Personalized Medicine in Oncology Ethical Implications for Supportive Care Dr. Béatrice Godard Professeur Titulaire École de santé publique Département de médecine sociale et préventive Université de Montréal
What Is Personalized Medicine? Tailoring medical management and patient care to the individual characteristics of each patient (Teng et al., 2012) Incorporating the genetic and genomic makeup of an individual along with: family medical history socioeconomic context environment healthrelated behaviors culture values Classifying individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment (PCAST, 2009) Reactive Trial-and and-error One size fits all Delivery of care Proactive Predictive Precise ETHICAL IMPLICATIONS Individual Clinical Societal
Personalized Medicine in Oncology Especially suited: response to nonspecific chemotherapy is suboptimal in most patients yet exposes them to adverse effects (Teng et al., 2012) Personalized cancer management rooted in history of cancer classification (tumor, staging, subtypes) Denotes a variety of approaches Cancer risk identification in a population Biomarker testing to target therapy Pharmacogenomics Tissue analysis to detect recurrence before physical symptoms Molecular characterization = thinking of the patient from a genome-based perspective Image source: NYAS. Retrieved from bit.ly/1i0kotf
Table 1: Examples of Personalized Medicine Use in Clinical Practice in North America Personalized Therapy test Breast cancer HER2 Herceptin (trastuzumab) Oncotype DX Adjuvant chemotherapy Why personalize? Targeted therapy for HER2 protein overexpression Determine risk of disease recurrence (prognostic) Chronic myeloid leukemia BCR-ABL Gleevec (imatinib) Targeted therapy to inhhibit role of BRC-ABL protein in uncontrolled cell proliferation Colorectal cancer KRAS Erbitux(cetuximab) & Targeted therapy for EGFR Vectibix expression if KRAS gene has no (panitumumab) mutation Malignant melanoma BRAF Zelboraf (vemurafenib) Targeted therapy to cause programmed cell death if BRAF gene has mutation small-cell lung cancer Large cell lymphoma and non-small ALK Xalkori (crizotinib) Targeted therapy to inhibit protein caused by mutations in ALK gene Outcomes More effective drug response in 18%- 23% of patients Differentiate between candidates for adjuvant chemotherapy and those who will NOT benefit Improved survival. Genetic and cytogenetic techniques to better monitor treatment efficacy. Avoid therapy for 50% of patients who would be subjected to toxicity without benefit before administering treatment Effective in reducing tumor size and extending progression-free and overall survival Better disease control Source: Butts et al.(2013), Curr Oncol. Hamburg and Collins (2010), N Engl J Med
Clinical Practice Guidelines for Personalized Medicine in Oncology Table 2: North American Professional Recommendations for Selected Personalized Tests Personalized Test [Therapy] Breast cancer HER2 [trastuzumab] Positive Recommendation in Guidelines United States American Society of Clinical Oncology/ College of American Pathologists (2007) 1 Positive Recommendation in Guidelines Canada Canadian National Consensus Meeting on HER2/neu testing in breast cancer (2007) 2 Oncotype DX [adjuvant chemotherapy] American Society of Clinical Oncology (2007) 3 Ontario Health Advisory Committee (2010) 4 Chronic myeloid leukemia BCR-ABL [imatinib] Colorectal cancer KRAS [cetuximab, American Society of Clinical Oncology (2009) 5 Canadian Expert Group consensus recommendations: KRAS testing in panitumumab] colorectal cancer ( 2011) 6 Malignant melanoma BRAF [vemurafenib] Large cell lymphoma and non-small small-cell lung cancer ALK [crizotinib] College of American Pathologists et al.(2013) 7 Sources: 1.Wolff et al.(2007) Arch Pathol Lab Med 2. Hanna et al.(2007) Curr Oncol 3.Harris et al.(2007) 4. Medical Advisory Secretariat (2010) Ont Health Technol Assess Ser 5.Allegra et al.(2009) J Clin Oncol 6. Aubin et al.(2011) Curr Oncol 7.Lindeman et al.(2013) Arch Pathol Lab Med
Figure 1: Total Cancer Care, a prospective longitudinal outcomes study, Moffitt Cancer Center (Florida, US). Source: Fenstermacher et al.(2011), Cancer J
NGS: A Disruptive Innovation for Personalized Medicine Next-generation sequencing technologies: disease-targeted gene panels, exome sequencing, whole genome sequencing Greater depth of coverage for analytical sensitivity and specificity for detecting mosaicism or low level heterogeneity in oncology applications (ACGM, 2013) Known-disease associated genes: greater ability to interpret findings in clinical context (ACGM, 2013) Recent personalized oncology research using NGS: characterizing patient genome (Roychowdhury et al., 2011) sequencing tumors (Nickel et al., 2012) identifying possible candidate genes (Marquis-Nicholson et al., 2011) Proliferation of NGS will have impact on ethical provision of oncology treatment, particularly in regards to informed consent, return of results, privacy.
Implications for Supportive Care: The Promise of Better Health Outcomes Potential for new targeted therapies Refined treatment decisions Reduced probability of adverse reactions from medications and treatments (e.g. less pain, better quality of life) Reduction of diagnostic errors and unnecessary/ineffective treatments Better prediction and earlier disease intervention Source: Teng et al.(2012), Cleve Cl J Med
Implications for Supportive Care: Emerging Responsibilities for Providers Making sense of genetic information, new tests, evidence base Attuned to the needs of diverse populations (according to age, ethnicity) Clinical management throughout the illness trajectory (cancer rehab, primary care providers) Genetic testing and surveillance for family members New roles for support staff; interdisciplinary teams working together Source: Juengst et al.(2012) Per Med. Personalized Medicine Coalition (2007)
Implications for Supportive Care: Moving Towards Truly Patient-centered Care Communication and access to information including electronic platforms Patient education about risk factors, progression of disease, recurrence Contributing to psychosocial support and survivorship plans Empowering patients to take more responsibility for their health Source: Juengst et al.(2012) Per Med. PMHCP Strategy Report (2013)
Implications for Supportive Care: Overcoming Obstacles to the Implementation of Personalized Medicine Lack of timely evaluation of new discoveries through published clinical trial data Infrastructure not adapted for personalized health care (especially in light of NGS) Concerns over costs and access Gaps in provider and patient understanding Ensuring adequate protection for individuals who undergo genetic testing (incl. direct-to-consumer) Source: Personalized Medicine Coalition (2007). Kelley et al. (2011) J Natl Compr Canc Netw.
