1 00:00:00,180 --> 00:00:02,537 [Instructor] Here we're going to talk about 2 00:00:02,537 --> 00:00:05,220 the general approach to targeted therapeutics in oncology 3 00:00:05,220 --> 00:00:08,970 and also some genetic predisposition to oncology. 4 00:00:08,970 --> 00:00:13,170 So here, I'm not, my intention is not to be, not 5 00:00:13,170 --> 00:00:16,713 to cover everything and not to give you all the details 6 00:00:16,713 --> 00:00:17,610 of all the different types of therapies 7 00:00:17,610 --> 00:00:20,670 or all the different genetic tests that people can have done 8 00:00:20,670 --> 00:00:22,380 for genetic predispositions. 9 00:00:22,380 --> 00:00:25,200 It's more to give you a few case examples 10 00:00:25,200 --> 00:00:30,150 of what these targeted therapeutics 11 00:00:30,150 --> 00:00:33,330 and genetic testing results can mean, 12 00:00:33,330 --> 00:00:36,720 so that way you can understand how these processes work. 13 00:00:36,720 --> 00:00:40,029 Because unless you practice regularly in oncology, 14 00:00:40,029 --> 00:00:43,410 knowing all the details about all the different therapeutics 15 00:00:43,410 --> 00:00:44,490 and all the different genetic tests 16 00:00:44,490 --> 00:00:45,840 isn't really gonna be that useful for you. 17 00:00:45,840 --> 00:00:47,040 But hopefully understanding 18 00:00:47,040 --> 00:00:50,254 the concepts of these therapeutics 19 00:00:50,254 --> 00:00:52,800 and the genetic predisposition will actually 20 00:00:52,800 --> 00:00:53,950 be more useful for you. 21 00:00:55,230 --> 00:00:58,080 So somatic versus germline mutations, 22 00:00:58,080 --> 00:00:59,808 this is really what we're talking about. 23 00:00:59,808 --> 00:01:01,860 And somatic mutations are acquired 24 00:01:01,860 --> 00:01:04,530 by individual cells in the body over a person's lifetime. 25 00:01:04,530 --> 00:01:06,090 Remember what somatic cells are, 26 00:01:06,090 --> 00:01:07,740 those are basically all cells in your body 27 00:01:07,740 --> 00:01:08,924 that are not your germline cells. 28 00:01:08,924 --> 00:01:12,280 As a result, cancer cells will have a unique set 29 00:01:12,280 --> 00:01:14,100 of mutations that are not found 30 00:01:14,100 --> 00:01:16,260 in other normal cells in the body. 31 00:01:16,260 --> 00:01:17,418 So while you could say, 32 00:01:17,418 --> 00:01:19,972 all of your cells in the body have the same genome, 33 00:01:19,972 --> 00:01:22,792 that's true, but each cell has accumulated a unique set 34 00:01:22,792 --> 00:01:25,465 of mutations for it. 35 00:01:25,465 --> 00:01:27,870 And in cancer cells, this is especially true 36 00:01:27,870 --> 00:01:31,590 because as you remember, those particular kinds of genes, 37 00:01:31,590 --> 00:01:35,550 those caretaker genes that repair DNA mutations, 38 00:01:35,550 --> 00:01:38,215 DNA damage, well, if they're inactivated 39 00:01:38,215 --> 00:01:40,230 or they're not functioning normally, 40 00:01:40,230 --> 00:01:43,551 those cells that have those caretaker genes mutated, 41 00:01:43,551 --> 00:01:46,350 they're going to accumulate a lot more mutations 42 00:01:46,350 --> 00:01:50,070 very, very quickly compared with other cells in the body. 43 00:01:50,070 --> 00:01:52,230 And some mutations are found in all cells. 44 00:01:52,230 --> 00:01:55,020 And these were inherited, so these are germline cells. 45 00:01:55,020 --> 00:01:57,268 They started out from day one, fertilized egg. 46 00:01:57,268 --> 00:01:59,730 This individual had this particular mutation, 47 00:01:59,730 --> 00:02:01,350 so it's found in every single cell 48 00:02:01,350 --> 00:02:02,981 in their body, exact same mutation. 49 00:02:02,981 --> 00:02:05,130 Why? Because they inherited it. 50 00:02:05,130 --> 00:02:08,370 So it's a germline mutation, something they inherited. 51 00:02:08,370 --> 00:02:09,543 They didn't acquire it over time. 52 00:02:09,543 --> 00:02:13,680 Somatic mutations, which happen in all 53 00:02:13,680 --> 00:02:17,280 of us and all of our cells, those are acquired over time. 54 00:02:17,280 --> 00:02:19,620 And those are gonna be very unique in each cell 55 00:02:19,620 --> 00:02:20,820 within a person's body. 56 00:02:20,820 --> 00:02:23,545 It's not just person to person, but cell to cell. 57 00:02:23,545 --> 00:02:26,796 So these mutations, 58 00:02:26,796 --> 00:02:30,360 the germline mutations may predispose a person to cancer, 59 00:02:30,360 --> 00:02:32,670 but they require additional somatic 60 00:02:32,670 --> 00:02:34,216 mutations before cancer forms. 61 00:02:34,216 --> 00:02:37,860 Remember, it's the, if you kind of go back to the idea 62 00:02:37,860 --> 00:02:42,860 of three strikes, you're out idea then people who start out 63 00:02:42,930 --> 00:02:45,780 with a germline mutation that is in, 64 00:02:45,780 --> 00:02:47,077 say, a tumor suppressor gene 65 00:02:47,077 --> 00:02:51,180 or in a caretaker gene, that person already has one strike. 66 00:02:51,180 --> 00:02:53,760 But then they have to accumulate those other two strikes 67 00:02:53,760 --> 00:02:56,640 in certain parts of, in certain cells in their body. 68 00:02:56,640 --> 00:02:59,342 And those strikes come from acquiring mutations 69 00:02:59,342 --> 00:03:04,342 either randomly, from DNA replication errors, 70 00:03:04,830 --> 00:03:08,610 or they occur from exposure to carcinogens. 71 00:03:08,610 --> 00:03:13,610 In any case, the predisposing germline mutations, 72 00:03:13,680 --> 00:03:16,110 it's not sufficient to actually cause cancer by itself, 73 00:03:16,110 --> 00:03:17,490 but they actually require 74 00:03:17,490 --> 00:03:19,833 some additional somatic mutations to happen. 75 00:03:20,910 --> 00:03:24,240 Germline mutations can be tested using any cells in the body 76 00:03:24,240 --> 00:03:27,390 while somatic mutations causing a person's cancer can only 77 00:03:27,390 --> 00:03:28,830 be found in the tumor itself. 78 00:03:28,830 --> 00:03:30,660 So think about why that's the case. 79 00:03:30,660 --> 00:03:33,480 And germline mutations, those were inherited. 80 00:03:33,480 --> 00:03:35,700 So they're going to be found in every cell in the body, 81 00:03:35,700 --> 00:03:37,830 whereas somatic mutations are gonna be different 82 00:03:37,830 --> 00:03:39,960 in each cell, depending upon what it was exposed to, 83 00:03:39,960 --> 00:03:42,489 how well it was able to repair the damage, 84 00:03:42,489 --> 00:03:45,602 and any other additional mutations 85 00:03:45,602 --> 00:03:47,880 that might have happened in that particular cell 86 00:03:47,880 --> 00:03:50,016 that are gonna be different from any other cell in the body. 87 00:03:50,016 --> 00:03:55,016 Targeted therapies target somatic mutations, 88 00:03:55,140 --> 00:03:58,260 somatic mutations specific to the cancer cells, 89 00:03:58,260 --> 00:03:59,865 while genetic predisposition tests 90 00:03:59,865 --> 00:04:04,590 for mutations in all cells that all cells have, 91 00:04:04,590 --> 00:04:08,550 that might make cells more susceptible to becoming cancer. 