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New Data and Clinical Perspectives on the Treatment of Metastatic Hormone-Sensitive Prostate Cancer

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New Data and Clinical Perspectives on the Treatment of Metastatic Hormone-Sensitive Prostate Cancer

  1. 1. New Data and Clinical Perspectives on the Treatment of Metastatic Hormone-Sensitive Prostate Cancer Oliver Sartor, MD Laborde Professor of Cancer Research Medical Director,Tulane CancerCenter Assistant Dean for Oncology Tulane Medical School 1
  2. 2. Provided by i3 Health ACCREDITATION i3 Health is accredited by the ACCME to provide continuing medical education for physicians. i3 Health designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. i3 Health is accredited with distinction as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation. A maximum of 1.0 contact hour may be earned by learners who successfully complete this nursing continuing professional development activity. INSTRUCTIONS TO RECEIVE CREDIT An activity evaluation form has been distributed. To claim credit, you must turn in a completed and signed evaluation form at the conclusion of the program. Your certificate of attendance will be mailed or emailed to you in approximately 2 weeks for physicians and nurses. UNAPPROVED USE DISCLOSURE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. DISCLAIMER The information provided at this CME/NCPD activity is for continuing education purposes only and is not meant to substitute for the independent medical/clinical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. COMMERCIAL SUPPORT This activity is supported by an independent educational grant from Sanofi Genzyme.
  3. 3. Disclosures Consultant: Advanced AcceleratorApplications, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Clarity, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Janssen, Myovant, Myriad, Noria Therapeutics, Novartis, Noxopharm, Pfizer, POINT Biopharma, Progenics, Sanofi, Teneobio,Telix,Theragnostics Grants/research support: Advanced AcceleratorApplications, AstraZeneca, Bayer, Constellation, Dendreon, Endocyte, Innocrin, Invitae, Janssen, Merck, Progenics, Sanofi, SOTIO
  4. 4. Learning Objectives Discuss patient and tumor characteristics that can inform tailored therapeutic approaches for patients with metastatic HSPC Evaluate emerging data on novel treatment combinations and sequences for patients with metastatic HSPC Assess strategies to optimize the safety and tolerability of novel therapies for metastatic HSPC HSPC = hormone-sensitive prostate cancer.
  5. 5. Case Study 1 54-year-old man post-radical prostatectomy Gleason 8, T2a disease (negative on bone scan and CT scan for metastatic disease) with PSA 2.3 ng/mL measured 10 weeks postoperatively What to do? a. Hormones b. Hormones and radiation c. Radiation alone d. Something else CT = computed tomography; PSA = prostate-specific antigen.
  6. 6. Case Study 1 (cont.) What to do? a. Hormones b. Hormones and radiation c. Radiation alone d. Something else With new PET imaging, detection of recurrent disease is now feasible for many patients The possibility of image-guided therapy should be considered Rowe et al, 2016.
  7. 7. To Optimally Manage Prostate Cancer Surgery Radiation therapy Hormonal therapy Chemotherapy Genetic testing (germline and somatic) Targeted therapy Immunotherapy Molecular imaging NCCN, 2020. Multiple Modalities Needed
  8. 8. Genetics
  9. 9. Inherited DNA Repair Gene Mutations 11.8% of men with metastatic prostate cancer BRCA2: 5.3% CHEK2: 1.9% ATM: 1.6% BRCA1: 0.9% RAD51D and PALB2: 0.4% each BRCA = breast cancer gene; CHEK2 = checkpoint kinase 2; ATM = ataxia telangiectasia mutated; RAD51D = RAD51 homolog D; PALB2 = partner and localizer of BRCA2. Pritchard et al, 2016.
