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Fall 2014 VOLUME 27, ISSUE 1 Editorial: Personalized Medicine in Lung Cancer - The Time is Now Mike R. Sung, B.Sc. Natasha B. Leighl, MD, MMSc, FRCPC Mike R. Sung Mr. Sung is a young graduate who is spending the year at the Princess Margaret Cancer Centre working with the lung cancer research team, he wishes to pursue a career in medicine. Dr. Natasha Leighl Dr. Leighl is an Associate Professor at the Department of Medicine at the University of Toronto as well as a Medical Oncologist with the Division of Medical Oncology, Princess Margaret Cancer Centre. The discovery of genomic abnormalities that drive progression of lung cancer has resulted in recognition of new lung cancer subtypes, and the development of new treatments that target these subtypes. Cheema et al. provide an exciting overview of current and future personalized lung cancer treatment pathways (1). EGFR TKIs in EGFR-mutant lung carcinoma and ALK inhibitors in ALK-rearranged lung carcinoma yield superior outcomes compared to standard chemotherapy, with dramatic Volume 27, Issue 1 An official publication of the Ontario Thoracic Society, a medical section of the Ontario Lung Association 18 Wynford Drive, Suite 401 Toronto ON M3C 0K8 Local Callers: (416) 864-9911 ext. 254 Toll Free: 1 (888) 344-5864 (lung) Fax (416) 864-9916 E-mail: [email protected] Website: www.on.lung.ca/ots Ontario Thoracic Reviews Editorial Board, 2014-2015 Dr. Christopher Li (Co-Editor) Dr. Mark Soth (Co-Editor) Dr. Robert Hyland (Editor Emeritus) Dr. Thomas Kovesi (Chair, OTS) Ms. Hélène Michaud (Chair, OLA) Mr. George Habib (President and CEO, OLA) Dr. Hedy Ginzberg (Medical Director, OTS) Ms. Jeanne Castellanos (OTS Administrator) Ms. Pam Richards (Health Sciences Librarian) Ontario Thoracic Society Executive Committee, 2014-2015 Dr. Thomas Kovesi (Chair) Dr. George Chandry (Chair Elect) Dr. Michael Fitzpatrick (OTS/OLA Board Representative) Dr. Shawn Aaron (Research Advisory Committee Chair) Dr. Marcel Tunks (2015 Better Breathing Conference Chair) Dr. Dhenuka K. Radhakrishnan Dr. Virjanand Naraine Dr. Eric Hentschel Dr. Onofre Moran Dr. Frank Vincent Ritacca Dr. Khalil Sivjee Dr. John Granton Dr. Helen Ramsdale (OMA Representative) Dr. Chris Li (Program Director Rep) Dr. Sharon Dell (Pediatric Rep) Dr. Jade Coyne (Resident Representative) Dr. Hedy Ginzberg (OTS Medical Director) Ms. Jeanne Castellanos (OTS Administrator) Mission Statement To Promote Respiratory Health through Medical Research and Education Fall 2014 Ontario Thoracic Review Page 1 of 10 efficacy and improved tolerability (2,3). But within one to two years, even patients responding to these new therapies will develop resistance. Growing understanding of the molecular basis of resistance has led to our ability to target resistance mutations after initial treatment failure, like the EGFR T790M mutation or one of several ALK resistance mutations (4). Today’s lung cancer patient may be able to avoid chemotherapy for longer than ever before, moving from one targeted therapy to another. Additional oncogenic drivers in lung cancer with active targeted therapies have been identified, including ROS-1 translocations (5), BRAF mutations, HER2 insertion mutations, MET amplification, RET translocations and more (4). Even for patients without oncogenic driver mutations in their lung cancer, there is progress. Immune-based therapies targeting the programmed cell death protein-1 (PD-1) pathway may provide new opportunities for targeting lung cancer. Response rates range from 17-24% with prolonged response duration, and mild toxicity profile for most patients (6). But there are important challenges as we move forward. Cheema et al. highlight the challenges of diagnostic sampling and pathology (1). It is critical that our respirology and radiology colleagues understand that today’s lung cancer diagnosis requires more than just a few cells. Larger tissue samples are needed for molecular diagnostics, such as cytology or biopsy samples with at least 30% tumour cellularity (7). Some techniques are less likely to yield sufficient samples, such as bronchoalveolar lavage, and likely should not be the primary method of diagnosing suspected lung cancer. Routine feedback should be available from pathologists about adequacy of samples for diagnostic and molecular testing. In the pathology laboratory, lung cancer tissue must be prioritized for molecular testing (8,9). This may include minimizing unnecessary sectioning and extensive immunohistochemistry panels. Once the diagnosis of lung cancer with an adenocarcinoma component has been made, initiation of molecular testing by pathologists should occur within three days, and results should be available to clinicians within five to ten days (8,9). As targeted therapy for resistance mutations becomes available, more patients will be referred for repeat tumour biopsies in the setting of disease progression. The difficulty in obtaining repeat biopsies – lack of system capacity and patient safety concerns - has led to the evaluation of circulating biomarkers, including circulating tumor cells (CTC) and