92 00:04:08,550 --> 00:04:10,770 Okay, and we'll talk about each of those, 93 00:04:10,770 --> 00:04:13,320 but first, let's look at what types of tissues 94 00:04:13,320 --> 00:04:14,613 or samples are taken. 95 00:04:15,720 --> 00:04:19,140 So an inherited, so that's gonna be a germline mutation. 96 00:04:19,140 --> 00:04:21,570 An inherited mutation versus an acquired mutation. 97 00:04:21,570 --> 00:04:23,490 Acquired is a somatic mutation 98 00:04:23,490 --> 00:04:25,467 because it's acquired over the person's lifetime. 99 00:04:25,467 --> 00:04:28,851 So an inherited versus acquired mutation testing, 100 00:04:28,851 --> 00:04:30,450 the blood sample. 101 00:04:30,450 --> 00:04:31,770 So really, I mean, blood, 102 00:04:31,770 --> 00:04:33,750 it's gonna be a relatively easy sample to take. 103 00:04:33,750 --> 00:04:35,550 You could also just do a cheek swab 104 00:04:35,550 --> 00:04:37,988 or something like that to test for 105 00:04:37,988 --> 00:04:40,890 a mutation found in those cells 106 00:04:40,890 --> 00:04:42,450 because it's found in all cells in the body. 107 00:04:42,450 --> 00:04:45,330 So it's not as though a person needs to have leukemia, 108 00:04:45,330 --> 00:04:47,730 for example, before you can take a blood sample to test 109 00:04:47,730 --> 00:04:50,130 for an inherited mutation, 110 00:04:50,130 --> 00:04:51,690 because that inherited mutation is going 111 00:04:51,690 --> 00:04:53,250 to be found in all cells in their body. 112 00:04:53,250 --> 00:04:56,010 So you just take whatever is easiest type of sample 113 00:04:56,010 --> 00:04:56,982 to take for that. 114 00:04:56,982 --> 00:05:00,450 For acquired mutations, on the other hand, 115 00:05:00,450 --> 00:05:03,840 you have to have the cells that are causing the problem. 116 00:05:03,840 --> 00:05:07,720 So at this point, a person already has some kind of tumor, 117 00:05:07,720 --> 00:05:10,350 and so a biopsy is taken 118 00:05:10,350 --> 00:05:12,674 and tested for which specific mutations 119 00:05:12,674 --> 00:05:16,770 are found in those cells specifically. 120 00:05:16,770 --> 00:05:18,390 And those mutations are not gonna be found 121 00:05:18,390 --> 00:05:19,440 in the other normal cells, 122 00:05:19,440 --> 00:05:21,420 but they're just gonna be found in the tumor cells. 123 00:05:21,420 --> 00:05:24,630 So you need the tumor in order to test for those mutations. 124 00:05:24,630 --> 00:05:26,161 You can't do a blood sample test 125 00:05:26,161 --> 00:05:29,580 and know that well, your colon tumor 126 00:05:29,580 --> 00:05:33,360 or your colon cancer has these has a mutation 127 00:05:33,360 --> 00:05:35,640 in the epidermal growth factor receptor. 128 00:05:35,640 --> 00:05:37,682 And so we're going to start you on this kind of therapy. 129 00:05:37,682 --> 00:05:39,030 It won't tell you that, 130 00:05:39,030 --> 00:05:41,460 you need to actually get a biopsy from the tumor 131 00:05:41,460 --> 00:05:42,990 because it's only in those cells 132 00:05:42,990 --> 00:05:44,880 where they have those specific mutations, 133 00:05:44,880 --> 00:05:46,330 not in all cells in the body. 134 00:05:47,695 --> 00:05:49,146 So targeted therapeutics. 135 00:05:49,146 --> 00:05:53,100 So one other point I want to mention here 136 00:05:53,100 --> 00:05:54,390 is that the genetic testing 137 00:05:54,390 --> 00:05:55,830 for inherited mutations can be done 138 00:05:55,830 --> 00:05:57,150 at any point in a person's life. 139 00:05:57,150 --> 00:05:58,959 I mean, even before they ever have any 140 00:05:58,959 --> 00:06:00,810 signs or symptoms of cancer. 141 00:06:00,810 --> 00:06:02,640 And they may never develop cancer, actually, 142 00:06:02,640 --> 00:06:04,620 even if the genetic test comes back saying 143 00:06:04,620 --> 00:06:06,397 that they do have an inherited mutation 144 00:06:06,397 --> 00:06:07,996 which could lead to cancer, 145 00:06:07,996 --> 00:06:10,170 it's simply that it could lead to cancer. 146 00:06:10,170 --> 00:06:11,468 It's not a diagnosis of cancer. 147 00:06:11,468 --> 00:06:14,030 When you're looking at acquired mutations. 148 00:06:14,030 --> 00:06:17,310 That only happens when a person already has been diagnosed 149 00:06:17,310 --> 00:06:19,620 with some form of a tumor at least. 150 00:06:19,620 --> 00:06:22,260 And they want to know if the two, 151 00:06:22,260 --> 00:06:24,840 like what specifically what mutations are found 152 00:06:24,840 --> 00:06:25,923 in that tumor. 153 00:06:27,090 --> 00:06:28,410 Targeted therapeutics, 154 00:06:28,410 --> 00:06:32,100 of the 57 FDA approved indications, detailing genotype 155 00:06:32,100 --> 00:06:35,670 or gene expression information 47 are in oncology. 156 00:06:35,670 --> 00:06:36,840 So what do I mean by that? 157 00:06:36,840 --> 00:06:40,480 So in the actual indication for 57 drugs 158 00:06:42,270 --> 00:06:44,010 that are approved by the FDA, 159 00:06:44,010 --> 00:06:47,190 those indications actually specify this drug 160 00:06:47,190 --> 00:06:50,684 is to be used in individuals who have this genotype. 161 00:06:50,684 --> 00:06:52,592 And 47 of those. 162 00:06:52,592 --> 00:06:54,928 So the vast majority, 163 00:06:54,928 --> 00:06:59,820 over 80% of those are for drugs in oncology. 164 00:06:59,820 --> 00:07:02,610 So why are oncology therapies particularly well suited 165 00:07:02,610 --> 00:07:04,324 for a targeted genetic approach? 166 00:07:04,324 --> 00:07:06,690 Well, cancer is the most common genetic 167 00:07:06,690 --> 00:07:08,250 disease as we talked about. 168 00:07:08,250 --> 00:07:11,220 There's also inherent variability in cancer genotypes. 169 00:07:11,220 --> 00:07:12,510 And what do I mean by that? 170 00:07:12,510 --> 00:07:15,450 So as we've been talking about these acquired mutations, 171 00:07:15,450 --> 00:07:17,592 they're going to be very different person to person, 172 00:07:17,592 --> 00:07:18,900 or even a person 173 00:07:18,900 --> 00:07:20,690 who might have two different kinds of cancer, 174 00:07:20,690 --> 00:07:22,616 might develop two different kinds of cancer. 175 00:07:22,616 --> 00:07:24,810 Those can be very different from one another 176 00:07:24,810 --> 00:07:26,190 because each of their cells 177 00:07:26,190 --> 00:07:28,848 has acquired different set of mutations. 178 00:07:28,848 --> 00:07:33,060 So it's not as though cancer is one disease 179 00:07:33,060 --> 00:07:36,030 that can be treated with one type of approach. 180 00:07:36,030 --> 00:07:37,678 I mean, cancer is, I mean, it's almost 181 00:07:37,678 --> 00:07:42,678 an infinite number of different kinds of causes 182 00:07:43,050 --> 00:07:44,845 of the disease because you could have mutations 183 00:07:44,845 --> 00:07:46,710 in so many different genes 184 00:07:46,710 --> 00:07:49,637 or regions of the DNA that can lead to cancer. 