Introduction

Top Abstract Introduction Participants and methods Results Discussion Conclusion References

The belief that the onset of cancer may be associated with a stressful experience is found in the British, French, and United States medical literature at least as far back as 1701.¹ In a recent survey of South Australian women, 40% reported that they believed that stress was a cause of breast cancer.² Research into the association, however, has methodological weaknesses.³

Four recent studies of breast cancer have used the life events and difficulties schedule, a semistructured interview of proved reliability⁴: two examined the association between stress and relapse, and two examined the association between stress and onset of breast cancer.^5-8 The results are not clear cut. In the most recent study, Chen et al found that severe life events were associated with breast cancer, with an odds ratio of 11.6 after adjustment for confounders. The result provoked speculation about biological mechanisms for the effect,⁹ and widespread media coverage of the association between stress and cancer followed.¹⁰

We have attempted to replicate the findings of Chen et al, but with improvements in five areas of study design. Firstly, we included a larger sample of women presenting with a suspicious breast lump. Secondly, we obtained a consecutive series of women from a defined geographical area presenting with a breast lump, to reduce selection bias. Thirdly, we examined more social and physical risk factors for breast cancer to correct for potential confounding. Fourthly, we used two researchers who held regular consensus rating meetings to reduce observer bias. Finally, we examined the effect of the participant's knowledge of diagnosis on reporting of severe life events.

	Participants and methods

Top Abstract Introduction Participants and methods Results Discussion Conclusion References

Participants
Outpatient services for diagnosing suspicious breast lumps in Leeds were provided by two NHS trusts at the time of the study (September 1996 to February 1998). The two services were similar, and we identified no obvious systematic bias in general practitioners' referral patterns to the two units. We therefore sited the study in the three clinics that form the service for the west of Leeds. We recruited all women attending breast clinics at Leeds General Infirmary, Chapel Allerton Hospital, and Wharfedale General Hospital, Otley who were to have tissue checked from a suspicious breast lump. Women aged between 40 and 79 years residing at a Leeds address were asked to participate by their surgeon. Exclusions were previous breast cancer and inability to comply with an interview owing to poor English or serious physical or mental illness. We obtained research ethics approval for our study.

Study protocol
The women were introduced to the research interviewer (DP or KT) immediately after the surgical consultation, and a home interview was arrangedusually for the next day. Written consent was obtained. The life events and difficulties schedule was administered to cover a 5 year period before the clinical presentation. Social and physical risk factors for breast cancer were recorded, and the participants were asked to predict their diagnosis. The women completed the Beck depression inventory.¹¹ If the interview reminded them of painful emotional issues, they were offered appropriate professional counselling. Weekly consensus rating meetings were held, and borderline or unusual events and difficulties were rated over the telephone with one of the originators of the life events and difficulties schedule.

Cancer diagnosis
Cancer was diagnosed by cytological examination of breast tissue and confirmed by histopathological examination. Participants diagnosed with cancer were cases and those whose biopsy showed normal breast tissue or benign breast disease were controls.

Assessment of life stress
Events and difficulties were rated according to their severity and content, and difficulties were rated according to their duration. Life events were rated on a four point scale, and severity of difficulties lasting at least 4 weeks was rated on a six point scale. We followed the usual convention in recording those events rated 1 or 2 and those difficulties rated 1 to 3 as severe.

Analysis
We performed univariate analysis to calculate odds ratios and to examine the predictive effect of each factor on the risk of breast cancer. Those risk factors that were significant (P<0.25) were entered into a forward selection multivariate logistic regression analysis,¹² either as continuous variables or categorised as quartiles.

	Results

Top Abstract Introduction Participants and methods Results Discussion Conclusion References

Participants and non-participants
In total, 409 women were eligible for our study. Ten women were not interviewed; six had severe mental or physical illness and four had poor English. Overall, 333 of 399 women agreed to participate (84%). We excluded one woman diagnosed with a lymphoma. One hundred and six women (32%) were diagnosed with breast cancer and 226 (68%) with benign breast disease. Forty six women (32 cancer, 14 benign) had been given a tissue diagnosis by the time of the interview

Factors
Table 1 shows the characteristics of the cases and controls. Table 2 shows the risk factors for breast cancer, which were identified as potential confounders and entered into the multivariate analysis. The main risks for breast cancer were increasing age, postmenopausal status, later menopause, and increased body mass index. Factors associated with benign disease were history of benign breast lumps and exposure to the oral contraceptive pill. Factors that might have been expected to be associated with breast cancer but which were not were family history of breast cancer, nulliparity, and early menarche.

Stressors
Table 3 shows the final model, which includes results for the four categories of life stress. The most important risk factors for breast cancer were increasing age, increasing body mass index, and increasing alcohol consumption. Factors that predicted benign disease were history of benign breast lumps and exposure to hormone replacement therapy. Women diagnosed with malignant breast lump were no more likely to have experienced any of the stressors than women diagnosed with benign lumps or normal breasts.

Severe life events
We wondered whether a severe life event or a mood disorder around the time of clinical presentation could affect the presenting behaviour of the control group.¹³ If there were high rates of severe life events among the control group this might obscure a relation between breast cancer and severe life events when one existed. We found no evidence of an increase in severe life events among controls before clinical presentation (fig). Because the events and difficulties we have identified are known to be associated with the onset of depressive disorders, we examined depression in the two groups. For those who were unaware of their diagnosis at the time of interview, scores on the Beck depression inventory were the same in both groups (mean 8.6 v 8.5, t=0.04, df=281, P=0.97). Seven (7%) cases and 21 (9%) controls were taking an antidepressant at the time of the interview (²=0.67, df=1, P=0.411). This suggests that the experience of life events of women before diagnosis had been the same in both groups.