cell free tumor DNA (cfDNA), as methods of less invasive sampling for molecular testing (10). While promising, these assays are not yet available for routine use. Treatment access is also a challenge. Provinces have required randomized trials Volume 27, Issue 1 before funding targeted therapies in standard practice. But does each new treatment require randomized data? For example, crizotinib demonstrates similar activity in ROS-1-rearranged lung cancer, (about 1% of cases), as it does in ALK-rearranged lung cancer, where early phase and randomized trials demonstrate superiority over chemotherapy (3,5). Must we really repeat these trials in ROS-1 positive patients? How can we move targeted therapies into standard care faster, and how can we make them more affordable? With current pricing of novel agents crizotinib (~$10,000/month) and ceritinib (~$13,500/month), drug cost will be an important consideration in accessing personalized medicine in lung cancer (11,12). In this new era of lung cancer therapeutics, optimal diagnostic sampling and molecular testing is a cornerstone. Our ability to ensure that Canadians with lung cancer can access the best possible treatment and outcomes begins with our colleagues in respirology, radiology, surgery and pathology who make that initial diagnosis. REFERENCES: 1. Cheema PK, Raphael S, Burkes RL. Personalized Approach to Systemic Therapy in Advanced Non Small Cell Lung Cancer – One Size Does Not Fit All. Ontario Thoracic Review (in press) 2. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han BH, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang HY, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009; 361(10):947-957. 3. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O’Byrne KJ, MoroSibilot D, Camdige DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Janne PA. Crizotinib versus chemotherapy in advanced ALKpositive lung cancer. N Engl J Med. 2013; 368(25):2385-94. 4. Korpanty GJ, Graham DM, Vincent MD, Leighl NB. Biomarkers That Currently Affect Clinical Practice in Lung Cancer: EGFR, ALK, MET, ROS-1, and KRAS. Front Oncol. 2014; 4: 204. 5. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer. N Engl J Med. 2014 Sep 27 [Epub ahead of print]. 6. Brahmer JR, Pardoll DM. Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer. Cancer Immunology Research. 2013 1(2):85-91. 7. Shiau CJ, Babwah JP, da Cunha Santos G, Sykes JR, Boerner SL, Geddie WR, Leighl NB, Wei C, KamelReid S, Hwang DM, Tsao MS. Sample features associated with success rates in population-based EGFR mutation testing. J Thorac Oncol 2014; 9(7):947-56. 8. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac oncol 2013; 8(7):823-59. 9. Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR. Molecular Testing Fall 2014 Ontario Thoracic Review Page 2 of 10 for Selection of Patients with Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists Guideline. J Clin Oncol 2014 Oct 13 [Epub ahead of print]. 10. Esposito A, Bardelli A, Criscitiello C, Colombo N, Gelao L, Fumagalli L, Minchella I, Locatelli M, Goldhirsch A, Curigliano G. Monitoring tumorderived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat Rev 2014; 40(5):648-55. 11. Djalalov S, Beca J, Hoch JS, Krahn M, Tsao MS, Cutz JC, Leighl NB. Cost effectiveness of EML4-ALK fusion testing and first-line crizotinib treatment for patients with advanced ALK-positive non-smallcell lung cancer. J Clin Oncol 2014;32(10):1012-9. 12. Leighl NB, Beca JM, Tsao MS, Hoch JS. Reply to C.G. Azzoli et al and C. Chouaid et al. J Clin Oncol 2014 Sep 8 [Epub ahead of print]. Funding acknowledgements – Princess Margaret Cancer Foundation OSI Pharmaceuticals Chair in New cancer Drug Development; Grant funding from the Ontario Institute of Cancer Research/Cancer Care Ontario Health Services Research Program Feature Article: Personalized Approach to Systemic Therapy in Advanced Non Small Cell Lung Cancer - One Size Does Not Fit All Parneet K. Cheema, Simon Raphael and Ronald L. Burkes Dr. Parneet K. Cheema, HBSc, MD, MBiotech, FRCPC Dr. Cheema is a Medical Oncologist, Sunnybrook Odette Cancer Centre. Her professional Interests: Thoracic, Gastrointestinal and Skin Malignancies Dr. Simon Raphael, M.Ed., M.D., FRCPC Associate Professor at the University of Toronto. Chief Pathologist and Director of Laboratories, North York General Hospital Department of Laboratory Medicine Volume 27, Issue 1 Dr. Ronald Burkes, MD, FRCPC Dr. Burkes is a Medical Oncologist at Mount Sinai Hospital, Princess Margaret Cancer Center/University Health Network and a Professor of Medicine at the University of Toronto. His personal interests include: Sports, Reading and Travelling Introduction Non-small-cell lung (NSCLC) remains the leading cause of cancer-related deaths globally for both men and women.1,2 It is estimated that in 2012 there were 25,600 new cases and 20,100 deaths associated with NSCLC in Canada with an incidence and mortality rate of 54/100,000 and 42/100,000 population, respectively.3 The most important risk factor for developing lung cancer remains tobacco use, accounting for an estimated 86% of lung cancer cases in high-income countries