185 00:07:49,637 --> 00:07:54,060 And so it's important to identify which genes are disrupted 186 00:07:54,060 --> 00:07:55,380 or which pathways are disrupted 187 00:07:55,380 --> 00:07:57,147 in a particular tumor 188 00:07:57,147 --> 00:07:59,910 in order to know how to best target it. 189 00:07:59,910 --> 00:08:02,898 So targeting cancer cells from normal cells is critical 190 00:08:02,898 --> 00:08:05,190 for safe and effective therapeutics, 191 00:08:05,190 --> 00:08:08,160 as I'm sure you're probably aware, that in general, 192 00:08:08,160 --> 00:08:13,160 chemotherapy, the more general type of treatment 193 00:08:13,350 --> 00:08:16,890 for cancer really just targets any kind 194 00:08:16,890 --> 00:08:19,710 of cells that are rapidly dividing and kills them. 195 00:08:19,710 --> 00:08:23,691 Whether those cells are part of the cancer itself 196 00:08:23,691 --> 00:08:26,580 or whether those cells are the normal cells in the body, 197 00:08:26,580 --> 00:08:29,217 which rapidly divide anyway, which would include 198 00:08:29,217 --> 00:08:34,217 the cells that are involved in follicle formation. 199 00:08:36,090 --> 00:08:38,874 So hair cells that line the gut 200 00:08:38,874 --> 00:08:42,532 and many other kinds of cells as well. 201 00:08:42,532 --> 00:08:44,100 And so that's why people 202 00:08:44,100 --> 00:08:46,470 who undergoing chemotherapy, they lose their hair, 203 00:08:46,470 --> 00:08:50,748 they have significant amounts of nausea and vomiting, 204 00:08:50,748 --> 00:08:53,640 and they're just depleted. 205 00:08:53,640 --> 00:08:57,260 And that's because they are exactly that their cells, 206 00:08:57,260 --> 00:08:59,580 any cell, any cell in the body that happens 207 00:08:59,580 --> 00:09:00,999 to be rapidly dividing is killed. 208 00:09:00,999 --> 00:09:03,690 And that's not a great approach 209 00:09:03,690 --> 00:09:05,555 because it leads to the safety issues, 210 00:09:05,555 --> 00:09:09,030 these side effects which are significant for these patients. 211 00:09:09,030 --> 00:09:11,940 So what the idea is in target therapeutics 212 00:09:11,940 --> 00:09:13,397 is let's just target cancer cells. 213 00:09:13,397 --> 00:09:16,232 Let's try not to hurt our normal naturally 214 00:09:16,232 --> 00:09:17,850 occurring healthy cells. 215 00:09:17,850 --> 00:09:20,265 Let's just target cancer cells and let's kill those. 216 00:09:20,265 --> 00:09:22,945 So personalized medicine 217 00:09:22,945 --> 00:09:26,301 is really the approach that's being taken. 218 00:09:26,301 --> 00:09:28,890 And so this time actually is all about you. 219 00:09:28,890 --> 00:09:30,353 We all like it when things are about us. 220 00:09:30,353 --> 00:09:33,540 And I just put a little funny little comic strip there, 221 00:09:33,540 --> 00:09:37,860 but it personalized medicine when we're talking about that, 222 00:09:37,860 --> 00:09:40,740 that's kind of the targeted therapeutic approach. 223 00:09:40,740 --> 00:09:43,860 So which drug is most likely to generate a response in you 224 00:09:43,860 --> 00:09:45,960 and which diseases are you predisposed to? 225 00:09:45,960 --> 00:09:48,814 So that way we can personalize both the therapy 226 00:09:48,814 --> 00:09:51,129 for if when a person, 227 00:09:51,129 --> 00:09:53,566 or when a person does develop a disease, 228 00:09:53,566 --> 00:09:57,990 but also can identify those who are more likely 229 00:09:57,990 --> 00:09:59,070 to develop the disease. 230 00:09:59,070 --> 00:10:04,012 So we can have better approach to surveillance 231 00:10:04,012 --> 00:10:07,950 and to preventive measures as well 232 00:10:07,950 --> 00:10:09,480 to hopefully prevent a person 233 00:10:09,480 --> 00:10:11,403 from ever even developing cancer. 234 00:10:12,840 --> 00:10:14,790 And why are pharmaceutical companies interested 235 00:10:14,790 --> 00:10:16,804 in making targeted therapies? 236 00:10:16,804 --> 00:10:20,370 Well, it's very expensive as you may already be aware, 237 00:10:20,370 --> 00:10:23,372 but it's very expensive to get to bring a drug to market. 238 00:10:23,372 --> 00:10:26,850 And I mean the estimates 239 00:10:26,850 --> 00:10:29,528 for dollars spent per drug approved 240 00:10:29,528 --> 00:10:32,300 are in the billion dollar range per drug. 241 00:10:32,300 --> 00:10:36,030 So to bring a single drug from, for basically 242 00:10:36,030 --> 00:10:37,770 for each new drug that's approved 243 00:10:37,770 --> 00:10:39,943 for these pharmaceutical companies 244 00:10:39,943 --> 00:10:42,390 and you divide the number 245 00:10:42,390 --> 00:10:45,289 of dollars they invest in bringing all their drugs 246 00:10:45,289 --> 00:10:48,660 to through clinical trials, through development divided 247 00:10:48,660 --> 00:10:50,160 by the number of drugs that are actually approved, 248 00:10:50,160 --> 00:10:52,657 you can come up with billions of dollars per drug. 249 00:10:52,657 --> 00:10:56,970 And why is it so expensive? 250 00:10:56,970 --> 00:10:58,935 Well, if you have 6,000 251 00:10:58,935 --> 00:11:02,250 or 6,000 circles here, just stress me on that one. 252 00:11:02,250 --> 00:11:06,611 If you have 6,000 different compounds that start out in say 253 00:11:06,611 --> 00:11:11,585 in early development for in a pharmaceutical company, 254 00:11:11,585 --> 00:11:14,160 how many of those do you think will actually go 255 00:11:14,160 --> 00:11:15,693 on to ever be approved? 256 00:11:16,740 --> 00:11:18,390 Well, it's actually only one of them. 257 00:11:18,390 --> 00:11:21,870 This one, let's say this little guy right here, that one out 258 00:11:21,870 --> 00:11:25,500 of the 6,000 compounds they start out in testing will 259 00:11:25,500 --> 00:11:28,883 actually ever make it all the way through clinical trials 260 00:11:28,883 --> 00:11:31,397 and be approved and sold. 261 00:11:31,397 --> 00:11:34,320 So why do so many fail? 262 00:11:34,320 --> 00:11:35,792 Well, their safety and efficacy fails 263 00:11:35,792 --> 00:11:40,620 to improve over existing standard of care in the population 264 00:11:40,620 --> 00:11:43,680 or the response rates and adverse events rates vary greatly 265 00:11:43,680 --> 00:11:46,180 person to person, largely because of genetic diversity. 266 00:11:46,180 --> 00:11:48,990 But all data are combined in the analyses 267 00:11:48,990 --> 00:11:50,420 and they lose significance. 268 00:11:50,420 --> 00:11:53,430 So while you might think in a clinical trial, 269 00:11:53,430 --> 00:11:55,773 well we have five apples and of the five apples, 270 00:11:55,773 --> 00:11:58,560 well it worked really well in four of them, 271 00:11:58,560 --> 00:11:59,520 but one of them it didn't. 272 00:11:59,520 --> 00:12:01,350 So if we average all that together, 273 00:12:01,350 --> 00:12:03,210 it didn't really work all that great. 