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Cancer of the Breast—by Janet Lane-Claypon (1926):
A Reanalysis
David J. Press
MPhil Public Health, Candidate
Dissertation Supervisor: Dr. Paul Pharoah
Course Supervisor: Dr. John Powles
University of Cambridge
Department of Public Health and Primary Care
31 July 2008
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Overview
Section Number Page Number 1. Abstract 6 2. Introduction 7 2.1: Biography of Lane‐Claypon 7 2.2: Historical perspective of Lane‐Claypon’s work 9 2.3: Epidemiology of breast cancer to date 11 2.3.1: Age, nationality, and socioeconomic status 12
2.3.2: Age at menarche and age at menopause 13 2.3.3: Parity and age at first birth 15 2.3.4: Duration of lactation 17
2.4: Background of 1926 UK study 19 3. Methods 21
3.1: Historical studies 21 3.1.1: 1926 UK study 21 3.1.2: 1931 US study 22 3.1.3: Both studies 23 3.2: Reanalysis 25 4. Results 29
4.1: Historical studies 31 4.1.1: Comparability within and across studies 31 4.1.1.1: Nationality 31 4.1.1.2: Age 31 4.1.1.3: Civil status 32 4.1.1.4: Occupation 32 4.1.1.5: Deaths among children 32
4.1.2: Aetiologic findings in historical studies 33 4.1.2.1: Age at menarche 33 4.1.2.2: Age at menopause 33
4.1.2.3: Parity 34 4.1.2.4: Age at marriage 34 4.1.2.5: Duration of lactation 35
4.2: Reanalysis 36 4.1.1: Comparability within and across studies 36 4.2.1.1: Nationality 40 4.2.1.2: Age 40 4.2.1.3: Civil status 40 4.2.1.4: Occupation 41 4.2.1.5: Deaths among children 41
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Overview (continued)
Section Number Page Number 4. Results (continued) 29
4.2: Reanalysis (continued) 36 4.2.2: Aetiologic findings in reanalysis 41 4.2.2.1: Age at menarche 44 4.2.2.2: Age at menopause 45 4.2.2.3: Parity 46 4.2.2.4: Age at marriage 47 4.2.2.5: Duration of lactation 48
5. Discussion 49
5.1: Pioneering work and limitations 49 5.1.1: Limitations discussed by Lane‐Claypon 49 5.1.2: Limitations not fully considered by Lane‐Claypon 51 5.1.3: Limitations of the 1931 US study 53 5.2: Comparison of findings to contemporary epidemiological evidence 54
5.2.1: Age at menarche and age at menopause 55 5.2.1.1: Findings in historical studies 55 5.2.1.2: Findings in reanalysis 56 5.2.2: Parity and age at first birth 57 5.2.2.1: Findings in historical studies 57 5.2.2.2: Findings in reanalysis 58 5.2.3: Duration of lactation 59 5.2.3.1: Findings in historical studies 59 5.2.3.2: Findings in reanalysis 61
5.3: Implications—changing approaches, expanding knowledge 64 5.3.1: Changes in epidemiologic methodology and conceptualisation 66 5.3.1.1: Study design and sample selection 66 5.3.1.2: Statistical understanding and interpretation 66 5.3.1.3: Presentation of results 67 5.3.2: Changes in understanding of aetiology and clinical treatment 67 5.3.2.1: Breast cancer aetiology 67 5.3.2.2: Clinical treatment of breast cancer 68
6. Acknowledgments 70
7. References 71 8. Appendix 79
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List of Tables and Figures
Table/Figure Number Page Number Table 1: Indicators of breast cancer risk 11 Table 2: Data extraction 26 Table 3: Comparability of demographic variables within and across studies 37 Table 4: Historical reanalysis of reproductive risk factors and breast cancer risk 43 Table 5: Limitations not fully considered by Lane‐Claypon 52 Table 6: Comparison of current evidence and results from reanalysis 54 Figure 1: Age‐specific incidence rates of breast cancer among women in different countries 13 Figure 2: Age‐specific incidence rates of breast cancer and fitted curve 14 Figure 3: RR of breast cancer according to age at first birth 16 Figure 4: RR of breast cancer in relation to duration of lactation in 2002 CGHF report 18 Figure 5: Nationality in 1926 UK study 38 Figure 6: Nationality in 1931 US study 38 Figure 7: Age in 1926 UK study 38 Figure 8: Age in 1931 US study 38 Figure 9: Civil status in 1926 UK study 38 Figure 10: Civil status in 1931 US study 38 Figure 11: Occupation in 1926 UK study 39 Figure 12: Occupation in 1931 US study 39 Figure 13: Child mortality in 1926 UK study 39 Figure 14: Child mortality in 1931 US study 39 Figure 15: Age at menarche and breast cancer risk 44 Figure 16: Age at menopause and breast cancer risk 45 Figure 17: Parity and breast cancer risk 46 Figure 18: Age at marriage and breast cancer risk 47 Figure 19: Duration of lactation and breast cancer risk 48 Figure 20: Association between breast feeding and breast cancer risk by study 62
Total: 13,675 words (excluding tables, figures, acknowledgements, references, and appendix)
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List of Historical Tables and Figures (found in Appendix)
Table/Figure Page number number Historical Figure 1 [1926]: Questionnaire from 1926 UK study 79 Historical Figure 2 [1926]: Table of Contents for 1926 UK study 80 Historical Table 1 [1926]: Nationality in 1926 UK study 81 Historical Table 1a [1931]: Nationality in 1931 US study 81 Historical Table 1c [1931]: Nationality in 1931 US study 82 Historical Table 2 [1926]: Age in 1926 UK study 83 Historical Table 2 [1931]: Age in 1931 US study 84 Historical Table 3 [1926]: Civil status in 1926 UK study 85 Historical Table 3 [1931]: Civil status in 1931 US study 85 Historical Table 4 [1926]: Occupation in 1926 UK study (cases) 86 Historical Table 4 [1931]: Occupation in 1931 US study 88 Historical Table 5 [1926]: Occupation in 1926 UK study (controls) 87 Historical Table 8 [1926]: Deaths among children in 1926 UK study 88 Historical Table 8 [1931]: Deaths among children in 1931 US study 89 Historical Table 9 [1926]: Age at menarche in 1926 UK study 90 Historical Table 9 [1931]: Age at menarche in 1931 US study 90 Historical Table 10 [1926]: Age at menopause in 1926 UK study 91 Historical Table 10 [1931]: Age at menopause in 1931 US study 91 Historical Table 22 [1926]: Age at marriage in 1926 UK study 92 Historical Table 22 [1931]: Age at marriage in 1931 US study 93 Historical Table 25 [1926]: Parity in 1926 UK study 94 Historical Table 25 [1931]: Parity in 1931 US study 95 Historical Table 32 [1926]: Duration of lactation in 1926 UK study (cases) 96 Historical Table 32 [1931]: Duration of lactation in 1931 US study (cases) 97 Historical Table 33 [1926]: Duration of lactation in 1926 UK study (controls) 98 Historical Table 33 [1931]: Duration of lactation in 1931 US study (controls) 99 Historical Table 33g [1931]: Duration of lactation in 1931 US study 99
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1. Abstract
The first major case‐control study was published by Janet Lane‐Claypon in 1926, which provided the first
epidemiologic evidence that low fertility increases breast cancer risk. This study was a multi‐centre,
hospital‐based case‐control study of 508 women with breast cancer and 509 unmatched controls.
Demographic variables and reproductive histories were collected during in‐person interviews. Lane‐
Claypon’s study was replicated in 1931 by JM Wainwright using a US sample of 679 breast cancer cases
and 567 unmatched controls. Together, the 1926 UK study and 1931 US study provided the first, albeit
crude, evidence from observational studies that parity, age at marriage, and artificial menopause were
associated with breast cancer risk. The present report aims to re‐analyse and reconsider the 1926 UK
study, alongside the 1931 US study, in order to explore how Lane‐Claypon’s work helped to inform and
advance the field of epidemiology and to compare how well the findings from these historical studies
fits with subsequent epidemiologic studies on breast cancer. The Chi‐squared p‐value of demographic
variables was used to re‐assess the suitability of comparison of the distribution of cases and controls
within studies and across studies. The Mantel‐Haenszel odds ratio (OR) technique was used to estimate
crude ORs and corresponding 95% confidence intervals (CIs) to examine the relationship between
reproductive risk factors and breast cancer risk in the historical studies, separately and combined.
Qualitative results provided within the historical studies generally agreed with the quantitative
reanalysis provided here for parity and age at marriage, but a disagreement was observed between
qualitative and quantitative findings for demographic variables, age at menarche, age at menopause,
and duration of lactation. With the exception of age at menarche, findings from the quantitative
reanalysis were consistent with contemporary epidemiological evidence for reproductive risk factors,
supporting the role of estrogens in the aetiology of breast cancer. Lane‐Claypon’s work, as manifested in
the 1926 UK study, is an excellent example of how one investigator’s work can help to develop fields of
scientific enquiry and expand the global stock of knowledge.
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2. Introduction
2.1 Biography of Lane‐Claypon
Janet Elizabeth Lane‐Claypon (1877‐1967) is one of the early examples of a physician‐scientist, having
earned both a DSc in physiology in 1905 and an MD in 1910 from University College, London. Lane‐
Claypon is best known for her pioneering work in the field of epidemiology, as manifested in her
applications of retrospective cohort studies and case‐control studies, which places her among the
important figures that helped to lay the foundations for modern epidemiology (1). In addition to her
contributions to the field of epidemiology, Lane‐Claypon was also involved in laboratory research and
public health, for which she is less well‐known.
Lane‐Claypon was the first woman to receive a research scholarship from the British Medical Society,
which she used to research the bacteriology and biochemistry of milk at the Lister Institute of Preventive
Medicine. Lane‐Claypon then received a Jenner Fellowship and moved into the field of public health,
providing recommendations for maternal and child health programmes in Europe (2). She advocated for
breastfeeding, midwife training and prenatal services. Her publication of The Child Welfare Movement
(1920), was aimed primarily at the reduction of infant and child mortality via the provision of
institutional mobilisation to promote child and maternal welfare (3). In Hygiene of Women and Children
(1921), Lane‐Claypon provided public health recommendations on wide‐ranging topics including: the
home and garden, water supply, fresh air and ventilation, personal cleanliness, exercise, sleep, milk
production and supply, feeding infants and children, and growth factors in infancy and childhood (4). Of
the 3 books and 30 papers that Lane‐Claypon published, three may be considered classics.
Lane‐Claypon is credited with several epidemiologic “firsts.” A 1912 study of weight gain in infants fed
boiled cows’ milk compared with human breast milk is considered the first: a) historical (retrospective)
cohort study; b) study to describe confounding and analyse data to investigate the possibility that
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confounding explained the findings, and; c) study to use the Student’s t test to evaluate the observed
differences in an epidemiologic study (1). Further, her landmark 1926 report entitled, A Further Report
on Cancer of the Breast, with special reference to its associated antecedent conditions (5) is considered
the first case‐control study, and contains the first published epidemiologic questionnaire (Historical
Figure 1). Another Lane‐Claypon study that followed a large sample of women with breast cancer for up
to 10 years after their surgery is considered the first “end results” study (6). Due to restrictions on the
employment of married women in the civil service, Lane‐Claypon’s career ended prematurely when she
married at the age of 52. She retired to the countryside, and lived with her husband until her death at
the age of 90 (2).
Lane‐Claypon’s contributions coincided with drastic changes that were occurring for the societal role of
women, further adding to the historicity of her work (7). In his vignettes on Lane‐Claypon,
epidemiologist Warren Winkelstein, Jr. describes Lane‐Claypon as a “Forgotten Epidemiologic Pioneer”
and advocates for more attention to be paid to the historical and theoretical foundations of
epidemiology (1, 2, 8). This call has been answered, in part, by attempts of contemporary leaders in the
field to generate a cohesive picture of how modern epidemiology has evolved (9). Lane‐Claypon’s work
marks a transition from pre‐formal nineteenth‐century epidemiology, involving population thinking to
address health determinants, to the rapid expansion after the Second World War of a more formal
epidemiology, involving rigorous observational research (10). The present report is based on Lane‐
Claypon’s 1926 study, which provides the first epidemiologic evidence that low fertility increases breast
cancer risk.