like Canada and the median age at diagnosis is 70.4,5 The prognosis of NSCLC remains poor with 5 year survival rates across all stages being only 16% with a majority of patients presenting with advanced incurable stage disease.6 If left untreated, patients with advanced incurable NSCLC have a median survival after diagnosis of 4-5 months.7 The goal of systemic therapy in this setting is to prolong survival and improve quality of life (QoL) by treating cancer related symptoms. Traditionally NSCLC was thought of as 3 predominant histological subtypes; adenocarcinoma, squamous cell and large cell carcinoma and was treated as a "one-sizefits-all" therapeutic approach using cytotoxic chemotherapy.8,9 We now recognize that within these subtypes of NSCLC exists a collection of discrete malignancies with distinct molecular aberrations that drive carcinogenesis and result in different outcomes and responses to therapies.8,9 Several biomarkers have emerged as predictive of response to targeted therapies in advanced NSCLC, including the epidermal growth factor receptor (EGFR) and Echinoderm microtubule associated protein like-4/anaplastic lymphoma kinase (ALK) rearrangement.10,11 Fall 2014 Ontario Thoracic Review Page 3 of 10 Personalized Chemotherapy Palliative chemotherapy with a platinum based doublet (in combination with vinorelbine, gemcitabine, pemetrexed or taxane) has been the cornerstone of treatment for patients with advanced stage NSCLC and has resulted in a modest increase in prolonging survival and associated QoL.12 In treatment naïve patients platinum doublets offer response rates of 25% and a median survival of 8-11 months. Although a majority of patients will experience disease progression at a median of 4 months.13,14 Platinum doublet chemotherapy is also accompanied by significant toxicity and due to advanced age, poor performance status and/or co-morbidities many patients do not receive treatment.5, 15 NSCLC histology has become an important factor to select optimal chemotherapy for a patient with advanced NSCLC. The chemotherapy agent pemetrexed has become a preferential drug for patients with nonsquamous NSCLC due to randomized trials showing favourable responses and survival with better tolerability than older chemotherapy agents.13, 16,17 Cisplatinpemetrexed has been shown to be modestly superior to cisplatin-gemcitabine in non-squamous NSCLC, and has become the preferred platinum-doublet for this subtype of patients if they do not have an activating EGFR mutation or an ALK rearrangement [Figure 1]. Conversely, in patients with squamous cell carcinoma subtype, pemetrexed is associated with inferior outcomes compared to older chemotherapy regimens, highlighting the importance of reporting the subtype of NSCLC to be able to offer personalized chemotherapy. The pathology report stating NSCLC “not otherwise specified” is no longer acceptable. EGFR mutation positive advanced NSCLC In 2004, two pivotal studies revealed that the presence of somatic activating mutations in the kinase domain of EGFR of NSCLC tumours, particularly small in frame deletions in exon 19 (deletion 19) and the L858R missense mutation in exon 21 (L858R) which accounts for 90% of EGFR mutations, strongly correlated with increased responsiveness to EGFR tyrosine kinase inhibitors (TKIs).18,19 EGFR activating mutations are generally limited to nonsquamous histology and mutually exclusive to other oncogenic driver mutations including ALK rearrangements and KRAS (KRAS has been shown to be associated with poor prognosis but no effective targeted therapies to this biomarker have been demonstrated to date).20 The rate of EGFR mutations in the general Volume 27, Issue 1 NSCLC adenocarcinoma population is 12% and in a subset of patients this rate can be as high as 60%.10,20 These mutations are more common in never smokers, those of east Asian ethnicity, and females.20 The first clinical study to demonstrate the correlation of EGFR mutations and optimal systemic therapy in advanced NSCLC was the IPASS study.10 This phase III trial evaluated the EGFR TKI gefitinib versus standard chemotherapy (carboplatin/paclitaxel) in treatment naïve patients. The study enrolled patients with known clinical characteristics that are associated with harbouring the EGFR mutation (adenocarcinoma subtype, Asian decent, non smokers). In patients with tumours harbouring EGFR mutations and treated with gefitinib, response rates and delaying cancer progression were significantly improved compared to chemotherapy (HR 0.48, 95% CI 0.36-0.64, p<0.001). Subsequently, numerous randomized phase III studies of EGFR TKIs in EGFR mutation positive advanced NSCLC patients with erlotinib, gefitinib or afatinib have reported high response rates of up to 50% - 70% and compared to chemotherapy offer a significant improvement in delaying disease progression (median progression free survival is 9 - 11 months with EGFR TKIs), improved tolerability and health related QoL compared with platinum-based doublet chemotherapy.21-25 However, these trials demonstrated no difference in prolonging survival most likely because of the high proportion of