274 00:12:03,210 --> 00:12:05,265 But in reality, instead of having five apples, 275 00:12:05,265 --> 00:12:07,890 what you have is four apples and an orange. 276 00:12:07,890 --> 00:12:10,593 And it was the orange where something didn't, 277 00:12:10,593 --> 00:12:11,426 where it didn't work 278 00:12:11,426 --> 00:12:13,260 or there was a major safety concern, say for example. 279 00:12:13,260 --> 00:12:16,890 And that limited the ability to bring that product 280 00:12:16,890 --> 00:12:17,970 through clinical trials. 281 00:12:17,970 --> 00:12:19,920 And the FDA did not approve it 282 00:12:19,920 --> 00:12:21,222 because of the safety concerns. 283 00:12:21,222 --> 00:12:23,360 But if they can identify which 284 00:12:23,360 --> 00:12:25,110 of these apples is actually an orange 285 00:12:25,110 --> 00:12:27,030 through genetic testing, for example, 286 00:12:27,030 --> 00:12:29,730 and say, hey, you are not gonna be likely to respond 287 00:12:29,730 --> 00:12:32,220 to this therapy or you are not gonna be likely to, 288 00:12:32,220 --> 00:12:35,065 you're likely to have a bad response 289 00:12:35,065 --> 00:12:37,050 and a safety concern 290 00:12:37,050 --> 00:12:38,820 or an adverse event that will happen. 291 00:12:38,820 --> 00:12:40,860 That's a lot more likely to happen 292 00:12:40,860 --> 00:12:43,993 because of your particular genotype 293 00:12:43,993 --> 00:12:46,116 than they can identify those people 294 00:12:46,116 --> 00:12:49,770 and they can divide out the data when they're actually doing 295 00:12:49,770 --> 00:12:51,739 the analysis of safety and efficacy data. 296 00:12:51,739 --> 00:12:55,440 They can divide out based upon a patient's particular 297 00:12:55,440 --> 00:12:58,380 genotype, their response rates 298 00:12:58,380 --> 00:13:02,250 and their adverse event rates. 299 00:13:02,250 --> 00:13:04,732 And it'll make it a lot more likely for drugs 300 00:13:04,732 --> 00:13:05,850 to be approved 301 00:13:05,850 --> 00:13:10,320 and be useful not for the general population necessarily, 302 00:13:10,320 --> 00:13:11,461 but for subsets. 303 00:13:11,461 --> 00:13:14,913 And those subsets can be identified through genetic testing. 304 00:13:16,890 --> 00:13:18,960 So in actual clinical practice, genetic testing 305 00:13:18,960 --> 00:13:20,480 for specific somatic mutations 306 00:13:20,480 --> 00:13:23,453 in the tumor help inform therapy selection. 307 00:13:23,453 --> 00:13:26,400 And in oncology it is just as important to know 308 00:13:26,400 --> 00:13:28,711 what will work as what will not work. 309 00:13:28,711 --> 00:13:29,820 And why is that? 310 00:13:29,820 --> 00:13:31,461 I'm sure you're all probably pretty familiar 311 00:13:31,461 --> 00:13:33,889 with why that's important to know in your patients, 312 00:13:33,889 --> 00:13:36,510 but not wasting precious time with therapies 313 00:13:36,510 --> 00:13:38,477 that will not work across all cancer types. 314 00:13:38,477 --> 00:13:41,280 Earlier treatment equals greater clinical success. 315 00:13:41,280 --> 00:13:44,730 Like hands down, that's the most important factor in terms 316 00:13:44,730 --> 00:13:48,001 of success in treating cancer is how early it was detected. 317 00:13:48,001 --> 00:13:51,810 So wasting those precious months trying 318 00:13:51,810 --> 00:13:52,957 a therapy that's not going to work. 319 00:13:52,957 --> 00:13:54,690 You know, as you're probably aware, 320 00:13:54,690 --> 00:13:57,159 there's like first line therapies, second line, third line 321 00:13:57,159 --> 00:14:00,390 that a patient will progress through if they fail each 322 00:14:00,390 --> 00:14:01,560 of those therapies along the way. 323 00:14:01,560 --> 00:14:02,872 But that takes time 324 00:14:02,872 --> 00:14:05,070 and some therapies cannot be co-administered 325 00:14:05,070 --> 00:14:07,680 with other therapies due to reduced safety or efficacy. 326 00:14:07,680 --> 00:14:09,120 So they can't just try everything at once. 327 00:14:09,120 --> 00:14:11,601 They have to do it in a staged approach. 328 00:14:11,601 --> 00:14:14,152 And why also it's important not to know 329 00:14:14,152 --> 00:14:17,340 what will not work but by avoiding 330 00:14:17,340 --> 00:14:19,860 or reducing unnecessary exposure of patients to drugs 331 00:14:19,860 --> 00:14:21,390 with significant side effects 332 00:14:21,390 --> 00:14:23,850 and also avoiding the expense associated with purchasing 333 00:14:23,850 --> 00:14:26,040 and administering targeted cancer therapies 334 00:14:26,040 --> 00:14:27,750 if that particular cancer therapy 335 00:14:27,750 --> 00:14:30,030 is never going to work in that patient. 336 00:14:30,030 --> 00:14:31,800 So here's a quick case study 337 00:14:31,800 --> 00:14:35,744 and please don't bother to know all the details 338 00:14:35,744 --> 00:14:38,460 of the picture I'm showing you here on the right. 339 00:14:38,460 --> 00:14:41,244 That's just to give you a pictorial representation 340 00:14:41,244 --> 00:14:42,746 of the actual pathway 341 00:14:42,746 --> 00:14:44,730 and some of the different proteins involved 342 00:14:44,730 --> 00:14:46,170 in signaling in that pathway. 343 00:14:46,170 --> 00:14:47,880 But not really important for you, 344 00:14:47,880 --> 00:14:49,080 not important at all actually 345 00:14:49,080 --> 00:14:50,460 for you to know the details of this. 346 00:14:50,460 --> 00:14:52,848 This is just a case study to give you an example 347 00:14:52,848 --> 00:14:55,713 of what we're talking about here. 348 00:14:56,610 --> 00:14:57,450 So EGFR, 349 00:14:57,450 --> 00:15:00,728 which is called the epidermal growth factor receptor. 350 00:15:00,728 --> 00:15:03,045 Epidermal growth factor receptor is a receptor 351 00:15:03,045 --> 00:15:07,260 that exists on the surface of the cell. 352 00:15:07,260 --> 00:15:09,890 So remember that receptors are proteins, pretty much all 353 00:15:09,890 --> 00:15:11,160 of these things we're talking about here, 354 00:15:11,160 --> 00:15:13,419 they're all proteins so they're all encoded by genes, right? 355 00:15:13,419 --> 00:15:16,860 They all have gene sequence that is transcribed 356 00:15:16,860 --> 00:15:19,620 and translated into these proteins 357 00:15:19,620 --> 00:15:20,970 that have these different functions. 358 00:15:20,970 --> 00:15:23,954 So they're all subject to mutations in their genes 359 00:15:23,954 --> 00:15:26,070 and those mutations in their genes 360 00:15:26,070 --> 00:15:27,986 might affect their function or their ability 361 00:15:27,986 --> 00:15:29,940 to do what it is they need to do 362 00:15:29,940 --> 00:15:32,670 or even whether or not they're there, okay? 363 00:15:32,670 --> 00:15:35,100 So there's a drug called Cetuximab, 364 00:15:35,100 --> 00:15:36,510 it's a monoclonal antibody 365 00:15:36,510 --> 00:15:38,247 to epidermal growth factor receptor 366 00:15:38,247 --> 00:15:40,303 and it's used to treat colorectal cancer 367 00:15:40,303 --> 00:15:45,180 and EGFR is often highly active in colorectal cancers. 