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Breast cancer


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  • On January 26, 2006, the California Air Resources Board adopted a regulation adding secondhand smoke (environmental tobacco smoke) to the state’s list of “toxic air contaminants.” Other toxic air contaminants include diesel particulate exhaust, benzene, formaldehyde, and PAHs. The Board unanimously approved this regulation based on a report that assessed the exposures and health effects of secondhand smoke. This report, an update of the widely praised 1996 report CalEPA published (and that NCI republished in 1997 as Smoking and Health Monograph 10) was developed beginning in 2001 by the CalEPA Air Resources Board and Office of Environmental Health Hazard Assessment.
  • There were three review drafts of the report before it was finalized. The report was made available for “public comment” and the CalEPA had, by law, to respond to these public comments by a combination of modifying the report or explaining why they were not changing it. The Board acted on a recommendation of the state’s Scientific Review Panel on Toxic Air Contaminants (for members, see, which held four public hearings on the report and required many changes before unanimously approving it. While there are many new conclusions in the report, the one that has attracted the most attention is the one that secondhand smoke causes breast cancer in younger, primarily prememopausal women.
  • The International Agency of Research on Cancer (IARC) has identified 20 mammary carcinogens found in tobacco smoke including several polycyclic aromatic hydrocarbons and nitrosamines. Other studies have shown that human breast tissue is susceptible to the formation of DNA adducts following exposure to these carcinogens and that these tobacco smoke carcinogens can be measured in breast tissue. This provides a likely mechanism for tobacco smoke exposure to cause breast cancer.
  • Studies of the biology of breast cancer indicate that one would expect these carcinogens to induce breast cancer, based on several lines of basic science investigations.
  • Secondhand smoke exposure misclassification is common in epidemiologic studies. Cotinine is a metabolite of nicotine that is widely used to determine if people have been exposed to secondhand smoke. While the people who report no exposure to secondhand smoke at home or at work (yellow) have lower levels of cotinine than people who report exposure at home or work (red), there is a large overlap (orange). This overlap indicates that many people who report no exposure are actually being exposed to secondhand smoke. This so-called non-differential exposure bias will make it more difficult to detect an association between exposure and disease when one truly exists.
  • Let’s look at an example. Take this hypothetical study. Among 1000 people truly exposed, 10 are cases or 1%. Among the 1000 people who are truly not exposed, there are only 2 cases or 0.2%. The relative risk for this exposure is 1% divided by 0.2% or 5.
  • Now, suppose that 2 people who were actually exposed reported that they were not (i.e., the people in the orange area two slides earlier). As a result, we will list 8 people as exposed and 4 people as being unexposed. The result of this exposure missclassification will be to reduce the estimated relative risk from 5 to 2, a substantial underestimate of the true risk.
  • This is the summary figure from the Cal EPA report (Figure 7.4.4) that presents the findings from all of the studies considered in the review by menopausal status as well as by those studies that were deemed to be most informative (solid points) by virtue of the completeness of their exposure measurement and their ability to categorize women as never current and never passive smokers throughout their lifetime as the referent group. Of the 14 studies evaluating breast cancer risk in younger/premenopausal women, 13 found risk estimates greater 1. 7 were statistically significant individually, including all 6 of the most informative studies. The pooled risk estimate from meta-analysis is 1.68 with a 95% confidence interval ranging from 1.31 to 2.15. In contrast to younger women, the risk estimates for post-menopausal women are clustered around 1. For that reason, CalEPA considered the evidence linking breast cancer and breast cancer in older women “inconclusive.” Many previous investigators have combined all the studies on breast cancer, regardless of age, into a single analysis. Doing so leads to a less definitive picture than treating the pre- and post-menopausal studies separately because the effects of secondhand smoke – and the disease processes involved in breast cancer – are different in younger and older women. Even so, combining all the studies in a meta-analyses still yields a statistically significant increase in risk of 1.25.
  • CalEPA identified 14 studies that examined the effect of ETS exposure in women who were never smokers and developed breast cancer prior to menopause or age 50. The summary risk for all 14 studies found an almost 60% increase in breast cancer risk in women exposed to ETS (this is any exposure as identified in the studies vs no exposure – though many studies did not actually identify all exposures and therefore report risks biased to the null). For the 5 studies that did the best job of assessing exposure throughout the women’s lifetime the resulting risk of breast cancer was more than doubled.
  • Here’s another example of how selecting a truly unexposed referent group can impact the findings. In the Morabia, et al study that looked at active smoking and breast cancer risk, when passive smoking nonsmokers are included in the reference group, the relationship between active smoking and disease is weak. When the referent group has the passive smoking nonsmokers removed so that only never active / never passive smokers are considered, the risk estimates for active smoking increase and a strong dose response is observed.