patients in the chemotherapy arms of these trials that were treated with EGFR TKIs after study completion (65% - 95% crossover rates; one pivotal study with erlotinib included crossover in the study design). The median survival among advanced NSCLC patients in these trials ranged from 18.6 to 39 months, compared to chemotherapy trials of 8 to 11 months, reflecting the improved prognosis of EGFR mutated NSCLC patients treated with EGFR TKIs. Conversely, advanced NSCLC patients that do not have tumours that harbour activating EGFR mutations have improved outcomes with chemotherapy opposed to EGFR TKIs. In the IPASS study, despite patients having clinical characteristics that are associated with harbouring the EGFR mutation, those patients without an EGFR mutation had a delay in disease progression and improved response rate with chemotherapy compared to the EGFR TKI. This supports the fact that the presence of the EGFR mutation predicts efficacy to EGFR TKIs as opposed to just clinical characteristics. In fact in the IPASS study which consists of a highly selected population likely to harbor an EGFR mutation 40% of Fall 2014 Ontario Thoracic Review Page 4 of 10 patients did not demonstrate one. Also, the IPASS study was preceded by the TORCH study that evaluated the EGFR TKI erlotinib versus chemotherapy in treatment naïve patients with advanced NSCLC in an unselected patient population (defined as EGFR mutation unknown). In this patient population chemotherapy was associated with superior outcomes compared to the EGFR TKI.26 Based on the aforementioned data, optimal treatment for advanced NSCLC follows a personalized approach in which an EGFR TKI with erlotinib, gefitinib or afatinib is now standard first-line treatment for patients with advanced NSCLC whose tumours harbour activating EGFR mutations, and chemotherapy is standard first-line therapy for advanced EGFR negative NSCLC patients [Figure 1].27 EGFR TKIs have a very different side effect profile compared to standard chemotherapy and are generally better tolerated. 10, 21-25 The most frequent side effects are a result of inhibition of systemic wild type EGFR, which includes acneaform rash, stomatitis, paronychia and diarrhea. The life threatening risk of these agents is interstitial pneumonitis, fortunately reported in only 1% 3% of patients.10, 21-25 Dosing of the EGFR TKIs is also more convenient with once a day oral dosing as opposed to regular clinic visits to the cancer centre which is required for intravenous chemotherapy. Because of this side effect profile and ease of administration, EGFR TKIs offer an effective systemic therapy option for most patients with an EGFR mutation, including elderly patients or patients with multiple comorbidities that may not be candidates for chemotherapy. ALK positive advanced NSCLC The ALK gene rearrangement has been found in 2% - 7% of NSCLC patients with adenocarcinoma, with approximately 400-500 ALK positive advanced NSCLC cases occurring each year in Canada.28 There is a higher prevalence in young patients (median age 49 - 59), never smokers and may be more likely in men.29, 30 In an enriched population of non smoker adenocarcinoma NSCLC the rate is 12%.30 Without targeted therapy, ALK positive NSCLC may have a less favourable prognosis and appears to be associated with more advanced disease stage compared with patients with ALK negative tumours.29,31 Crizotinib, an oral ALK selective inhibitor is currently the only approved ALK inhibitor by Health Canada and is indicated as monotherapy in patients with ALK positive Volume 27, Issue 1 advanced (not amenable to curative therapy) or metastatic NSCLC. Following a platinum doublet crizotinib delayed cancer progression to a median of 7.7 months compared to 3.0 months among those patients who received chemotherapy (HR 0.49, 95% CI 0.37-0.64; p<0.0001). The overall response rate was also significantly higher in those treated with crizotinib (65% vs 20%; p<0.0001)11. Crizotinib is also associated with high response rates (57%) in heavily pretreated advanced ALK positive NSCLC patients and compared to historical controls it appears to prolong survival.32, 33 Although patients with advanced ALK positive NSCLC could be offered crizotinib in the treatment naïve setting, in Ontario drug reimbursement for crizotinib is currently limited to patients who have previously been treated with a platinum doublet which reflects the patient population studied in the phase III clinical trial.27 However, this may change once the phase III trial of crizotinib versus chemotherapy in treatment naïve ALK positive advanced NSCLC is reported. Crizotinib has also shown efficacy in a phase I/II trial in advanced NSCLC patients with tumours that harbour a ROS1 gene rearrangement with reported response rates of 54%.34 The ROS1 rearrangement is found in approximately 1% of all NSCLC patients. Similar to ALK positive NSCLC, ROS1 gene rearrangement is more commonly found in NSCLC tumours of young, non smokers with adenocarcinoma subtype.35 Due to the rarity of this mutation, it is unlikely that a phase III trial will be conducted, thus crizotinib is a valid