Friday 23 December 2011

The magic 25%

A handful of anti-smoking extremists have long hoped that smoking is linked to breast cancer. The pink ribbon breast cancer campaign is arguably the best-publicised and best-funded initiative in pubic health. Because breast cancer is the most common form of cancer amongst women, even a small association with smoking would allow tobacco control advocates to claim that millions of cases could be prevented by stamping out tobacco.

The problem is that there really isn't any reason to think the two are related. Sixty years of epidemiological research has failed to find a link and, unlike with diseases of the lung and airways, there is no obvious causal mechanism. As recounted in Velvet Glove, Iron Fist (pp. 236-38), neither the International Agency for Research on Cancer (IARC) nor the American Cancer Society believe there is a link and even the otherwise outré Surgeon General's report of 2006 didn't claim smoking to be a cause of breast cancer.

Outside of California, it is generally accepted that breast cancer is not a smoking-related disease. Inside California, things are always a little different. From his pulpit at UCSF, Stanton Glantz has been insisting on a connection for years, and the California Environmental Protection Agency (Cal-EPA) conducted a meta-analysis in 2004 which found an association between breast cancer and passive smoking. When the American Cancer Society expressed reservations about this meta-analysis (amongst other flaws, it excluded a notable cohort study which would have wiped out the association), Glantz went berserk and referred to doubters as "religious fanatics", thus displaying an extraordinary lack of self-awareness.

Glantz has been at it again this month following a review of breast cancer risks conducted by the Institute of Medicine. Getting rather excited at the prospect at linking arms with the pink-ribbon campaign, he overstated the conclusions of the IOM report and announced:

It's time for the large breast cancer advocacy groups to join the tobacco control community.

Glantz seems to think that the IoM report implicated smoking (and passive smoking) as a cause of breast cancer. That is not how I read it, nor is it how the New York Times read it. What the IoM actually found was this:

The evidence also indicates a possible, though currently less clear, link to increased risk for breast cancer from exposure to benzene, 1,3-butadiene, and ethylene oxide, which are chemicals found in some workplace settings and in gasoline fumes, vehicle exhaust, and tobacco smoke.

This was the only reference to tobacco in a 700 word press release. In the report itself, the IoM say that they cannot rule out a link, but that the evidence is equivocal. Tobacco remains a "possible" cause in the same way that mobile phones were found to be a possible cause of brain cancer in a recent IARC report. In other words, the collated evidence does not suggest a causal link, but some studies have found an association.

There are two interesting aspects of the breast cancer/smoking hypothesis. The first is that there was barely a hint of a link for the first 40 years of epidemiological research, as the IoM acknowledge:

Before 1993, more than 50 epidemiologic studies examined the relationship between breast cancer and exposure to tobacco smoke. Although the quality of studies was highly variable, the better conducted studies did not suggest a causal relationship (Palmer and Rosenberg, 1993). An IARC review published in 2004 included studies conducted before 2002, and it relied heavily on a pooled analysis of 53 case–control and cohort studies by the Collaborative Group on Hormonal Factors in Breast Cancer Study (2002) that contended that apparent associations with smoking were confounded by alcohol consumption. The IARC (2004) conclusions were that neither active nor passive smoking was associated with increased risk of breast cancer.

In any other field of research this would be enough to put the matter to bed, but tobacco control was flooded with money in the 1990s and so it continued. This coincided with the rise of ultra-low risk epidemiology and cherry-picked meta-analyses which, in turn, was accompanied by the burden of proof being relaxed in the science to the point where statistically insignificant findings were taken seriously.

Breast cancer is a very common disease and smoking is a very common behaviour. Given these facts, any association between the two should have been evident very early on (by the 1950s, if not even earlier). That no one found an association despite smoking being the most studied risk factor of the twentieth century strongly suggests that none exists. "If smoking was a major cause of breast cancer, we would have found it by now," says Dale Sandler, chief of the NIEHS Epidemiology Branch.

Those who say that smoking (active or passive) causes breast cancer are making an extraordinary claim and, despite efforts being redoubled in the last fifteen years, there is no extraordinary evidence and very little ordinary evidence.

