WEBVTT 1 00:00:00.510 --> 00:00:01.650 Hi, everyone. 2 00:00:01.650 --> 00:00:02.550 In today's lecture, 3 00:00:02.550 --> 00:00:05.850 we'll be discussing the epidemiology of breast cancer. 4 00:00:05.850 --> 00:00:07.800 This lecture has several goals. 5 00:00:07.800 --> 00:00:09.690 We'll begin by reviewing the anatomy and function 6 00:00:09.690 --> 00:00:12.780 of the human breast and then describing the global impact 7 00:00:12.780 --> 00:00:15.810 of breast cancer, including trends in breast cancer rates 8 00:00:15.810 --> 00:00:17.760 in different parts of the world. 9 00:00:17.760 --> 00:00:20.820 We'll continue to look at breast cancer detection 10 00:00:20.820 --> 00:00:25.080 and tumor staging, studies of risk factors, genetics, 11 00:00:25.080 --> 00:00:27.513 and breast cancer prevention and control. 12 00:00:28.470 --> 00:00:30.420 So to begin with, 13 00:00:30.420 --> 00:00:35.040 we see some interesting differences when we look at 14 00:00:35.040 --> 00:00:36.780 the annual incidents and mortality rates 15 00:00:36.780 --> 00:00:38.613 of breast cancer in 2012. 16 00:00:39.810 --> 00:00:41.880 So on the left here, 17 00:00:41.880 --> 00:00:45.450 we see incidents a rate increasing going from top to bottom 18 00:00:45.450 --> 00:00:47.040 of the chart 19 00:00:47.040 --> 00:00:50.400 with the US of all countries listed having 20 00:00:50.400 --> 00:00:55.400 the highest incidence rate of breast cancer at 101.1 cases 21 00:00:56.130 --> 00:00:58.230 per 100,000 women. 22 00:00:58.230 --> 00:00:59.430 Though at the same time, 23 00:00:59.430 --> 00:01:01.833 the US does not have the highest mortality rate. 24 00:01:03.603 --> 00:01:05.970 That would be, it appears to be the Netherlands 25 00:01:05.970 --> 00:01:10.970 with the rate of 27.5 deaths per 100,000 women 26 00:01:11.250 --> 00:01:12.573 of breast cancer. 27 00:01:13.530 --> 00:01:17.460 We also see that of the nations included 28 00:01:17.460 --> 00:01:20.080 China has the lowest incidence of breast cancer 29 00:01:21.000 --> 00:01:25.170 and that the nation with the lowest mortality 30 00:01:25.170 --> 00:01:26.883 of breast cancer is also China. 31 00:01:28.800 --> 00:01:32.190 When we look at global statistics for 2020, 32 00:01:32.190 --> 00:01:34.230 we see that the age standardized incidents 33 00:01:34.230 --> 00:01:38.940 of breast cancer is 47.8 cases per 100,000 34 00:01:38.940 --> 00:01:42.420 and that the age standardized mortality is 13.6 cases 35 00:01:42.420 --> 00:01:43.743 per 100,000. 36 00:01:45.660 --> 00:01:47.790 So to begin with, let's discuss a little bit 37 00:01:47.790 --> 00:01:49.980 of the anatomy of the female breast. 38 00:01:49.980 --> 00:01:52.170 So the human female breast consists primarily 39 00:01:52.170 --> 00:01:54.600 of fat and glandular tissue. 40 00:01:54.600 --> 00:01:58.440 Each breast contains a complex network of saclike lobules 41 00:01:58.440 --> 00:02:00.690 or milk glands that produce breast milk 42 00:02:00.690 --> 00:02:02.160 and ducts that carry milk 43 00:02:02.160 --> 00:02:04.020 from the lobules to the nipple openings 44 00:02:04.020 --> 00:02:05.133 during breastfeeding. 45 00:02:06.060 --> 00:02:09.150 Adult women have 15 to 20 distinct clusters of lobules 46 00:02:09.150 --> 00:02:11.700 in each breast which are called the breast lobes 47 00:02:11.700 --> 00:02:15.303 and each breast lobe can have 20 to 40 lobules. 48 00:02:16.620 --> 00:02:19.170 There are also small ducts that emanate from the lobules 49 00:02:19.170 --> 00:02:21.420 of the breast and join together in branch into 50 00:02:21.420 --> 00:02:24.330 increasingly larger ducts that carry breast milk 51 00:02:24.330 --> 00:02:26.730 to openings of the surface of the nipple. 