targeted therapy option for this patient population. Similar to the EGFR inhibitors, ALK inhibitors such as crizotinib are oral agents with a tolerable safety profile. Common side effects are visual disturbances, gastrointestinal side effects as well as a transaminitis.11 Future developments Ultimately, tumours harboring EGFR activating mutations or ALK gene rearrangements treated with the appropriate targeted therapies develop resistance. Currently the standard of care is to treat with chemotherapy after failure of the targeted therapy. However, there are a plethora of new targeted agents that are currently in development to target this resistant population. The most common mechanism of resistance to EGFR TKIs in EGFR mutated NSCLC is the development of a second mutation in the EGFR, the T790M ‘gatekeeper’ mutation, which is found in approximately 60% of patients with acquired resistance.36 Targeted Fall 2014 Ontario Thoracic Review Page 5 of 10 agents to the T790M mutation are currently in phase I/II studies and have reported high response rates of up to 67% in this resistant population.37,38 Also, preliminary results with second generation ALK inhibitors after failure of crizotinib have reported response rates of 50% - 60%.39,40 As well these second generation ALK inhibitors appear to cross the blood brain barrier and may be effective in treating brain metastases. Currently approved targeted agents and newer chemotherapy agents such as pemetrexed are generally limited to adenocarcinoma subtype. However, there are ongoing studies looking for driver mutations in squamous cell carcinoma.41 One of the new targets in NSCLC is hepatic growth factor/cMET overexpression which is found in approximately 25% - 75% of NSCLC including both adenocarcinoma and squamous cell histologies.42 cMET overexpression is associated with a poor prognosis and is also a mechanism of acquired resistance to EGFR TKIs. There appears to be a synergistic effect of cMET activation and EGFR. MET inhibitors are currently in clinical trials.42,43,44 Other driver mutations that have been identified include, but are not limited to, FGFR1, PIK2CA, PTEN, HER2, and BRAF mutations. The impact of these mutations and response to matching targeted therapies will need to be validated in future clinical trials.41 The Lung Cancer Mutation Consortium presented data recently that found that two thirds of NSCLC patients have an oncogenic driver and those patients with these drivers have been shown to live longer if they receive the corresponding targeted agent.45 The Importance of Tissue Testing for EGFR and ALK mutations requires paraffinembedded tissues whether obtained by thin needle biopsies in cytologic samples or traditional core biopsies. Insuring this tissue is available requires co-operation of the physician obtaining the sample (usually an interventional radiologist) as well as the pathologist. Both have to adapt their practice patterns to obtain the necessary information regarding EGFR and ALK mutations for the treating oncologist. for these purposes. In the pathology lab cytology technologists should use all material for cell blocks rather than cytospin preparations as the latter cannot be used for molecular testing. Specimens are usually very small and there is significant patient morbidity incurred to obtain them, therefore the tissue should be used in the most effective manner. Pathologists must minimize the use of immunostains to diagnose these specimens and save as much tissue possible for mutation analysis. The number and type of immunostains must be the minimum to determine that the lesion is non-small cell primary lung carcinoma and to distinguish squamous carcinoma from adenocarcinoma. Each case is judged on its clinical and histologic context but for what appears to be a straightforward lung adenocarcinoma TTF1 is useful to support primary adenocarcinoma while p63 will be negative in these cases.46 Mutational analysis can be performed on primary tumours or on metastases including effusions as long as a cell block is created. The only tissue often unsuitable for analysis are those that have been decalcified such as bone biopsies. If a bone lesion is the only appropriate target for a biopsy, advising the interventional radiologist to target a soft tissue component will improve the success of mutational testing. From time of initiation of EGFR and ALK testing to time of reporting results, this takes a median of 18 +/- 9.7 days (range: 15 - 26 days).47 Patients with advanced NSCLC are often quite symptomatic from their disease, thus the weeks required to report EGFR and ALK results creates a barrier for medical oncologists to offer personalized medicine. Pathologists can play a crucial role in reducing this turnaround time by ordering EGFR and ALK testing once the diagnosis of NSCLC non-squamous subtype is made. A majority of patients with NSCLC present with advanced stage disease, therefore a significant number of patients would benefit from having their EGFR and ALK mutation results known at the time of first consultation with a medical oncologist. Also, given the poor prognosis of NSCLC across all