{"version":"1.0.0","segments":[{"startTime":0.56,"endTime":3.3,"body":"[upbeat intro music]"},{"startTime":3.3,"endTime":5.68,"body":"[Dr. Handy] Hi, welcome"},{"startTime":3.3,"endTime":5.68,"body":"to Harrison's PodClass,"},{"startTime":5.68,"endTime":8.83,"body":"where we discuss important"},{"startTime":5.68,"endTime":8.83,"body":"concepts in internal medicine."},{"startTime":8.83,"endTime":9.95,"body":"I'm Cathy Handy."},{"startTime":9.95,"endTime":11.665,"body":"[Dr. Wiener] And I'm Charlie"},{"startTime":9.95,"endTime":11.665,"body":"Wiener, and we're coming to you"},{"startTime":11.665,"endTime":13.84,"body":"from the Johns Hopkins School of Medicine."},{"startTime":15.96,"endTime":19.01,"body":"Welcome to episode 96, a"},{"startTime":15.96,"endTime":19.01,"body":"patient with a lung mass."},{"startTime":19.01,"endTime":20.93,"body":"Cathy, we're going to go"},{"startTime":19.01,"endTime":20.93,"body":"with a slightly different"},{"startTime":20.93,"endTime":23.36,"body":"format again today, and"},{"startTime":20.93,"endTime":23.36,"body":"we're going to be focusing on"},{"startTime":23.36,"endTime":26.36,"body":"typical patients and"},{"startTime":23.36,"endTime":26.36,"body":"precision medicine oncology."},{"startTime":26.36,"endTime":27.99,"body":"[Dr. Handy] Well, good,"},{"startTime":26.36,"endTime":27.99,"body":"one of my favorite topics,"},{"startTime":27.99,"endTime":29.08,"body":"and I will put in a plug,"},{"startTime":29.08,"endTime":30.78,"body":"I do think some of the work in oncology"},{"startTime":30.78,"endTime":32.27,"body":"has really moved far towards"},{"startTime":32.27,"endTime":34.35,"body":"utilizing precision medicine approaches."},{"startTime":34.35,"endTime":36.28,"body":"Although obviously we still"},{"startTime":34.35,"endTime":36.28,"body":"have a long way to go."},{"startTime":36.28,"endTime":37.196,"body":"[Dr. Wiener] Yeah, I think we'll touch on"},{"startTime":37.196,"endTime":39.2,"body":"some of those issues"},{"startTime":37.196,"endTime":39.2,"body":"during this discussion."},{"startTime":39.2,"endTime":40.43,"body":"Here's the question."},{"startTime":40.43,"endTime":42.46,"body":"As an oncologist, you are considering"},{"startTime":42.46,"endTime":45.27,"body":"treatment options for your"},{"startTime":42.46,"endTime":45.27,"body":"patients with lung cancer,"},{"startTime":45.27,"endTime":46.92,"body":"including small molecule therapy"},{"startTime":46.92,"endTime":50.98,"body":"targeting the epidermal growth"},{"startTime":46.92,"endTime":50.98,"body":"factor receptor or eGFR."},{"startTime":50.98,"endTime":52.16,"body":"Which of the following patients"},{"startTime":52.16,"endTime":53.94,"body":"is most likely to have a tumor"},{"startTime":53.94,"endTime":58.83,"body":"with a high degree of"},{"startTime":53.94,"endTime":58.83,"body":"expression of the eGFR mutation?"},{"startTime":58.83,"endTime":60.3,"body":"So your options are,"},{"startTime":60.3,"endTime":63.66,"body":"A. a 23-year-old man with a hamartoma;"},{"startTime":63.66,"endTime":67.64,"body":"B. a 33-year-old woman"},{"startTime":63.66,"endTime":67.64,"body":"with carcinoid tumor;"},{"startTime":67.64,"endTime":70.75,"body":"C. a 45-year-old woman"},{"startTime":67.64,"endTime":70.75,"body":"who has never smoked"},{"startTime":70.75,"endTime":73.52,"body":"and has an adenocarcinoma of the lung;"},{"startTime":73.52,"endTime":75.39,"body":"D. is a 56-year-old man"},{"startTime":75.39,"endTime":77.7,"body":"with a hundred pack year"},{"startTime":75.39,"endTime":77.7,"body":"history of tobacco use"},{"startTime":77.7,"endTime":80.34,"body":"and has small cell lung cancer;"},{"startTime":80.34,"endTime":83.807,"body":"and E. is a 76-year-old man"},{"startTime":80.34,"endTime":83.807,"body":"with a squamous cell carcinoma"},{"startTime":83.807,"endTime":86.46,"body":"who also has a history"},{"startTime":83.807,"endTime":86.46,"body":"of asbestos exposure"},{"startTime":86.46,"endTime":88.4,"body":"and heavy cigarette smoking."