368 00:15:45,180 --> 00:15:46,013 And why is that? 369 00:15:46,013 --> 00:15:50,840 Well, EGFR is one of those types of proteins 370 00:15:51,780 --> 00:15:52,619 that falls into the category 371 00:15:52,619 --> 00:15:57,619 of activating cell proliferation and inhibiting apoptosis. 372 00:15:58,230 --> 00:16:00,840 So it's really, you could think of it as sort 373 00:16:00,840 --> 00:16:03,240 of an oncogene, a proto-oncogene 374 00:16:03,240 --> 00:16:04,835 when it's not been mutated, 375 00:16:04,835 --> 00:16:06,960 it's normal function is to respond 376 00:16:06,960 --> 00:16:08,760 to those growth factors in the environment 377 00:16:08,760 --> 00:16:10,440 and to basically tell the cell let's go. 378 00:16:10,440 --> 00:16:11,850 We need to divide and replicate 379 00:16:11,850 --> 00:16:16,678 and do all those fun things when it is in its normal state, 380 00:16:16,678 --> 00:16:21,600 it's responsive to the external environment 381 00:16:21,600 --> 00:16:24,453 and growth factors that may be around there. 382 00:16:26,390 --> 00:16:28,230 So EGFR is, 383 00:16:28,230 --> 00:16:32,460 so basically why are we targeting EGFR in cancer? 384 00:16:32,460 --> 00:16:34,380 Well again, because it's often highly active 385 00:16:34,380 --> 00:16:35,987 and it's also on the surface of cells 386 00:16:35,987 --> 00:16:38,280 'cause it's a receptor, it senses 387 00:16:38,280 --> 00:16:40,560 and detects what's going on outside the cell. 388 00:16:40,560 --> 00:16:45,560 But because of that, it's really an easier target 389 00:16:46,020 --> 00:16:49,830 for drugs because it's like the drug doesn't actually have 390 00:16:49,830 --> 00:16:51,960 to get into the cell to do its thing. 391 00:16:51,960 --> 00:16:54,150 It can just be on the outside of the cell 392 00:16:54,150 --> 00:16:57,930 and the environment around it and can affect this protein 393 00:16:57,930 --> 00:17:00,510 because this protein is actually going through the cell. 394 00:17:00,510 --> 00:17:01,800 So it's through the cell membrane. 395 00:17:01,800 --> 00:17:04,650 Part of it's on the inside, part of it's on the outside. 396 00:17:04,650 --> 00:17:06,300 So it can be affected 397 00:17:06,300 --> 00:17:09,753 by whatever is on the outside of the cell. 398 00:17:11,087 --> 00:17:14,100 So Cetuximab is a monoclonal antibody. 399 00:17:14,100 --> 00:17:15,390 And what is an antibody? 400 00:17:15,390 --> 00:17:16,770 Remember that from last week. 401 00:17:16,770 --> 00:17:21,240 An antibody is going to bind to its particular antigen. 402 00:17:21,240 --> 00:17:25,694 In this case, this antibody is against EGFR. 403 00:17:25,694 --> 00:17:28,031 And so it will bind to EGFR 404 00:17:28,031 --> 00:17:33,022 and will both block the activity of EGFR 405 00:17:33,022 --> 00:17:36,570 and stimulate immune cells to destroy the cancer cells. 406 00:17:36,570 --> 00:17:39,030 So this is going to elicit that immune response 407 00:17:39,030 --> 00:17:40,650 and have the immune cells come in 408 00:17:40,650 --> 00:17:42,977 and say, oh, you've got a weird antibody on you 409 00:17:42,977 --> 00:17:44,670 and so we are detecting you 410 00:17:44,670 --> 00:17:46,200 as something that needs to be destroyed. 411 00:17:46,200 --> 00:17:47,940 And that's exactly what it does. 412 00:17:47,940 --> 00:17:50,970 So it can specifically target those cells 413 00:17:50,970 --> 00:17:53,198 that have too much EGFR on the surface. 414 00:17:53,198 --> 00:17:56,575 It will bind to and coat those cells with this antibody 415 00:17:56,575 --> 00:17:59,370 and then it'll do two things. 416 00:17:59,370 --> 00:18:01,675 It'll induce the immune cells to destroy the cancer 417 00:18:01,675 --> 00:18:06,480 and it'll block the pathway of EGFR, 418 00:18:06,480 --> 00:18:09,704 which activates cell proliferation, angiogenesis, 419 00:18:09,704 --> 00:18:12,750 inhibiting apoptosis, all of that stuff. 420 00:18:12,750 --> 00:18:14,790 So it really has like a two-pronged approach 421 00:18:14,790 --> 00:18:17,340 and it's actually quite effective therapy 422 00:18:17,340 --> 00:18:21,087 for colorectal cancer in some patients. 423 00:18:21,087 --> 00:18:24,480 However, there are some patients 424 00:18:24,480 --> 00:18:29,217 that have a mutation in a completely, in a different gene, 425 00:18:29,217 --> 00:18:31,560 which is called KRAS. 426 00:18:31,560 --> 00:18:35,070 So we say KRAS not KRAS, but it's KRAS gene 427 00:18:35,070 --> 00:18:38,310 and KRAS is, let's just go back for one quick second. 428 00:18:38,310 --> 00:18:39,930 Again, you don't need to know the details of this, 429 00:18:39,930 --> 00:18:42,993 but just in case you're interested, RAS is right here. 430 00:18:42,993 --> 00:18:44,458 KRAS is a type of RAS, 431 00:18:44,458 --> 00:18:47,365 which is just another protein in the cell within the cell 432 00:18:47,365 --> 00:18:50,402 that responds to EGF receptor being activated. 433 00:18:50,402 --> 00:18:52,500 It then goes on through 434 00:18:52,500 --> 00:18:53,730 and activates a bunch of other stuff 435 00:18:53,730 --> 00:18:55,410 which activates transcription factors 436 00:18:55,410 --> 00:18:57,317 to turn on cell proliferation. 437 00:18:57,317 --> 00:19:01,728 So if there's actually quite a few individuals, 438 00:19:01,728 --> 00:19:04,862 but maybe about 20, 30% 439 00:19:04,862 --> 00:19:08,892 of individuals will have a mutation in KRAS, 440 00:19:08,892 --> 00:19:13,360 which KRAS is normally activated normal KRAS, 441 00:19:13,360 --> 00:19:16,230 unmutated KRAS is activated by EGF receptor 442 00:19:16,230 --> 00:19:18,780 to turn on growth and proliferation. 443 00:19:18,780 --> 00:19:20,580 But there are common mutations in KRAS 444 00:19:20,580 --> 00:19:22,545 which result in its constitutive activation. 445 00:19:22,545 --> 00:19:24,060 What do I mean by that? 446 00:19:24,060 --> 00:19:24,893 It's always on. 447 00:19:24,893 --> 00:19:27,919 So EGF receptor does not need to activate it. 448 00:19:27,919 --> 00:19:31,020 And here you're just seeing basically 449 00:19:31,020 --> 00:19:32,790 where the KRAS gene is located, 450 00:19:32,790 --> 00:19:34,500 it's located on chromosome 12 451 00:19:34,500 --> 00:19:37,600 and there's a single amino acid difference. 452 00:19:37,600 --> 00:19:40,104 It's this glycine, it's normally glycine 453 00:19:40,104 --> 00:19:45,104 at codon 12 is now availing a single base change 454 00:19:47,760 --> 00:19:52,290 from G to T can result in a completely different function 455 00:19:52,290 --> 00:19:56,280 for this protein, which now is always on. 456 00:19:56,280 --> 00:19:58,320 So it doesn't like in normal cells, 457 00:19:58,320 --> 00:20:02,550 this KRAS protein sits around, doesn't do anything 458 00:20:02,550 --> 00:20:04,780 until EGF receptor detects growth factors. 