  10. 10. Who to Test for Germline Alterations? Those with prostate cancer NCCN prostate cancer guidelines were deficient until 2018 They now recommend testing everybody with “high-risk localized and metastatic cancer” They recommend genetic testing for any prostate cancer patient with a “strong family history” or “intraductal/cribriform histology” Perform confirmatory testing if select somatic mutations (BRCA2, etc) are found NCCN = National Comprehensive Cancer Network. NCCN, 2020. The Current NCCN Guidelines
  11. 11. Who to Test for Germline Alterations? (cont.) Those without prostate cancer are beyond the scope of this talk, BUT consider: Anyone with a history of male breast cancer Anyone with known genetic mutations in their family NCCN = National Comprehensive Cancer Network. NCCN, 2020. The Current NCCN Guidelines
  12. 12. Who to Test for Germline Alterations? (cont.) The reality sinks in: failure to genetic test is a disservice to our patients
  13. 13. Who to Test for Germline Alterations? (cont.) After starting testing in our clinics, immediate backlogs with genetic counselors arose Messy delays, especially out-of-town referrals Our solution: hire someone for the clinic Controversially, not a genetic counselor Information on cost and consequences of testing Life and disability insurance can be denied on the basis of genetic testing results Online free genetic counseling is available at multiple genetic companies (if you use their products)
  14. 14. Germline Variants in Prostate Cancer MUTYH = mutY DNA glycosylase; HOXB13 = homeobox B13; APC = adenomatous polyposis coli; MSH2 = mutS homolog 2. Nicolosi et al, 2019. Prevalence and Implications for Current Genetic Testing Guidelines Most Frequently Detected Variants in Patients With a Personal History of Prostate Cancer Gene No. of requisitions Variants of uncertain significance detected Positive variants detected, n=674 (%) Positive variants requisition, % BRCA2 3,459 75 164 (24.3%) 4.74 CHEK2 3,300 71 95 (14.1%) 2.88 ATM 3,207 160 65 (9.6%) 2.03 MUTYH 2,322 27 55 (8.2%) 2.37 BRCA1 3,436 38 43 (6.4%) 1.25 HOXB13 2,667 0 30 (4.5%) 1.12 APC 2,345 76 30 (4.5%) 1.28 MSH2 3,350 48 23 (3.4%) 0.69
  15. 15. Germline Variants in Prostate Cancer (cont.) TP53 = tumor protein 53; PMS2 = PMS1 homolog 2; NBN = nibrin; BRIP1 = BRCA interacting protein 1. Nicolosi et al, 2019. Prevalence and Implications for Current Genetic Testing Guidelines Most Frequently Detected Variants: Patients With a Personal History of Prostate Cancer Gene No. of requisitions Variants of uncertain significance detected Positive variants detected, n=674 (%) Positive per requisition, % TP53 3,329 30 22 (3.3) 0.66 PALB2 3,014 42 17 (2.5) 0.56 PMS2 3,345 50 18 (2.7) 0.54 MSH6 3,346 75 15 (2.2) 0.45 NBN 3,145 41 10 (1.5) 0.32 RAD50 2,173 40 7 (1.0) 0.32 BRIP1 2,461 36 7 (1.0) 0.28 RAD5IC 2,438 21 5 (0.7) 0.21 RAD51D 2,689 12 4 (0.6) 0.15 Upon extended testing, only 30.7% of mutations were BRCA1/2 Important genes such as HOXB13 should not be neglected
  16. 16. GermlineVariants in Prostate Cancer (cont.) Nicolosi et al, 2019. Distribution of Genes inWhich Pathogenic, Likely Pathogenic, and Increased- Risk AlleleVariantsWere Detected Note the very “long tail” for rare pathogenic genetic alterations when using extended panels
  17. 17. Cascade Testing of Family Members Tedious, time-consuming, and rewarding Arranging testing and follow-up: another whole job…. NCCN, 2020. An Obligation, Not an Option
  18. 18. Molecular Imaging
  19. 19. The Critical Role of Imaging Many local therapy failures are simply due to poor staging CT and bone scan detect 1 cc tumors, but 1 cc tumors contain about 108 to 109 cells Current imaging is grossly inadequate for proper staging
  20. 20. PSMA PET Imaging Radioactive diagnostic agent approved in December 1, 2020, at UCLA and UCSF First approved drug for PSMA-targeted PET imaging of prostate cancer Indicated for patients with suspected metastasis who are eligible for surgery and for patients with suspected recurrence based on elevated PSA levels May detect metastatic disease not previously detected on CT or bone scan Can produce false positives that can mimic tumor Training required in order to appropriately interpret scans PSMA = prostate-specific membrane androgen; PET = positron emission tomography; Ga = gallium. Fendler et al, 2019; US FDA, 2020. Ga 68 PSMA-11