From the IoM report:

Active smoking 

The summary risk ratio was 1.10 (95% CI, 1.07–1.14), indicating a weak association with increased risk for early initiation of smoking. For women who smoked only after a first pregnancy, the summary risk ratio was 1.07, but it was not a statistically significant increase in risk (95% CI, 0.99–1.15). A subsequent report from the NHS found a statistically significant increase in risk associated with greater smoking intensity (i.e., pack-years of smoking) from menarche to a first birth (p for trend <0.001) (Xue et al., 2011). At 1–5 pack-years of smoking before a first birth the hazard ratio (HR) is 1.11 (95% CI, 1.04–1.20); for 16 or more pack-years, the HR is 1.25 (95% CI, 1.11–1.40).

No increase in risk was evident for pack-years smoked from after a first pregnancy to menopause. For 31 or more pack-years, the HR was 1.05 (95% CI, 0.92–1.19). However, pack-years of smoking after menopause may be associated with a slight reduction in risk (p for trend = .02) (Xue et al., 2011). For 16 or more pack-years of postmenopausal smoking, the HR was 0.88 (95% CI, 0.79–0.99).

... For women who started smoking between ages 15 and 19, the HR was 1.21 (95% CI, 1.01–1.44); whereas those who initiated smoking after age 30, the HR was 1.00 (95% CI, 0.76–1.32).

Brown et al. (2010) concluded that their data did not show a consistent association between smoking and significant increases in breast cancer risk among U.S.- or foreign-born Asian women. For example, the results for current smokers showed an OR of 0.9 (95% CI, 0.6–1.3) while ex-smokers had an OR of 1.6 (95% CI, 1.1–2.2).

A study that examined risk for triple-negative breast cancer found no statistically significant increase in risk over nonsmokers based on smoking status, age at initiation, or duration of smoking (Kabat et al., 2011). By comparison, women with estrogen-receptor- positive cancers (ER+) were at significantly increased risk with earlier initiation (< age 20: HR = 1.16, 95% CI, 1.05–1.28) and longer duration of smoking (≥30 years: HR = 1.14, 95% CI, 1.01–1.28).

These relative risks are low or non-existent and even the positive findings are often not statistically significant. The most interesting thing about these associations is that they are actually lower than the associations claimed for passive smoking.

Passive Smoking

A 2005 review by the California Environmental Protection Agency of various health hazards associated with exposure to secondhand smoke included a meta-analysis of 19 epidemiologic studies of breast cancer ... The meta-analysis produced an overall estimate for exposed women of RR = 1.25 (95% CI, 1.08–1.44) (CalEPA, 2005; also reported in Miller et al., 2007). When the analysis was restricted to five studies with more comprehensive exposure assessment, the overall estimate was RR = 1.91 (95% CI, 1.53–2.39).

In 2006, the U.S. Surgeon General’s report The Health Consequences of Involuntary Exposure to Tobacco Smoke, which included consideration of many of the same studies as the California review, concluded, “The evidence is suggestive but not sufficient to infer a causal relationship between secondhand smoke and breast cancer” (HHS, 2006, p. 13). The conclusion was based on a review of the findings from seven prospective cohort studies, 14 case–control studies, and a meta-analysis of all of these studies. The meta-analysis found that women who had ever been exposed to secondhand smoke (10 studies) were at increased risk of breast cancer (RR = 1.40, 95% CI, 1.12–1.76).

The idea that passive smoking is more dangerous than active smoking is patently absurd, but that didn't stop ASH (USA) hyping Cal-EPA's meta-analysis with this headline in 2005:

Secondhand Tobacco Smoke More Dangerous Than Smoking Itself

It is fitting that an organisation that endorses so much flim-flam should wind up embracing the principles of homeopathy, but any reasonable person understands that the dose makes the poison. In its understated way, the IoM acknowledges that it is a tad unlikely that people who inhale less than 1% of the dose inhaled by smokers would be at greater risk.

For most other smoking-related diseases, the relative risks are much stronger for active smoking than passive smoking. Thus findings of equivalent or stronger relative risks for breast cancer with passive smoking than with active smoking are difficult to explain mechanistically.