View larger version (23K): [in this window] [in a new window]   Rates of reporting of severe life events in 3 month intervals from time of interview over 5 years

	Discussion

Top Abstract Introduction Participants and methods Results Discussion Conclusion References

Possible sampling bias
Case-control studies are notoriously susceptible to bias. We have tried to reduce sampling bias by recruiting from all three clinics serving a defined catchment area, and by making an initial contact with participants in the breast clinic so that losses and refusals were kept to a minimum. Even so we cannot be sure that our controls were representative of all women with benign breast disorders. Such women had, for example, the same rates of family history of breast cancer as the cancer group, probably because this increased the chances of an apparently benign lump being biopsied. Alternatively, they may have been referred to the clinic, or biopsied, because of a recent life stress. Our other results do not support the inference of serious bias in selection of cases or controls.

Confounding
The main potential bias comes from age being a confounderthere was a 10 year difference in age between women with benign and malignant disease. We dealt with this by adjusting for age in the multivariate analysis rather than by recruiting a second sample from the general population, because the latter approach introduces other potential biases, due mainly to difficulties in recruitment for research in life events from community samples.

Other biases
To reduce reporting and measurement bias, we used two interviewers and ensured that borderline events and difficulties were rated at consensus meetings, and that equivocal stressors were rated by a third person unaware of the diagnosis. In addition we avoided subgroup reanalysis,¹⁴ restricting our study to the association between onset of breast cancer and the experience of four types of stressor, which were specified before data were collected.

	Conclusion

Top Abstract Introduction Participants and methods Results Discussion Conclusion References

Our data provide no support for the theory that severe life stresses may be concerned with the cause of breast cancer. This finding agrees with the results of a recent meta-analysis of observational studies examining the relation of life events to risk of breast cancer; the authors found evidence of bias in the literature, but larger and better quality studies showed no association between breast cancer and bereavement or other severe life events.¹⁵ We believe that women with breast cancer can be told that life stresses are unlikely to have played an important part in the development of their disease. The issue of stress and breast cancer relapse is unresolved.

	Acknowledgments

We thank David Dodwell for invaluable help and encouragement setting up the study, Tirril Harris for advice and help with consensus ratings, and Jenny Barratt for additional statistical advice. We thank the nursing and administrative staff at all three hospitals for their help, and the participants.

Contributors: DP conceived the idea, designed the study with AH, and conducted and rated the interviews with KT. KH and EB advised on confounding variables and logistical problems, explained the study to their patients, and obtained initial consent. DB gave statistical advice and performed the analyses. DP and AH wrote the paper; they will act as guarantors for the paper.

	Footnotes

Funding: Cookridge Hospital trust funds at the Yorkshire centre for clinical oncology, and the Ivy Hobson bequest.

Competing interests: None declared.

	References

Top Abstract Introduction Participants and methods Results Discussion Conclusion References

1.	LeShan L. Psychological states as factors in the development of malignant disease: a critical review. J Natl Cancer Inst 1959; 22: 1-18[Medline].
2.	Baghurst KI, Baghurst PA, Record SJ. Public perceptions of the role of dietary and other environmental factors in cancer causation or prevention. J Epidemiol Comm Health 1992; 46: 120-126[Abstract/Free Full Text].
3.	McGee R, Williams S, Elwood M. Are life events related to the onset of breast cancer? Psychol Med 1996; 26: 441-447[Medline].
4.	Brown GW, Harris TO. The social origins of depression: a study of psychiatric disorder in women. London: Tavistock, 1978.
5.	Ramirez A, Craig TKJ, Watson JP, Fentiman IS, North WRS, Rubens RD. Stress and relapse of cancer. BMJ 1989; 298: 291-293.
6.	Barraclough J, Pinder P, Cruddas M, Osmond C, Taylor I, Perry M. Life events and breast cancer prognosis. BMJ 1992; 304: 1078-1081.
7.	Geyer S. Life events prior to manifestation of breast cancer: a limited prospective study covering eight years before diagnosis. J Psychosom Res 1991; 35: 355-363[Medline].
8.	Chen CC, David AS, Nunnerley H, Michell M, Dawson JL, Berry H, et al. Adverse life events and breast cancer: a case control study. BMJ 1995; 311: 1527-1530[Abstract/Free Full Text].
9.	Reed MJ, Ghilchik MW. Association may be due to imbalance in ratio of adrenal androgen to glucocorticoid. BMJ 1996; 312: 845[Free Full Text].
10.	Cassileth BR. Stress and the development of cancer. Cancer 1996; 77: 1015-1016[Medline].
11.	Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psych 1961; 4: 561-585.
12.	Hosmer DW, Lemeshow S. Model building strategies and methods for logistic regression. In: Applied logistic regression. New York: John Wiley, 1989.
13.	Mechanic D. Social psychologic factors affecting the presentation of bodily complaints. N Engl J Med 1972; 286: 1132-1139.
14.	Counsell CE, Clarke MJ, Slattery J, Sandercock PAG. The miracle of DICE therapy for acute stroke: fact or fictional product of subgroup analysis? BMJ 1994; 309: 1677-1681[Abstract/Free Full Text].
15.	Petticrew M, Fraser JM, Regan MF. Adverse life-events and risk of breast cancer: a meta-analysis. Br J Health Psychol 1999; 4: 1-17.

(Accepted 21 June 1999)