  21. 21. A B C D 50X better than CT? PSMA PET Imaging (cont.) Images courtesy of Steve Y. Cho (University of Washington) and Martin G. Pomper (Johns Hopkins University). Rowe et al, 2016. 18F-DCFPyL: Improved Sensitivity of Both Nodal and Bone Metastases
  22. 22. Molecular Imaging met = metastasis. Photo courtesy of Eugene Kwon. Drives the Diagnosis of Oligometastatic Disease
  23. 23. The Evolutionary History of Lethal Metastatic Prostate Cancer L. = left; BM = bone marrow; sem. = seminal; R. = right; LN = lymph node; media. = mediastinal; nod. = nodule; GL = Gleason score; EPE = extraprostatic extension; ligam. = ligament; WGS = whole genome sequencing. Gundem et al, 2015. Metastasis-to-metastasis seeding occurs either by a linear or by a branching pattern of spread. a–c: Body maps show the seeding of all tumor sites from A22 (a), A21 (b), andA24 (c).Sites shown include samples subject to targeted sequencing (A22-L,A24-F, A24-G) in addition toWGS samples. Seeding events are represented with arrows color-coded according to SupplementaryTable 3 and with double heads when seeding could be in either direction.When the sequence of events may be ordered from the acquisition of mutations, arrows are numbered chronologically. Subclones on branching clonal lineages are labelled with the same number but with different letters, for example, 4a and 4b.
  24. 24. Does metastasis-directed therapy make a difference for those with metastatic disease? Uncontrolled and retrospective studies suggest potential benefit in low- volume disease, BUT controlled studies are still small Unresolved Question
  25. 25. PSA Changes After PSMA-Targeted Radiotherapy or Surgery Fendler et al, 2019. Best PSA response of individual patients (n=39) Shown as % change from baseline (bars) and given as absolute change in ng/mL Patients stratified by treatment Best PSA Response Following FocalTherapy to PET Lesions
  26. 26. PSMA-Detected DiseaseTreatedWith SBRT SBRT = stereotactic body radiotherapy; PFS = progression-free survival. Kneebone et al, 2018. PFS Time (mo)
  27. 27. Oligometastatic Prostate Cancer Recurrence surv = surveillance; MDT = metastasis-directed therapy; ADT = androgen deprivation therapy; HR = hazard ratio; CI = confidence interval. Ost et al, 2018. Surveillance or Metastasis-Directed Therapy: Choline PET PSA progression ADT- sparing
  28. 28. ORIOLE Recurrent HSPC and 1-3 metastases detectable by conventional imaging and no ADT within 6 months All patients had prior definitive treatment of the primary tumor with surgery or radiotherapy PSMA-targeted PET CT scans (performed at baseline) Phillips et al, 2020. Observation vs Stereotactic Ablative Radiation
  29. 29. ORIOLE: Stereotactic Ablative Radiation (cont.) SABR = stereotactic ablation radiation. Phillips et al, 2020. Results Median PFS SABR = not reached Observation = 5.8 months Median PFS SABR = not reached Observation = 6.4 months
  30. 30. ORIOLE: Stereotactic Ablative Radiation Within the SABR arm, total consolidation of PSMA-avid lesions improved PFS Phillips et al, 2020. Results (cont.) HR: 0.26 95% CI: 0.09-0.76 P=0.0055
  31. 31. Metastasis-Directed Therapy CORE (UK): not just prostate PLATON/PR.20 (Canadian) STEREO-OS (French) PCS IX (Canadian): CRPC CRPC = castration-resistant prostate cancer. Clinicaltrials.gov, 2019; Clinicaltrials.gov, 2020b; Clinicaltrials.gov, 2020f; Clinicaltrials.gov, 2020c. Selected Additional Randomized Trials
  32. 32. Oligo-Met Treatments Today: Confusion Reigns ADT: yes/no…“new” or “old” (duration?) Treat the prostate: yes/no, radiation/surgery Treat metastases: yes/no, radiation/surgery Observation of asymptomatic patients? ADT alone? ADT + novel hormones (abi/enza) ADT + novel hormones (abi/enza) + SBRT to mets SBRT to mets and avoid ADT Etc, etc, etc…something for everyone Patient preferences suggest no one size fits all!!! Oligo-met = oligometastatic; abi = abiraterone; enza = enzalutamide. Palacios-Eito et al, 2019.
