With more than 40 peer-reviewed scientific publications, findings from the POG program are influencing precision oncology approaches around the world.
The most common benign salivary tumour is a pleomorphic adenoma. Transformation to malignancy, carcinoma ex pleomorphic adenoma (cxpa), occurs in 6% of cases. Management focuses on surgical resection and radiotherapy; however, rare cases require systemic management. We present the case of a 60-year-old woman with a cxpa of the left parotid gland who required systemic therapy for locally recurrent disease. Treatment options were guided by the literature concerning malignant salivary gland tumour and by whole-genome and transcriptome sequencing of the tumour. The patient received multiple systemic agents during the course of her disease, with cyclophosphamide–doxorubicin–cisplatin providing the best control (partial response). Genomeand transcriptome-directed therapy, including sorafenib and vismodegib, were utilized with limited clinical benefit. Malignant transformation in cxpa is a complex process, and therapy directed at a single tumour pathway might not be sufficient to control disease.
It has been over a decade since the completion of the Human Genome Project (HGP), genomic sequencing technologies have yet to become parts of standard of care in Canada. This study investigates medical oncologists’ (MOs) genomic literacy and their experiences based on their participation in a cancer genomics trial in British Columbia, Canada.
The authors conducted a survey of MOs from British Columbia, Canada (n = 31, 52.5% response rate), who are actively involved in a clinical genomics trial called Personalized Onco-Genomics (POG). The authors also measured MOs’ level of genomic knowledge and attitudes about clinical genomics in cancer medicine.
The findings show a low to moderate level of genomic literacy among MOs. MOs located outside the Vancouver area (the major urban center) reported less knowledge about new genetics technologies compared to those located in the major metropolitan area (26.7 vs 73.3%, P < 0.07, Fisher exact test). Forty-two percent of all MOs thought medical training programs do not offer enough genomic training. The majority of the respondents thought genomics will have major impact on drug discovery (67.7%), and treatment selection (58%) in the next 5 years. They also thought the major challenges are cost (61.3%), patient genomic literacy (48.3%), and clinical utility of genomics (42%).
The data suggest a high need to increase genomic literacy among MOs and other doctors in medical school training programs and beyond, especially to physicians in regional areas who may need more educational interventions. Initiatives like POG play a critical role in the education of MOs and the integration of big data clinical genomics into cancer care.
Background: Limited data exist on the real-world costs of applying whole-genome analysis (WGA) in a clinical setting. We estimated the costs of applying WGA to guide treatments for patients with advanced cancers and characterized how costs evolve over time.
Methods: The setting is the British Columbia Cancer Agency Personalized OncoGenomics (POG) program in British Columbia, Canada. Cost data were obtained for patients who enrolled in the program from 2012 to 2015. We estimated mean WGA costs using bootstrapping. We applied time series analysis and produced 10-year forecasts to determine when costs are expected to reach critical thresholds.
Results: The mean cost of WGA over the study period was CDN$34,886 per patient (95% CI: $34,051, $35,721). Over time, WGA costs decreased, driven by a reduction in costs of sequencing. Yet, costs of other components of WGA increased. Forecasting showed WGA costs may not reach critical thresholds within the next 10 years.
Conclusion: WGA costs decreased over the studied time horizon, but expenditures needed to realize WGA remain significant. Future research exploring costs and benefits of WGA-guided cancer care are crucial to guide health policy.
Background: Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways.
Methods: We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma.
Results: In the first case, genomic profiling revealed an IDH1 somatic mutation, supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin, and further guided therapy by identifying epidermal growth factor receptor amplification. In the second case, a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma. The third case was an appendiceal adenocarcinoma defined by a p53 inactivation; Ras/raf/mek, Akt/mtor, Wnt, and notch pathway activation; and overexpression of ret, erbb2 (her2), erbb3, met, and cell cycle regulators.
Summary: We show that whole-genome and transcriptome sequencing can be achieved within clinically effective timelines, yielding clinically useful and actionable information.
Background: This study is the first survey of the genomic literacy of medical oncologists as co-investigators on a trial using medical genomic “big data”. The Personalized Onco-Genomics Program (POG) conducts whole genome DNA and RNA sequencing and in-depth bioinformatic analyses on patients with metastatic cancers to identify somatic variants and gene expression changes that may be targetable cancer “drivers”. Aberrant pathways are matched to drug databases and this data is reported to the clinician for each individual patient.
Methods: We conducted a survey of medical oncologists based at the six tertiary care cancer hospitals of the BC Cancer Agency (n = 31, 52.5% response rate) who enroll patients into POG. We measured oncologists’ level of genomic knowledge and their experience and attitudes about genomic science and technologies.