stages, a significant number of patients with earlier stage disease will progress to advanced disease in which EGFR and ALK mutation results will eventually guide their therapy. This supports the notion to test all tumour samples for EGFR and ALK mutations at time of diagnosis of non-squamous NSCLC irrespective of stage, a term coined “reflex testing”. For the radiologist the number of smears prepared should be minimized to allow most of the specimen to be placed in the “rinse” for preparation of a cell block. A cell block is a centrifuged button of tissue embedded in paraffin in the cytology laboratory. These may be used for EGFR and ALK testing while smears cannot be used Volume 27, Issue 1 Fall 2014 Ontario Thoracic Review Page 6 of 10 There has been some exploration of searching for mutations in plasma using highly sensitive molecular techniques. Although these methods appear less sensitive than tissue assays they may be used in the future to monitor therapy, or in selected patients where a biopsy is not possible.48, 49 Summary Over the last decade the treatment of advanced incurable NSCLC has evolved considerably and a personalized approach to treatment is now a reality. There are effective therapies for advanced NSCLC that are beyond chemotherapy and offer a tolerable safety profile. Given that the median age of patients with NSCLC is 70, patients are often elderly with a poor performance status or have multiple comorbidities which makes them ineligible for chemotherapy. However, they may be eligible for a targeted therapy assuming they have the appropriate target. It is important for physicians involved in the diagnosis and treatment of lung cancer to be aware that maximizing tissue yield for histologic subtyping and molecular testing is essential to be able to offer patients a personalized treatment approach. Furthermore, clinical trials in advanced NSCLC routinely include biomarker analysis and a tissue sample is often required for eligibility. Testing all patients with advanced NSCLC adenocarcinoma subtype for EGFR mutations and ALK gene rearrangements is now the standard of care.27 Relying on patient demographics to select patients for EGFR and ALK testing (i.e. non smokers) would miss eligible patients for potentially effective targeted therapies or the corollary is true in that one might select patients who do not harbor a mutation thus exposing them to an ineffective treatment. This is an exciting time to be involved in the care of patients with NSCLC as we are just at the tip of the iceberg for personalized systemic therapies. With increasing knowledge of the genomic landscape of NSCLC it is expected that further driver mutations will be identified and the development of matching targeted therapies will continue to grow. References: 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90. 2. Cancer Care Ontario. Cancer Fact: Lung cancer is the leading cause of cancer death among Ontario women Volume 27, Issue 1 [internet]. Toronto, Cancer Care Ontario; 2012 January. [cited 2014 March 03] Available from: https://www.cancercare.on.ca/cms/One.aspx?portalId=137 7&pageId=122389 3. Canadian Cancer Society's Steering Committee on Cancer Statistics. Canadian cancer statistics 2012 [Internet]. Toronto: Canadian Cancer Society; 2012 May. [cited 2014 March 03]. Available from: http://www.cancer.ca/Canadawide/About%20cancer/~/media/CCS/Canada%20wide/Files %20List/English%20files%20heading/PDF%20%20Policy%20-%20Canadian%20Cancer%20Statistics%20%20English/Canadian%20Cancer%20Statistics%202012%20%20English.ashx 4. Danaei G, Vander Hoorn S, Lopez AD, Murray CJL, Ezzati M, and the Comparative Risk Assessment collaborating group (Cancers). Lancet 2005; 366: 1784–1793. 5. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008; 359 (13): 1367-1380. 6. American Cancer Society: Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012. Available from: http://www.cancer.org/acs/groups/content/@epidemiolog ysurveilance/documents/document/acspc-031941.pdf page 18. Last assessed January 29, 2014. 7. Rapp E, Pater JL, Willan A, Cormier Y, Murray N, Evans WK, Hodson DI, Clark DA, Feld R, Arnold AM, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer-report of a Canadian multicenter randomized trial. J Clin Oncol. 1988; 6: 633-641. 8. West L, Vidwans SJ, Campbell NP, Shrager J, Simon GR, Bueno R, Dennis PA, Otterson GA, Salgia R. A Novel Classification of Lung Cancer Into Molecular Subtypes. PLoS One. 2012; 7(2): e31906. 9. Mok TS. Personalized Medicine in Lung Cancer: What We Need to Know. Nat Rev Clin Oncol. 2011; 8 (11): 661-668. 10. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361: 947-957. 11. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O'Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 ; 368 (25): 2385-2394. 12. NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and metaanalysis of individual patient data from 16 randomized controlled trials. J Clin Oncol. 2008; 26 (28): 4617-4625. 13. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Fall 2014 Ontario Thoracic Review Page 7 of 10 Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced stage non-small-cell lung cancer. J Clin Oncol. 