52 00:02:26.730 --> 00:02:30.720 Adipose tissue or fat furnishes the energy for lactation 53 00:02:30.720 --> 00:02:34.350 and is the most abundant tissue of the human female breast. 54 00:02:34.350 --> 00:02:35.760 There's also connective tissue 55 00:02:35.760 --> 00:02:37.800 and ligaments that provide structural support 56 00:02:37.800 --> 00:02:41.520 and nerves that provide sensation to the breast. 57 00:02:41.520 --> 00:02:43.890 Finally, the breast also contains blood vessels, 58 00:02:43.890 --> 00:02:45.900 lymph vessels, and lymph nodes 59 00:02:45.900 --> 00:02:49.263 as depicted in the figure above. 60 00:02:50.220 --> 00:02:52.320 Next we'll turn to look at incidents 61 00:02:52.320 --> 00:02:56.310 and mortality of breast cancer globally in 2012. 62 00:02:56.310 --> 00:02:59.280 So breast cancer was diagnosed in 1.68 million women 63 00:02:59.280 --> 00:03:02.550 and caused 521,817 deaths 64 00:03:02.550 --> 00:03:05.250 in the world population during 2012. 65 00:03:05.250 --> 00:03:07.707 This makes breast cancer the most commonly diagnosed cancer 66 00:03:07.707 --> 00:03:09.810 and the second leading cause of cancer death 67 00:03:09.810 --> 00:03:12.993 among women, only lung cancer causes more deaths. 68 00:03:13.890 --> 00:03:16.230 Breast cancer incidences also highly variable, 69 00:03:16.230 --> 00:03:19.590 ranging from low rates of 19 per 100,000 in China, 70 00:03:19.590 --> 00:03:23.700 Africa, and India to rates exceeding 80 cases per 100,000 71 00:03:23.700 --> 00:03:27.510 in Scandinavian and European countries, the United States 72 00:03:27.510 --> 00:03:31.290 and Great Britain, and then among income countries 73 00:03:31.290 --> 00:03:33.780 the US is the highest annual incidence rates 74 00:03:33.780 --> 00:03:37.083 of breast cancer exceeding 100 cases per 100,000. 75 00:03:37.920 --> 00:03:42.920 In contrast, the lifetime risk of breast cancer is only 76 00:03:43.080 --> 00:03:45.600 one in 66 for Chinese women, 77 00:03:45.600 --> 00:03:48.813 where for American women the risk is one in eight. 78 00:03:49.770 --> 00:03:52.110 Breast cancer mortality rates show a narrower range 79 00:03:52.110 --> 00:03:55.530 than incidence rates, and as we previously mentioned, 80 00:03:55.530 --> 00:03:59.010 they ranged from 5.5 deaths per 100,000 Chinese women 81 00:03:59.010 --> 00:04:03.090 to 27.8 deaths per 100,000 Danish women. 82 00:04:03.090 --> 00:04:04.290 The incidents and mortality rates 83 00:04:04.290 --> 00:04:05.760 of breast cancer tend to be higher 84 00:04:05.760 --> 00:04:07.830 for women in high income countries compared 85 00:04:07.830 --> 00:04:10.443 to those in low and middle income countries. 86 00:04:11.880 --> 00:04:13.950 And as we just discussed, 87 00:04:13.950 --> 00:04:16.860 this map shows the mortality rates globally 88 00:04:16.860 --> 00:04:18.633 for breast cancer in 2012. 89 00:04:19.710 --> 00:04:24.340 Next, turning to the tumor staging of breast cancer 90 00:04:25.230 --> 00:04:29.280 this chart depicts the five year survival rate 91 00:04:29.280 --> 00:04:33.720 for the various stages of diagnosis for breast cancer. 92 00:04:33.720 --> 00:04:36.660 So tumor staging refers to the microscopic evaluation 93 00:04:36.660 --> 00:04:39.240 of tissues by a pathologist to assess size, 94 00:04:39.240 --> 00:04:41.550 exact anatomic location, growth, 95 00:04:41.550 --> 00:04:43.260 and spread of a cancerous lesion. 