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2.2 Historical perspective of Lane‐Claypon’s work
Factors in a woman’s reproductive life had been implicated as having an association with breast cancer
prior to the early 20th century epidemiologic work of Lane‐Claypon. In 1713, Ramazzini first revealed the
importance of reproductive factors when he observed an excess of breast cancer among practising nuns
(11). Risk factors that were discussed in the 1926 UK study as having been proposed prior to that study
included: age at menopause, being unmarried, duration of lactation, ethnicity, genetic predisposition,
structural breast abnormalities, injuries, and a group of conditions known as ‘mastitis,’ in which breast
tissue becomes inflamed (5). Although many of these risk factors have subsequently been confirmed to
be associated with breast cancer, the validity of such aetiologic hypotheses was unsubstantiated at the
time because epidemiologic methodologies had not been rigorously applied to test such hypotheses.
The future of epidemiology may involve reflections on ethics that require a grounding in epidemiology’s
past (12), but such considerations are outside of the scope of the present report, which focuses on the
genesis of epidemiologic concepts, methods, and breast cancer research, to which Lane‐Claypon was a
major contributor.
In the 1926 UK study, Lane‐Claypon’s apt observation that “It is clearly not possible to secure a full
control” (5, p. 2) has subsequently been a challenge to all epidemiologists seeking to ascertain
underlying associations. Lane‐Claypon’s work was innovative and laid the groundwork for subsequent
aetiologic research and new methods to minimise bias. Just five years later, JM Wainwright replicated
Lane‐Claypon’s study design using a population of US women (1931 US study) (13). In his report,
Wainwright attempts to improve upon Lane‐Claypon’s methodologies and carefully explain why he
decided to alter her approach. These historical efforts to fully and accurately describe study methods,
including strengths and potential limitations, expressed a scientific integrity that has been a key
component to the advancement of epidemiology ever since.
10
During the twentieth century, epidemiologic inquiries using increasingly more rigorous statistical and
epidemiologic methodologies have led to a higher degree of precision in the calculation of relative risks
and an increased understanding of disease aetiology. Improvements in, and additions to, study design,
statistical know‐how, and case‐finding within institutions, have occurred alongside an enhanced
understanding of how to interpret scientific findings. As a whole, this has meant a furthering of the
objectives of epidemiological enquiry—that is, to describe and analyse the frequency, progression,
prognosis, and causes of health‐related states and events (14). Together, this increase in knowledge of
diseases and populations at risk has resulted in more specialised clinical management.
11
2.3 Epidemiology of breast cancer to date, with special reference to risk factors considered in the
historical studies
Breast cancer is the most common neoplasm among females worldwide (second overall when both
sexes considered together), with an estimated 1.05 million new cases in 2000 and with more than half
the caseload occurring in industrialised countries (15). The marked international variation in breast
cancer incidence is primarily due to non‐genetic, hormonal factors (16). Cumulative exposure to ovarian
hormones is implicated in the pathenogenesis of breast cancer. Factors that alter a woman’s cumulative
exposure to ovarian hormones have thus repeatedly been associated with breast cancer risk (17).
Hormonally‐mediated indicators of breast cancer risk include: age, age at menarche, age at menopause
(natural or induced), parity, age at first full‐term pregnancy, and breastfeeding. Table 1 provides relative
risk (RR) estimates of the indicators of breast cancer risk that were considered in the historical studies
and re‐analysed in the present report.
The interdependence of childbearing indices such as lactation, timing of births, and parity is a potential
confounder in studies attempting to assess the independent effect of reproductive risk factors on breast
cancer risk (28). Because virtually all breast cancers are adenocarcinomas and the aetiology and natural
Table 1: Indicators of breast cancer risk Indicator Risk Group Relative Risk Reference High Low Age (yr.) 70‐74 30‐34 17.0 Hulka (18), Ries (19) Income (tertiles) Upper 2/3 Lower 1/3 1.7 Madigan (20) Age at menarche (yr.) ≤11 ≥15 1.1‐1.5 Colditz (21), Clavel‐Chapelon (22), Hulka (18) Age at menopause (yr.) ≥54 ≤45 1.4‐1.5 Colditz (21), Hulka (18) Parity 0 ≥4 1.5‐1.6 Clavel‐Chapelon (22), Holmberg (23) Age at first birth (yr.) ≥30 <22 1.4‐1.6 Clavel‐Chapelon (22), Iwasaki (24)
≥30 <20 1.9‐2.0 Madigan(20), Hulka (18) ≥35 <20 2.0‐2.3 Li (25), Tulinius (26)
Breastfeeding (mo.) Never ≥55 1.4 Collaborative Group (27)
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history of in situ lesions are largely unknown (29), the present report focused on invasive cancers.
However, the historical studies included a few sarcomas and a few cases of Paget’s disease; a disease
presenting with an eczema‐like change in the skin of the nipple, in which approximately 50% of patients
with Paget’s disease also present with a palpable breast mass, and of those, approximately 90‐94% have
an invasive disease (30).The risk factors that are emphasised in the present report (select demographics,
age at menarche, age at menopause, parity, age at first birth, and duration of lactation) were those that
were considered in the historical studies.
2.3.1 Age, nationality, and socioeconomic status
Increasing age is the most important risk factor for breast cancer in terms of magnitude, aside from
being female. In the US during 2000‐2004, breast cancer incidence rates per 100,000 women ranged
from 25.5 for 30‐34 year olds, to 432.3 for 70‐74 year olds (19), indicating an approximate RR of 17.0
between these two risk groups (Table 1). There is a general similarity in the shape of age‐specific
incidence curves across countries, but marked differences in absolute rates at every age exist (Figure 1)
(31). The Pike model provides a quantitative description of ‘breast tissue age’ using key hormonal risk
factors that explains a large proportion of country‐specific differences in breast cancer rates (32).
Differences between countries in absolute rates indicate that breast cancer risk is due, at least in part, to
lifestyle, environmental, and genetic differences (29). These differences may also explain the moderate
risk modifications that have been observed by socioeconomic status. Data from the first National Health
and Nutrition Examination Survey (NHANES I) observed a RR of 1.7 (95% CI, 1.2‐2.4) for women whose
household income was among the upper two thirds of the US population, compared to women whose
household income was among the lower third of the US population (20).
2.3.2
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14
other macronutrient and anthropometric variables (36). Age‐specific incidence rates of breast cancer
increase dramatically with increasing age, with rates increasing most rapidly between the ages of 30 and
50 years, with a tapering off of increasing risks around the time menopause. The slowing of rapidly
increasing breast cancer rates around age 50 years, near the time of natural menopause, strongly
suggests that reproductive hormones are involved in breast cancer aetiology (Figure 2).
In addition to age at natural menopause, it has been readily observed that women undergoing induced
menopause also experience a modification in breast cancer risk. Observational studies have shown that
women undergoing bilateral oophorectomy experience breast cancer risk reductions, likely due to
reductions in levels of circulating ovarian hormones following removal of the ovaries (37‐42). The effect
of other surgeries involving female reproductive organs on breast cancer risk remains unclear, with
inconsistent findings from observational studies (37, 40, 41, 43‐48). It is often difficult to impute age at
menopause for women undergoing surgeries involving female reproductive organs—particularly
Figure 2: Age‐specific incidence rates of breast cancer in US white females and fitted curve from Pike et. al. (32)
15
hysterectomy—and thus, it is difficult to assess the independent effect of surgeries involving female
reproductive organs on breast cancer risk and also to control for age at menopause in epidemiologic
studies (49). Another potential confounder in epidemiologic studies is the effect of hormone
replacement therapy, which may alter age at menopause and modify breast cancer risk (50).
Having an early or late age at menarche does not predict age at menopause and thus, the two risk
factors are considered independent (51). These risk factors have the same effect for nulliparous
women. That is, women who do not have children also experience a reduced breast cancer risk with
increasing age at menarche and an elevated breast cancer risk with increasing age at menopause (52). It
is unclear whether these associations are present among women at a genetically elevated risk (53, 54).
2.3.3 Parity and age at first birth
It has been well‐established that lifetime breast cancer risk reductions are experienced by women with
an early age at first birth and that increasing parity further reduces risk (33) (Table 1). Specifically,
women with an age at first full‐term pregnancy before age 20 years have an approximate 50% lifetime
reduction in breast cancer risk compared to nulliparous women (55). Early epidemiological findings by
MacMahon et. al. (56) were the first to conclude that age at first birth was related to breast cancer risk.
Results from this international collaborative study indicated a linear relationship between age at first
birth and RR of breast cancer (Figure 3).
16
Compared to nulliparous women in this study, women whose first birth was before age 30 years
experienced a reduction in breast cancer risk and women whose first birth was after age 35 years
experienced an increase in breast cancer risk. MacMahon et. al. mentioned that the association
between age at first birth and breast cancer risk had been reported previously (first reported in terms of
age at marriage in the 1926 UK study and 1931 US study), but not given sufficient consideration (56).
MacMahon’s groundbreaking findings for age at first birth have been repeatedly supported by
observational studies investigating breast cancer (18, 20, 22, 24‐26). Almost all observational studies
conducted today that investigate breast cancer contain data on parity and age at first birth. Hence, most
studies may be used for a general comparison of RR estimates between uniparous with nulliparous
Figure 3: Relative risk of breast cancer according to age at first birth. Reproduced from MacMahon et. al. (56)
17
women. A Norwegian prospective study of 1.7 million women has suggested that interaction effects
between age at birth, time since birth and time intervals between births may help to explain how these
factors combine to affect breast cancer risk. This study showed long‐term protective effects of the first
and subsequent births, a transient increase in risk after subsequent births, and a wide birth interval
related to larger adverse effects (57). In addition to observational studies, findings for age at first birth
and parity on breast cancer risk have been supported by experimental studies describing putative
effects of pregnancy on breast tissue susceptibility. Russo et. al. (58), for example, described changes in
breast tissue due to pregnancy in terms of neoplastic transformations of lobule structures via stem cells.
In addition to the role of stem cells, other proposed mechanisms for the reduced breast cancer risk due
to parity include: changes to the hormonal profile of parous women, more differentiated thus less
susceptible mammary glands, and alterations in particular subpopulations of epithelial cells (55). The
International BRCA 1/2 Carrier Cohort Study showed that BRCA1 and BRCA2 mutation carriers older than
40 years experience a similar reduction in breast cancer risk due to increasing parity (59). Despite this
evidence, it remains unclear whether parity has a differential influence on BRCA1 and BRCA2 mutation
carriers compared to the general population (60‐62).
2.3.4 Duration of lactation
There is convincing evidence from prospective and case‐control studies that breastfeeding reduces
breast cancer risk, with evidence of a dose‐response relationship. Plausible mechanisms for observed
risk reductions from breastfeeding include: a lower exposure to endogenous sex hormones, increased
differentiation of breast cells, and epithelial apoptosis which may eliminate cells with potential DNA
damage (63). The Collaborative Group on Hormonal Factors in Breast Cancer provided epidemiological
evidence on lactation and breast cancer risk from 47 epidemiological studies in 30 countries. The study
found a 4.3% breast cancer RR reduction per 12 months of breastfeeding (27) (Figure 4). It remains
18
unclear what influence breastfeeding has on breast cancer risk for women with BRCA1 and BRCA2
mutations (59‐62).
Figure 4: RR of breast cancer in parous women in relation to lifetime duration of lactation in 2002 CGHF report (27)
19
2.4 Background of 1926 UK study
The first major case‐control study of a non‐infectious disease was completed by Lane‐Claypon in 1926
using a sample of women from the United Kingdom (henceforth 1926 UK study) (5). Prior to the 1926 UK
study, Lane‐Claypon was commissioned by the British Ministry of Health to conduct a systematic review
on the surgical treatment of breast cancer from all countries (64). In this report, Lane‐Claypon
recommended that women more likely to develop breast cancer should be diagnosed and treated
earlier, which supported the conclusions of a 1923 study by the Cancer Commission of the League of
Nations (65). The findings of the 1923 League of Nations investigation, along with those from Lane‐
Claypon’s 1924 systematic review, led the British Ministry of Health to commission the 1926 UK study
designed to identify the existence and importance of what they termed “antecedent conditions” (risk
factors), in order to ascertain what influence certain previous life events had in the production of breast
cancer with the hope of diagnosing and treating breast cancer at an earlier stage.