North American Structures for Additional Guidance on Personalized Medicine Personalized Medicine in Oncology US: The Genomic Applications in Practice and Prevention Network, CDC-NIH Initiative (2009) Canada: Personalized Medicine Stakeholders Consortium (2012) Drug Development, Pharmacogenomics, Companion Diagnostics US: FDA note 4c Guidance on clinical pharmacogenomics: Premarketing evaluation in early phase clinical studies (2011) Canada: Health Canada Committee to Evaluate Drugs (2011) Laboratory Standards US: American Clinical Laboratory Association US: ACMG Clinical Laboratory Standards for NGS (2013) Canada: Immunohistochemistry Quality Program, Canadian Association of Pathologists (2009) Source: Butts et al.(2013), Curr Oncol.
Guiding the Implementation of Personalized Medicine in Canada Recommendation for the future: establishing a National Genetics Advisory Panel for personalized medicine in oncology Outline standards for laboratory quality assurance Provide expert guidance on clinical data analysis and interpretation of genetic tests Review research evidence; harmonize best practices across the country Issue funding and reimbursement recommendations to reduce inequities in access and delivery between provinces by building on the model of the Pan- Canadian Oncology Drug Review Program Develop guidelines and service delivery models for implementation in practice; defining professional roles (genetic counsellors, clinical geneticists, oncologists, laboratory staff) Source: Butts et al.(2013), Curr Oncol.
ACMG Clinical Laboratory Standards for NGS Reporting Standards (2013): Data Interpretation: If variant(s) of potential clinical significance is/are identified, the interpretation should discuss the likely relevance of each variant to the patient s phenotype and prioritize variants accordingly. For ES/WGS reporting, it is at the discretion of the lab to decide whether to report variants in genes without any known disease association. Labs are strongly encouraged to deposit data from clinical sequencing into public databases (ClinVar), in order to rapidly build knowledge that will lead to improved care. Medically Actionable Incidental Findings: labs should carefully develop a policy and process for returning such information and ensure that it conforms to accepted medical and ethical obligations Data Reanalysis: Recommended that labs suggest periodic inquiry by physicians to determine if knowledge has changed on any variants of uncertain significance, according to ACMG guidelines on duty to recontact regarding physician responsibility (1999). Source: Rehm et al. (2013) Genet Med
New Guidelines: Incidental Findings (American College of Medical Genetics, 2013) Individualization of cancer treatment = use of DNA sequencing increases likelihood of recognition and reporting of incidental (or secondary) findings ACGM recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes for: hereditary breast and ovarian cancer familial medullary thyroid cancer Still insufficient data on penetrance and clinical utility, recommendations will have to be updated annually Far-reaching implications for personalized cancer care Source: Green et al. (2013) Genet Med
Ethical Issues in Personalized Medicine: Concerns over Costs Expensive = disincentive to develop treatments. Patents and Licensing issues. Infrastructure for data storage and management; extra costs for genetic testing, support staff, etc. Corresponding investment in research ( bench to bedside ) required to inform real-world practice Health economist assessment of value of personalized medicine, help set priorities Source: Deverka et al. (2012) Genet Med. Vogenberg et al.(2010) P&T
Ethical Issues in Personalized Medicine: Ensuring Equitable Access US : Uninsured/Underinsured/Varying degrees of coverage Canada: Some provincial public health insurance plans/ hospitals cover the cost while others do not Strength of evidence along with professional guidelines are a strong predictor of private reimbursement (Meckley&Neumann, 2010) Notion of good responders for cancer treatments. Greater social claim to treatment? (Fleck, 2012) Distributive Justice. Collective decision on allocation of resources.
Ethical Issues in Personalized Medicine: Need for Oversight Drug safety: Insufficient testing + smaller groups = higher risks? (Schleigden, 2013) Proper committees to review evidence and issue recommendations Monitoring and evaluation for service delivery. Quick results of pharmacogenomics testing. Training for providers in how to interpret and communicate data. Creating decision tools to guide therapeutic treatment decisions
Ethical Issues in Personalized Supportive Care: Informing Patients in an era of Consumer Genomics Implications for informed consent Potential for therapeutic misconception Health Literacy: Patients increasingly researching internet, relying on social media Trustworthiness of direct-to-consumer genetic testing discourse, advertisements, educational materials (Buckmaster and Gallagher, 2009) Biohype/Managing expectations Source: PHG Foundation (2011)
Ethical Issues in Personalized Supportive Care: Protecting Patients from Potential Harms Incidental findings, return of results in clinical context: Honoring the right to know AND the right NOT to know Genetic counselling and adequate psychosocial support Supporting families given familial nature of genetic information Avoid reinforcing existing social inequalities. Medicalization of the genome
Conclusion Supportive care in oncology will be impacted by the uptake of personalized medicine in a multitude of ways Complex ethical issues affecting patients, providers, administrators, regulators Benefit from in-depth study, empirical research with stakeholders Towards development of an ethical framework for personalized medicine in oncology?