  • Realizing the importance of utilizing an appropriate control group of never active/never passive smokers, the most informative studies that allow for these comparisons all have risk estimates above 1 both for exposure to active and to passive smoking with the majority of the individual studies reaching statistical significance. The right exposure assessment makes the difference! This comparison also indicates that the risks for active smoking are larger than passive smoking, but the difference is not great. This relatively small difference in risk between active and passive smokers helps understand why many of the older studies of active smoking did not report an increased risk of active smoking. These studies compared smokers to all nonsmokers, including passive smokers. By doing so, they had a contaminated comparison group and the risk estimate was biased towards the null. The oft heard statement question, “Since active smoking does not cause breast cancer, how can passive smoking?” is based on an incorrect predicate: Active smoking does increase the risk of breast cancer.
  • Some say that passive smoking can’t cause breast cancer if active smoking doesn’t. The CalEPA report has a detailed appendix on active smoking and breast cancer (Appendix A of Chapter 7 in Part B); meta analyses do show a significant risk estimate. The data were summarized in the previous slide. IARC and the US Surgeon General reviewed the data on SHS and did not concluded breast cancer was caused by SHS. While these reports were published in 2004, the research on which they were based essentially ended in 2001. (Indeed, the 1997 CalEPA report on secondhand smoke, which was largely based on the same sets of studies as IARC and the Surgeon General reached the same conclusion that they did.) The 2005 CalEPA report is based on a much larger collection of studies than the IARC and Surgeon General reports were. These agencies also did not consider the exposure misclassification or the effects of age/menopausal status like the Cal EPA has. (See Section of Part B of the CalEPA report for the details of this comparison.) Epidemiologists are trained to believe cohort studies over case-control studies in general and the cohort studies generally show no association. However, the cohort studies fail to ascertain lifetime exposure that allows for a clean control group of never active / never passive smokers so their results are not unexpected. (Chapter 1 of Part B of the CalEPA report addresses these issues in detail and Section applies them specifically to breast cancer.) The 1 case control study that did find a significant association was among Japanese women who’s spouses smoked. Japanese women were rarely exposed to SHS outside the home because of their culture, so there is little misclassification.
  • The evidence that SHS causes breast cancer today is stronger and more consistent than the evidence that SHS caused lung cancer back in the 1986 Surgeon General’s Report. The epi data are comparable; however, there is a wealth of toxicological and molecular epi data to support the population-based epi studies. Are people who refuse the accept the CalEPA conclusions applying a double standard to lung and breast cancer?
  • In some ways history is repeating itself. In 1981 Hirayama published the first study linking secondhand smoke with lung cancer in nonsmoking women married to men who smoked. Shortly thereafter, ACS published a study showing an elevated point estimate of risk, but it did not reach statistical significance. This difference in results probably reflected the fact that in Japan few women were exposed to secondhand smoke from sources other than their spouses, making marriage to a smoker a good surrogate marker for secondhand smoke exposure. In contrast, in the United States women had many other sources of exposure. Exposure missclassification was a problem. The American Cancer Society was slow to accept the evidence that passive smoking caused lung cancer.
  • The tobacco industry exploited the fact that the ACS study did not report an increase in lung cancer risk and used this fact to attack the Hirayama study, such as in this full page newspaper ad. (Note reference to ACS in the second column). It took five years for the ACS to change its position, and in the meantime people died unnecessarily and tobacco companies raked in more profits. The tobacco industry is already exploiting ACS’s refusal to accept the CalEPA conclusion on breast cancer. A consistent message is needed from the public health community. Let’s hope this scenario doesn’t continue to play itself again today.
  • Why is this important? Everyone knows SHS is bad for you in lots of different ways, so why press the breast cancer finding? The reason is that hospitality workers are the least protected occupational class from SHS. Young women are the people who typically work in bars and restaurants. Great public health gains can be made by protecting these women from this exposure. With a relative risk of 1.7, this translates to an attributable fraction of 30%. In other words, about 1/3 of premenopausal breast cancer cases could be prevented in SHS exposure were eliminated. That’s not too bad for a disease with few modifiable risk factors!
  • The ACS and CDC have justified their reluctance to accept the CalEPA findings on the grounds that they need to be “conservative” and provide the public with accurate information. That is everyone’s goal, including CalEPA. Indeed, the entire public and peer review process (which took 4 years to complete) is designed by law to produce the best current science. The Scientific Review Panel is specifically charged with certifying that the report represents the best current science. At the same time, it is important that there are two kinds of errors, what statisticians call “false positive” and “false negative” errors. A false positive (Type I) error is when you say that secondhand smoke increases the risk of breast cancer in younger women when, in fact, it does not. The ACS and CDC seem most worried about this kind of error. The tobacco industry’s aggressive attacks on science has conditioned them (and many others) to worry about such errors. At the same time, there is another kind of error, false negatives (Type II), when you do not say that passive smoking causes breast cancer when, in fact, it does. The consequences of this error mean that more young women will die of breast cancer. Given the very strong evidence reviewed in the CalEPA report, we can be confident that neither kind of error is being made. The conclusion that secondhand smoke causes breast cancer in younger, primarily premonopausal women is almost certainly a true positive statement.