And yet these perverse findings exist and they require explanation. At first glance, it seems that the epidemiological research into breast cancer and tobacco don't tell us very much at all. Certainly, they don't tell us very much about the environmental causes of breast cancer, but I think they tell us quite a bit about the state of epidemiology. They show how easy it is to find a relative risk of around 1.25 (ie. a 25% increase) in an observational study. It takes only moderate recall bias or deficiencies in a study's design to come up with such associations. In the case of secondhand smoke and breast cancer we can surmise that the associations are false because there is no link with active smoking, but it is curious that the claimed associations with other diseases also fall in the same ultra-low bracket, regardless of the magnitude of the risk from active smoking.

Smokers are around 1,000 to 2,000% more likely to develop lung cancer. The passive smoker's excess risk is said to be around 25%.

Smokers are around 70% to 100% more likely to develop coronary heart disease. The passive smoker's excess risk is, again, around 25%.

Smokers are not any more likely to develop breast cancer, but the passive smoker's excess risk is said to be—you guessed it—25%.

Despite huge variations in the effects of smoking, the effects of secondhand smoke—if we are to take the epidemiological studies at face value—are remarkably consistent. Consistent with each other, that is. Not consistent with the rest of science.


Jonathan Bagley said...

Unfortunately, the last time I looked, the Wikipedia passive smoking page claims even passive smoking causes breast cancer - quoting the EPA, if I recall correctly. This causes distress in families where women get breast cancer. I had a go years ago at trying to sort out the wiki page but it is controlled by half a dozen anonymous fanatics. It should be possible to keep a POV (point of view) label on it permanently, but I couldn't figure out how. Anyone who knows about these things and has time on their hands - have a go.

Anonymous said...


Nah, brassieres are what 'causes' breast cancer!!!

Studies have shown that wearing those deadly devices will increase an adults chance of breast cancer by 2500%.

Gary K.

Anonymous said...

The vast majority of people I know that died had grey/white hair.

However,coloring their hair would have had made NO change in their deaths.

Risk factors are not diseases, most of the time, and risk factors do not cause diseases.

Gary K.

Fredrik Eich said...

Yup, I have never understood the supposed dose response relationship between smoking and heart disease. I worked in bars at the uni of sussex for 9 years and apparently my risk from passive smoking was ~25% , my risk from working irregular hours was ~40% but having exposed myself to 300 fold smoke exposure
by smoking 20 a day my risk is only ~70%. If I give up smoking my risk is still ~25%. Go figure. None of that makes any sense to me whatsoever, especially when one considers that smoking attenuates one (BMI) of the four main risk factors for heart disease and maybe attenuates another (hypertensive risk), although there seems to be some evidence that quitters have a marginally reduced risk of hypercholesterolaemia. But that is not even talking about the fact that the second most bioavalable component of cigarette smoke is Niacin which is used to treat ... yes thats right hypercholesterolaemia.

Beats me.

Ann W. said...

“Outside of California, it is generally accepted that breast cancer is not a smoking-related disease.”
Chris, you might be interested in taking a look at what our Canadian Anti’s have been doing on this issue.
Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk - April 2009
Active Smoking
Based on the weight of evidence from epidemiologic and toxicological studies and understanding of biological mechanisms, the associations between active smoking and both pre- and postmenopausal breast cancer are consistent with causality.
Secondhand Smoke
The association between SHS and breast cancer in younger, primarily premenopausal women who have never smoked is consistent with causality. The evidence is considered insufficient to pass judgement on SHS and postmenopausal breast cancer.

Attributable Risk
It would be premature at this time to estimate the magnitude of breast cancer incidence and mortality attributable to active and SHS; this could be a topic for further research.

Ann W. said...

Interesting enough, even though a member of the Physicians for a Smoke Free Canada was part of this 2009 Expert Panel and are included in the acknowledgments for their contribution of staff time and support, they had no issues giving a number two BEFORE the expert panel’s conclusions. “We estimate that about 2,100 or 47% of new premenopausal breast cancer cases every year in Canada are attributed to passive and active smoking. We attribute about 280 Canadian premenopausal breast cancer deaths in 2006 to passive and active smoking. If we could get rid of all exposure to second hand smoke, we could eventually prevent about 1.000 new cases of premenopausal breast cancer every year.” (Breast Cancer and Tobacco Smoke, PSC 2007)