When Lane‐Claypon was selected as the principal investigator of the 1926 UK study, no formal
epidemiologic study had been conducted to assess the aetiology of breast cancer, although previous
hypotheses had been posed. In a “prefatory note” within the 1926 UK study George Newman, the first
Chief Medical Officer to the Ministry of Health in England, lists risk factors that had been proposed as
possibly associated with breast cancer risk:
[The occurrence of breast cancer] has been thought to be favoured, for example, by certain phases of the reproductive life of women, and by the existence of racial and family pre‐disposition. Much importance has been attributed to the antecedent emergence of a variety of non‐cancerous affections of the breast, such as troubles associated with lactation, structural abnormalities of the organ, antecedent injuries and a group of conditions described as ‘mastitis’ (5, p. iv).
20
That various aspects of a woman’s reproductive life had previously been implicated in the aetiology of
breast cancer made reproductive risk factors, among a host of other possible antecedent conditions,
candidates for investigation in the 1926 UK study.
The 1926 UK study design was replicated by J.M. Wainwright in 1931 using a sample of women in the
United States in order to assess whether the UK findings could be generalised to populations in the US
and also to validate the UK findings (13). The current report aims to re‐analyse these two studies using a
contemporary format, terminology, statistical approach, and theoretical foundation in order to make
these studies more accessible to scientific readers today. Reproductive risk factors in particular will be
re‐analysed because they have subsequently been the subject of substantial epidemiologic enquiry,
whereas the other risk factors that were analysed in the historical studies have not (with the exception
of family history, which was too incomplete for reanalysis). In order to increase early recognition and
diagnosis of breast cancer with the provision of effective surgical treatment, the 1926 UK study was a
case‐control study designed to assess a range of possible risk factors of breast cancer, including
reproductive risk factors.
21
3. Methods
3.1 Historical studies
3.1.1 1926 UK study
A multi‐centre, hospital‐based, unmatched case‐control study was designed to evaluate risk factors for
breast cancer among women generally aged 45 years and above. Eight English hospitals (The Cancer
Hospital, University College Hospital, St. Bartholomew’s Hospital, The Middlesex Hospital, The Elizabeth
Garrett Anderson Hospital, The Samaritan Hospital, Florence Nightingale Hospital, and Guy’s Hospital)
and three Scottish hospitals (The Western Infirmary, The Royal Infirmary, and The Victoria Infirmary)
participated in this study. Participants provided verbal consent, with a few of unknown proportion
refusing study entry. Protocols were in accord with the scheme of the League of Nations Cancer
Commission.
Case Group
Case patients were English‐speaking women who had been diagnosed with breast cancer. Women who
had applied to the hospitals for breast cancer treatment were identified as potentially eligible for
inclusion, usually without regard to the surgeon under whose care they were placed. One letter was
sent to each eligible woman, requesting attendance at the hospital for follow‐up. Railway, tram, and/or
bus fares were offered as an inducement to cover the expense of hospital attendance for in‐person
questionnaires and medical examinations. Response rates were not collected, but were reported to be
high. Of those who did not respond to the letter, it was unclear whether the women were alive, dead, or
changed their address. Case patients were not excluded on the basis of age or nationality. Women who
had died and women who were unable to attend the hospital for an interview were excluded.
Additionally, women who lived more than 20 miles from the hospital where they applied for treatment
were excluded to avoid high transport fares for the investigation. In total, 508 case patients completed
22
in‐person questionnaires administered by trained interviewers and were included in the analysis. In
some instances, older case patients had their memory aided by a relative who was present with them at
hospital. Pathological reports were confirmed for 452 case patients (89.0%) and were unavailable for 56
(11.0%). Of the laboratory confirmed malignancies, five cases of Paget’s disease and three sarcomas
were identified, but were not excluded.
Control Group
Control subjects were English‐speaking women who had never been diagnosed with cancer of any type.
A convenience sample of in‐patients at hospital for some ailment other than cancer, either surgical or
medical, and women applying for out‐patient treatment was obtained. Approximately 400 of the control
subjects were in‐patients (78.6%) and the remainder were out‐patients (21.4%).The number of women
under age 45 years or over age 70 years was minimised, but there was no formal exclusion on the basis
of age. For controls, the percentage of women under age 45 years was 9.6% and over age 70 years was
3.9% (compared to case patients with respective percentages of 25.6% and 7.4%). Case patients and
control subjects were not matched on any factors. Response rates were not collected. In total, 509
control subjects completed in‐person questionnaires administered by trained interviewers and were
included in the analysis.
3.1.2 1931 US study
A multi‐centre, hospital‐based, unmatched case‐control study was designed to replicate the 1926 UK
study described above, using a sample of women in the US. Hospitals from mostly Pennsylvania, New
York, and Ohio participated, with less than a dozen patients contributed from hospitals in New England,
and Baltimore. Verbal consent may or may not have been obtained prior to inclusion in the study.
23
Case Group
Case patients were English‐speaking women who had been diagnosed with breast cancer. A
convenience sample of mostly women applying for breast cancer treatment was taken. Diagnoses of
malignancy were laboratory‐confirmed, including seven cases of sarcoma. Response rates were not
collected. In total, 679 case patients completed at least part of the in‐person questionnaires
administered by the author’s medical friends and their assistants, and were included in the analysis.
Control Group
Control subjects were English‐speaking women who had never been diagnosed with cancer of any type.
A convenience sample of women under treatment for other complaints in the same hospitals or clinics
as the case patients was obtained. Women under age 45 years or over age 70 years were excluded as
control subjects in some instances, although no formal exclusion criteria was applied. For controls, the
percentage of women under age 45 years was 6.9% and over age 70 years was 6.7% (compared to case
patients with respective percentages of 22.5% and 7.4%). Case patients and control subjects were not
matched on any factors. Response rates were not collected. In total, 567 control subjects completed at
least part of the in‐person questionnaires administered by the author’s medical friends and their
assistants and were included in the analysis.
3.1.3 Both studies
In‐person, structured questionnaires were administered that queried participants about their
demographics (age at record taking, age at operation for cases, civil state, occupation, child deaths),
reproductive history (including age at menarche, age at menopause, duration of menstrual life,
menstrual patterns, age at marriage, parity, type and outcome of delivery, and frequency and duration
of lactation for each childbirth), family history of cancer, recurrence, structural and functional breast
24
abnormalities, and history of breast injuries. For the purposes of the present report, the following five
risk factors were considered: age at menarche, age at menopause, parity, age at marriage (as a proxy for
age at first pregnancy), and duration of lactation for each childbirth (as a proxy for lifetime duration of
lactation). Family history of cancer, previous breast troubles including abnormalities and injuries, and
recurrence were not considered in the present report, but were included in the original historical
studies.
Qualitative Analyses
The results provided in section 4.1 (4.1.1 and 4.1.2) of the present report were those presented in the
1926 UK study and 1931 US study based on general observations of the data by Lane‐Claypon and
Wainwright, respectively. Whether or not a difference was reported between cases and controls for
demographic variables and reproductive risk factors in section 4.1 was not determined by qualitative
analyses in addition to what was provided in the historical studies. By contrast, the results provided in
section 4.2 (4.2.1 and 4.2.2) are quantitative re‐analyses not provided in the historical studies.
Exclusions
Methods of data exclusion varied by risk factor and by study (Table 1). For age at menarche, all women
who could recall the age at onset of menstruation were reported in both studies. For age at menopause,
pre‐menopausal women and women who could not recall age at cessation of menstruation were
excluded (numbers not explicit). Women who had undergone artificial menopause induced by either
hysterectomy or bilateral ovariectomy (15 cases, 29 controls) were excluded from the 1926 UK study
data on age at menopause and parity. Pre‐menopausal women, and women with a marital status of
single were excluded from the parity data in the 1926 UK study, but pre‐menopausal women were
included in the parity data in the 1931 US study. Both livebirths and stillbirths were included in parity
25
data. As a proxy of lifetime duration of lactation, both studies report the duration of lactation for all
livebirths.
3.2 Reanalysis
Data was extracted from the contingency tables provided in the 1926 UK study and 1931 US study for
demographic variables and reproductive risk factors, including: age at menarche, age at menopause,
parity, age at marriage, and lactation (Historical Tables 9 [1926] and 9 [1931], 10 [1926] and 10 [1931],
25 [1926] and 25 [1931], 22 [1926] and 22 [1931], and 32 [1926] and 32 [1931], in respective pairs). Data
was extracted as presented in the Historical Tables provided in the two studies, without any further
exclusions, or alteration of operational definitions. Table 2 shows the number of women included in the
analyses for reproductive risk factors, by risk factor. The original Historical Tables for all demographic
variables and reproductive risk factors that are re‐considered in the present report have been provided
in the Appendix. Historical Table numbers refer to the Table numbers provided in the historical studies.
26
Table 2: Data extraction
1926 UK Study 1931 US Study
Cases Controls Cases Controls
All women 508 509 679 567 Age at menarche
Excluded from Historical Tables 9 [1926] & 9 [1931] 13 4 100 11 Women in analysis 495 505 579 556 Nature of exclusions Age at menarche unknown (13 cases,
4 controls) Missing data (numbers not explicit)
Age at menopause Excluded from Historical Tables 10 [1926] & 10 [1931] 180 177 278 235 Women in analysis 328 332 401 332 Nature of exclusions Pre‐menopausal women (numbers
not explicit); artificial menopause (15 cases, 20 controls); age at menopause unknown (2 cases, 3 controls)
Missing data (numbers not explicit); pre‐menopausal women (numbers not explicit)
Parity Excluded from Historical Tables 25 [1926] & 25 [1931] 247 229 165 55 Women in analysis 261 280 514 512 Nature of exclusions Pre‐menopausal women (numbers
not explicit); artificial menopause (15 cases, 20 controls); marital status of single (numbers not explicit)
Missing data (numbers not explicit); marital status of single (numbers not explicit)
Age at marriage Excluded from Historical Tables 22 [1926] & 22 [1931] 117 86 202 86 Women in analysis 391 423 477 481 Nature of exclusions Marital status of single (numbers not
explicit); age at marriage unknown (1 case, 0 controls)
Missing data (numbers not explicit); marital status of single (numbers not explicit)
All livebirths 921 1392 1714 from 665 women 2451 from 539 women Duration of lactation
Excluded from Historical Tables 32 [1926] & 32 [1931] 52 55 100 244 Children in analysis 869 1337 1614 2207 Nature of exclusions
Still‐births (46 case births, 50 control births); duration of lactation unknown (6 case births, 5 control births)
Missing data (numbers not explicit); duration of lactation unknown (100 case births, 244 control births)
27
Quantitative Analyses
The frequency of categorical variables was compared between cases and controls within study and
between cases or controls across studies using the two‐tailed Pearson Chi‐squared test (66). The
following demographic variables were reported in the 1926 UK study and 1931 US study and were re‐
analysed in the present report, using different categorical cut‐points than those presented in the
historical studies: age (<45 years, 45‐49, 50‐54, 55‐59, 60‐64, 65+) , civil status (single, married,
widowed), nationality (English, Scottish, Irish, American, Other), occupation (housework and domestic
service, factory or warehouse, machinists, dressmakers, etc., clerks and shop assistants, laundry‐work
and housekeepers, manageresses, etc., cooks and kitchen work, and sundry callings, skilled trade, and
teachers and nurses), and child mortality (number of child deaths under age 5 years by category of
viable children per household). For within study analyses, the frequencies of cases were compared to
the frequencies of controls within each study. For across study analyses, the frequencies in cases from
the 1926 UK study were compared to the frequencies in cases from the 1931 US study. Similarly, the
frequencies in controls from the 1926 UK study were compared to the frequencies in controls from the
1931 US study. The original demographic data tables for the 1926 UK study and 1931 US study are
provided in the Appendix (Historical Tables 1 [1926], 1a [1931], 1c [1931], 2 [1926], 2 [1931], 3 [1926], 3
[1931], 4 [1926], 4 [1931], 5 [1926], 8 [1926], and 8 [1931]).
The risk of breast cancer by different reproductive categories was estimated separately for each study
using the odds ratio (OR) calculated from the standard cross‐product of the relevant contingency table.
For the combined data analyses, the Mantel‐Haenszel (M‐H) method (66) was used to estimate ORs and
corresponding 95% confidence intervals (CIs) and to test for homogeneity of estimated ORs across
studies. For ordinal variables with more than two categories, unconditional logistic regression modelling
(67) was used to test for trend and to estimate the OR per category and the associated 95% CIs. In the
28
analyses combining data from both studies, an indicator variable for study was included in the logistic
regression model. The original contingency tables for reproductive factors are provided in the Appendix
(Historical Tables 9 [1926], 9 [1931], 10 [1926], 10 [1931], 22 [1926], 22 [1931], 25 [1926], 25 [1931], 32
[1926], 32 [1931], 33 [1926], 33 [1931], and 33g [1931]).