2008; 26: 3543-3551. 14. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002; 346 (2): 92-98. 15. Weiss J, Stinchcombe TE. Treatment of elderly patients with stage IV non-small-cell lung cancer. Expert Rev Anticancer Ther. 2012; 12 (1): 111-120. 16. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004; 22: 1589-1597. 17. Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, Shepherd FA. The differential efficacy of pemetrexed according to NSCLC histology: A review of two phase III studies. Oncologist 2009; 14: 253-263. 18. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350: 2129-2139. 19. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 14971500. 20. Shigematso H, Gasdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers Int J Cancer. 2006; 118 (2): 257-262. 21. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 2010; 11: 121-128. 22. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362: 2380-2388. Volume 27, Issue 1 23. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive nonsmall cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12: 735-742. 24. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Français de PneumoCancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 239-246. 25. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31 (27): 3327-3334 26. Gridelli C, Ciardiello F, Gallo C, Feld R, Butts C, Gebbia V, Maione P, Morgillo F, Genestreti G, Favaretto A, Leighl N, Wierzbicki R, Cinieri S, Alam Y, Siena S, Tortora G, Felletti R, Riccardi F, Mancuso G, Rossi A, Cantile F, Tsao MS, Saieg M, da Cunha Santos G, Piccirillo MC, Di Maio M, Morabito A, Perrone F. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non– small-cell lung cancer: The TORCH randomized trial. J Clin Oncol. 2012; 30: 3002–3011. 27. NCCN Guidelines Non Small Cell Lung Cancer. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nscl. pdf. Assessed March 02, 2014 28. pan Canadian Oncology Drug Review. Final Guidance Report. Crizotinib (xalkori) resubmission for advanced NSCLC. Sept 09, 2013. http://www.pcodr.ca/idc/groups/pcodr/documents/pcodrd ocument/pcodr-xalkoriresub-fn-cgr.pdf. Assessed March 02, 2014 29. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ. Clinical Features and Outcome Fall 2014 Ontario Thoracic Review Page 8 of 10 of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK. J Clin Oncol. 2009; 27( 26): 4247–4253. 30. Koh Y, Kim DW, Kim TM, Lee SH, Jeon YK, Chung DH, Kim YW, Heo DS, Kim WH, Bang YJ. Clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase-positive advanced pulmonary adenocarcinoma. J Thorac Oncol. 2011; 6: 905–912. 31. Yang P, Kulig K, Boland JM, Erickson-Johnson MR, Oliveira AM, Wampfler J, Jatoi A, Deschamps C, Marks R, Fortner C, Stoddard S, Nichols F, Molina J, Aubry MC, Tang H, Yi ES. Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. Thorac Oncol. 2012; 7 (1): 90–97. 32. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010; 363 (18): 1693-1703. 33. Shaw AT, Yeap BY, Solomon BJ, Riely GJ, Gainor J, Engelman JA, Shapiro GI, Costa DB, Ou SH, Butaney M, Salgia R, Maki RG, Varella-Garcia M, Doebele RC, Bang YJ, Kulig K, Selaru P, Tang Y, Wilner KD, Kwak EL, Clark JW, Iafrate AJ, Camidge DR. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011; 12 (11): 1004-1012. 34. Shaw AT, Camidge RD, Engelman JA. Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. J Clin Oncol. 2012; 30: (suppl; abstr 7508). 35. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012; 30 (8): 863-870. 36. Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W. New Strategies in Overcoming Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer. Clin Cancer Res. 2011; 17: 5530–5537. 37. Ranson M, Pao W, Kim DW, et al. Preliminary results from a Phase I study with AZD9291: an irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance mutations in non-small cell lung cancer (NSCLC). European Cancer Conference 2013. Abstract 33. 38. Soria JC, Sequist LV, Gadgeel S. First-In-Human Evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (Activating and T790M). J Thorac Oncol. 2013; 8 (suppl 2; abstract 1354). CH5424802/RO5424802, in ALK+ non-small cell lung cancer (NSCLC) patients who have failed crizotinib (AF002JG/NP28761, NCT01588028). J Thorac Oncol 2013; 8 (suppl 2; abstract O16.06). 40. Shaw AT, Mehra R, Kim D-W, Felip E, Chow LQM, Camidge DR, Tan DS-W, Vansteenkiste JF, Sharma S, De Pas T, Wolf J, Katayama R, Lau Y-Y, Goldwasser M, Boral A, Engelman JA. Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. J Clin Oncol. 2013; 31 (suppl; abstract 8010). 41. Kim HS, Mitsudomi T, Soo RA, Cho BC. Personalized therapy on the horizon for squamous cell carcinoma of the lung. Lung Cancer 2013; 80 (3): 249-255. 42. Landi L, Minuti G, D'Incecco A, Salvini J, Cappuzzo F. MET overexpression and gene amplification in NSCLC: a clinical perspective. Lung Cancer: Targets and Therapy 2013; 15-25. 43. Spigel DR, Ervin TJ, Ramlau R, Daniel DB, Goldschmidt JH, Blumenschein GR, Krzakowski MJ, Robinet G, ClementDuchene C, Barlesi F, Govindan R, Patel T, Orlov SV, Wertheim MS, Zha J, Pandita A, Yu, W, Yauch RL, Patel PH, Peterson AC. