLC patients. Overall, analysis of PD-L1 on CTCs is feasible and could be detected prior to and after frontline therapy. However, there is no evidence on whether PD-L1 expression on CTCs could predict the response to anti-PD-1/PD-L1 treatment. This review examines the challenges that need to be addressed to demonstrate the clinical validity of PD-L1 analysis in CTCs as a biomarker capable of predicting the response to immune checkpoint blockade.

Incidence, features and management of radionecrosis in melanoma patients treated with cerebral radiotherapy and anti-PD-1 antibodies.

BACKGROUND: Brain radiotherapy is used in the management of melanoma brain metastases (MBM) and can result in radionecrosis. Anti-PD-1 is active in the brain and may increase the risk of radionecrosis when combined with radiotherapy. We studied the incidence, associated factors and management of radionecrosis in longer-term survivors with MBM treated with this combination. METHODS: Patients with MBM treated with radiotherapy and anti-PD-1 who survived >1 year were identified to determine radionecrosis incidence (Cohort A, n = 135). Cohort A plus additional radionecrosis cases were examined for factors associated with radionecrosis and management (Cohort B, n = 148). RESULTS: From Cohort A, 17% developed radionecrosis, with a cumulative incidence at 2 years of 18%. Using Cohort B, multivariable analysis confirmed an association between radionecrosis and elevated lactate dehydrogenase (p = 0.0496) and prior treatment with ipilimumab (p = 0.0319). Radionecrosis was diagnosed based on MRI (100%), symptoms (69%) and pathology (56%). Treatment included corticosteroids, bevacizumab and neurosurgery. CONCLUSIONS: Radionecrosis is a significant toxicity in longer-term melanoma survivors with MBM treated with anti-PD-1 and radiotherapy. Identification of those at risk of radionecrosis who may avoid radiotherapy is required.

Survey of practices around pharmaceutical company funding for continuing professional development among medical oncologists and trainees in Australia.

BACKGROUND: The completion of continuing professional development (CPD) is mandatory for medical oncologists and trainees (MO&T). Pharmaceutical companies may fund some CPD activities, but there is increasing debate about the potential for conflicts of interest (COI). AIM: To assess current practices around funding to attend CPD activities. METHODS: An electronic survey was distributed to Australian MO&T. The survey asked questions about current practices, institutional policies and perceptions about attending CPD funded by pharmaceutical companies. The design looked at comparing responses between MO&T as well as their understanding of and training around institutional and ethical process. RESULTS: A total of 157 of 653 (24%) responses was received, the majority from MO (76%). Most CPD activities attended by MO&T were self-funded (53%), followed by funding from institutions (19%), pharmaceutical companies (16%) and salary award (16%). Most institutions allowed MO&T to receive CPD funding from professional organisations (104/157, 66%) or pharmaceutical companies (90/157, 57%). A minority of respondents (13/157, 8%) reported that the process to use pharmaceutical funds had been considered by an ethics committee. Although 103/157 (66%) had received pharmaceutical funding for CPD, most (109/157, 69%) reported never receiving training about potential COI. The lack of education was more noticeable among trainees (odds ratio (OR) 8.61, P = 0.02). MO&T acknowledged the potential bias towards a pharmaceutical product (P = 0.05) but believed there was adequate separation between themselves and pharmaceutical companies (P < 0.01). CONCLUSION: Majority of CPD attended by MO&T is self-funded. There is lack of clarity in institutional policies regarding external funding support for CPD activities. Formal education about potential COI is lacking.

Role of endobronchial ultrasound in diagnosis and molecular assessment of metastatic melanoma.

