Re: breast cancer and antibiotics

[Guest guest]

Hi All,

See:

It seems that breast cancer might be caused by using antibiotics.

A review and the original abstract of the pdf-available articles

are below.

JAMA, February 18, 2004—Vol 291, No. 7 880-881

Antibiotics and Breast Cancer—

What's the Meaning of This?

a B. Ness, Jane A. Cauley

...... In this issue of THE JOURNAL,

Velicer and colleagues 1 report another

potential risk factor: the use of prescribed antibiotics.

Among 2266 women with breast cancer, as compared

with 7953 controls, the use of antibiotics was more common;

the risk of breast cancer was greater with longer duration

of antibiotic use and was consistent across antibiotic

classes. This observation is potentially worrisome in that antibiotic

exposure is common and sometimes nonessential.

Thus, if real, the risk of breast cancer attributable to the use

of antibiotics could be large and partially preventable.

A number of strengths lend validity to the study's findings.

Cases and controls were numerous and chosen from

a single clinical source. Cancer diagnoses were confirmed

using data from the Surveillance, Epidemiology, and End

Results program. Among patients with the highest use of

antibiotics, risk of breast cancer was similarly increased regardless

of the indication (acne, rosacea, or respiratory tract

infections). Computerized pharmacy records were used to

validate antibiotic prescriptions and adjustment was made

for a number of potentially confounding factors.

At the same time, the study methods engender certain concerns.

A randomized clinical trial would have been the criterion

standard design, since randomization generates an

equivalent distribution of both known and unknown confounding

factors across treatment groups. However, randomizing

women to an intervention hypothesized to increase

the risk of disease would have been unethical. The

authors appropriately chose an observational design, specifically

a case-control study. Yet case-control studies have

important limitations; a major one is confounding.

Confounding by indication occurs if women using antibiotics

differ from nonusers in ways that elevate their breast cancer

risk. Women with greater cumulative use of antibiotics were

older, had earlier age at menarche, had higher body mass indexes,

were more likely to have a family history of breast cancer,

and were more likely to report postmenopausal use of hormones,

all of which could have increased their risk of breast

cancer. The authors adjusted for these factors and state that

doing so did not materially influence their results. Nevertheless,

the frequency of missing data, especially among controls,

limited the validity of this adjustment. Residual confounding

may have occurred, for instance, because physicians

may have prescribed more antibiotics to women of upper socioeconomic

status, who may have been more likely to adhere

to preventive health recommendations such as routine

mammograms. Indeed, women with a greater cumulative exposure

to antibiotics tended (albeit non-significantly) to report

educational attainment beyond high school. Furthermore,

restricting the analysis to women who filled at least 1

antibiotic prescription reduced the size of the associations.

Confounding by unknown or unmeasured factors also could

have inflated observed associations. However, a confounding

factor with a prevalence of 20% would have had to increase

the relative odds of both outcome and exposure by factors of

4 to 5 before an observed relative risk of 1.57 would have been

reduced to 1.00. 2 Thus, for residual confounding to explain

the findings, the confounding would have to have a large impact

on both use of antibiotics and risk of breast cancer.

Detection bias also may have inflated the observed risks.

Mammography rates were quite low in the control group: only

42% had received a mammogram within 2 years of their reference

date. Failure to detect breast cancer in the control group

would lead to an underestimate of their breast cancer risk.

Beyond methodological considerations, the observed association,

to be believable, must also be biologically plausible.

Velicer et al raise 2 mechanistic possibilities: antibiotics may

reduce the capacity of intestinal microflora to metabolize

phytochemicals

that might protect against carcinogenesis; and tetracyclines

stimulate prostaglandin E2, implicating an over-expression

of cyclooxygenase 2, the enzyme that synthesizes

prostaglandin E2 and that has been associated with mammary

carcinogenesis.1,3,4 Along this same line of reasoning, antibiotics

reduce commensural bacteria in the gut, and thus may

lower the absorption of cholesterol. Cholesterol lowering has

been associated with a reduced risk of breast cancer in some

studies 5 but with an increased risk in others.