459 00:20:04,780 --> 00:20:08,310 And then EGF receptor says, hey, hey KRAS, guess what? 460 00:20:08,310 --> 00:20:09,270 It's time to go. 461 00:20:09,270 --> 00:20:11,010 It's go time KRAS 462 00:20:11,010 --> 00:20:14,400 and KRAS then becomes activated and it goes on 463 00:20:14,400 --> 00:20:16,620 and turns on a bunch of transcription factors 464 00:20:16,620 --> 00:20:18,630 and then they turn on cell proliferation 465 00:20:18,630 --> 00:20:20,100 and dah da da da da da. 466 00:20:20,100 --> 00:20:21,353 Okay, so that's what happens normally. 467 00:20:21,353 --> 00:20:24,600 KRAS is just like taking a nap until EGF receptor turns 468 00:20:24,600 --> 00:20:25,560 it on and says, hey, guess what? 469 00:20:25,560 --> 00:20:26,850 It's go time. 470 00:20:26,850 --> 00:20:29,490 That's normal, that's what we want. 471 00:20:29,490 --> 00:20:30,690 We want the cell 472 00:20:30,690 --> 00:20:33,721 to be able to respond to growth factors. 473 00:20:33,721 --> 00:20:37,062 But in some cases of colorectal cancers, 474 00:20:37,062 --> 00:20:41,092 some people will have this mutation, this point mutation 475 00:20:41,092 --> 00:20:46,092 which actually will cause the KRAS to always be awake, 476 00:20:46,320 --> 00:20:49,680 always be on, always be hyperactive, and it's zipping around 477 00:20:49,680 --> 00:20:51,561 and it's activating transcription factors 478 00:20:51,561 --> 00:20:54,540 whether or not EGF receptor is present, 479 00:20:54,540 --> 00:20:57,270 whether or not EGF receptor is being turned on 480 00:20:57,270 --> 00:20:59,250 by the presence of a growth factor or not. 481 00:20:59,250 --> 00:21:01,170 It doesn't care, it's not listening anymore, 482 00:21:01,170 --> 00:21:04,858 it's just on all the time is always go time when KRAS 483 00:21:04,858 --> 00:21:07,111 is in a constitutively active form. 484 00:21:07,111 --> 00:21:12,111 So what does that mean in terms of, for these patients? 485 00:21:12,780 --> 00:21:15,030 Well the end results is the same 486 00:21:15,030 --> 00:21:17,400 in that it still results in abnormal growth 487 00:21:17,400 --> 00:21:20,972 and proliferation of those cells leading to cancer, 488 00:21:20,972 --> 00:21:23,370 but the way it got there was quite different. 489 00:21:23,370 --> 00:21:25,768 So the way that we would treat that is different. 490 00:21:25,768 --> 00:21:30,768 So now if you took that particular person 491 00:21:30,905 --> 00:21:34,260 who has, let's say you have two people, 492 00:21:34,260 --> 00:21:37,071 one person has too much EGF receptor present 493 00:21:37,071 --> 00:21:41,850 and so, it's inappropriately activating itself all the time. 494 00:21:41,850 --> 00:21:45,774 And so it's turning on the normal KRAS in the cell. 495 00:21:45,774 --> 00:21:49,290 Well if you shut down EGF receptor in those patients, 496 00:21:49,290 --> 00:21:50,371 if you just turn it off, 497 00:21:50,371 --> 00:21:55,371 if you basically send those antibodies in to bind to it 498 00:21:55,470 --> 00:21:57,360 and you target the immune cells, 499 00:21:57,360 --> 00:21:59,160 you can stop your problem right there. 500 00:21:59,160 --> 00:21:59,993 That's great. 501 00:21:59,993 --> 00:22:04,860 It will target those cells to be killed by the immune system 502 00:22:04,860 --> 00:22:08,790 or at least shut down EGF receptor activity, perfect. 503 00:22:08,790 --> 00:22:13,421 But in those people who have constitutively active KRAS, 504 00:22:13,421 --> 00:22:17,670 you can, they don't have too much EGF receptor. 505 00:22:17,670 --> 00:22:19,980 EGF receptor isn't even in the game anymore 506 00:22:19,980 --> 00:22:21,597 because KRAS has gone rogue. 507 00:22:21,597 --> 00:22:23,880 It's now on all the time whether 508 00:22:23,880 --> 00:22:28,020 or not that EGF receptor is there and turned on 509 00:22:28,020 --> 00:22:30,600 or not, doesn't care, doesn't matter. 510 00:22:30,600 --> 00:22:33,840 KRAS don't care, KRAS is now on all the time. 511 00:22:33,840 --> 00:22:37,080 And so not only do these cells not have too much 512 00:22:37,080 --> 00:22:41,340 EGF receptor on their surface, so if you add that antibody, 513 00:22:41,340 --> 00:22:44,010 it's not going to really bind to anything, right? 514 00:22:44,010 --> 00:22:46,560 So you're not gonna have any response in these patients 515 00:22:46,560 --> 00:22:48,870 'cause it has nothing to do with EGF receptor. 516 00:22:48,870 --> 00:22:51,339 It's downstream of that. 517 00:22:51,339 --> 00:22:55,590 So in 30 to 40% of patients with colorectal cancer, 518 00:22:55,590 --> 00:22:58,190 they have one of these activating mutations in KRAS. 519 00:22:58,190 --> 00:22:59,803 And I think you can pretty much come 520 00:22:59,803 --> 00:23:02,558 to the conclusion of would you be more or lesser 521 00:23:02,558 --> 00:23:06,000 or equally likely to prescribe Cetuximab to patients 522 00:23:06,000 --> 00:23:07,650 with colorectal cancer whose tumor 523 00:23:07,650 --> 00:23:09,720 has an activating KRAS mutation. 524 00:23:09,720 --> 00:23:10,650 Hopefully you can see 525 00:23:10,650 --> 00:23:13,230 that you would be a lot less likely to prescribe it. 526 00:23:13,230 --> 00:23:16,500 Why? Because they're not going to respond, 527 00:23:16,500 --> 00:23:18,210 they don't have too much EGF receptor, 528 00:23:18,210 --> 00:23:19,666 they have too much active KRAS 529 00:23:19,666 --> 00:23:21,795 and that's on the inside of the cell. 530 00:23:21,795 --> 00:23:24,000 So if you shut down EGF receptor, 531 00:23:24,000 --> 00:23:26,190 it's not gonna have any effect on KRAS 532 00:23:26,190 --> 00:23:28,402 because KRAS is acting independently of that 533 00:23:28,402 --> 00:23:33,270 in these individuals with the activating KRAS mutation. 534 00:23:33,270 --> 00:23:35,220 There was a clinical trial called the CRYSTAL trial, 535 00:23:35,220 --> 00:23:37,346 which demonstrated that patients with colorectal tumors 536 00:23:37,346 --> 00:23:40,590 that have activating mutations in KRAS fail to respond 537 00:23:40,590 --> 00:23:43,020 to Cetuximab as part of their therapy. 538 00:23:43,020 --> 00:23:45,420 So in 2009, the FDA added the provision 539 00:23:45,420 --> 00:23:48,060 that Cetuximab is indicated only in patients 540 00:23:48,060 --> 00:23:50,451 with colorectal cancer who have wildtype KRAS. 541 00:23:50,451 --> 00:23:51,900 Remember what wildtype means? 542 00:23:51,900 --> 00:23:53,370 Just the normal version of KRAS, 543 00:23:53,370 --> 00:23:54,766 so not the activating mutation, 544 00:23:54,766 --> 00:23:57,002 which makes a standard practice 545 00:23:57,002 --> 00:24:02,002 to perform a genetic test on colorectal tumor tissue 546 00:24:02,550 --> 00:24:05,550 for activating KRAS mutations to inform treatment approach. 