  • It’s OK to be skeptical. But if these data pique your interest, please read the report and look at the evidence. You can also read the ACS’s (and tobacco industry’s) criticisms (in Part C of the report) and how the CalEPA responded to them. (The CalEPA was required by law to respond in writing to all such “public comments” by explaining how the report was changed or why it was not. The ACS criticisms were carefully considered by both the agency and the independent Scientific Review Panel on Toxic Air Contaminants, which has legal responsibility for providing independent peer review of such documents. Both the Panel and the California Air Resources Board unanimously endorsed the report. Lives depend on the public health community getting the answer to this right.
  • The ACS made its position clear during the public comment period on the drafts of the report and the CalEPA carefully considered its views in revising the report. (CDC and NCI seem to be following ACS's lead.) Unfortunately, ACS is repeating its historical behavior of being slow to respond to new scientific information. While this may be appropriate when confronted with new claims of "miracle cures for cancer“, it is not appropriate for ACS to ignore the findings of one of the leading scientific governmental agencies in the world. Scientists should take the time to read and disgest the report (Chapter 7 of Part B, including the appendix on active smoking) as well as the ACS (Michael Thun) comments and the agency responses. After absorbing this information, make your views known. Advocates should keep in mind that CalEPA has historically led the nation on issues of the environment and public health. Most of the nation's air pollution laws are modeled on the CalEPA Air Resources Board's initiatives. For example, the same CalEPA process that identified secondhand smoke as a toxic air contaminant was used to identify diesel exhaust (and develop subsequent regulations), something that the federal government has yet to do. The 1997 CalEPA report was the first governmental agency to conclude that secondhand smoke caused heart disease. Like breast cancer today, that conclusion was controversial at the time; it is now widely accepted. Use the data in the policymaking process. Would this finding help get more young women involved in pushing for smoke-free worksites? Would it create media opportunities to keep the dangers of SHS in the public eye? Would hospitality owners be more receptive to adopting smoke-free places if they knew they were putting their employees, friends, and family at risk for early onset breast cancer? I bet it would but nobody has tried before. Its OK to be skeptical. Before taking a stand on breast cancer and SHS, read the report. Lives depend on the public health community getting the answer to this right.
  • Transcript

    • 1. The international journal for all the latest news and research Online Power Point Presentation
    • 2. New CalEPA report and Breast Cancer
    • 3. ARB Public Hearing to Decide if TAC ARB Public Hearing to Decide if TAC Scientific Review Panel Scientific Review Panel Prioritization/Selection Toxic Substance OEHHA Health Evaluation ARB Exposure Assessment Draft Report Public Workshop/ Comments Draft Report Public Workshop/ Comments Toxic Air Contaminants ProgramToxic Air Contaminants Program IdentificationIdentification
    • 4. Mammary Carcinogens in Tobacco Smoke Aromatic hydrocarbons Benzene Benzo[a]pyrene Dibenz[a,h]anthracene Dibenzo[a,e]pyrene Dibenzo[a,h]pyrene Dibenzo[a,I]pyrene Dibenzo[a,l]pyrene Nitrosamines N-nitrosodiethylamine N-Nitrosodi-n-butyl-amine Aliphatic compounds Acrylamide Acrylonitrile 1,3-Butadiene Isoprene Nitromethane Propylene oxide Urethane Vinyl chloride Arylamines and nitrarenes 4-Aminobiphenyl Nitrobenzene Ortho-Toluidine
    • 5. Biology  Tobacco smoke contains multiple fat- soluble compounds known to induce mammary tumors in rodents. (PAH’s, heterocyclic amines, aromatic amines, and nitro-PAH’s)  These carcinogens can be activated into electrophilic intermediates by enzymes active in the human breast epithelial cell.