96 00:04:43.260 --> 00:04:46.440 And the second column of this chart gives 97 00:04:46.440 --> 00:04:50.610 a brief description for some factors that play a role 98 00:04:50.610 --> 00:04:52.983 in determining what stage a tumor is at. 99 00:04:53.850 --> 00:04:56.250 It's important to note that early stage breast cancer 100 00:04:56.250 --> 00:05:00.900 so stage 0, I, or even IIA is effectively cured 101 00:05:00.900 --> 00:05:03.870 by complete surgical excision with clear margins 102 00:05:03.870 --> 00:05:06.420 while late stage disease is resistant to therapy 103 00:05:06.420 --> 00:05:08.850 and treated by chemotherapy, radiation therapy, 104 00:05:08.850 --> 00:05:11.730 and hormonal therapy and does not have nearly as high 105 00:05:11.730 --> 00:05:15.003 a five-year survival rate as the lower staged cancers. 106 00:05:18.090 --> 00:05:21.540 So there's three key aspects of breast cancer detection. 107 00:05:21.540 --> 00:05:23.850 Those are self-examination, mammography, 108 00:05:23.850 --> 00:05:25.413 and clinical examination. 109 00:05:26.820 --> 00:05:29.070 So as some of you may have seen, 110 00:05:29.070 --> 00:05:32.670 the breast cancer screening guidelines are different 111 00:05:32.670 --> 00:05:36.390 according to what age someone is, and there recently was 112 00:05:36.390 --> 00:05:39.210 a decision by the US Preventative Services Task Force 113 00:05:39.210 --> 00:05:42.510 that encourages all women aged 40 and older to receive 114 00:05:42.510 --> 00:05:44.700 mammograms every two years 115 00:05:44.700 --> 00:05:48.000 if they're at regular risk of breast cancer. 116 00:05:48.000 --> 00:05:50.970 As we'll discuss later on in this presentation 117 00:05:50.970 --> 00:05:52.980 there are different genetic factors that can lead 118 00:05:52.980 --> 00:05:55.440 to people being at elevated risk for breast cancer. 119 00:05:55.440 --> 00:05:59.220 So these general guidelines may not apply to everyone 120 00:05:59.220 --> 00:06:02.340 but typically those ages 20 to 29 are 121 00:06:02.340 --> 00:06:06.000 at lower risk of breast cancer than those aged older. 122 00:06:06.000 --> 00:06:08.490 So they're not recommended to have mammograms 123 00:06:08.490 --> 00:06:11.493 and mammography is not recommended to start until age 40. 124 00:06:15.000 --> 00:06:18.330 We also see that the risk of breast cancer increases 125 00:06:18.330 --> 00:06:21.150 with exposure to high dose radiation. 126 00:06:21.150 --> 00:06:24.270 So there is increased risk for atomic bomb survivors, 127 00:06:24.270 --> 00:06:28.050 acute mastitis patients, and tuberculosis patients 128 00:06:28.050 --> 00:06:30.480 due to their exposure to radiation. 129 00:06:30.480 --> 00:06:33.090 However, there's no evidence to support adverse effects 130 00:06:33.090 --> 00:06:34.340 of screening mammography. 131 00:06:36.330 --> 00:06:38.400 So to discuss a little bit of the mechanisms 132 00:06:38.400 --> 00:06:40.083 of breast carcinogenesis, 133 00:06:41.280 --> 00:06:43.140 we see that breast cancer typically arises 134 00:06:43.140 --> 00:06:45.420 from the epithelial cells that line the ductal 135 00:06:45.420 --> 00:06:48.120 and glandular structures of the mammary gland. 136 00:06:48.120 --> 00:06:50.130 So as you'll recall when we talked about 137 00:06:50.130 --> 00:06:55.130 the anatomy of the breast, there's several different tissues 138 00:06:55.200 --> 00:06:57.453 that are present in that zone of the body. 139 00:06:58.290 --> 00:07:00.420 Breast carcinogenesis is most probably due 140 00:07:00.420 --> 00:07:05.250 to excess stimulation of these epithelial cells by estrogen. 