29
4. Results
Section 4.1 (including 4.1.1, 4.1.2, and all relevant subsections) reports the qualitative conclusions of the
original 1926 UK study and 1931 US study and does not contain my own interpretations. Words and
phrases such as “general similarity,” “practically identical,” “fairly consistent,” and “appreciable” mirror
those used in the historical studies and are repeated in section 4.1 to indicate the qualitative nature of
the findings reported in the historical reports. For qualitative results, reference is made to Historical
Tables only, which are provided in the Appendix. By contrast, section 4.2 (including 4.2.1, 4.2.2, and all
relevant subsections) reports the quantitative conclusions from the reanalysis, looking at the same
variables considered in the qualitative results, but with contemporary statistical techniques and my own
interpretations. Contemporary statistical terminology is used in section 4.2 to convey the strength of
associations and degree of statistical certainty, but such terminology is intentionally absent in section
4.1. For quantitative results, reference is made to Tables and Figures provided in the main body of this
report.
For demographic variables, the qualitative findings reported differences across studies for nationality,
occupation, and deaths among children. Within study considerations reported that cases and controls
were suitable for comparison, although the 1931 US study indicated that social status was higher among
cases. The quantitative reanalysis reported statistically significant differences within studies for all
demographic variables except civil status in the 1926 UK study and statistically significant differences
across studies for all demographic variables except control‐control differences for age and child
mortality. For reproductive risk factors, the qualitative findings reported no effect for age at
menopause, a protective effect for high parity, a protective effect for low age at marriage, elevated risk
for duration of lactation more than two years, and age at menarche data was null in the 1931 US study
but unclear in the 1926 UK study. The quantitative reanalysis reported protective effects in the 1926 UK
30
study, 1931 US study, and studies combined for early age at menopause, increasing parity, early age at
first birth (marriage), and increasing duration of lactation; but results were contradictory for late age at
menarche, with the 1926 UK study reporting an increased risk, the 1931 US study reporting a decreased
risk, and a null effect for both studies combined.
31
4.1 Historical studies
4.1.1 Comparability within across studies
4.1.1.1 Nationality (Historical Tables 1 [1926], 1 [1931a], and 1 [1931c])
The 1926 UK study reported a qualitative similarity between the nationalities of the cases and controls,
with most women reporting a nationality within the UK (Historical Table 1 [1926]). The 1931 US study
was comprised of a mostly American‐born sample, with qualitatively more American cases (81%) than
American controls (62%) (Historical Table 1 [1931a]). Of the foreign‐born women in the 1931 US study,
most reported coming from countries in Europe and the United Kingdom (Historical Table 1 [1931c]).
The 1931 US study indicated that proportions of nationalities between cases and controls were different
within the 1931 US study, and across studies, with comparatively few English, Scottish, and Irish women
in the 1931 US study.
4.1.1.2 Age (Historical Tables 2 [1926], and 2 [1931])
For the 1926 UK study, the mean ages of women in 1924 were 53.8 years among cases and 53.6 years
among controls (Historical Table 2 [1926]). The mean age for British cases was 51.4 years, and for
American cases was 52.9 years; and the mean age for British controls was 53.6 years, and for American
controls was 54.3 years (Historical Table 2 [1931]). Due to differential exclusion criteria between cases
and controls, both studies reported: a) more cases than controls with age less than 45 years (differences
of 81 women in the 1926 UK study and 102 women in the 1931 US study); and b) more controls than
cases in the age period 45‐49 years (differences of 41 women in the 1926 UK study and 47 women in the
1931 US study). A qualitative between‐study comparison of proportions, including those within age
groupings less than 35 years, less than 45 years, and 45‐54 years indicated that the age data in the two
countries appeared “practically identical” (for 1926 UK study: 5.3%, 20.1%, 39.9%, respectively; and for
1931 US study: 5.7%, 18.7%, 34.3%, respectively).
32
4.1.1.3 Civil status (Historical Tables 3 [1926], and 3 [1931])
The frequency of single women in the 1926 UK study was higher among cases (n=116) than controls
(n=87) (Table 3 [1926]). The frequency of single women in the 1931 US study was also higher among
cases (n=91) than controls (n=32) (Historical Table 3 [1931]). The ratio of single cases to single controls
was higher in the 1931 US study (2.84) than the 1926 UK study (1.33). In general, qualitative
comparisons across studies were in agreement.
4.1.1.4 Occupation (Historical Tables 4 [1926], 5 [1926], and 4 [1931])
A qualitative comparison of the women’s occupations in the 1926 UK study found similar frequencies
between cases (Historical Table 4 [1926]) and controls (Historical Table 5 [1926]), indicating no
relationship between breast cancer and either outside work in general, or of any special occupation in
particular. In the 1931 US study, the percentage of women who did outside work before marriage,
regardless of civil state, was broadly comparable between cases (41.1%) and controls (34.0%) (Historical
Table 4 [1931]). Smaller percentages of women reported outside work in the 1931 US study compared
to the 1926 UK study. However, the data indicated “a general similarity” within the 1931 US study and
across studies.
4.1.1.5 Deaths among children (Historical Tables 8 [1926], and 8 [1931])
Number of deaths among children under age five years, from families of completed size and excluding
families of pre‐menopausal women, was considered as a proxy of social status (Historical Table 8 [1926]
and 8 [1931]). The 1926 UK study did not indicate any definite difference in deaths among children
between cases and controls, and reported no appreciable differences “in general” between the social
status (occupation and deaths among children considered together) of cases and controls in the 1926 UK
study. The 1931 US study showed that there were slightly more deaths among children of the controls
33
than children of the cases (Historical Table 8 [1931]), and indicated that social status was higher among
cases.
4.1.2 Aetiologic findings in historical studies
4.1.2.1 Age at menarche (Historical Tables 9 [1926], and 9 [1931])
The mean ages at menarche differed by 0.11 years, or approximately 32 days, between cases (14.8
years) and controls (14.7 years) in the 1926 UK study. The distribution for age at menarche was more
widely spread among controls, with 20.0% reporting an age at menarche less than 13 years and 25.7%
reporting an age at menarche above 15 years, compared to 13.3% and 22.4%, respectively among cases
(Historical Table 9 [1926]). It was unclear whether these differences were appreciable in the 1926 UK
study. In the 1931 US study, the mean ages at menarche were 13.8 years for cases and 13.9 years for
controls (Historical Table 9 [1931]). Findings across studies were considered to be “fairly consistent.”
The 1931 US study utilised within study and across study comparisons to report that the age at onset of
menstruation was not related with the subsequent development of breast cancer.
4.1.2.2 Age at menopause (Historical Tables 10 [1926], and 10 [1931])
Women in the 1926 UK study reported a wide range for age at menopause, from 20 to 60 years. The
mean reported age at menopause was 48.27 years for cases and 47.56 years for controls (Historical
Table 10 [1926]). There appeared to be no difference in age at menopause between all cases and all
controls. However, a difference that appeared to be appreciable was observed in the age at menopause
of married versus widowed women (difference ± probable error of the difference was 1.20 ± 0.627 for
cases and 2.82 ± 0.396 for controls). The 1931 US study reported similar proportions and indicated no
evidence that age at menopause and breast cancer were associated. However, data on artificial
menopause indicated that artificial menopause protected against breast cancer (23 cases and 38
controls in the 1931 US study; and 15 cases and 29 controls in the 1926 UK study).
34
4.1.2.3 Parity (Historical Tables 25 [1926], and 25 [1931])
In the 1926 UK study, post‐menopausal married controls birthed more children (1392 children and
stillbirths) than post‐menopausal married cases (921 children and stillbirths) (Historical Table 25 [1926]).
A statistical inquiry contributed by Dr. Major Greenwood (Chapter 8 of the 1926 UK study) that
considered married women separately for each marriage, reported a mean of 3.48 viable children with a
standard deviation of 2.88 for cases, and a mean of 5.34 viable children with a standard deviation of
3.68 for controls. A crude multiple regression equation for estimating the number of children in terms of
age at marriage and duration of marriage was used, with the equations for the cases predicting the
mean of the controls and vice versa. This technique predicted a mean for cases of 4.72±0.13 and for
controls of 3.89±0.10. The reported respective differences of 1.24±0.18 and 1.45±0.18 were “highly
significant,” indicating that the cases were less fertile than the controls. The 1931 US study reported
findings similar to the 1926 UK study, with an elevated fertility in the controls. The average difference
between cases and controls was 2.01 viable children per married woman in the 1931 US study, agreeing
with the corresponding value of 1.44 in the 1926 UK study (Historical Tables 26 [1931] and 26 [1926],
respectively).
4.1.2.4 Age at marriage (Historical Tables 22 [1926], and 22 [1931])
For all married and widowed women in the 1926 UK study, the mean age at marriage of cases was
26.21, and of controls was 24.93, with the distribution for the controls generally being lower throughout
(Historical Table 22 [1926]). The age at marriage in the 1931 US study for cases and controls were
considered “exactly similar” to those in the 1926 UK study (Historical Table 22 [1931]). The age at
marriage was observed to be lower in the controls than in the cases, indicating that marriage protected
against subsequent breast cancer, with women who married earlier experiencing a lower risk of breast
cancer.
35
4.1.2.5 Duration of lactation (Historical Tables 32 [1926], 33 [1926], 32 [1931], and 33 [1931])
The 1926 UK study found a higher percentage of cases with non‐lactation (14.5% of cases versus 7.4% of
controls) and with excessively prolonged lactation, defined as suckling for over 2 years (3.0% in cases
versus 0.3% in controls). The probable error for these extremes was considered of “definite
significance,” with reported differences of 7.2±1.4 percent for non‐lactation cases and 2.8±0.16 for
excessive lactation cases (Historical Table 32 [1926] and 33 [1926]). Accordingly, the evidence showed
that lactation for an ordinary time protects against cancer, but that lactation either for too brief or too
long a period predisposed to cancer. The 1931 US study considered stillbirths among those non‐lactated
and found that for each 100 fertile married women, among cases there were 56 full‐term babies who
were not nursed compared to 85 full‐term babies among controls (Historical Table 32 [1931] and 33
[1931]). This finding was deemed contradictory to the 1926 UK study, in which for each 100 fertile
married women, there were 81 full‐term babies who were not nursed reported among cases and 60 full‐
term babies who were not nursed among controls. For duration of lactation more than two years,
evidence in the 1931 US study supported the 1926 UK study, with notably fewer babies nursed over two
years, per 100 fertile married women, in controls than in cases (2.3% in cases versus 0.3% in controls
(Historical Table 32g [1931]).
36
4.2 Reanalysis
4.2.1 Comparability within and across studies (Table 3)
Demographic characteristics of women varied across levels of covariates (Figures 5‐14). Statistically
significant differences within studies for all demographic variables were observed, except for data on
civil status in the 1926 UK study, which was borderline (P = 0.063). Statistically significant differences
across studies for all demographic variables were observed, except for the control‐control differences
for age (P = 0.17) and child mortality (P = 0.071) (Table 3).
37
Table 3: Comparability of demographic variables within and across studies Within study comparison Across study comparison
1926 UK Study 1931 US Study Cases Controls
Demographic Factor Cases Controls Cases Controls 1926 UK 1931 US 1926 UK 1931 US
Nationality English 296 307 12 16 296 12 307 16 Scotch 178 146 3 0 178 3 146 0 Irish 23 46 11 36 23 11 46 36 American 0 0 493 349 0 493 0 349 Other 11 10 103 138 11 103 10 138 χ2 P‐value 0.011 <0.001 <0.001 <0.001Age <45 years 130 49 137 35 130 137 49 35 45‐49 101 142 95 142 101 95 142 142 50‐54 102 127 114 111 102 114 127 111 55‐59 68 74 91 91 68 91 74 91 60‐64 57 69 73 63 57 73 69 63 65+ 50 48 98 64 50 98 48 64 χ2 P‐value <0.001 <0.001 0.023 0.17Civil Status Single 116 87 91 32 116 91 87 32 Married 292 321 420 381 292 420 321 381 Widowed 100 101 126 128 100 126 101 128 χ2 P‐value 0.063 <0.001 0.001 <0.001Occupation
Housework, domestic 162 158 26 34 162 26 158 34Factory, machinists 35 26 38 36 35 38 26 36Dressmakers, etc. 38 19 48 40 38 48 19 40Clerks, shop assistants 30 19 71 31 30 71 19 31Laundry‐work, manageresses, etc.