    • 6. Biology (contd)  Genes coding for activation/detoxification enzymes (e.g. NAT2, NAT1, CYP1a1, COMT, BRCA1 And BRCA2) have been reported to modify the relationship of tobacco smoke to breast cancer risk (although results are inconsistent).  Electrophilic metabolites of tobacco compounds bind to DNA and form DNA adducts that can be detected in human breast epithelial Morabia A., Environmental and Molecular Mutagenesis 39:89-95 2002
    • 7. Biology (contd)  Genomic alterations observed in vitro after exposure of human breast epithelial cells to tobacco carcinogens resemble those in familial breast cancer.  p53 damage in some breast tumors of smokers, but not nonsmokers Morabia A., Environmental and Molecular Mutagenesis 39:89-95 2002
    • 8. Problems with exposure assessment
    • 9. Effect of Exposure Misclassification on Estimates of Relative Risk 0 1 2 3 4 5 6 7 8 9 10 # Cases/1000 People Exposed Not Exposed Relative Risk: 1000 2 1000 10 = 5
    • 10. Effect of Exposure Misclassification on Estimates of Relative Risk 0 1 2 3 4 5 6 7 8 9 10 # Cases/1000 People True Mis- Classification Exposed Not Exposed Relative Risk: 1000 2 1000 10 = 5 8 1000 4 1000 = 2
    • 11. SHS Breast Cancer Risk 0.1 1 10 100 Hirayama84 Sandler85 Smith94 Morabia96 Millikan98 Zhao99 Delfino00 Johnson00 Wartenburg00 Kropp02 Shrubsole04 Gammon04 Reynolds04a Hanaoka05 Hirayama84 Sandler85 Millikan98 Zhao99 Delfino00 Johnson00 Gammon02 Reynolds04a Hanaoka05 RelativeRisk(95%CI) Premenopausal Postmenopausal Solid symbols designate studies OEHHA considered most informative
    • 12. SHS and Breast Cancer in Younger/Premenopausal Women  14 studies evaluated breast cancer risk in younger/premenopausal women strata.  13/14 found elevated risks (1.1-7.1), and 7 were statistically significant.  Pooled risk estimate from meta-analysis = 1.68 (95% CI 1.31-2.15).  Pooled risk estimate for studies with lifetime exposure information from all sources = 2.2 (95% CI 1.69-2.87)  Some evidence of dose-response.
    • 13. Utilizing Unexposed Referent Raises Risk Estimate (within study comparison, Morabia et al. 1996) Exposure Smokers vs non- smokers with no ETS Smokers vs non- smokers (includes ETS exposed) Active 1-9 cpd 2.2 (1.0; 4.4) 1.2 (0.8; 2.0) 10-19 cpd 2.7 (1.4; 5.4) 1.7 (1.1; 2.5) ≥ 20 cpd 4.6 (2.2; 9.7) 1.9 (1.2; 2.9) Ever passive 3.2 (1.7; 5.9) (Similar within study comparison results in Johnson et al., 2000, Lash and Aschengrau, 1999, and Kropp and Chang Claude, 2002)
    • 14. Comparison of breast cancer risk from active and passive smoke exposure in studies CalEPA considered most informative 0.1 1 10 Smith Morabia Zhao Johnson Kropp Hanaoka Smith Morabia Zhao Johnson Kropp Hanaoka OR(95%CI) Active Passive
    • 15. Arguments Raised  If active smoking does not cause breast cancer, how can passive smoking?  Active smoking does cause breast cancer  IARC says no effect  2004 report based on meeting in 2001  Considered essentially the same studies as CalEPA 1997 (which did not say SHS caused breast cancer)  Only considered 4 studies published between 2000 and 2002  Surgeon General says no effect  2004 report essentially completed in 2001  Considered 5 studies published after 2000  CalEPA considered 23 studies between 2000 and 2005  Cohort studies negative
    • 16. Evidence for breast cancer in younger women stronger than lung cancer in 1986 Lung cancer 1986  11/13 elevated risk  5 significant  1/3 cohort studies significant  Hirayama*, Garfinkle,Gillis  No toxicology  No molecular epi Breast cancer 2006  13/14 elevated risk  7 significant  1/3 cohort studies significant  Hanaoka*, Reynolds, Wartenberg  Positive toxicology  Molecular epi
    • 17. Passive smoking and lung cancer  First study, Hirayama 1981  Cohort study in Japan  Nonsmoking women married to men who smoked • Few women smoked • Few women worked outside the home  Significant elevation in risk  ACS CPS study, Garfinkle  Cohort study in USA  Nonsignificant elevation in risk  Many women smoked and worked outside the home
    • 18. Implications for Workplace Exposure of Waitresses  Highest occupational exposure to SHS: 72.3%  These women tend to get exposed at the most vulnerable times  1.7 relative risk  30% of breast cancer in younger waitresses
    • 19. What if you are wrong?  Type I (false positive)  Women unnecessarily alarmed about passive smoking and breast cancer  Tobacco industry attacks  Type II (false negative)  Young women die of breast cancer  Tobacco industry quotes ACS
    • 20. Where to read the full CalEPA report  finalreport/finalreport.htm  Passive smoking and breast cancer starts on page 7-76 of Part B  Active smoking and breast cancer in Appendix 7A  Discussion on exposure missclassification and criteria for causality in Chapter 1 of Part B
    • 21. What Can You Do? For scientists: Read the report and make your views known For advocates: Use the data. CalEPA has a reputation for being first, ahead of the ACS and CDC, and being right.