141 00:07:05.250 --> 00:07:07.980 Estrogen is a steroid 142 00:07:07.980 --> 00:07:10.740 and a powerful mitogen that stimulates cell proliferation 143 00:07:10.740 --> 00:07:12.660 by activating estrogen receptors of 144 00:07:12.660 --> 00:07:14.700 the cell surface membrane. 145 00:07:14.700 --> 00:07:17.190 Sustained excessive estrogen stimulation may lead to 146 00:07:17.190 --> 00:07:19.290 heightened proliferation and atypia 147 00:07:19.290 --> 00:07:21.120 of the mammary epithelium, 148 00:07:21.120 --> 00:07:23.883 which are believed to be forerunners of breast cancer. 149 00:07:24.930 --> 00:07:27.060 While breast cancer primarily occurs in women, 150 00:07:27.060 --> 00:07:29.460 it occasionally develops in men, 151 00:07:29.460 --> 00:07:32.550 particularly in association with Klinefelter syndrome 152 00:07:32.550 --> 00:07:36.120 where there's an extra X chromosome and the karyotype 153 00:07:36.120 --> 00:07:39.540 or the chromosomal make up of the individual. 154 00:07:39.540 --> 00:07:42.570 So rather than a man being XY, 155 00:07:42.570 --> 00:07:45.483 his chromosomal make up will be XXY. 156 00:07:46.590 --> 00:07:49.860 This also can, the risk can increase 157 00:07:49.860 --> 00:07:53.970 by the ingestion of synthetic estrogens like diethyl, 158 00:07:53.970 --> 00:07:56.730 diethylstilbestrol that can be used 159 00:07:56.730 --> 00:07:58.930 for the treatment of cancer of the prostate. 160 00:08:00.630 --> 00:08:02.460 There's two different theories that are important 161 00:08:02.460 --> 00:08:03.360 to note here. 162 00:08:03.360 --> 00:08:06.000 The first is the estrogen stimulus theory 163 00:08:06.000 --> 00:08:08.310 which holds that the risk of breast cancer is enhanced 164 00:08:08.310 --> 00:08:11.070 with a sustained continuum of estrogen cycles 165 00:08:11.070 --> 00:08:13.560 unbroken by pregnancy or other mechanisms 166 00:08:13.560 --> 00:08:17.703 of estrogen ablation like an ovariectomy. 167 00:08:18.570 --> 00:08:23.310 Another important theory is the estrogen window hypothesis 168 00:08:23.310 --> 00:08:26.700 or theory, which holds its susceptibility to breast cancer 169 00:08:26.700 --> 00:08:29.040 is increased by unopposed estrogen stimulation 170 00:08:29.040 --> 00:08:30.810 during the onset of puberty 171 00:08:30.810 --> 00:08:33.840 and later in life with the onset of menopause. 172 00:08:33.840 --> 00:08:36.090 By this theory, susceptibility to induction 173 00:08:36.090 --> 00:08:38.190 of breast cancer declines with the establishment 174 00:08:38.190 --> 00:08:42.000 of normal ludial phase progesterone secretion 175 00:08:42.000 --> 00:08:44.103 and becomes very low during pregnancy. 176 00:08:45.120 --> 00:08:46.590 So this theory holds 177 00:08:46.590 --> 00:08:48.510 that becoming pregnant can actually serve 178 00:08:48.510 --> 00:08:52.470 as a protective factor to breast cancer 179 00:08:52.470 --> 00:08:57.470 due to the presence of another hormone called progesterone. 180 00:09:00.150 --> 00:09:03.180 So as mentioned, there's several different key risk factors 181 00:09:03.180 --> 00:09:04.920 for breast cancer. 182 00:09:04.920 --> 00:09:07.860 These include family history, early menses, 183 00:09:07.860 --> 00:09:10.380 late first pregnancy, late menopause, 184 00:09:10.380 --> 00:09:14.490 estrogen replacement therapy, and high body mass obesity 185 00:09:14.490 --> 00:09:17.130 or high body mass index or obesity. 