},{"startTime":88.4,"endTime":89.981,"body":"[Dr. Handy] Okay, this is"},{"startTime":88.4,"endTime":89.981,"body":"great because we've learned"},{"startTime":89.981,"endTime":92.83,"body":"so much about the molecular"},{"startTime":89.981,"endTime":92.83,"body":"characteristics of lung cancer"},{"startTime":92.83,"endTime":95.5,"body":"and some of these are"},{"startTime":92.83,"endTime":95.5,"body":"driving novel therapies."},{"startTime":95.5,"endTime":97.78,"body":"The key point is that"},{"startTime":95.5,"endTime":97.78,"body":"these targeted therapies"},{"startTime":97.78,"endTime":99.71,"body":"are only helpful in some patients,"},{"startTime":99.71,"endTime":101.28,"body":"in this case with lung cancer,"},{"startTime":101.28,"endTime":104.65,"body":"who have eGFR mutations"},{"startTime":101.28,"endTime":104.65,"body":"that lead to overexpression."},{"startTime":104.65,"endTime":106.12,"body":"[Dr. Wiener] Okay, so you're telling me"},{"startTime":106.12,"endTime":108.3,"body":"that some tumors do have expression"},{"startTime":108.3,"endTime":110.21,"body":"of eGFR and some don't."},{"startTime":110.21,"endTime":111.99,"body":"Okay, which of the"},{"startTime":110.21,"endTime":111.99,"body":"patients that I mentioned"},{"startTime":111.99,"endTime":113.26,"body":"is most likely to have a tumor"},{"startTime":113.26,"endTime":115.21,"body":"with a high expression of eGFR?"},{"startTime":115.21,"endTime":117.84,"body":"[Dr. Handy] So the answer"},{"startTime":115.21,"endTime":117.84,"body":"is C. the non-smoking woman"},{"startTime":117.84,"endTime":119.34,"body":"with adenocarcinoma."},{"startTime":119.34,"endTime":120.538,"body":"This demographic of patients"},{"startTime":120.538,"endTime":122.29,"body":"with lung cancer has grown dramatically"},{"startTime":122.29,"endTime":124.95,"body":"in the U. S. as smoking"},{"startTime":122.29,"endTime":124.95,"body":"has become less common."},{"startTime":124.95,"endTime":126.56,"body":"Traditionally, this"},{"startTime":124.95,"endTime":126.56,"body":"was a group of patients"},{"startTime":126.56,"endTime":129.4,"body":"who did very poorly with"},{"startTime":126.56,"endTime":129.4,"body":"traditional chemotherapy."},{"startTime":129.4,"endTime":131.53,"body":"10 to 15% of North American patients"},{"startTime":131.53,"endTime":133.46,"body":"diagnosed with non-small cell lung cancer"},{"startTime":133.46,"endTime":136.09,"body":"have cancers with eGFR mutations."},{"startTime":136.09,"endTime":138.21,"body":"Patients who are more"},{"startTime":136.09,"endTime":138.21,"body":"likely to have these cancers"},{"startTime":138.21,"endTime":141.88,"body":"are women, non-smokers, people from Asia,"},{"startTime":141.88,"endTime":145.03,"body":"and patients with"},{"startTime":141.88,"endTime":145.03,"body":"adenocarcinoma histopathology."},{"startTime":145.03,"endTime":146.173,"body":"[Dr. Wiener] Okay, well,"},{"startTime":145.03,"endTime":146.173,"body":"tell me a little bit"},{"startTime":146.173,"endTime":148.01,"body":"more about this targeted treatment."},{"startTime":148.01,"endTime":150.08,"body":"[Dr. Handy] Approximately"},{"startTime":148.01,"endTime":150.08,"body":"90% of these mutations"},{"startTime":150.08,"endTime":152.447,"body":"are point mutations within the eGFR"},{"startTime":152.447,"endTime":155.34,"body":"tyrosine kinase domain"},{"startTime":152.447,"endTime":155.34,"body":"resulting in hyperactivation"},{"startTime":155.34,"endTime":158.83,"body":"of both eGFR kinase activity"},{"startTime":155.34,"endTime":158.83,"body":"and downstream signaling."