However, a biological explanation based on mechanisms

attributed to a given class of antibiotics is difficult to reconcile

with the observation by Velicer et al that the risk of breast

cancer was elevated across multiple classes of antibiotics. Different

antibiotics have different effects. Whereas tetracyclines

stimulate prostaglandin E2, presumably by mediation of cyclooxygenase

2, macrolides inhibit this pathway.6 With regard

to microbiological mechanisms, antibiotic classes have various

effects on intestinal microflora. For instance, in 1 study,

phenoxymethylpenicillin had about half the effect on serum

levels of the phytoestrogen enterolactone as did the macrolide

class of antibiotics.7 Furthermore, sulfatrimethoprim and nalidixic

acid have only a minor impact on intestinal microflora.8

Another possible explanation for the association between

use of antibiotics and risk of breast cancer is that antibiotics

are an epiphenomenon marking chronic infection and chronic

inflammation. Inflammation, induced by infections or irritants,

has been linked to a substantial proportion (one sixth

to one third) of incident cancers worldwide.9 Compelling evidence

for a link between inflammation and breast cancer comes

from preclinical and epidemiologic observations suggesting

that nonsteroidal anti-inflammatory drugs (NSAIDs) protect

against the development of breast cancer. In both animal and

in vitro models NSAIDs inhibit mammary carcinogenesis, and

in case-control and cohort studies use of NSAIDs reduces the

risk of breast cancer by 22% overall and by 28% in frequent

users with 10 or more years of exposure.10,11

Further support for the idea that inflammation plays a role

in breast carcinogenesis comes from an evolving understanding

that immune mechanisms may contribute to a variety

of tumor-promoting actions when those mechanisms

are not in balance.12 This is the case in chronic inflammation.

Chronic inflammation can produce DNA damage via

reactive oxygen species, bypass key regulatory cellular mechanisms

such as p53, activate extra-cellular matrix proteins (e.g.,

matrix metalloproteinase 9) and endothelial growth factors

(e.g., vascular endothelial growth factor) that promote

tumor invasion, and inhibit apoptosis.9,13 Cytokines, key regulators

of inflammation, also stimulate the enzymes that convert

androsteinedione to estrogens in breast tissue. In turn,

local and systemic elevations in estrogen levels have been

consistently linked to risk of breast cancer.14,15

However, there is a complexity to the explanation that

chronic inflammation resulting from infection is the mediator

of the association between use of antibiotics and risk

of breast cancer. The multiple examples wherein chronic

inflammation has been convincingly linked to cancer have

involved inflammation and tumor development within the

same tissue. Some examples include asbestos fibers and mesothelioma,

16 schistosomiasis and bladder cancer,17 chronic

Helicobacter pylori infection and stomach cancer,18 and mastitis

and breast cancer.19 In addition, systemic inflammatory

diseases, such as rheumatoid arthritis, have been linked

to seemingly unrelated lymphoproliferative malignancies but

not to breast cancer.20 Moreover, the indications for chronic

use of antibiotics in the study by Velicer et al, such as rosacea

and respiratory tract infections, have known effects

on systemic immune activity.21

As is often true for reports of new associations, this study

provides many (or more) questions than answers. Is the

observed link between use of antibiotics and risk of breast cancer

confounded by unmeasured factors? Is the effect due to

use of antibiotics or to the indications for antibiotics? Does

the link suggest caution in the use of antibiotics or suggest

that infections at distant sites might promote inflammation

localized to the breast? And, whether antibiotics are markers

of inflammation or are themselves contributors to carcinogenesis,

is use of antibiotics a risk factor for cancers at other

sites? Time and further scrutiny will tell. While more research

is needed, this study raises the possibility that long-term use

of antibiotics may have harmful consequences, especially for

patients for whom other therapeutic options are available.

REFERENCES

1. Velicer CM, Heckbert SR, Lampe JW, Potter JD, on CA, Taplin

SH.

An-tibiotic

use in relation to the risk of breast cancer. JAMA. 2004;291:827-835.

2. Psaty BM, Koepsell TD, Lin D, et al. Assessment and control for

confounding

by indication in observational studies. J Am Geriatr Soc. 1999;47:749-

754.

3. Hwang D, Scollard D, Byrne J, Levine E. Expression of

cyclooxygenase-1 and

cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst.

1998;90:455-460.

4. Kundu N, Yang Q, Dorsey R, Fulton AM. Increased cyclooxygenase-2

(COX-2)

expression and activity in a murine model of metastatic breast

cancer. Int J

Cancer.

2001;93:681-686.

5. Cauley JA, Zmuda JM, Lui L-Y, et al. Lipid-lowering drug use and

breast cancer

in

older women: a prospective study. J Womens Health (Larchmt).

2003;12:749-756.

6. Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity

of macrolide

an-tibiotics.

J Pharmacol Exp Ther. 2000;292:156-163.

7. Kilkkinen A, Pietinen P, Klaukka T, Virtamo J, Korhonon P,

Adlercreutz H. Use

of oral antimicrobials decreases serum enterolactone concentration.

Am J

Epide-miol.

2002;155:472-477.

8. Nord CE, Edlund C. Impact of antimicrobial agents on human

intestinal

micro-flora.

J Chemother. 1990;2:218-237.