186 00:09:17.130 --> 00:09:22.130 And the first studies of breast cancer established 187 00:09:23.070 --> 00:09:26.730 these classical risk factors and one key study in 1923 188 00:09:26.730 --> 00:09:31.560 by Janet Elizabeth Lane-Claypon in the United Kingdom found 189 00:09:31.560 --> 00:09:34.530 compared women with breast cancer to women without 190 00:09:34.530 --> 00:09:39.450 breast cancer to determine their different risk factors. 191 00:09:39.450 --> 00:09:43.380 This study, a case control study, was the first to elucidate 192 00:09:43.380 --> 00:09:46.350 well-known profile of classical breast cancer risk factors 193 00:09:46.350 --> 00:09:49.830 like familial and genetic predisposition, early menses, 194 00:09:49.830 --> 00:09:52.560 delayed reproductive history, nolanparity, 195 00:09:52.560 --> 00:09:54.750 absence of lactation, late menopause, 196 00:09:54.750 --> 00:09:56.583 and natural process of aging. 197 00:09:59.940 --> 00:10:02.400 There also is a genetic predisposition 198 00:10:02.400 --> 00:10:04.860 to breast cancer in some cases. 199 00:10:04.860 --> 00:10:07.770 So we see that a strong family history increases the risk 200 00:10:07.770 --> 00:10:11.700 of breast cancer by three to five fold, and in fact, 201 00:10:11.700 --> 00:10:15.480 in 5 to 10% of women who are diagnosed with breast cancer, 202 00:10:15.480 --> 00:10:16.860 it's found that they have a genetic 203 00:10:16.860 --> 00:10:20.163 or familial predisposition to having breast cancer. 204 00:10:21.630 --> 00:10:23.970 Hallmarks of familial predisposition of breast cancer 205 00:10:23.970 --> 00:10:27.690 include early age of onset and excess of bilateral disease 206 00:10:27.690 --> 00:10:29.820 and breast cancer and familial association with 207 00:10:29.820 --> 00:10:32.340 other malignancies like ovarian cancer 208 00:10:32.340 --> 00:10:33.843 and endometrial cancer. 209 00:10:37.050 --> 00:10:39.990 Approximately 75% of breast cancers are diagnosed 210 00:10:39.990 --> 00:10:42.243 in women after they undergo menopause, 211 00:10:43.320 --> 00:10:45.780 and there's a general consensus that estrogen replacement 212 00:10:45.780 --> 00:10:48.930 therapy with or without progesterone elevates the risk 213 00:10:48.930 --> 00:10:52.440 of postmenopausal breast cancer by two to threefold 214 00:10:52.440 --> 00:10:55.170 as found in a 1992 study. 215 00:10:55.170 --> 00:10:57.090 Results from the randomized clinical trials 216 00:10:57.090 --> 00:10:59.280 and the prospective cohort of the Women's Health Initiative 217 00:10:59.280 --> 00:11:01.830 in the US found that breast cancer risk doubles 218 00:11:01.830 --> 00:11:05.040 after about five years of using exogenous hormones 219 00:11:05.040 --> 00:11:08.520 but declined soon after discontinuation of hormone therapy. 220 00:11:08.520 --> 00:11:10.440 It's important to note here 221 00:11:10.440 --> 00:11:15.440 that there was no significant risk found in 222 00:11:15.900 --> 00:11:18.270 individuals using hormone replacement therapy 223 00:11:18.270 --> 00:11:22.260 after less than five years, and there's going to be a couple 224 00:11:22.260 --> 00:11:25.260 of readings included in this week's module 225 00:11:25.260 --> 00:11:30.090 about recent findings or recent articles dissecting 226 00:11:30.090 --> 00:11:33.270 both the findings of the Woman Health Initiative 227 00:11:33.270 --> 00:11:36.960 and the other studies that really probe this relationship 228 00:11:36.960 --> 00:11:38.970 between estrogen replacement therapy 229 00:11:38.970 --> 00:11:43.323 or hormone replacement therapy and breast cancer risk. 230 00:11:45.330 --> 00:11:47.400 When we look at trends in breast cancer mortality, 231 00:11:47.400 --> 00:11:49.380 we see that rates of breast cancer are increasing 232 00:11:49.380 --> 00:11:51.870 in populations which historically have been at low risk 233 00:11:51.870 --> 00:11:53.580 but have remained relatively constant 234 00:11:53.580 --> 00:11:56.017 in populations at higher risk risk. 235 00:11:56.017 --> 00:11:59.010 Breast cancer mortality rates among Japanese, Indian, 236 00:11:59.010 --> 00:12:01.410 and Chinese women have increased approximately threefold 237 00:12:01.410 --> 00:12:02.940 in the past two decades. 