},{"startTime":158.83,"endTime":161.15,"body":"Lung tumors that harbor"},{"startTime":158.83,"endTime":161.15,"body":"activating mutations"},{"startTime":161.15,"endTime":163.3,"body":"within the eGFR kinase domain display"},{"startTime":163.3,"endTime":165.886,"body":"high sensitivity to small molecule eGFR"},{"startTime":165.886,"endTime":168.47,"body":"tyrosine kinase inhibitors, or TKIs."},{"startTime":168.47,"endTime":170.08,"body":"Now, when these TKIs were used"},{"startTime":170.08,"endTime":172.04,"body":"in unselected patient populations,"},{"startTime":172.04,"endTime":174.4,"body":"they didn't show significant efficacy."},{"startTime":174.4,"endTime":177.61,"body":"However, in the subset of"},{"startTime":174.4,"endTime":177.61,"body":"patients with eGFR mutations,"},{"startTime":177.61,"endTime":179.42,"body":"these treatments are efficacious"},{"startTime":179.42,"endTime":181.45,"body":"and represent the standard of care now."},{"startTime":181.45,"endTime":182.4,"body":"[Dr. Wiener] Okay, so what you're saying"},{"startTime":182.4,"endTime":184.1,"body":"is that when they did broad studies"},{"startTime":184.1,"endTime":186.33,"body":"with enrolling lots of"},{"startTime":184.1,"endTime":186.33,"body":"patients with lung cancer,"},{"startTime":186.33,"endTime":189.81,"body":"for trials of TKI, such as erlotinib,"},{"startTime":189.81,"endTime":191.52,"body":"they did not necessarily show an effect,"},{"startTime":191.52,"endTime":193.05,"body":"but they only showed an effect"},{"startTime":193.05,"endTime":195.11,"body":"when they kind of filtered out"},{"startTime":195.11,"endTime":197.8,"body":"for those who actually had"},{"startTime":195.11,"endTime":197.8,"body":"the relevant mutations."},{"startTime":197.8,"endTime":198.633,"body":"[Dr. Handy] That's correct,"},{"startTime":198.633,"endTime":201.48,"body":"in unselected, just general"},{"startTime":198.633,"endTime":201.48,"body":"lung cancer population,"},{"startTime":201.48,"endTime":204.39,"body":"these drugs are not"},{"startTime":201.48,"endTime":204.39,"body":"really that efficacious"},{"startTime":204.39,"endTime":205.59,"body":"but in the subset of patients"},{"startTime":205.59,"endTime":208.907,"body":"who have these eGFR mutations,"},{"startTime":205.59,"endTime":208.907,"body":"these drugs are very helpful."},{"startTime":208.907,"endTime":209.98,"body":"[Dr. Wiener] I think"},{"startTime":208.907,"endTime":209.98,"body":"that's really interesting"},{"startTime":209.98,"endTime":211.53,"body":"how these precision treatments"},{"startTime":211.53,"endTime":214.446,"body":"not only have to redefine not"},{"startTime":211.53,"endTime":214.446,"body":"only how we treat patients,"},{"startTime":214.446,"endTime":216.86,"body":"but also how we design"},{"startTime":214.446,"endTime":216.86,"body":"clinical trials, right?"},{"startTime":216.86,"endTime":218.94,"body":"[Dr. Handy] Yeah, we're"},{"startTime":216.86,"endTime":218.94,"body":"using more and more of these"},{"startTime":218.94,"endTime":220.78,"body":"within oncology clinical trials"},{"startTime":220.78,"endTime":223.6,"body":"and developing more targeted"},{"startTime":220.78,"endTime":223.6,"body":"agents for patients."},{"startTime":223.6,"endTime":225.6,"body":"[Dr. Wiener] Okay, so you"},{"startTime":223.6,"endTime":225.6,"body":"told us that the woman"},{"startTime":225.6,"endTime":227.11,"body":"who has the adenocarcinoma"},{"startTime":227.11,"endTime":230.2,"body":"is most likely to have eGFR mutations"},{"startTime":230.2,"endTime":231.69,"body":"upregulated in her tumor,"},{"startTime":231.69,"endTime":235.09,"body":"such that she would probably"},{"startTime":231.69,"endTime":235.09,"body":"benefit from one of these TKIs,"},{"startTime":235.09,"endTime":236.67,"body":"but let's talk about the other patients."