And they repeat this again at the 5th National Conference on Tobacco or Health October 1-3, 2007 : Edmonton, AB
The Jury HAS Deliberated. Smoke Causes Breast Cancer
• Neil Collishaw Research Director, Physicians for a Smoke-Free Canada
Estimated breast cancer incidence and mortality attributable to active and passive smoking [slideshow]
OBJECTIVE: To estimate the number of breast cancer cases and deaths in Canada and the United States attributable to passive and active smoking for premenopausal and postmenopausal breast cancer, based on the best information available on risk and exposure. METHODS: Pooled estimates of risk were constructed, based on the studies with the best measures of lifetime exposure to active and passive smoking and then population attributable risks were calculated for Canada and the United States in 2006. CONCLUSION: We estimate that 21.6% of premenopausal breast cancer cases incidence and mortality are attributable to passive smoking exposure and 25.6% of premenopausal breast cancer incidence and mortality are attributable to active smoking. In total 47.2% - nearly half – of all premenopausal breast cancer is attributable to active and passive smoking, with nearly equal proportions for each. There is also reason to be concerned that a large proportion of postmenopausal breast cancer incidence and mortality may be attributable to active and passive smoking. However, more studies of postmenopausal breast cancer with good measures of lifetime exposure to tobacco smoke are needed to improve our estimates of tobacco smoke-attributable incidence and mortality for postmenopausal breast cancer. The analysis suggests that effective prevention of exposure of girls and women to tobacco smoke would be the single most effective public health measure to reduce breast cancer incidence and mortality in Canada and the United States.

They even have a mock up of the package warning about breast cancer risk

Ann W. said...

And finally, in 2006 The Physicians for a Smoke Free Canada went as far to try and recruit a popular Canadian TV show host (another Heather Crowe?) three years before the their Expert Panel with full acknowledgment that they didn’t know what caused Ms. Mesley’s breast cancer....
An open letter to Wendy Mesley
What’s new in breast cancer research?
The most important new finding on breast cancer is that environmental tobacco smoke has now been clearly identified as a cause of breast cancer, particularly in premenopausal women. This was the conclusion of the California Air Resources Board that recently conducted an exhaustive scientific review of the health effects of passive smoking.

A leading researcher in the world on breast cancer and tobacco smoke is Dr. Kenneth Johnson of the Public Health Agency of Canada. His research, and other similar research, leads us to strongly suspect that both active and passive smoking are causes of both premenopausal
and post-menopausal breast cancer.

An important finding of this research is that even limited exposure to tobacco smoke early in life can be a cause of breast cancer later in life.Wendy, unfortunately, we may never know for sure what caused your breast cancer. But you are widely known in Canada as an excellent communicator. You could do great service to breast cancer prevention by clearly communicating to Canadians this important new information about tobacco smoke as a cause of breast cancer. It is now more important than ever that people not smoke and that non-smokers be protected from
exposure to tobacco smoke.

Ann W. said...

Another name that you might find interesting (connecting the dots) is one Kenneth C. Johnson PhD Senior Epidemiologist/Research Scientist, Evidence and Risk Assessment Division, Centre for Chronic Disease Prevention and Control, Public Health Agency of Canada.
Expert Panel Member of Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk
Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk - April 2009 and a Consultant on the Proposed Identification of Environmental Tobacco Smoke as a Toxic Air Contaminant Part B: Health Effects As approved by the Scientific Review Panel, June 24, 2005