BACKGROUND AND OBJECTIVE: Vemurafenib is a new inhibitor of the mutated BRAF oncogene. In the presence of mutated BRAF in metastatic melanoma, treatment with vemurafenib leads to a reduction in mortality and in tumour progression when compared with chemotherapy. This study describes nine cases in which endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) was used to assess mediastinal and hilar lymph nodes for the presence of metastatic melanoma and demonstrates the ability to detect mutations in BRAF on the tissue obtained. METHODS: A retrospective review was performed of all patients who had a history of melanoma and underwent EBUS TBNA to investigate hilar or mediastinal lymphadenopathy for the presence of metastatic melanoma. RESULTS: In seven of the nine cases, metastatic melanoma was confirmed on cytology. The two negative cases were proven to be true negatives by follow up or by demonstrating an alternate diagnosis. In five cases, analysis for BRAF mutation was performed. Four cases were positive for mutation and one demonstrated wild-type BRAF. CONCLUSIONS: Tissue samples obtained from EBUS TBNA are adequate to diagnose metastatic melanoma in hilar and mediastinal lymph nodes and to detect the presence or absence of mutations in the BRAF gene. Our findings suggest that close collaboration between bronchoscopists and pathologists will be needed to implement BRAF testing in routine practice in the era of targeted therapy.

Applying global frameworks to assessment in medical education: an example of a nationally produced curriculum for cancer education.

The past decade has seen an increased effort to standardized medical curricula internationally. Despite these efforts, a lack of standardization remains evident, most likely owing to the lack of specificity with which such frameworks are often (out of necessity) constructed. As such, inconsistencies may arise owing to differences in adopted definitions and approaches to assessment. The authors highlight six key points to aid the individual educator in translating overarching frameworks into specific learning objectives that are measurable, written at a level of generality, complexity and difficulty that is clear, appropriate and explicit in what is required of the student.

Cost effectiveness of trastuzumab in the adjuvant treatment of early breast cancer: a lifetime model.

BACKGROUND: Recent randomised trials have demonstrated a statistically significant effect of trastuzumab on disease-free survival when used as adjuvant therapy for human epidermal growth factor receptor 2 protein (HER2)-positive resectable early stage breast cancer, with a treatment course lasting either 9 or 52 weeks. However, the cost effectiveness of adjuvant trastuzumab with respect to mortality remains uncertain, especially in an Australian setting. OBJECTIVE: To estimate the cost effectiveness of trastuzumab in Australia, in a cohort of 50-year-old patients with HER2-positive breast cancer over a lifetime, using (i) disease-free survival and cardiotoxicity data from recent randomised trials; (ii) information on long-term survival of patients with treated primary breast cancer; and (iii) costs of treating local and distant relapses and disease from causes other than breast cancer. METHODS: A Markov model consisting of four health states (remission, loco-regional recurrence, metastatic disease and death) was developed. Transition probabilities corresponded to patterns of relapse and metastases seen in recent trials. The model was run until age 100 years to allow calculation of average survival. Outcome measures were life-years and QALYs (calculated using utility weights reported in the literature). The model was calibrated to reflect literature evidence that the risk of breast cancer recurrence following primary treatment diminishes progressively to zero after about 20 years. It was assumed that the morbidity benefit of trastuzumab observed in trials would be present for 5 years but would then diminish progressively to zero after 8 years. Costs (year 2005 values) and benefits were discounted at 3% per annum. RESULTS: For every 1000 patients treated with a 52-week course of trastuzumab, there were 136 fewer breast cancer deaths (relative risk reduction 28%). The incremental cost-effectiveness ratios (ICERs) were Australian dollars ($ A)13 730 per year of life saved (YOLS) and $ A22 793 per QALY. The net incremental cost was $ A56.3 million ($ A414 012/cancer death avoided). Cost effectiveness declined (ICER = $ A27 734/QALY) in older patients (age 65 years at treatment initiation). The ICER was driven mainly by the drug acquisition costs, the assumption of the duration of benefit and the discount rate. Cost offsets from reduced costs of treating recurrent or metastatic breast cancer during follow-up were present but these factors were of less importance according to sensitivity analyses. The 9-week treatment schedule approached economic dominance (ICER = $ A1700/QALY) because of decreased costs, improved relative risk for prevention of metastases and more cancer deaths avoided (196). CONCLUSION: The results suggest that trastuzumab as adjuvant therapy for early breast cancer may be cost effective when given over either 52 or 9 weeks at current acquisition costs in Australia. However, the overall budget impact of the 52-week course is significant, and the 9-week course appears economically attractive.