  33. 33. Prostate Cancer Clinical States Rx = therapy. NCCN, 2020. Recurrent After Initial HormonalTherapy Hormone Sensitive Rising PSA Salvage rx, ADT, or no therapy Radiographic metastases: ADT-resistant First-line chemo Docetaxel Radiographic metastases: ADT-resistant Pre-chemo Sipuleucel-T Abiraterone Enzalutamide Radium-223 Localized disease Local therapy or no therapy Rising PSA: ADT-resistant No standard of care Overt metastases ADT + docetaxel or abiraterone or apalutamide or enzalutamide Radiographic metastases: ADT-resistant Post-chemo Cabazitaxel Abiraterone Enzalutamide Radium-223 Next focus
  34. 34. Case Study 2 68-year-old man with 2 lesions on bone scan, PSA 32, T3a prostate, and Gleason 4+3 What to do? a. Hormonal therapy b. Surgery c. Radiation d. Hormonal therapy + radiation
  35. 35. Case Study 2 (cont.) 68-year-old man with 2 lesions on bone scan, PSA 32, T3a prostate, and Gleason 4+3 What to do? a. Hormonal therapy b. Surgery c. Radiation d. Hormonal therapy + radiation STAMPEDE Arm H analysis: radiation to the prostate with ADT improves survival for those with low metastatic burden by CHAARTED criteria CHAARTED = Chemo Hormonal Therapy Versus Androgen Ablation Randomized Trial. Parker et al, 2018.
  36. 36. Factors to Consider Does treatment of the prostate make a difference for those with metastatic disease? New data with radiation Toxicity and tolerance
  37. 37. STAMPEDE: Arm H Update SOC = standard of care; RT = radiotherapy. Parker et al, 2018. Radiation to Prostate in Those Treated With ADT Alone Using CHAARTED Criteria RT better RT not better
  38. 38. Hormone-Naive Metastatic Prostate Cancer: Present Day Consensus: docetaxel + ADT appropriate for high-volume metastatic disease Controversy: docetaxel + ADT debatable for low-volume metastases Discussion: novel hormones + ADT or docetaxel + ADT??? What do HRQOL data tell us about tolerability and safety Kyriakopoulos et al, 2018. Consensus, Controversy, and Change
  39. 39. CHAARTED: ADT ± Docetaxel OS = overall survival. Kyriakopoulos et al, 2018. Long-Term Follow-Up: High-Volume vs Low-Volume Disease High-Volume Disease Low-Volume Disease Note: Almost all patients with low-volume disease recurrent HR = 0.63 HR = 1.04
  40. 40. Clarke et al, 2019. Long-Term Survival Results STAMPEDE Addition of Docetaxel to HormonalTherapy in Low- and High-Burden Metastatic HSPC Note: Almost all patients with low-volume disease de novo
  41. 41. Management of Patients With Advanced Prostate Cancer 68% of panelists considered it important to distinguish de novo treatment-naive (synchronous) oligometastatic prostate cancer from oligometastatic prostate cancer recurring after local therapy (metachronous) 32% viewed this distinction as unimportant Gillessen et al, 2020. Advanced Prostate Cancer Consensus Conference 2019
  42. 42. Drugs Targeting Androgen Synthesis AR = androgen receptor; SARD = selective androgen receptor degrader; GnRH = gonadotropin-releasing hormone; HSP = heat shock protein. Hahn et al, 2018. Androgen Synthesis Pathway Throughout the Body
  43. 43. ADT Plus Abiraterone Acetate Plus Prednisone Fizazi et al, 2017. LATITUDE Trial: Metastatic Hormone-Sensitive Prostate Cancer FDA approved Feb 2018 HR = 0.30 HR = 0.62