},{"startTime":236.67,"endTime":239.25,"body":"Do the other patients have"},{"startTime":236.67,"endTime":239.25,"body":"typical molecular defects"},{"startTime":239.25,"endTime":241.92,"body":"that can help us define"},{"startTime":239.25,"endTime":241.92,"body":"them or their therapy?"},{"startTime":241.92,"endTime":243.86,"body":"[Dr. Handy] The first"},{"startTime":241.92,"endTime":243.86,"body":"patient had a hamartoma,"},{"startTime":243.86,"endTime":246.32,"body":"and we should remember that"},{"startTime":243.86,"endTime":246.32,"body":"those are benign tumors,"},{"startTime":246.32,"endTime":248.37,"body":"in fact, about 5 to 10% of lung"},{"startTime":248.37,"endTime":251.47,"body":"solitary pulmonary nodules"},{"startTime":248.37,"endTime":251.47,"body":"turn out to be hamartomas."},{"startTime":251.47,"endTime":254.09,"body":"Those are the most common"},{"startTime":251.47,"endTime":254.09,"body":"benign lung nodules."},{"startTime":254.09,"endTime":255.69,"body":"That said, they can grow slowly,"},{"startTime":255.69,"endTime":256.99,"body":"so should be on the differential"},{"startTime":256.99,"endTime":258.62,"body":"of a slowly growing lung mass."},{"startTime":258.62,"endTime":261.12,"body":"And they're part of the"},{"startTime":258.62,"endTime":261.12,"body":"neurofibromatosis type 1"},{"startTime":261.12,"endTime":263.16,"body":"or tuberous sclerosis syndrome."},{"startTime":263.16,"endTime":265.55,"body":"[Dr. Wiener] How about the"},{"startTime":263.16,"endTime":265.55,"body":"woman with carcinoid tumor?"},{"startTime":265.55,"endTime":268.29,"body":"[Dr. Handy] So carcinoids"},{"startTime":265.55,"endTime":268.29,"body":"are neuroendocrine tumors"},{"startTime":268.29,"endTime":270.89,"body":"and surgery is the mainstay of treatment."},{"startTime":270.89,"endTime":274.04,"body":"There aren't many recommended"},{"startTime":270.89,"endTime":274.04,"body":"targeted molecular medications,"},{"startTime":274.04,"endTime":276.24,"body":"although somatostatin analogs can be used"},{"startTime":276.24,"endTime":279.5,"body":"in the treatment regimen"},{"startTime":276.24,"endTime":279.5,"body":"for those types of cancers."},{"startTime":279.5,"endTime":280.333,"body":"[Dr. Wiener] Okay, well, let's move on."},{"startTime":280.333,"endTime":282.58,"body":"How about the man with"},{"startTime":280.333,"endTime":282.58,"body":"small cell carcinoma?"},{"startTime":282.58,"endTime":284.29,"body":"[Dr. Handy] So small cell"},{"startTime":282.58,"endTime":284.29,"body":"lung cancer is typically"},{"startTime":284.29,"endTime":286.94,"body":"very responsive initially"},{"startTime":284.29,"endTime":286.94,"body":"to traditional chemotherapy,"},{"startTime":286.94,"endTime":288.81,"body":"but the recurrence rates are high."},{"startTime":288.81,"endTime":291.58,"body":"The most common genetic"},{"startTime":288.81,"endTime":291.58,"body":"mutation is in TP53,"},{"startTime":291.58,"endTime":293.81,"body":"a common oncogene and there aren't any"},{"startTime":293.81,"endTime":295.46,"body":"targeted treatments for that yet."},{"startTime":295.46,"endTime":296.64,"body":"[Dr. Wiener] Okay, and now, lastly,"},{"startTime":296.64,"endTime":299.83,"body":"the asbestos squamous cell"},{"startTime":296.64,"endTime":299.83,"body":"lung carcinoma in the smoker."},{"startTime":299.83,"endTime":301.982,"body":"[Dr. Handy] Thankfully, the"},{"startTime":299.83,"endTime":301.982,"body":"frequency of asbestos-related"},{"startTime":301.982,"endTime":303.95,"body":"tumors in the United States is declining"},{"startTime":303.95,"endTime":305.67,"body":"with federal and state regulation,"},{"startTime":305.67,"endTime":307.21,"body":"plus an increased awareness"},{"startTime":307.21,"endTime":309.15,"body":"of the toxicity of asbestos."