41 37 0 2 41 0 37 2
Cooks, kitchen work, sundry callings
16 20 13 3 16 13 20 3
Skilled trade 12 1 2 0 12 2 1 0Teachers, nurses 28 27 62 38 28 62 27 38χ2 P‐value 0.028 0.004 <0.001 <0.001
Child mortality
1‐3 viable children 32 child deaths
24 46 52 32 46 24 52
4‐6 44 65 54 121 44 54 65 121 7‐9 58 93 32 112 58 32 93 112 10+ 16 107 33 149 16 33 107 149 χ2 P‐value <0.001 <0.001 0.001 0.071
38
4.2.1.1 Nationality (Table 2)
Nationality was significantly different between cases and controls within studies (1926 UK study: χ2 =
11.1, P = 0.011; 1931 US study: χ2 = 40.9, P = <0.001). In the 1926 UK study, women were predominantly
from the United Kingdom (97.9%), and in the 1931 US study, women were predominantly from America
(72.5%).
4.2.1.2 Age (Table 2)
The age of case patients was statistically different than the age of control subjects within both studies
(1926 UK study: χ2 = 47.7, P <0.001; 1931 US study χ2 = 69.0, P <0.001). This difference was explained, in
part, by differences in the age less than 45 years category in which control patients, but not case
subjects, were minimised at the study design stage. When excluding the lowest age category, the cases
and controls were no longer statistically different in the 1926 UK study, but remained statistically
different in the 1931 US study (χ2 = 3.09, P = 0.54; χ2 = 17.23, P = 0.002, respectively). Across study
comparisons revealed that the ages of controls were not different between the 1926 UK study and the
1931 US study (χ2 = 5.26, P = 0.26), but the ages of cases were (χ2 = 13.0, P = 0.020). Due to differential
inclusion criteria for the bottom two age groupings, it was difficult to assess whether breast cancer was
associated with age in either sample.
4.2.1.3 Civil status (Table 2)
The civil status of cases and controls was different within both the 1926 UK and 1931 US studies (χ2 =
5.52, P = 0.063; and χ2 = 22.54, P <0.001, respectively). More cases than controls were single in both
studies. However, the proportions of women in the 1926 UK study reporting a civil status of single was
higher than those reporting a civil status of single in the 1931 US study (14.3% of cases and 5.9% of
controls versus 22.8% of cases and 17.1% of controls, respectively), differences that were statistically
41
significant (χ2 = 32.8, P <0.001, for case difference and χ2 = 14.7, P = 0.001 for control difference). These
data indicated that single women were at an elevated risk of breast cancer.
4.2.1.4 Occupation (Table 2)
Respondent occupation was significantly different between cases and controls within studies (1926 UK
study: χ2 = 15.7, P = 0.028; 1931 US study: χ2 = 21.2, P = 0.004), and across studies (comparing cases: χ2 =
165, P <0.001; comparing controls: χ2 = 115.3, P <0.001). The most marked difference across studies was
the smaller frequency of “Housework and domestic service.” It was difficult to assess occupation in
relation to breast cancer risk, as response rates varied within and across studies. Notably more cases
provided information on occupation within both studies (362 cases and 307 controls in 1926 UK study
and 260 cases and 184 controls in 1931 US study) and more women provided data in the 1926 UK study
(669 total women) than in the 1931 US study (444 total women).
4.2.1.5 Deaths among children (Table 2)
The number of deaths among children, by grouping of the number of viable children in that family, was
different within studies (1926 UK study: χ2 = 40.7, P <0.001; 1931 US study: χ2 = 29.6, P <0.001), and
across studies (comparing cases: χ2 = 16.3, P = 0.001; comparing controls: χ2 = 7.03, P = 0.071), with
more controls reporting deaths among children than cases in both studies. This data indicated that
higher socioeconomic status was positively associated with breast cancer risk in both study samples. It
was not possible to ascertain how many women provided data for deaths among children.
4.2.2 Aetiologic findings in reanalysis
Study‐specific and combined risk estimates varied by reproductive risk factor (Table 4). Protective
effects for early age at menopause, increasing parity, early age at first birth (marriage), and high
duration of lactation were reported in the 1926 UK study, 1931 US study, and studies combined. Results
42
were contradictory for late age at menarche, with the 1926 UK study reporting an increased risk, the
1931 US study reporting a decreased risk, and a null effect for both studies combined.
Table 4: Historical reanalysis of reproductive risk factors and breast cancer risk 1926 UK Study 1931 US Study Combined
Risk Factor Cases Controls Crude OR (95% CI) Cases Controls Crude OR (95% CI) Combined OR (95% CI) Homogeneity of ORs (χ2 P‐value)
Age at menarche <13 years 66 101 1.00 (baseline) 134 123 1.00 (baseline) 1.00 (baseline) ‐ 13‐14 232 202 1.76 (1.22 ‐ 2.53) 277 244 1.04 (0.77 ‐ 1.41) 1.29 (1.02 ‐ 1.62) 0.030 15+ 197 202 1.49 (1.03 ‐ 2.16) 168 189 0.82 (0.59 ‐ 1.13) 1.06 (0.84 ‐ 1.35) 0.015 Age at menopause <44 years 51 66 1.00 (baseline) 60 66 1.00 (baseline) 1.00 (baseline) ‐ 44‐47 86 109 1.02 (0.64 ‐ 1.62) 102 109 1.03 (0.66 ‐ 1.60) 1.03 (0.75 ‐ 1.41) 0.98 48‐51 136 111 1.59 (1.01 ‐ 2.48) 167 111 1.65 (1.08 ‐ 2.54) 1.62 (1.19 ‐ 2.21) 0.89 52+ 55 46 1.55 (0.90 ‐ 2.66) 72 46 1.72 (1.03 ‐ 2.88) 1.64 (1.13 ‐ 2.38) 0.78 Parity 0 children 48 35 1.00 (baseline) 116 54 1.00 (baseline) 1.00 (baseline) ‐ 1 29 23 0.92 (0.46 ‐ 1.86) 107 47 1.06 (0.66 ‐ 1.70) 1.01 (0.69 ‐ 1.50) 0.74 2 33 28 0.86 (0.44 ‐ 1.68) 76 64 0.55 (0.35 ‐ 0.88) 0.64 (0.44 ‐ 0.94) 0.29 3 34 32 0.77 (0.40 ‐ 1.49) 75 68 0.51 (0.32 ‐ 0.82) 0.59 (0.40 ‐ 0.86) 0.31 4 33 25 0.96 (0.49 ‐ 1.90) 55 65 0.39 (0.24 ‐ 0.65) 0.53 (0.36 ‐ 0.79) 0.036 5 21 19 0.81 (0.38 ‐ 1.73) 29 43 0.31 (0.17 ‐ 0.57) 0.44 (0.28 ‐ 0.70) 0.053 6 16 31 0.38 (0.17 ‐ 0.81) 17 35 0.23 (0.11 ‐ 0.45) 0.28 (0.17 ‐ 0.47) 0.33 7 14 17 0.60 (0.26 ‐ 1.39) 11 24 0.21 (0.09 ‐ 0.48) 0.35 (0.20 ‐ 0.61) 0.080 8 20 20 0.73 (0.34 ‐ 1.56) 4 43 0.04 (0.01 ‐ 0.15) 0.22 (0.13 ‐ 0.37) <0.001 9 5 13 0.28 (0.09 ‐ 0.89) 8 18 0.21 (0.08 ‐ 0.52) 0.23 (0.11 ‐ 0.48) 0.69 10+ 8 37 0.16 (0.06 ‐ 0.41) 16 51 0.15 (0.07 ‐ 0.30) 0.15 (0.08 ‐ 0.27) 0.90 Age at marriage <20 years 41 75 1.00 (baseline) 98 149 1.00 (baseline) 1.00 (baseline) ‐ 20‐23 128 151 1.55 (0.99 ‐ 2.43) 157 172 1.39 (0.99 ‐ 1.94) 1.44 (1.10 ‐ 1.89) 0.70 24‐27 96 101 1.74 (1.08 ‐ 2.80) 99 89 1.69 (1.15 ‐ 2.49) 1.71 (1.27 ‐ 2.31) 0.93 28+ 126 96 2.40 (1.49 ‐ 3.86) 123 71 2.63 (1.77 ‐ 3.93) 2.53 (1.87 ‐ 3.44) 0.77 Duration of lactation 0‐3 months 190 248 1.00 (baseline) 449 552 1.00 (baseline) 1.00 (baseline) ‐ 4‐11 507 632 1.05 (0.84 ‐ 1.31) 693 937 0.91 (0.78 ‐ 1.07) 0.95 (0.84 ‐ 1.09) 0.31 12+ 172 457 0.49 (0.38 ‐ 0.64) 472 718 0.81 (0.68 ‐ 0.96) 0.69 (0.60 ‐ 0.80) 0.0017
4.2.2.1 Age at menarche (Figure 15 and Table 4)
The most marked variation across studies was observed for age at menarche. Compared to women with
age at menarche less than 13 years, the 1926 UK study found a modest increase in risk among women
with age at menarche 13‐14 years (Crude OR = 1.76, 95% CI = 1.22‐2.53) and 15+ years (Crude OR = 1.49,
95% CI = 1.03‐2.16), whereas the 1931 US study found no effect in the age at menarche 13‐14 years
group (Crude OR = 1.04, 95% CI = 0.77‐1.41) and a modest protective effect among women with age at
menarche 15+ years (Crude OR = 0.82, 95% CI = 0.59‐1.13). The M‐H test of homogeneity of ORs
reported significant heterogeneity between the study‐specific crude ORs within both age groups (χ2 =
4.72, P = 0.030, for age at menarche 13‐14 years; and χ2 = 5.89, P = 0.015, for age at menarche 15+
years) (Table 4). The study‐adjusted logistic regression test reported no effect for the categories of age
at menarche (OR = 1.00, 95% CI = 0.89‐1.12) (Figure 15).
0
0.5
1
1.5
2
2.5
3
<13 13‐14 15+
Crud
e OR (95%
CI)
Age at menstrual onset (years)
Figure 15: age at menarche
1926 UK Study
1931 US Study
Combined
45
4.2.2.2 Age at menopause (Figure 16 and Table 4)
The study‐adjusted logistic regression test reported an approximate 24% increase in risk of breast cancer
across categories of age at menopause (OR = 1.24, 95% CI = 1.11‐1.39). However, this elevation in risk
was not present in the age at menopause 44‐47 years grouping, but only in the groupings of 48‐51 years
and 52 or more years. In both studies, women with age at menopause 44‐47 years experienced no
modification in breast cancer risk compared to women with age at menopause less than 44 years (M‐H
combined OR = 1.03, 95% CI = 0.75‐1.41). Risk was significantly elevated among women undergoing
menopause above age 48 years, with approximately equal combined risk estimates within age groupings
48‐51 years (M‐H combined OR = 1.62, 95% CI = 1.19‐2.21) and 52 or more years (M‐H combined OR =
1.64, 95% CI = 1.13‐2.38) (Figure 16). The findings of the two studies were consistent, with no evidence
for heterogeneity across studies (Table 3).
0
0.5
1
1.5
2
2.5
3
3.5
<44 44‐47 48‐51 52+
Crud
e OR (95%
CI)
Age at menstrual cessation (years)
Figure 16: age at menopause
1926 UK Study
1931 US Study
Combined
46
4.2.2.3 Parity (Figure 17 and Table 4)
Logistic regression analyses controlling for study reported an approximate 18% reduction in breast
cancer risk per child birthed (OR = 0.82, 95% CI = 0.79‐0.85), with evidence of a statistical trend (z = ‐
10.50, p <0.001). Compared to nulliparous women, the protective effect of increasing parity was only
observed for women who birthed more than one child (Figure 17). Uniparous women experienced no
risk modification (M‐H combined OR = 1.01, 95% CI = 0.69‐1.50). Women who birthed two children
experienced an approximate 36% reduction in risk (M‐H combined OR = 0.64, 95% CI = 0.44‐0.94), and
risk reduction successively increased, with women who birthed ten or more children experiencing an
approximate 85% reduction in risk (M‐H combined OR = 0.15, 95% CI = 0.08‐0.27). Crude ORs were not
significantly heterogeneous across studies, except for the results of women having 4 children and 8
children (Table 4).