  44. 44. Abiraterone: Adverse Events LATITUDE: Abiraterone/Prednisone in mHSPC mHSPC = metastatic HSPC; LFTs = liver function tests. Fizazi et al, 2017. Monitor electrolytes, LFTs, blood pressure Monitor for cardiac disorders (especially atrial fibrillation) Adverse event Abiraterone (n=597) Placebo (n=602) All grades Grade Grade 4 All grades Grade 3 Grade Hypertension 37% 20% 0% 22% 10% <1% Hypokalemia 20% 10% 1% 4% 1% <1% ALT increased 16% 5% <1% 13% 1% 0% Hyperglycemia 13% 4% <1% 11% 3% 0% AST increased 15% 4% <1% 11% 1% 0% Bone pain 12% 3% 0% 15% 3% 0% Cardiac disorder Any Atrial fibrillation 12% 1% 3% <1% 1% 0% 8% <1% 1% <1% 0% 0% Anemia 9% 2% 1% 14% 4% <1% Back pain 18% 2% 0% 20% 3% 0% Fatigue 13% 2% 0% 14% 2% 0% Spinal cord compression 2% 2% 0% 2% 1% <1%
  45. 45. Abiraterone: STAMPEDE Randomized Trial James et al, 2017. Abiraterone Acetate/Prednisolone in Hormone-Naive Metastatic Prostate Cancer HR = 0.61 HR = 0.31
  46. 46. STAMPEDE:Abiraterone Acetate/Prednisolone (cont.) AAP = abiraterone acetate/prednisolone; pred = prednisolone. James et al, 2020. Hormone-Naive Metastatic Prostate Cancer HR 0.60 (0.50-0.71), P=0.00000000003 Proportion surviving 0 8 1 7 2 3 6 5 4 1.0 0.75 0.50 0.25 0 Long-Term Results From Metastatic (M1) Patients SOC+AAP vs SOC: Overall Survival
  47. 47. STAMPEDE: Abiraterone Acetate/Prednisolone (cont.) No disease burden or risk impact on efficacy outcomes James et al, 2020. Long-Term Results From Metastatic (M1) Patients Low Risk: OS High Risk: OS Proportion surviving 0 8 1 7 2 3 6 5 4 1.0 0.75 0.50 0.25 0 SOC + AAP SOC SOC + AAP SOC Proportion surviving 0 8 1 7 2 3 6 5 4 1.0 0.75 0.50 0.25 0
  48. 48. STAMPEDE: Abiraterone Acetate/Prednisolone (cont.) SOC+AAP vs SOC: Adverse Events James et al, 2020. Long-Term Results From Metastatic (M1) Patients
  49. 49. Enzalutamide in ENZAMET Trial Davis et al, 2019. Enzalutamide With Standard First-Line Therapy in Metastatic Prostate Cancer
  50. 50. EnzalutamideWith Concurrent Docetaxel NSAA = nonsteroidal anti-androgen. Sweeney et al, 2019. Prespecified Subgroup of Interest in ENZAMET Clinical Progression-Free Survival Overall Survival Testosterone Suppression + Docetaxel n=503 (71% high-volume disease) Testosterone Suppression Without Docetaxel n=622 (37% high-volume disease) Progression-Free Survival Overall Survival
  51. 51. ARCHES rPFS = radiographic PFS; NR = not reached. Armstrong et al, 2019. ADT ± Enzalutamide: rPFS Only rPFS (%)
  52. 52. ARCHES (cont.) Armstrong et al, 2019. ADT ± Enzalutamide: rPFS Only
  53. 53. Apalutamide Chi et al, 2019. Metastatic HSPC Hazard ratio for radiographic progression or death: 0.48 (95% CI, 0.39-0.60) P<0.001 Hazard ratio for death: 0.67 (95% CI, 0.51-0.89) P=0.005
  54. 54. Enzalutamide and Apalutamide: Safety Considerations Both medications: Not for patients with seizure history or risk factors (recent stroke, brain tumor) Risk of hypertension, falls, fractures Fatigue Additional risks: enzalutamide PRES Hypersensitivity reactions Ischemic heart disease Additional risks: apalutamide Hypothyroidism Cerebrovascular and ischemic cardiovascular events PRES = posterior reversible encephalopathy syndrome. Xtandi® prescribing information, 2020; ErleadaTM prescribing information, 2020.