9. Ames BN, Gold LS, Wilett WC. The causes and prevention of cancer.

Proc Natl

Acad Sci U S A. 1995;92:5258-5265.

10. Steele VE, Moon RC, Lubet RA, et al. Preclinical efficacy

evaluation of

poten-tial

chemopreventive agents in animal carcinogenesis models: methods and

re-sults

from the NCI drug chemoprevention drug development program. J Cell

Biol.

1994;20:32-53.

11. RE, Chlebowski RT, RD, et al. Breast cancer and

nonsteroidal

anti-inflammatory drugs: prospective results from the Women's Health

Initiative.

Cancer Res. 2003;63:6096-6101.

12. O'Byrne KJ, Dalgleish AG. Chronic immune activation and

inflammation as

the cause of malignancy. Br J Cancer. 2001;85:473-483.

13. Christensen S, Hagen TM, Shigenaga MK, Ames BN. Chronic

inflammation,

mutation, and cancer. In: Parsonnet J, ed. Microbes and Malignancy:

Infection as

a Cause of Human Cancers. New York, NY: Oxford University Press;

1999:35-88.

14. MJ, Purohit A. Breast cancer and the role of cytokines in

regulating

es-trogen

synthesis: an emerging hypothesis. Endocrine Rev. 1997;18:701-715.

15. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex

hor-mones,

and breast cancer risk in postmenopausal women. J Natl Cancer Inst.

2002;

95:1218-1226.

16. JG, Abrams KR, Leverment JN, et al. Prognostic factors

for malig-nant

mesothelioma in 142 patients: validation of CALGB and EORTC prognostic

scoring systems. Thorax. 2000;55:731-735.

17. Badawi AF, Mostafa MH, Probert A, O'Connor PJ. Role of

schistosomiasis in

human bladder cancer: evidence of association, aetiological factors,

and basic

mecha-nisms

of carcinogenesis. Eur J Cancer Prev. 1995;4:45-59.

18. MP, Pounder RE. Helicobacter pylori: from the benign to

the

ma-lignant.

Am J Gastroenterol. 1999;94:S11-S16.

19. Monson RR, Yen S, MacMahon B. Chronic mastitis and carcinoma of

the breast.

Lancet. 1976;2:224-226.

20. Cibere J, Sibley J, Haga M. Rheumatoid arthritis and the risk of

malignancy.

Arthritis Rheum. 1997;40:1580-1586.

21. Bamford JT. cea: current thoughts on origin. Semin Cutan Med

Surg. 2001;

20:199-206.

Antibiotic Use in Relation to the Risk of Breast Cancer

M. Velicer; R. Heckbert; Johanna W. Lampe;

D. Potter; Carol A. on; H. Taplin

JAMA. 2004;291:827-835.

......Design, Setting, and Participants Case-control study among 2266

women older than 19 years with primary, invasive breast cancer

(cases) enrolled in a large, non-profit

health plan for at least 1 year between January 1, 1993, and June 30,

2001, and 7953 randomly selected female health plan members

(controls), frequency-matched to cases on age and length of

enrollment. Cases were ascertained from the Surveillance,

Epidemiology, and End Results cancer registry. Antibiotic use was

ascertained from computerized pharmacy records......

Results Increasing cumulative days of antibiotic use were associated

with increased risk of incident breast cancer, adjusted for age and

length of enrollment. For

categories of increasing use (0, 1-50, 51-100, 101-500, 501-1000, and

=/>1001 days), odds ratios (95% confidence intervals) for breast

cancer were 1.00 (reference), 1.45 (1.24-1.69), 1.53 (1.28-1.83),

1.68 (1.42-2.00), 2.14 (1.60-2.88), and 2.07 (1.48-2.89) (P<.001 for

trend). Increased risk was observed in all antibiotic classes

studied and in a subanalysis having breast cancer fatality as the

outcome. Among women with

the highest levels of tetracycline or macrolide use, risk of breast

cancer was not

elevated

in those using these antibiotics exclusively for acne or rosacea

(indications that

could be risk factors for breast cancer due to altered hormone

levels), compared

with

those using them exclusively for respiratory tract infections,

adjusted for age

and length

of enrollment (odds ratio, 0.91; 95% confidence interval, 0.44-1.87).

Conclusions Use of antibiotics is associated with increased risk of

incident and

fatal

breast cancer. It cannot be determined from this study whether

antibiotic use is

causally

related to breast cancer, or whether indication for use, overall

weakened immune

function, or other factors are pertinent underlying exposures.

Although further

studies

are needed, these findings reinforce the need for prudent long-term

use of

antibiotics.

> The study was minimized on the evening news as only preliminary,

not worthy

> of such attention, and that the women may have had other factors

tto

> account for the results - such as weakened immune systems for

example.