547 00:24:05,550 --> 00:24:07,830 And it's not just to say, well, we're going 548 00:24:07,830 --> 00:24:09,573 to do this genetic test to see what, 549 00:24:09,573 --> 00:24:11,653 whether to basically confirm 550 00:24:11,653 --> 00:24:13,630 that we should give you Cetuximab. 551 00:24:13,630 --> 00:24:17,730 It's to say Cetuximab is just either it is likely 552 00:24:17,730 --> 00:24:19,740 or it is unlikely to work in you. 553 00:24:19,740 --> 00:24:21,540 And if it's unlikely, we're gonna find something 554 00:24:21,540 --> 00:24:22,590 better to start with. 555 00:24:22,590 --> 00:24:23,850 'Cause we're not gonna waste our time. 556 00:24:23,850 --> 00:24:26,820 We're not gonna waste the patient's precious time 557 00:24:26,820 --> 00:24:29,437 to start them on a therapy that's unlikely to work. 558 00:24:29,437 --> 00:24:33,300 So predisposition testing for hereditary cancer, 559 00:24:33,300 --> 00:24:35,190 there's a famous quote from the director 560 00:24:35,190 --> 00:24:37,380 of the National Institutes of Health, Francis Collins 561 00:24:37,380 --> 00:24:39,540 who says, "Genetics loads the gun 562 00:24:39,540 --> 00:24:41,790 and environment pulls the trigger." 563 00:24:41,790 --> 00:24:44,660 And I think that's a good analogy to use here 564 00:24:44,660 --> 00:24:46,860 because it's, again, it's not just 565 00:24:46,860 --> 00:24:49,203 that if you inherit these mutations, you will get cancer. 566 00:24:49,203 --> 00:24:51,719 It's that it loads the gun 567 00:24:51,719 --> 00:24:54,990 and if something else comes along to pull the trigger, 568 00:24:54,990 --> 00:24:56,296 then it pulls the trigger. 569 00:24:56,296 --> 00:24:59,340 And basically again, you're starting out 570 00:24:59,340 --> 00:25:00,510 with at least one strike 571 00:25:00,510 --> 00:25:04,170 and you're more likely to get struck out if you start out 572 00:25:04,170 --> 00:25:06,570 with one strike than if you start out with no strikes. 573 00:25:06,570 --> 00:25:07,680 So that's what we're talking about 574 00:25:07,680 --> 00:25:09,600 when we're talking about predisposition. 575 00:25:09,600 --> 00:25:11,820 Remember that five to 10% of cancers are inherited 576 00:25:11,820 --> 00:25:14,130 and most cancer susceptibility mutations 577 00:25:14,130 --> 00:25:16,530 are actually inherited in a dominant found, 578 00:25:16,530 --> 00:25:18,363 in a dominant way. 579 00:25:19,800 --> 00:25:22,020 There are cosmo mutations in tumor suppressor genes 580 00:25:22,020 --> 00:25:26,220 like TP53, APCP 10, BRCA one and two, 581 00:25:26,220 --> 00:25:28,600 these that regulate cell proliferation differentiation 582 00:25:28,600 --> 00:25:30,264 and DNA repair. 583 00:25:30,264 --> 00:25:33,900 So reasons why mutations in ubiquitously expressed tumor 584 00:25:33,900 --> 00:25:36,810 suppressor genes increase risk of specific types 585 00:25:36,810 --> 00:25:39,210 of cancer is an area of active research. 586 00:25:39,210 --> 00:25:40,043 So what do I mean 587 00:25:40,043 --> 00:25:42,640 by ubiquitously expressed tumor suppressed surgeon genes? 588 00:25:42,640 --> 00:25:44,850 Well these are basically, these are genes 589 00:25:44,850 --> 00:25:47,369 that are expressed in all cells really all the time. 590 00:25:47,369 --> 00:25:49,449 So they're never shut down or turned off. 591 00:25:49,449 --> 00:25:52,470 So why would a, say for example people 592 00:25:52,470 --> 00:25:54,549 who have BRCA one or two mutations, 593 00:25:54,549 --> 00:25:56,681 why do they just have a higher increased 594 00:25:56,681 --> 00:25:59,592 risk for breast cancer or ovarian cancer? 595 00:25:59,592 --> 00:26:01,830 It's not clear why, I mean, 596 00:26:01,830 --> 00:26:03,270 in theory they should have a higher risk 597 00:26:03,270 --> 00:26:04,560 of all kinds of cancers. 598 00:26:04,560 --> 00:26:07,920 We don't understand why that's the case yet, 599 00:26:07,920 --> 00:26:10,031 but that is definitely an active area of research. 600 00:26:10,031 --> 00:26:12,810 So let's take a look at BRCA one and two. 601 00:26:12,810 --> 00:26:14,815 'Cause I think these are two that you've probably heard of 602 00:26:14,815 --> 00:26:19,236 that are some of the most commonly tested genetic mutations. 603 00:26:19,236 --> 00:26:21,840 BRCA one and two are tumor suppressor genes 604 00:26:21,840 --> 00:26:24,072 whose proteins function to repair DNA damage. 605 00:26:24,072 --> 00:26:26,581 And so, we can think of them as tumor suppressor genes 606 00:26:26,581 --> 00:26:30,806 or caretaker genes if you want to use 607 00:26:30,806 --> 00:26:32,782 what the way we were defining them earlier. 608 00:26:32,782 --> 00:26:34,560 They have similar functions 609 00:26:34,560 --> 00:26:36,090 but are two different genes, right? 610 00:26:36,090 --> 00:26:38,100 So when people will talk about BRCA one, two, 611 00:26:38,100 --> 00:26:40,830 well that's not just one gene, it's two different genes. 612 00:26:40,830 --> 00:26:42,609 There's BRCA one and there's BRCA two, 613 00:26:42,609 --> 00:26:44,250 they're actually on two different chromosomes. 614 00:26:44,250 --> 00:26:45,083 They're two separate genes. 615 00:26:45,083 --> 00:26:49,383 BRCA one is located on chromosome 17Q21, 616 00:26:49,383 --> 00:26:52,557 BRCA two is located on chromosome 13Q12.3. 617 00:26:52,557 --> 00:26:54,900 And I just bring this up because sometimes it sounds like 618 00:26:54,900 --> 00:26:57,323 they're one gene, but they're actually two different genes. 619 00:26:58,200 --> 00:27:00,570 BRCA one mutations are associated with increased risk 620 00:27:00,570 --> 00:27:02,903 of breast cancer as well as fallopian tube cancer, 621 00:27:02,903 --> 00:27:05,067 male breast cancer and pancreatic cancer 622 00:27:05,067 --> 00:27:07,770 and BRCA two mutations are associated with increased risk 623 00:27:07,770 --> 00:27:10,410 of breast, ovarian as well as prostate cancer, 624 00:27:10,410 --> 00:27:13,020 pancreatic cancer, fallopian tube cancer, 625 00:27:13,020 --> 00:27:16,073 male breast cancer and melanoma. 626 00:27:16,073 --> 00:27:17,160 And BRCA two is especially associated 627 00:27:17,160 --> 00:27:18,420 with male breast cancer. 628 00:27:18,420 --> 00:27:20,250 But BRCA one certainly has, 629 00:27:20,250 --> 00:27:24,780 it does contribute an increased risk for men breast cancer. 630 00:27:24,780 --> 00:27:27,900 An inherited homozygous mutation in BRCA two leads 631 00:27:27,900 --> 00:27:30,990 to Fanconi anemia type D one as well 632 00:27:30,990 --> 00:27:33,180 as significantly higher rates of cancer. 633 00:27:33,180 --> 00:27:37,200 So it can actually cause a separate genetic disease, 634 00:27:37,200 --> 00:27:40,920 Fanconi anemia, if an individual is homozygous 635 00:27:40,920 --> 00:27:42,060 for mutations in BRCA two, 636 00:27:42,060 --> 00:27:43,680 but that also increases their risk 637 00:27:43,680 --> 00:27:45,315 of different types of cancer. 