Some Publications by Kenneth C. Johnson (reads like a who’s who)
-Johnson KC and Wells AJ. Re: Active and Passive Smoking in Breast Cancer: Prospective Results from the Nurses Health Study. Epidemiology. 2002 Nov; 13(6):745-6.
-Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, Coates RJ, Liff JM, Talamini R, Chantarakul N, Koetsawang S, Rachawat D, Morabia A, Schuman L, Stewart W, Szklo M, Bain C, Schofield F, Siskind V, Band P, Coldman AJ, Gallagher RP, Hislop TG, Yang P, Kolonel LM, Nomura AM, Hu J, Johnson KC, Mao Y, De Sanjose S, Lee N, Marchbanks P, Ory HW, Peterson HB, Wilson HG, Wingo PA, et al. Alcohol, tobacco and breast cancer -- collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 2002 Nov 18; 87(11):1234-45.
-Johnson KC. Accumulating evidence on passive and active smoking and breast cancer risk. Int J Cancer 2005; 117(4):619-628.
-Repace J, Johnson KC. Can Displacement Ventilation Control Secondhand ETS? ASHRAE IAQ Applications 2006; 7(4):1-6.
-Johnson KC. Re: Lissowska J, Brinton LA, Zatonski W, et al. Tobacco smoking, NAT2 acetylation genotype and breast cancer risk. (Int J Cancer 2006; 119:1961-69). More evidence for passive and active smoking and breast cancer risk among younger women. Int J Cancer 2007.
-Miller MD, Marty MA, Broadwin R, Johnson KC, Salmon AG, Winder B et al. The association between exposure to environmental tobacco smoke and breast cancer: a review by the California Environmental Protection Agency. Prev Med 2007; 44(2):93-106
-Johnson, KC, Glantz S. Evidence that secondhand smoke causes breast cancer in 2005 stronger than for lung cancer in 1986. Prev Med (epub ahead of print Dec 2007)
-Collishaw NE (Chair), Boyd NF, Cantor KP, Hammond SK, Johnson KC, Millar J, Miller AB, Miller M, Palmer JR, Salmon AG, Turcotte F. Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk. Toronto, Canada: Ontario Tobacco Research Unit, OTRU Special Report Series, April 2009.
-Bottorff, JL, McKeown, SB, Carey, J, Haines, R, Okoli, C, Johnson, KC, Easley, J, Ferrence, R, Baillie, L, & Ptolemy, E. (2010). Young women's responses to smoking and breast cancer risk information. Health Education Research. DOI: 10.1093/her/cyp067.
-Daviss, BA, Johnson, KC, Lalonde A. Evolving Evidence Since the Term Breech Trial: Canadian Response, European Dissent, and Potential Solutions. J Obstet Gynaecol 2010;32(3):217-224.
-Conlon MSC, Bewick M, Johnson KC, Lafrenie R, Donner A. Smoking (Active and Passive), N-Acetyltransferase 2, and risk of breast cancer. Cancer Epidemiology. Cancer Epidemiology 2010;34:142-149.

Pat Nurse MA said...

I just popped in to say Merry Christmas to you Chris and to thank you for all your hard work this year.

I hope 2012 brings you peace, success and all that you wish for.


jredheadgirl said...

"That no one found an association despite smoking being the most studied risk factor of the twentieth century strongly suggests that none exists."

Indeed. Good point Chris.

Merry Christmas!

Anonymous said...

It really is peculiar.
I was reading about pneumonia the other day. I was interested in finding out about the death toll from pneumonia. It appears that, in 2009 in England and Wales, 27 000 people died from pneumonia. Of these, 23 000 were over 75. 16 000 were over 85.

It seems that pneumonia is not 'a disease' - it is 'a condition'. It is fluid in the lungs.

It seems that the human body, when combating the effects of 'stuff' in the lungs, produces fluid. Normal, healthy, youngish bodies can deal with this fluid and eradicate it, but very old bodies cannot, and that is why so many very old people succumb to pneumonia. The 'stuff' in the lungs could be almost anything - flu virus, bacterium, spores, pollen and, I suppose, smoke. The 'stuff' in the lungs does not cause pneumonia. It is the failure of the body to deal with the fluid produced by the body's reaction to the 'stuff' which kills those people.

Is it possible that lung cancer is somewhat similar? After all, the vast majority of deaths from LC occur in old age, although not so massively accumulated in very old age.

And so let us make a supposition. Let us suppose that the body is constantly demolishing cancerous cells. Let us suppose that it is constantly fighting against the effects of 'stuff' in the lungs, whatever that may be. Every breath that we take brings 'stuff' into the lungs. I surmise that the P53 gene may have to work overtime in some circumstances and may 'run out of steam'.

So, like fluid in the lungs (pneumonia), it is not that smoking causes lung cancer - lung cancer is always with us. It is rather that smoke over-taxes the body's ability to cope.

So the cause of lung cancer is in the body itself. It is not external. that would explain why it is that LC predominates in old bodies and why enjoying tobacco rarely produces serious adverse effect in youngish people.

By the way, has any study ever 'proved' that smoking can cause lung cancer 20, 30, 40 years after a person has stopped smoking? Or is that a rationalisation?