Results: We found a low to moderate level of genomic literacy amongst the oncologists as 48% reported having little knowledge about newer genetic/genomic technologies. Clinicians outside of the Vancouver area (the major urban centre) reported having less knowledge about new genetics technologies compared to those located in the Vancouver area (26.7% vs 73.3%, P < 0.07, Fisher exact test). 42% of all clinicians think medical education programs do not offer enough genomics training. The majority of the respondents envision that in the next 5-years genomic technologies will have a major impact on drug discovery (67.7%) and on assisting in treatment selection (58%). The three top concerning issues pertaining to the application of genomics science and technologies into clinical practices were: cost (61.3%), patients’ genomic literacy (48.3%), and clinical utility of genomic data (42%).
Conclusions: The data suggests a high need to increase genomic literacy amongst oncologists beginning in medical school and with ongoing educational tools. Although these oncologists had variable experiences with POG directly informing treatment decisions; there was overall agreement that genomics and big data will play an increasingly important role in cancer care decision-making
Inhibitors of the programmed cell death 1 (PD-1) signaling axis have recently demonstrated efficacy and are rapidly being incorporated into the treatment of non-small cell lung cancers (NSCLCs). Despite clear benefits to certain patients, the association of these responses with a predictive biomarker remains uncertain. Several different biomarkers have been proposed, with differing results and conclusions. This study compares multiple methods of biomarker testing for treatment of NSCLCs with PD1-axis inhibitors. Tissue microarrays of matched primary and metastatic NSCLCs were used to compare four different PD-1 ligand (PD-L1) IHC techniques, as well as RNA ISH. Additional cases with whole genome and transcriptome data were assessed for molecular correlates of PD-L1 overexpression. Eighty cases were included in the IHC study. Multiple IHC methodologies showed a high rate of agreement (Kappa = 0.67). When calibrated to RNA expression, agreement improved significantly (Kappa = 0.90, p=0.0049). PD-L1 status of primary and metastatic tumors was discordant in 17 (22%) cases. This study suggests that different IHC methodologies for PD-L1 assessment provide slightly different results. There is significant discordance between the PD-L1 status of primary tumors and lymph node metastases. RNA ISH may be a useful adjunct to complement PD-L1 IHC testing.
Inflammatory myofibroblastic tumor (IMT) is a genetically heterogenous tumor of the viscera and soft tissues, with multiple molecular features having been demonstrated in this tumor type. About 50% of cases harbor an anaplastic lymphoma kinase (ALK) gene rearrangement, and recent studies have described novel fusions involving the ROS1 and PDGFRβ genes in a subset of ALK-negative cases. However, the molecular features of the remaining subset of cases are not yet defined. We report a case of a large, highly aggressive IMT of the lung in a 17-year-old girl. This case was molecularly characterized through whole-genome and transcriptome sequencing. Subsequently, we investigated a cohort of 15 ALK-negative IMTs of various anatomic sites. All cases were screened using fluorescence in situ hybridization (FISH) for rearrangement of the ETV6 locus and with reverse transcription polymerase chain reaction (RT-PCR) for the ETV6-NTRK3 fusion transcript. Whole-genome and transcriptome sequencing revealed an ETV6-NTRK3 fusion transcript in our index case. This was confirmed by FISH studies for ETV6 gene rearrangement, as well as by RT-PCR. In addition, 2 additional cases in our cohort demonstrated ETV6 rearrangement by FISH. The presence of ETV6-NTRK3 fusion transcript was demonstrated by RT-PCR in one of these additional cases. In summary, we demonstrate the expression of the ETV6-NTRK3 fusion oncogene in a small subset of IMTs, lending further support to the role of oncogenic tyrosine kinases in the pathophysiology of this tumor type. Our data also further expand the growing spectrum of tumor types expressing the ETV6-NTRK3 fusion.
In an attempt to assess potential treatment options, whole-genome and transcriptome sequencing were performed on a patient with an unclassifiable small lymphoproliferative disorder. Variants from genome sequencing were prioritized using a combination of comparative variant distributions in a spectrum of lymphomas, and meta-analyses of gene expression profiling. In this patient, the molecular variants that we believe to be most relevant to the disease presentation most strongly resemble a diffuse large B-cell lymphoma (DLBCL), whereas the gene expression data are most consistent with a low-grade chronic lymphocytic leukemia (CLL). The variant of greatest interest was a predicted NOTCH2-truncating mutation, which has been recently reported in various lymphomas.
Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted “panel” sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate “drivers.” Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.