238 00:12:02.940 --> 00:12:06.150 Whereas in the US, UK, and other European nations, 239 00:12:06.150 --> 00:12:09.420 rates have remained constant or slightly declined. 240 00:12:09.420 --> 00:12:11.640 Japanese, Indian, and Chinese diets have also changed 241 00:12:11.640 --> 00:12:14.760 dramatically with higher intake of fat and calories. 242 00:12:14.760 --> 00:12:17.190 Other risk factors may also be involved 243 00:12:17.190 --> 00:12:18.930 since birth rates are declining, 244 00:12:18.930 --> 00:12:21.000 age at first pregnancy is being delayed 245 00:12:21.000 --> 00:12:24.993 and noloparity is increasing in these populations. 246 00:12:27.930 --> 00:12:30.480 One well-known but controversial hypothesis 247 00:12:30.480 --> 00:12:32.100 of breast cancer etiology is known 248 00:12:32.100 --> 00:12:34.650 as the dietary fat hypothesis. 249 00:12:34.650 --> 00:12:37.110 And this hypothesis holds that breast cancer development is 250 00:12:37.110 --> 00:12:40.020 due to intake of certain types of essential polyunsaturated 251 00:12:40.020 --> 00:12:42.900 fatty acids that increase inflammation 252 00:12:42.900 --> 00:12:44.820 and estrogen biosynthesis 253 00:12:44.820 --> 00:12:47.670 and thus promote breast cancer development. 254 00:12:47.670 --> 00:12:51.000 Remember from before, that one theory of breast cancer holds 255 00:12:51.000 --> 00:12:53.970 that increased estrogen production or increased estrogen 256 00:12:53.970 --> 00:12:57.690 reaching the breast tissues will promote the development 257 00:12:57.690 --> 00:12:59.763 of breast cancer. 258 00:13:02.760 --> 00:13:04.350 There has been some supportive evidence 259 00:13:04.350 --> 00:13:06.480 for the dietary fat hypothesis of breast cancer 260 00:13:06.480 --> 00:13:09.030 and those have primarily come from chronological studies 261 00:13:09.030 --> 00:13:10.680 of Japanese women. 262 00:13:10.680 --> 00:13:12.900 Over the past half century, the age adjusted 263 00:13:12.900 --> 00:13:15.300 breast cancer mortality rate among Japanese women has 264 00:13:15.300 --> 00:13:17.070 increased more than twofold, 265 00:13:17.070 --> 00:13:20.340 rising from five deaths per 100,000 in 1950 266 00:13:20.340 --> 00:13:23.820 to 12 deaths per 100,000 in 2006. 267 00:13:23.820 --> 00:13:25.320 The increase in breast cancer mortality 268 00:13:25.320 --> 00:13:28.140 among Japanese women closely parallels a threefold increase 269 00:13:28.140 --> 00:13:31.440 in per capita fat consumption over the same time period. 270 00:13:31.440 --> 00:13:34.710 In 1950, less than 10% of kilo calories were derived 271 00:13:34.710 --> 00:13:39.233 from fat, whereas in 2005 the level had risen to nearly 30%. 272 00:13:41.910 --> 00:13:44.520 Other controversial risk factors of breast cancer include 273 00:13:44.520 --> 00:13:47.731 alcohol consumption, oral contraceptive use, 274 00:13:47.731 --> 00:13:51.633 preneoplastic lesions, and thyroid dysfunction. 275 00:13:52.680 --> 00:13:56.580 The evidence for these risk factors is not clear, 276 00:13:56.580 --> 00:13:59.010 so it can't be said definitively 277 00:13:59.010 --> 00:14:01.473 that any of these are risk factors.