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol 2011; 29 (suppl; abstract 7505). 44. Schiller JH, Akerley WL, Brugger W, Ferrari D, Garmey EG, Gerber D. Orlov ES, Ramlau R, Pawel JV, Sequist LV. Results from ARQ 197–209: A global randomized placebocontrolled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2010; 28 (suppl; abstract LBA7502). 45. Kris MG, Johnson B, Berry L, Kwiatowski D, Iafrate AJ, Wistuba I, Varella-Garcia M, Franklin W, Aronson S, Su PF, Shyr Y, Camidge R, Sequist LV, Glisson B, Khuri FR, Garon EB, Pao W, Rudin CM, Schiller J, Haura EB, Socinski MA, Shiraj K, Giaccone G, Ladany M, Kugler K, Minna JD, Bunn P. Treatment with therapies matched to oncogenic drivers improves survival in patients with lung cancers: results from the Lung Cancer Mutation Consortium (LCMC) J Thorac Oncol 2013; 8 (suppl 2; abstract PL03.7). 46. Travis WD1, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, Ishikawa Y, Wistuba I, Flieder DB, Franklin W, Gazdar A, Hasleton PS, Henderson DW, Kerr KM, Petersen I, Roggli V, Thunnissen E, Tsao M. Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med. 2013; 137 (5): 668-684. 47. Ellis PM, Verma S, Sehdev S, Younas J, Leighl N. Implementation of a national EGFR testing strategy in a publicly funded health system. J Thorac Oncol. 2011; 6 (suppl 2; abstract P4.199). 39. Gadgeel S, Ou S-H, Chiappori AA, et al. A phase 1 dose escalation study of a new ALK inhibitor, Volume 27, Issue 1 Fall 2014 Ontario Thoracic Review Page 9 of 10 48. Kim HR, Lee SY, Hyun DS, Lee MK, Lee HK, Choi CM, Yang SH, Kim YC, Lee YC, Kim SY, Jang SH, Lee JC, Lee KY. Detection of EGFR mutations in circulating free DNA by PNA-mediated PCR clamping. J Exp Clin Cancer Res. 2013 9; 32 (1): 50. 49. Bai H, Mao L, Wang HS, Zhao J, Yang L, An TT, Wang X, Duan CJ, Wu NM, Guo ZQ, Liu YX, Liu HN, Wang YY, Wang J. Epidermal Growth Factor Receptor Mutations in Plasma DNA Samples Predict Tumor Response in Chinese Patients With Stages IIIB to IV Non–Small-Cell Lung Cancer. J Clin Oncol. 2009; 27 (16): 2653-2659. Ontario Lung Health Action Plan Calling for an Ontario Lung Health Action Plan In the Spring/Summer 2014 edition of the Ontario Thoracic Review, we told you about our efforts to create a comprehensive Ontario Lung Health Action Plan. Of the four chronic diseases responsible for eight out of 10 deaths (cancers, cardiovascular diseases, lung disease and diabetes), lung disease is the only one without a dedicated province-wide strategy. If we don’t act quickly to stem the rising tide of lung disease in Ontario, the economic impact will reach a staggering $300 billion within the next 30 years. The time is approaching when Ontario simply will not be able to afford the high cost of treating people with lung disease. With a comprehensive and coordinated Ontario Lung Health Action Plan, however, we can prevent lung disease, improve patient outcomes and reduce costs. Over the past several months, OLA has continued to work with experts, patients, other health-care organizations and government to make lung health a priority in this province. The consultation session and reception at Queen’s Park on November 25 are the next major steps in developing a comprehensive plan for the province. Jeff Yurek, MPP for Elgin-Middlesex-London, is sponsoring this private member’s bill designed to make the province’s schools safe for children with asthma. The Bill is named in memory of Ryan Gibbons, who died in the fall of 2012 after suffering an asthma attack at school. To learn more about Ryan’s Law, please visit: www.passryanslaw.com. We are also urging all members of provincial parliament to support Bill 11, the Radon Awareness and Prevention Act. The legislation provides for creation of an Ontario Radon Registry and will reduce radon levels in dwellings and workplaces. Radon is a colourless, odourless gas that is produced from the natural breakdown of uranium in the ground. Radon can enter a home through tiny openings in floors and foundations and build up to dangerous levels. Longterm exposure to radon is the second leading cause of lung cancer in Canada. In September, we were pleased to join partners from Health Canada, the Canadian Association of Radon Scientists and Technologists (CARST), and a very special guest, Canada's most famous contractor Mike Holmes, to help a Niagara Falls couple install a radon mitigation system in their contaminated home. You can review the Global TV News coverage of the event here: www.globalnews.ca/news/1571387/whyyou-should-test-your-home-for-radon-gas. To learn more or to support our advocacy efforts please contact Chris Yaccato, Provincial Manager, Government Relations and Public Affairs, at: [email protected]. With your support the OLA will be better positioned to help Ontarians breathe with ease. Because when you can’t breathe, nothing else matters.™ Our advocacy efforts, however, don’t stop there. The OLA is also supporting other critical pieces of provincial legislation which align with the overall goals of the Action Plan. Currently, we are working to secure passage of Bill 20, Ryan’s Law. 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