},{"startTime":309.15,"endTime":310.26,"body":"Squamous cell lung cancer"},{"startTime":310.26,"endTime":312.8,"body":"has the strongest association"},{"startTime":310.26,"endTime":312.8,"body":"with cigarette smoking"},{"startTime":312.8,"endTime":315.14,"body":"and still accounts for about 20 to 30%"},{"startTime":315.14,"endTime":316.63,"body":"of new lung cancers."},{"startTime":316.63,"endTime":318.35,"body":"A huge number of genetic mutations"},{"startTime":318.35,"endTime":320.56,"body":"are common in squamous cell lung cancer."},{"startTime":320.56,"endTime":322.72,"body":"Unfortunately, targeted"},{"startTime":320.56,"endTime":322.72,"body":"molecular therapies"},{"startTime":322.72,"endTime":325.24,"body":"have not been as widely"},{"startTime":322.72,"endTime":325.24,"body":"applied in these cancers."},{"startTime":325.24,"endTime":327.06,"body":"For example, eGFR mutations,"},{"startTime":327.06,"endTime":328.37,"body":"which we started with today"},{"startTime":328.37,"endTime":330.7,"body":"are much less frequent"},{"startTime":328.37,"endTime":330.7,"body":"than in adenocarcinomas"},{"startTime":330.7,"endTime":332.08,"body":"and have had disappointing results"},{"startTime":332.08,"endTime":334.24,"body":"for squamous cell carcinoma of the lung."},{"startTime":334.24,"endTime":335.47,"body":"That being said, these tumors"},{"startTime":335.47,"endTime":338.09,"body":"are often responsive to immunotherapies,"},{"startTime":338.09,"endTime":339.74,"body":"another area where we need more science"},{"startTime":339.74,"endTime":342.71,"body":"and clinical trials but a"},{"startTime":339.74,"endTime":342.71,"body":"growing area of treatment."},{"startTime":342.71,"endTime":344.34,"body":"[Dr. Wiener] Okay, so the"},{"startTime":342.71,"endTime":344.34,"body":"teaching points in this case"},{"startTime":344.34,"endTime":346.51,"body":"are that molecular"},{"startTime":344.34,"endTime":346.51,"body":"characterization of tumors,"},{"startTime":346.51,"endTime":348.71,"body":"including lung cancer, is becoming part"},{"startTime":348.71,"endTime":351.473,"body":"of our diagnostic and"},{"startTime":348.71,"endTime":351.473,"body":"therapeutic armamentarium."},{"startTime":351.473,"endTime":352.89,"body":"Adenocarcinomas of the lung"},{"startTime":352.89,"endTime":355.06,"body":"may express eGFR mutations"},{"startTime":355.06,"endTime":358.07,"body":"and targeted therapy is"},{"startTime":355.06,"endTime":358.07,"body":"effective in these tumors."},{"startTime":358.07,"endTime":359.27,"body":"There is also a growing role"},{"startTime":359.27,"endTime":363.218,"body":"of immunotherapy in lung"},{"startTime":359.27,"endTime":363.218,"body":"cancer beyond adenocarcinomas."},{"startTime":363.218,"endTime":364.36,"body":"[Dr. Handy] And you can"},{"startTime":363.218,"endTime":364.36,"body":"read more about this"},{"startTime":364.36,"endTime":366.86,"body":"in Harrison's chapters on cancer genetics"},{"startTime":366.86,"endTime":369.735,"body":"and also the chapter on"},{"startTime":366.86,"endTime":369.735,"body":"neoplasms of the lung."},{"startTime":369.735,"endTime":373.82,"body":"[upbeat outro music]"},{"startTime":373.82,"endTime":376.78,"body":"[Mr. Shanahan] This is Jim"},{"startTime":373.82,"endTime":376.78,"body":"Shanahan, publisher at McGraw Hill."},{"startTime":376.78,"endTime":378.41,"body":"Harrison's Podclass is brought to you"},{"startTime":378.41,"endTime":380.39,"body":"by McGraw Hill's AccessMedicine,"},{"startTime":380.39,"endTime":382.49,"body":"the online medical resource that delivers"},{"startTime":382.49,"endTime":385.71,"body":"the latest trusted content from"},{"startTime":382.49,"endTime":385.71,"body":"the best minds in medicine."},{"startTime":385.71,"endTime":388.263,"body":"Go to accessmedicine.com to learn more."}]}