00.20.40.60.81
1.21.41.61.82
0 1 2 3 4 5 6 7 8 9 10+
Crud
e OR (95%
CI)
Births (n)
Figure 17: parity
1926 UK Study
1931 US Study
Combined
47
4.2.2.4 Age at marriage (Figure 18 and Table 4)
For the purposes of the present reanalysis, data for age at marriage was used as a proxy for age at first
birth. An approximate 2.5‐fold increase in breast cancer risk was observed among women who were
married at or above age 28 years compared to women who were married below age 20 years (M‐H
combined OR = 2.53, 95% CI = 1.87‐3.44). Breast cancer risk was also elevated, but to a lesser extent,
among women with age at marriage 20‐23 years (M‐H combined OR = 1.44, 95% CI = 1.10‐1.89) and 24‐
27 years (M‐H combined OR = 1.71, 95% CI = 1.27‐2.31) (Figure 18). This relationship of successive
increases in breast cancer risk by age at marriage grouping followed a statistical trend (z = 6.19, p
<0.001), with each increase in age at marriage grouping resulting in an increase in breast cancer risk (OR
= 1.33, 95% CI = 1.22‐1.46). The results of the studies were very consistent with no evidence for
heterogeneity of study‐specific crude ORs (Table 4).
00.51
1.52
2.53
3.54
4.5
<20 20‐23 24‐27 28+
Crud
e OR (95%
CI)
Age at marriage (years)
Figure 18: age at marriage
1926 UK Study
1931 US Study
Combined
48
4.2.2.5 Duration of lactation (Figure 19 and Table 4)
For duration of lactation, the historical studies provided the length of time that each child of case
mothers and control mothers were breastfed. Based on the data available, it was not possible to
determine duration of lactation for each woman. Instead, data using children as the unit of measure
provided a proxy for the risk of breast cancer for case mothers and control mothers. In total, the 1926
UK study included 869 children of cases and 1337 children of controls and the 1931 US study included
1614 children of cases and 2207 children of controls. Compared to the total children of cases and
controls who were breastfed for 0‐3 months, the M‐H combined OR for being fed 12 or more months
was 0.69 (95% CI = 0.60‐0.80), although the risk estimates were significantly different (P = 0.0017) in the
1926 UK study and 1931 US study (Crude OR = 0.49, 95% CI = 0.38‐0.64; and Crude OR = 0.81, 95% CI =
0.68‐0.96, respectively). The effect on breast cancer risk for the mothers of children who were breastfed
for 4‐11 months were contradictory between the two studies with respect to direction, but the effects
were small and non‐significant in both studies (1926 UK study: Crude OR = 1.05, 95% CI = 0.84‐1.31; and
Crude OR = 0.91, 95% CI = 0.78‐1.07) (Figure 19).
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0‐3 4‐11 12+
Crud
e OR (95%
CI)
Duration of lactation for each child (months)
Figure 19: duration of lactation
1926 UK Study
1931 US Study
Combined
49
5. Discussion
5.1 Pioneering work and limitations
Lane‐Claypon’s role as an epidemiologic pioneer has been made evident through considerations of the
epidemiologic “firsts” that have been attributed to her (1, 2, 6, 7, 10), including publishing the first
retrospective cohort study (68) and the first case‐control study (5). The 1926 UK study, together with the
1931 US study provided the first evidence from observational studies that low fertility, high age at
marriage, and induced menopause were associated with breast cancer risk. Underlying Lane‐Claypon’s
innovative work was a meticulous attention to the complexities of epidemiologic enquiry, including the
uncertainties exposed by her methodology, expressing what Leopold and Winkelstein describe as “an
extraordinarily rigorous and subtle intelligence at work” (6). In her attempts to ascertain associations of
interest in the 1926 UK study, there was a careful consideration of the potential limitations in study
design and sample selection.
The potential limitations discussed in the historic studies illustrate how the field of epidemiology has
benefited from, and advanced since, the first case‐control study. Indeed, many of the limitations
considered by Lane‐Claypon (section 5.1.1) have come to be considered fundamental epidemiologic
concepts. Additionally, a number of limitations not fully considered by Lane‐Claypon (section 5.1.2) have
subsequently been identified and ways to minimise their impact on study design have become standard
practice for case‐control studies.
5.1.1 Limitations discussed by Lane‐Claypon
When considering the suitability for comparison of the cases and controls, Lane‐Claypon noted that
cases were more likely to be “better‐to‐do” compared to controls who were admitted to hospital for
other diseases. This was supported by data for child mortality, although response rates were low. That a
hospital‐based convenience sample was prone to selection biases was not a concept that had entered
50
into the literature of the time, but nonetheless Lane‐Claypon expressed a relatively astute awareness
that this may have been a problem for the sample that was selected in the 1926 UK study. Lane‐Claypon
observed at length the difficulty of validly assessing socioeconomic status at that time and commented
on the limitations of using the following proxies as indicators of socioeconomic status: women’s
occupations before and after marriage; and the number of child mortalities in families.
In addition to the impracticability of securing a full control, Lane‐Claypon considered drawbacks in self‐
reporting, particularly among elderly women who “cannot remember the past with any real accuracy”
(5, p. 2), and expressed that potential errors may have affected the accuracy of retrospective data.
However, she did not quite articulate how drawbacks in recall may have biased estimates of breast
cancer risk, as she did not appear to consider that errors in recall would be most problematic when
differential between cases and controls. Lane‐Claypon did not appear to consider the accuracy of data
on duration of lactation to be affected by errors in recall, stating:
“…it was remarkable that the data are almost complete. The duration of lactation seemed to be a point which was readily remembered by the women. It is likely that the duration given was not always accurate to a few weeks, but this degree of accuracy is amply sufficient for the present purpose.” (5, p. 53)
Errors in recall were mentioned as potentially problematic both among elderly women, as above, and
also among women who had undergone a recent breast cancer operation or a distant breast cancer
operation several years previously. Other limitations were discussed in the context of the risk factors not
re‐analysed in the present report. Of particular interest was an inability to attain complete and reliable
data relating to family history of cancer (5, p. 58‐63).
51
5.1.2 Limitations not fully considered by Lane‐Claypon
In addition to the limitations considered by Lane‐Claypon, subsequent epidemiologic concepts and
methodologies have revealed further limitations unknown to Lane‐Claypon. Perhaps the most notable
limitation was the statistical techniques available during the 1926 UK study, which usually required
qualitative assessments about differences in proportions or means of cases and controls. The present
reanalysis has helped to elucidate whether differences were statistically significant using chi‐squared p‐
values as well as crude ORs (and study‐adjusted ORs for combined risk estimates) with 95% CIs.
In contrast to qualitative assessments that led Lane‐Claypon to conclude that the cases and controls
were “suitable for comparison,” Pearson chi‐squared tests revealed that all demographic variables were
statistically significantly different, with the exception of civil status, where the difference was borderline
(P =0.063). Using this information, modern epidemiologists would likely incorporate these and other
variables into a multivariate regression model in order to adjust for potential confounding. However, as
all data was extracted from unlinked contingency tables, adjustment for known confounders was not
possible in the reanalysis. The possibility of developing a model that controlled for aggregate values of
confounding factors was considered, but was deemed impractical because the interdependence of
breast cancer risk factors would require assumptions that would have limited the explanatory power of
such a model. Nonetheless, the crude ORs proved to agree relatively well with adjusted ORs reported
since the 1926 UK study, as discussed in section 5.3.
Epidemiologic practice has subsequently incorporated a number of ways to limit selection bias at the
design stage that were not considered in the 1926 UK study. Potential limitations that may have led to
selection biases and ways that such limitations could have been limited, respectively, are provided in
Table 5.
52
There was some indication of an imbalance in missing data, which implies that selection bias may have
been a problem in the 1926 UK study, as was particularly apparent in the case‐control imbalance for
age. An additional limitation of the 1926 UK study was that some older case patients, but not control
subjects, had their memories aided by relatives with them in the hospital, which may have biased
Table 5: Limitations not fully considered by Lane‐Claypon
Limitations not fully considered by Lane‐Claypon
Possible means to address potential limitations
i) Unmatched, unstratified cases and controls Match or stratify controls to balance confounding factors
ii) A convenience sample of cases who had applied to breast cancer treatment
Random sampling technique to include cases so that bias would be limited to chance
iii) Cases of breast cancer were eligible only if they had applied for treatment
All women diagnosed with breast cancer included as potentially eligible to account for any systematic differences in a woman’s decision to apply for treatment
iv) A convenience sample of controls attending hospital
Random sampling technique to include controls attending hospital so that bias would be limited to chance
v) Differing inclusion criteria of cases and controls on the basis of age
Ensure the same inclusion criteria and rates on the basis of age to minimise systematic differences between cases and controls
vi) Inducements offered to cases Not offering inducements because may limit generalisabilty by socioeconomic status
vii) Inducements offered to cases but not to controls
Using the same manner to contact/include cases and controls to minimise differentials in non‐response biases
viii) Requests for study participation via a letter for cases, but using in‐person requests for controls
Using the same manner to contact/include cases and controls to minimise differentials in non‐response biases
ix) Only one letter sent to request study participation
Utilisation of follow‐up letters to increase response rates and ascertain reasons for non‐entry to minimise and explain non‐response biases
x) Unknown response rates Collect accurate response rates of cases and controls to minimise and explain non‐response biases
53
results. Finally, not all cases had diagnoses pathologically confirmed, and of the cases with laboratory
confirmed diseases, Paget’s disease and sarcomas were included as having breast cancer, both which
are generally excluded in observational studies on breast cancer risk today. That the hospitals in the
1926 UK study were all located in and around London and Glasgow limits the generalisability of the
findings to those locales.
5.1.3 Limitations of the 1931 US study
The 1931 US study claimed to have improved upon the 1926 UK study with respect to method and
timing of case inclusion. According to Wainwright, recalling patients to hospital for the purposes of
study inclusion was a limitation in the 1926 UK study, particularly because many cases had been
operated upon several years prior whereas the 1931 US study included cases applying for treatment. By
including a convenience sample of women applying to hospital for breast cancer treatment in the 1931
US study, as compared to the 1926 UK study method of recalling a convenience sample of women who
had previously been treated for breast cancer, the 1931 US study minimises several of the potential
limitations in selection bias described above (points vi, vii, viii, ix), but potential limitations with respect
to selection bias were shared in both studies (points i, ii, iii, iv, v, xi).
Further, the 1931 US study had additional potential limitations that were not present in the 1926 UK
study. Most notably, the 1931 US study used doctors and nurses to fill in portions of the questionnaire
between their duties, rather than using trained interviewers to conduct the entire questionnaire at one
sitting as was done in the 1926 UK study. This led to additional missing data problems in the 1931 US
study, as not all respondents had completed the questionnaire; as well as potential biases, as
interviewers were untrained and the duration between separate questionings was not recorded. Missing
data problems were particularly apparent for data on occupation (Figure 12).
54
5.2 Comparison of findings to contemporary epidemiological evidence
Findings as stated in the 1926 UK study and the 1931 US study were consistent with contemporary
breast cancer epidemiological evidence for parity and age at first full‐term pregnancy only; and from the
quantitative reanalysis for age at menopause, parity, age at first birth, and breast feeding (Table 5).
Contemporary statistical techniques thus corrected erroneous conclusions in the historical studies for
age at menopause and lifetime duration of lactation. Despite bias and confounding in the historical
studies, it was surprising to note how well the findings from the reanalysis of the 1926 UK study and
1931 US study agreed with modern epidemiologic findings, supporting current evidence for four of the
five reproductive risk factors examined. Data for age at menarche however, was inconsistent with
current findings.
Table 6: Comparison of current evidence to results Breast cancer risk factor Evidence Quantitative reanalysis Qualitative findings 1926 UK 1931 US Combined 1926 UK 1931 US Late age at menarche ↓ ↑ ↓ − Unclear − Early age at menopause ↓ ↓ ↓ ↓ − − Increasing parity ↓ ↓ ↓ ↓ ↓ ↓ Early age at first birth (marriage) ↓ ↓ ↓ ↓ ↓ ↓ Increasing duration of lactation ↓ ↓ ↓ ↓ ↑ ↑
RR calculations for age, nationality, and socioeconomic status were not performed in the quantitative
reanalysis because the historical reports considered these factors for the purposes of comparability
between cases and controls only and reported a qualitative similarity, therefore concluding that the two
series were suitable for comparison. However, the utilisation of chi‐square tests in the quantitative
reanalysis indicated that there were significant within study and across study differences for these
variables. That age, nationality, and socioeconomic status have all been shown to be associated with
breast cancer risk indicates that these variables should have been considered potential confounders and
55
incorporated into a multivariate analysis. However, this was not considered in the historical qualitative
results, as reasonably homogeneous was sufficient at the time, and not possible in the quantitative
reanalysis, as all data was unlinked.