  55. 55. Comparing ADT + Docetaxel vs ADT + Abiraterone
  56. 56. STAMPEDE (cont.) KM = Kaplan-Meier; FFS = failure-free survival; DocP = docetaxel/prednisone. Sydes et al, 2018. Direct Comparison of ADT + Docetaxel vs ADT + Abiraterone OS = ADT + AAP = ADT + DocP Similar OS and better FFS with ADT + AAP implies better salvage rx
  57. 57. Quality of Life in STAMPEDE andTITANTrials QOL = quality of life; Doc = docetaxel; AA = abiraterone acetate; FACT-P = Functional Assessment of Cancer Therapy—Prostate; HRQOL = health-related quality of life. Rush et al, 2020; Agarwal et al, 2019. STAMPEDE Global QOL TITAN QOL
  58. 58. SystemicTreatment of mHSPC Agent Trial,Year Comparator OS End Point: HR Treatment vs Control AAP LATITUDE, 2019 (follow-up 4.3 years) ADT + PBO HR: 0.66 (0.56-0.78) P<0.0001 53.3 vs 36.5 mo STAMPEDE, 2017 (follow-up 3.3 years) ADT alone HR: 0.61 (0.49-0.75) 83% vs 73% alive at 3 years STAMPEDE, 2020 (follow-up 6.1 years) ADT alone HR: 0.60 (0.50-0.71) P<0.000000003 Median 6.6 vs 3.8 years Enza ENZAMET, 2019 ADT + nonsteroidal ART HR: 0.67 (0.52-0.86) P<0.002 80% vs 72% alive at 3 years Apa TITAN, 2019 ADT + PBO HR: 0.67 (0.51, 0.89) P<0.005 82.4% vs 73.5% alive at 2 years Doc CHAARTED, 2015 ADT alone HR: 0.61 (0.47-0.80) P<0.001 57.6 vs 44 months GETUG-AFU, 2013 ADT alone HR: 1.01 (0.75-1.36) NS 58.9 vs 54.2 months STAMPEDE, 2015 ADT alone HR: 0.81 (0.69-0.95) P<0.009 PBO = placebo; Apa = apalutamide; ART = androgen receptor therapy. James et al, 2020; Zytiga® prescribing information, 2020; ErleadaTM prescribing information, 2020; Taxotere® prescribing information, 2020; Xtandi® prescribing information, 2020. Accumulating Data and Experience
  59. 59. Prolonging Survival and Improving Tolerability Can a novel hormone improve outcomes after ADT + docetaxel? Can immunotherapy add to the combination of ADT + a novel hormonal therapy? Can treatment with surgery improve outcomes for metastatic disease? What Strategies Might Improve Upon the Standard of Care?
  60. 60. Next-Generation Studies Bayer (ARASENS): ADT + docetaxel ± darolutamide STAMPEDE Arm J: SOC ± abiraterone/enzalutamide STAMPEDE Arm K: SOC ± metformin STAMPEDE ARM L: SOC ± estradiol patches Alliance/NRG/Novartis: PSMA 617 Lu-177 SWOG: ADT ± TAK-700 SWOG: standard treatment ± treatment of the prostate with surgery or radiation Merck KEYNOTE-991: ADT + enzalutamide ± pembrolizumab Smith et al, 2018; Clinicaltrials.gov, 2020g; Clinicaltrials.gov, 2020a; Clinicaltrials.gov, 2020d; Clinicaltrials.gov, 2020e; Gratzke et al, 2020.
  61. 61. Key Takeaways Germline testing and cascade testing add important value Molecular imaging is here to stay Novel hormones are going earlier Selecting docetaxel vs a novel hormone is a matter of personal preference QOL is better with the novel hormone Cost is less with docetaxel Be aware of adverse events and patient risk factors; plan accordingly in order to enhance safety and tolerability More trials are ongoing… we are anxious to learn more so our patients can benefit
  62. 62. Thanks for joining me today! osartor@tulane.edu
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