638 00:27:45,315 --> 00:27:47,070 Genetic tests for BRCA one 639 00:27:47,070 --> 00:27:48,870 and two mutations are widely available 640 00:27:48,870 --> 00:27:51,243 and I'm sure you are probably aware of them. 641 00:27:53,040 --> 00:27:55,087 So BRCA one two mutations in breast cancer. 642 00:27:55,087 --> 00:27:57,240 So it increases the lifetime risk 643 00:27:57,240 --> 00:27:59,590 of breast cancer in women from 12% to 60%. 644 00:27:59,590 --> 00:28:02,520 It increases the lifetime risk of ovarian cancer 645 00:28:02,520 --> 00:28:05,212 from 1.5% to 39%. 646 00:28:05,212 --> 00:28:08,895 Ovarian cancer is, you're probably, you may be familiar, 647 00:28:08,895 --> 00:28:11,820 is really difficult to treat successfully. 648 00:28:11,820 --> 00:28:14,340 And it's usually, I mean, in large part, 649 00:28:14,340 --> 00:28:16,920 that's because it's not diagnosed until commonly 650 00:28:16,920 --> 00:28:18,240 until a late stage. 651 00:28:18,240 --> 00:28:20,242 So knowing a person has a much higher risk 652 00:28:20,242 --> 00:28:23,048 of ovarian cancer, even if a person, 653 00:28:23,048 --> 00:28:26,355 even if a woman decides not to have, for example, 654 00:28:26,355 --> 00:28:30,685 a prophylactic oophorectomy, if nothing else, 655 00:28:30,685 --> 00:28:34,050 knowing this information can be so helpful 656 00:28:34,050 --> 00:28:36,900 because again, ovarian cancer isn't usually diagnosed 657 00:28:36,900 --> 00:28:38,220 until stage three or four, 658 00:28:38,220 --> 00:28:40,289 in which case survival rate is very, very low. 659 00:28:40,289 --> 00:28:44,866 If it's diagnosed early, the survival rate is very high, so, 660 00:28:44,866 --> 00:28:46,426 or much higher I should say. 661 00:28:46,426 --> 00:28:51,000 So being able to diagnose it early, which is the result 662 00:28:51,000 --> 00:28:52,860 of potentially greater surveillance, 663 00:28:52,860 --> 00:28:55,170 getting more ultrasounds 664 00:28:55,170 --> 00:28:57,330 or just being aware of what the signs 665 00:28:57,330 --> 00:28:59,361 and symptoms are of ovarian cancer, 666 00:28:59,361 --> 00:29:03,750 could really significantly improve a person's odds 667 00:29:03,750 --> 00:29:06,360 if she does develop ovarian cancer of survival 668 00:29:06,360 --> 00:29:09,573 because it could lead to earlier diagnosis. 669 00:29:10,620 --> 00:29:12,867 So if we break down the prevalence of these BRCA one 670 00:29:12,867 --> 00:29:14,580 and two mutations in ethnic 671 00:29:14,580 --> 00:29:18,420 and racial groups in the US, Asian Americans about usually 672 00:29:18,420 --> 00:29:20,473 have the lowest rate about half a percent 673 00:29:20,473 --> 00:29:22,860 for BRCA one mutations. 674 00:29:22,860 --> 00:29:26,193 And really it's Caucasians 675 00:29:26,193 --> 00:29:30,457 and Hispanic individuals who have the higher mutation, 676 00:29:30,457 --> 00:29:32,641 have the higher rates of mutations 677 00:29:32,641 --> 00:29:36,600 and then the Ashkenazi Jewish population as well, especially 678 00:29:36,600 --> 00:29:40,320 for BRCA one mutations, is present in about 10% 679 00:29:40,320 --> 00:29:42,783 of individuals of that heritage. 680 00:29:43,860 --> 00:29:47,239 So it certainly varies depending upon the group, 681 00:29:47,239 --> 00:29:51,690 but any person, any woman especially who comes in 682 00:29:51,690 --> 00:29:54,378 who has a family history, as you're all very familiar, 683 00:29:54,378 --> 00:29:57,236 go back to those red flags that we talked about 684 00:29:57,236 --> 00:29:59,161 of inherited genetic disease, 685 00:29:59,161 --> 00:30:03,048 which we talked about I think in module seven 686 00:30:03,048 --> 00:30:05,670 when we were looking at risk factors. 687 00:30:05,670 --> 00:30:07,728 Go back and review those again 688 00:30:07,728 --> 00:30:11,400 if you'd like to really become familiar 689 00:30:11,400 --> 00:30:15,060 with what should pop up as a red flag when you're going 690 00:30:15,060 --> 00:30:16,923 through patient's family history. 691 00:30:18,720 --> 00:30:20,910 So quick summary of the targeted therapeutics 692 00:30:20,910 --> 00:30:22,080 and genetic predisposition. 693 00:30:22,080 --> 00:30:25,740 Targeted therapeutics, target cancer cells specifically. 694 00:30:25,740 --> 00:30:27,120 These require genetic testing 695 00:30:27,120 --> 00:30:29,670 of the somatic mutations in the tumor itself 696 00:30:29,670 --> 00:30:31,830 to identify the right therapy to use 697 00:30:31,830 --> 00:30:33,480 and the therapies unlikely to work. 698 00:30:33,480 --> 00:30:37,590 So the example I gave you was of the individuals 699 00:30:37,590 --> 00:30:40,247 who have the KRAS mutations that was of what not to use. 700 00:30:40,247 --> 00:30:42,169 So you would not want to use Cetuximab. 701 00:30:42,169 --> 00:30:44,730 There are certainly are therapies 702 00:30:44,730 --> 00:30:46,200 where you do a genetic test to tell you 703 00:30:46,200 --> 00:30:48,690 what is likely to work. 704 00:30:48,690 --> 00:30:51,060 And so, but I just gave you one example, 705 00:30:51,060 --> 00:30:54,063 but just know that it goes both directions that way. 706 00:30:55,290 --> 00:30:56,670 The presence of certain mutations 707 00:30:56,670 --> 00:30:58,860 in tumor suppressor genes can predispose someone 708 00:30:58,860 --> 00:31:01,098 to develop cancer at some point in his or her life. 709 00:31:01,098 --> 00:31:05,390 If additional somatic mutations accumulate 710 00:31:05,390 --> 00:31:09,330 and actually cause that basically fire the gun, 711 00:31:09,330 --> 00:31:10,980 fire the gun. 712 00:31:10,980 --> 00:31:13,830 Genetic predisposition can be tested for in blood 713 00:31:13,830 --> 00:31:16,110 or cheek swab while identifying somatic mutations 714 00:31:16,110 --> 00:31:18,570 in the cancer requires a biopsy of the tumors 715 00:31:18,570 --> 00:31:22,053 as we talked about in the previous lecture as well. 716 00:31:22,980 --> 00:31:26,862 All right, well with that I will say goodbye. 717 00:31:26,862 --> 00:31:30,750 And what are we looking forward to in the next module? 718 00:31:30,750 --> 00:31:33,210 We'll dive into the psychiatric disorders 719 00:31:33,210 --> 00:31:35,786 and the genetic components there 720 00:31:35,786 --> 00:31:39,690 and I will tell you straight away, this is a much more 721 00:31:39,690 --> 00:31:43,535 hazy topic because while there may be 722 00:31:43,535 --> 00:31:46,278 some genetic factors which have been linked 723 00:31:46,278 --> 00:31:50,970 to certain psychiatric disorders, it's not as black 724 00:31:50,970 --> 00:31:53,790 and white as some of what we've been looking at before. 725 00:31:53,790 --> 00:31:55,333 But for now, I will say goodbye 726 00:31:55,333 --> 00:31:57,420 and I look forward to talking 727 00:31:57,420 --> 00:32:00,660 with you more about cancer genetics in the discussion board. 728 00:32:00,660 --> 00:32:01,623 Thanks very much.