5.2.1 Age at menarche and age at menopause
5.2.1.1 Findings in historical studies
Findings as stated in the historical studies were inconsistent with contemporary evidence for both age at
menarche and age at menopause in both studies. As stated by Lane‐Claypon: “Those points which do
not show appreciable differences between the two series are: (a) The age at onset of the catamenia. (b)
The age at cessation of the catamenia…” (5, p. 131) Potential limitations described above may help to
explain the discrepancy for age at menarche. Recall bias may have been an issue. However, self‐
reported age at menarche has been shown to be highly correlated with actual age at menarche (69). It is
more likely that selection biases posed a problem, as has been discussed previously.
Lane‐Claypon postulated that previous reports of higher breast cancer rates by age at menopause were
due to a sort of survival bias. That is, differences in the ages of women attending hospital, rather than
differential ages at menopause, explained increased breast cancer risks. For age at menopause, the
mean ages did not show an appreciable difference between cases and controls in either study. Had
more precise statistical methodologies been available, it is likely that an association would have been
observed in both studies. The reason underlying the observed difference in the age at menopause of
married versus widowed women between cases and controls in the 1926 UK study is unclear, but may
either express a real difference within a subset of all women included, or a spurious association, as the
conclusion was based on small numbers.
Wainwright reported a difference in both studies between the proportion of cases and controls that
underwent induced menopause. Wainwright concluded that “…an artificial menopause to an unknown
56
extent helps protect against breast cancer” (13, p. 2622). As far as can be ascertained, this was the first
evidence from observational studies that induced menopause reduces breast cancer risk. As discussed
above, this finding has repeatedly been observed in subsequent epidemiologic enquiries (37‐42).
5.2.1.2 Findings in reanalysis
Data indicate that women who undergo an early age at menarche experience a moderate increase in
breast cancer risk, with risk estimates ranging from 1.1 to 1.5 (Table 1). In general, breast cancer risk
declines 10‐20% with each year that menarche is delayed (70). Findings from the quantitative reanalysis
of the historical studies were inconsistent with contemporary epidemiological evidence. This
inconsistency was more apparent in the 1926 UK study, which found a moderate, but statistically
significant, increase in risk among women with age at menarche 13‐14 years (Crude OR = 1.76, 95% CI =
1.22‐2.53) and 15 or more years (Crude OR = 1.49, 95% CI = 1.03‐2.16) compared to women with age at
menarche less than 13 years. The 1931 US study, however, found no effect in the age at menarche 13‐14
years group (Crude OR = 1.04, 95% CI = 0.77‐1.41) and a modest protective effect among women with
age at menarche 15 or more years (Crude OR = 0.82, 95% CI = 0.59‐1.13). While the risk estimate for age
at menarche 15 or more years in the 1931 study is consistent with contemporary evidence, the risk
estimates for age at menarche 13‐14 years in the 1931 US study, both age groupings in the 1926 UK
study, and both combined risk estimates were inconsistent with contemporary evidence.
Chance, bias, and confounding are all possible explanations for these inconsistencies. Chance imbalance
is always a problem for observational studies (71) and cannot be ruled out in this instance. It is difficult
to assess the extent that bias and confounding may have played a role because we don’t have access to
the original data. However, the imbalance in age distribution between cases and controls for age group
less than 45 (Table 3) may explain part of the inconsistency. Cohort effects in age at menarche have
57
been previously reported (72), which indicates that the imbalance in age distribution by case‐control
status may have led to biased risk estimates for age at menarche and breast cancer risk.
Contemporary data indicates that women with late age at menopause experience an elevated breast
cancer risk of approximately 40‐50% (Table 4). Findings from the quantitative reanalysis of the historical
studies were consistent with contemporary evidence indicating, with a high degree of homogeneity
across studies, that women who underwent menopause between ages 48‐51 years and above 52 years
experienced an approximate 60% increase in breast cancer risk, compared to women with age at
menopause less than 44 years (M‐H combined OR = 1.62, 95% CI = 1.19 ‐ 2.21; and M‐H combined OR
1.64, 95% CI = 1.13 ‐ 2.38, respectively). It is likely that, had multivariate analyses been possible, risk
estimates would have been attenuated and would therefore be likely to agree even more closely with
contemporary evidence.
5.2.2 Parity and age at first birth
5.2.2.1 Findings in historical studies
Findings as stated in the historical studies were consistent with subsequent epidemiological evidence for
both parity and age at first birth (using age at marriage as a proxy for age at first birth). According to
Lane‐Claypon:
The women of the control series are more fertile than the women of the cancer series, when full allowance has been made for age at marriage and duration of marriage. The difference is of the order of 22 per cent…The average age at marriage was lower in the control series. (5, p. 131)
Lane‐Claypon was thus the first to conclude with observational evidence that there is a fundamental
connection between low fertility and breast cancer risk, a finding that has found abundant
epidemiological support (33); including findings from the 1931 US study (13).
58
MacMahon’s claim (56) that the 1926 UK study and 1931 US study (along with other studies prior to this
1970 publication that investigated the impact of reproductive risk factors on breast cancer) did not
recognise the importance of age at first birth as an independent reproductive risk factor was apparent.
Otherwise, the two historical investigators would have been likely to examine age at first birth directly
rather than use age at marriage as a proxy. To Lane‐Claypon, the importance of age at marriage may
have either been related to reproductive or occupational issues. Lane‐Claypon did, in fact, postulate that
physiological sequelae of sexual intercourse was a possible mechanism to describe why unmarried
women experienced a higher risk. However, she also proposed that women’s breast cancer risk was
increased due to greater frequency of prior industrial employment, as well as deprivation of
psychological sequelae of sexual intercourse.
The 1931 US study also reported a relationship between age at marriage and breast cancer risk. As
stated in the 1931 report, “[s]ince marriage with its accompanying circumstances seems to offer a
protection against breast cancer, the women who marry early should have less breast cancer than those
who marry later” (13, p. 2624). It was unclear whether Wainwright predicted reproductive issues to be
the most likely mechanism for such a relationship, or whether other ‘accompanying circumstances’ of
early age at marriage were more plausible.
5.2.2.2 Findings in reanalysis
The quantitative reanalysis of the 1926 UK study and 1931 US study was consistent with contemporary
epidemiological evidence for both parity and age at first birth (using age at marriage as a proxy for age
at first both), showing reductions in breast cancer experienced by women with more children and by
women with an early age at marriage. Data on parity indicated a linear trend (z = ‐10.5, p<0.001), with
each additional child conferring an 18% RR reduction (OR = 0.82, 95% CI = 0.79‐0.85). Risk estimates
from prospective studies are comparable to these results (22, 23).
59
Women who married at or above age 28 years experienced a large, approximately 2.5‐fold increase in
RR of breast cancer compared to women who married at age less than 20 years (M‐H combined OR =
2.53, 95% CI = 1.87‐3.44). Contemporary risk estimates for age at first birth depend on the level of
contrast between high and low risk groups examined. When comparing age at first birth less than 20
years to age at first birth at or above age 30 years (comparable to the contrast examined in the
reanalysis), contemporary risk estimates are 1.9‐2.0 (18, 20) (Table 1). Age at marriage is highly
confounded by number of births, but adjustment for parity was not possible. Considering this, data on
age at marriage from the historical studies worked relatively well as a proxy for age at first birth, with CIs
from the reanalysis overlapping contemporary risk estimates for age at first birth.
5.2.3 Duration of lactation
5.2.3.1 Findings in historical studies
The qualitative results reported in the historical studies are inconsistent with evidence that increasing
lactation reduces breast cancer risk. According to Lane‐Claypon, duration of lactation from six months to
two years didn’t show any detrimental effect on the later development of breast cancer, but that breast
cancer was related to either “absence of or to excessive lactation” (5, p. 74), with excessive lactation
specified as two or more years. That “some degree of injury produced by the strain of suckling older and
heavier children” (5, p. 74) was the proposed mechanism for the association.
In the historical studies, more children of cases were reported to have been breastfed for two or more
years compared to the children of controls, although numbers were small (in 1926 UK study: 27 case
children, 4 control children; in 1931 US study: 39 case children, 7 control children). Using modern
statistical techniques, a higher risk of breast cancer was experienced in the grouping two or more years
of lactation, compared to the baseline of total children breastfed 0‐3 months (combined M‐H OR = 7.54,
95% CI = 3.90‐14.56). As an alternative explanation to these results, maternal recall of breastfeeding
60
may have been a problem, particularly for older women. However, it has been shown that when recall
bias of breastfeeding is nondifferential with respect to outcome, the dose‐response relationship would
be attenuated (73), which did not occur in this instance. However, it is possible that the direction of
recall bias for breastfeeding was opposite of what it is today, as excessive lactation in the 1920s was
regarded as a possible predisposing condition for breast cancer.
It is important to note that the qualitative results for duration of lactation over two years were based on
small numbers, and that women who were inclined to have longer durations of lactation were included
multiple times, as the numbers reported were children rather than women. In theory, it would thus be
possible that two cases who had breastfed ten children for more than two years could alone explain
differences. It would therefore have been more appropriate to consider duration of lactation over one
year as the highest exposure category (including the small numbers of children that were lactated more
than two years), as was done in the reanalysis. Had the historical studies considered duration of
lactation over one year as the highest exposure category, their qualitative results would have supported
a dose‐response effect of lactation, along with the results of the quantitative reanalysis.
Prior to the historical investigations, there was a working hypothesis that excessive lactation was
harmful to child health (5). The authors of the historical studies may therefore have been trying to
distinguish breastfeeding cut‐points for public health recommendations. Both studies reported more
children of cases with duration of lactation more than two years compared to children of controls, which
led Lane‐Claypon and Wainwright to public health recommendations that are at odds with current
practice. To illustrate, Wainwright’s concluding remarks regarding duration of lactation would likely
amuse most public health practitioners today: “The evidence of the harmful effect of nursing over two
years seems to be so definite and so great that it should be considered in cancer control propaganda”
61
5.2.3.2 Findings in re‐analysis
A 2002 report by the Collaborative Group on Hormonal Factors in Breast cancer (henceforth CGHF
report) provided comprehensive epidemiological evidence (47 studies in 30 countries) that
breastfeeding reduced breast cancer risk, with an observed 27% breast cancer risk reduction among
women with lifetime duration of breastfeeding equal to or greater than 55 months when compared to
never breastfed (RR=0.73, 95% CI 0.63‐0.83) (27). An unpublished systematic review by me (74)
reviewed 18 epidemiological reports published after the 2002 CGHF report and not included in its
analysis in order to make an initial assessment of whether effect sizes for breastfeeding studies
published post‐2002 agreed with the 2002 CGHF report. Duration of breastfeeding “never” was
compared to highest exposure category of breastfeeding, looking at pre‐MP and post‐MP women
together. Findings supported the protective effect of breastfeeding on breast cancer risk, without a
consistent modification by subgroup of menopausal status or ethnic group. Not including the 2002 CGHF
report, ten studies found a statistically significant protective effect of breastfeeding on breast cancer
risk for all women (22, 75‐83), one observed a protective effect of borderline statistical significance (84),
and six found a protective effect, but results were not significant at a nominal P<0.05 (24, 81, 85‐88). No
study reported a positive association between breastfeeding and breast cancer risk (Figure 21). One
cohort study published after the 2002 CGHF report and excluded from the unpublished systematic
review because it evaluated several types of cancer reported a non‐significant increase in breast cancer
risk (HR = 1.62, 95% CI 0.89‐2.94) (89).
62
Summary RRs varied considerably by study design, with significant heterogeneity within population‐
based and hospital‐based case‐control studies. Seven of the ten studies that observed a statistically
significant protective effect were hospital‐based case‐control studies. In general, these seven studies
Figure 20: Association between breast feeding and breast cancer risk by study from Press (74)
Heterogeneity between groups: p = 0.000Overall (I-squared = 84.3%, p = 0.000)
Okobia (2006)HOSPITAL-BASED CASE-CONTROL STUDIES
ID
Shema (2007)
Subtotal (I-squared = 84.5%, p = 0.000)
Kuru (2002)
Oran (2004)
Norsa'adh (2005)
Beji (2007)
Lee (2003)
Hall (2005)
Kamarudin (2006)
Wrensch (2003)
Yavari (2005)
Subtotal (I-squared = 84.1%, p = 0.000)
Ursin (2004)
Lumachi (2002)
COHORT STUDIES
Ceber (2005)
Subtotal (I-squared = 0.0%, p = 0.550)
Tessaro (2003)
POPULATION-BASED CASE-CONTROL STUDIES
Faheem (2007)
Iwasaki (2007)Clavel-Chapelon (2002)
Subtotal (I-squared = .%, p = .)Collaborative Group (2002)META-ANALYSIS
Study
0.68 (0.64, 0.73)
0.88 (0.70, 1.10)
ES (95% CI)
0.30 (0.10, 0.40)
0.49 (0.43, 0.56)
0.31 (0.26, 0.53)
0.41 (0.21, 0.81)
0.19 (0.08, 0.42)
0.37 (0.26, 0.53)
0.60 (0.30, 1.00)
0.86 (0.70, 1.06)
0.70 (0.40, 1.22)
0.98 (0.58, 1.70)
0.43 (0.24, 0.75)
0.71 (0.63, 0.79)
0.71 (0.60, 0.84)
0.35 (0.26, 0.49)
0.29 (0.07, 1.18)
0.83 (0.72, 0.95)
1.00 (0.60, 1.90)
0.16 (0.09, 0.29)
0.86 (0.65, 1.15)0.84 (0.71, 0.99)
0.73 (0.64, 0.84)0.73 (0.63, 0.83)
100.00
8.53
Weight
0.91
22.12
3.43
0.96
0.63
3.43
1.20
10.12
1.40
1.51
1.34
32.65
15.38
4.34
0.22
22.31
1.31
1.27
5.3515.76
22.9122.91
%
0.68 (0.64, 0.73)
0.88 (0.70, 1.10)
ES (95% CI)
0.30 (0.10, 0.40)
0.49 (0.43, 0.56)
0.31 (0.26, 0.53)
0.41 (0.21, 0.81)
0.19 (0.08, 0.42)
0.37 (0.26, 0.53)
0.60 (0.30, 1.00)
0.86 (0.70, 1.06)
0.70 (0.40, 1.22)
0.98 (0.58, 1.70)
0.43 (0.24, 0.75)
0.71 (0.63, 0.79)
0.71 (0.60, 0.84)
0.35 (0.26, 0.49)
0.29 (0.07, 1.18)
0.83 (0.72, 0.95)
1.00 (0.60, 1.90)
0.16 (0.09, 0.29)
0.86 (0.65, 1.15)0.84 (0.71, 0.99)
0.73 (0.64, 0.84)0.73 (0.63, 0.83)
100.00
8.53
Weight
0.91
22.12
3.43
0.96
0.63
3.43
1.20
10.12
1.40
1.51
1.34
32.65
15.38
4.34
0.22
22.31
1.31
1.27
5.3515.76
22.9122.91
%
1.25 .5 1 1.5
63
reported the highest risk reductions. The summary RRs showed that breastfeeding was associated with a
reduction in RR among all study designs, ranging from a moderate risk reduction of approximately 17%
in cohort studies to a large risk reduction of approximately 51% in hospital‐based case‐control studies
(cohort studies: summary RR=0.83 (95% CI 0.72‐0.95) population‐based case control studies: summary
RR=0.71 (95% CI 0.63‐0.79); hospital‐based case‐control studies: summary RR=0.49, 95% CI (0.43‐0.56)).
The overall summary RR was 0.68 (95% CI 0.64‐0.73), with CIs overlapping those of the 2002 CGHF
report (Figure 21).
Surprisingly, the risk estimate in the unpublished systematic review and the M‐H combined OR estimate
from the reanalysis for the historical studies were almost identical (Overall OR=0.68, 95% CI = 0.64‐0.73;
and M‐H combined OR=0.69, 95% CI = 0.60‐0.80, respectively). This was a particularly striking finding,
given that: 1) significant heterogeneity was reported within population‐based and hospital‐based case‐
control studies in the systematic review (I2=84.1%, P < 0.001 and I2=84.5%, P < 0.001, respectively); 2)
the two historical reports used total children who were breastfed by category of duration of lactation as
a proxy of lifetime duration of lactation for women, rather than lifetime duration of lactation as
reported in the systematic review; and 3) obtained risk estimates from the historical studies were crude,
unadjusted for variables that may confound the association.
64
5.3 Implications—Changing approaches, expanding knowledge
Economic, institutional, and cultural changes have facilitated many of the scientific advancements
during the twentieth century. Economic prosperity, larger and more technically advanced universities,
increasing attendance at those universities from the general population and from women in particular,
as well as perspectives towards women in the workforce and of scientific enquiry in general have all led
to an expanding stock of global knowledge. Powles (90) explores ways that knowledge has been
developed and applied to help address leading adult health risks in the context of public health policies.
Such an approach is also relevant here in the context of epidemiologic enquiry. As one of the first
observational studies to receive government funding, the 1926 UK study was a forerunner to the
numerous retrospective and prospective studies that have relied on public support to elucidate causes
and treatment of simple and complex diseases for the betterment of society. Lane‐Claypon led the way
both for future physician‐scientists, female academics, epidemiologists, and others to further expand
their respective fields and, in doing so, develop shared knowledge. In particular, Lane‐Claypon’s
contribution, as manifested in part within the 1926 UK study, is an excellent example of how one
investigator’s work can help to advance the field of scientific enquiry (as seen in changing approaches to
epidemiologic methodology and conceptualisation) and expand the international knowledge‐base (as
seen in the increasing understanding of breast cancer aetiology and treatment).
This reanalysis and reconsideration of the 1926 UK study and 1931 US study helped to elucidate how
perspectives and approaches to scientific enquiry have evolved since the 1920s and 1930s. Among the
most notable changes included issues of: study design and sample selection, statistical understanding
and interpretation, and presentation of results. Improvements in, and additions to, study design,
statistical know‐how, and case‐finding within institutions have occurred alongside an enhanced
understanding of how to interpret scientific findings. As a whole, this has meant a furthering of the
65
knowledge of diseases and populations at risk, which has resulted in more specialised clinical
management.
In the present report, public health implications of reproductive risk factors for breast cancer, and
trends thereof, will not be considered closely. However, implications for public health and preventive
medicine are of relevance. The 2002 CGHF report (27) used international data from 47 epidemiologic
studies to predict that the cumulative incidence of breast cancer by age 70 would decrease from 6.3 to
2.7 per 100 if women in developed countries had larger family sizes and longer durations of
breastfeeding and reported that almost two‐thirds of this reduction was due to breastfeeding. Changes
in public health trends over time for reproductive risk factors are not considered closely either, but
include trends in cohort fertility and breast cancer rates, which have been examined elsewhere. Studies
investigating changes in cohort fertility over time have reported an association between cohort fertility
and breast cancer rates and indicated that changing patterns of contraception and surgeries involving
reproductive organs may be important factors (91‐93). It is unclear whether regional differences in
reproductive risk factors help to explain variations in breast cancer incidence (94, 95), but such
questions are also of potential public health interest.
Changes in the role of ethics in observational and interventional studies are also evident, as may be
gleaned from the fact that no signed informed consent was obtained from the participants included in
the historical studies. Formalised ethical frameworks have become a mainstay of epidemiologic
enquiries and will continue to evolve along with the fields of epidemiology and clinical medicine.
However, changes in ethical practices since the historical studies were not examined closely in the
present report either.
66
5.3.1 Changes in epidemiologic methodology and conceptualisation
5.3.1.1 Study design and sample selection
Approaches to minimising potential limitations in case‐control studies introduced after the 1926 UK
study (Table 5) indicate that technical improvements have led to study designs with better internal
validity. One interesting example is the usage of proxies in the historical studies. Rather than self‐
reported annual household income, as is often used today as an indicator of socioeconomic status, the
historical studies use deaths among children per number of viable children. This also indicates how
changes in culture over time and place are important considerations in epidemiologic practice. In
addition to refinements of the case‐control study, the prospective cohort study and the randomised
controlled trial have become more common in epidemiological enquiry and address some of the
limitations inherent in the case‐control study. Advancing healthcare institutions and surveillance
systems has allowed for more complete case‐finding and thus, more accurate estimates of disease rates
in populations of interest and in samples under study.
5.3.1.2 Statistical understanding and interpretation
Changes in statistical techniques have led to more robust and precise estimates of relative and absolute
risks. Rather than comparing means and proportions, as was done in the historical studies, the present
analysis was able to use a more quantitatively accurate technique, the M‐H OR. Newer statistical
techniques involve making assumptions about data that may not be completely accurate (including, in
the case of the M‐H OR the assumption of a fixed effect), but making such assumptions allows
conclusions about statistical significance that were previously not possible to be drawn. In this instance,
newer statistical techniques led to different results for demographic variables, age at menarche, age at
menopause, and duration of lactation. Issues of chance, bias, confounding, interaction, and causality
67
have been further investigated and incorporated into epidemiological and statistical conceptual
understandings of aetiological enquiry.
5.3.1.3 Presentation of results
The 1926 UK study was a 189‐page report, complete with a prefatory note by the UK Chief Medical
Officer, a Table of Contents (Historical Figure 2 [1926]), twenty‐one chapters, and Appendices. The
format of the report was much different than the standard epidemiologic write‐up today. Whereas the
latter usually contains a section for abstract, introduction, methods, results, and discussion, the former
consisted of a number of sections and chapters that contained aspects of many of the five modern
sections for a particular variable or aspect of enquiry. By contrast, publications on observational studies
today strive to be concise, usually around or less than a few thousand words, and generally report on
one or a few related variables that are of particular interest or had particularly striking findings.
Whereas the 1926 UK study was published “FOR OFFICIAL USE” by a government entity, most case‐
control studies today would be accepted by the publisher of a relevant scientific journal. These changes
express attempts to make mounting scientific evidence readily available and concisely presented.
5.3.2 Changes in understanding of breast cancer aetiology, and clinical treatment
5.3.2.1 Breast cancer aetiology
Since the publication of the 1926 UK study, much has been added to our aetiologic understanding of
breast cancer. The protective effect of increasing parity that was first reported in the 1926 UK study has
found substantial epidemiologic support (18, 22, 23, 33, 96). The null effect that was reported in the
historical studies for other reproductive factors on breast cancer risk has been repeatedly disproved,
with well‐established moderate RR associations for age at menarche (18, 21, 22), age at menopause (18,
21), and duration of lactation (27, 74) (Table 1). Family history, ionising radiation, hormone replacement
therapy, body fatness, adult height, alcoholic drinks, physical activity and birth weight are among the
68
other risk factors that are considered to be associated with breast cancer risk (28). Additionally,
contemporary evidence is mounting as to the role of genetic susceptibility and breast cancer risk (29).
Improvements in case‐finding within institutions and national surveillance systems have occurred
alongside advances in epidemiologic study design, statistical techniques, and technical innovations.
Together, these changes have allowed for more precise and robust estimates of risks and rates to be
determined as well as a better understanding of individuals and populations to whom those risks and
rates may apply.
5.3.2.2 Clinical treatment of breast cancer
The 1926 UK study was conducted during a time when surgical intervention was controversial. The
Halstead mastectomy had become the treatment of choice for breast cancer, but was losing popularity
among some surgeons due to negative sequelae of disfigurement, pain, and also because it was
impossible to ascertain whether the cancer had spread beyond the scope of the operation (97). In order
to determine whether women undergoing complete or incomplete surgical treatment of the breast
experienced prolonged survival as compared to women with breast cancer not undergoing surgical
treatment, Lane‐Claypon was commissioned by the British Ministry of Health to conduct a literature
review of all previously published data on the surgical treatment of breast cancer from all countries.
Among other conclusions, her‐ findings indicated that: a) surgical treatment of the breast at that time
was more effective than previous decades in terms of prolonged survival; and b) “in all countries the
proportion of victims of breast cancer who present themselves at a sufficiently early stage of the disease
to give a good prospect of cure is much too small” (64). Lane‐Claypon’s findings supported those from a
previous 1923 international study that reported differences in breast cancer mortality between
countries and suggested that such differences were due to earlier diagnosis and earlier operative
treatment in some countries (65).
69
The Breast Cancer Wars (97) describes breast cancer debates during the 20th century concerning
aggressive treatment, early detection, and statistical uncertainty. In this book, Lerner describes changes
in breast cancer treatment during the 20th century, including the implementation of the Halsted radical
mastectomy during the turn of the century, reasons for the fall of the radical mastectomy in the late
1970s, and subsequent breast cancer treatment strategies. Today, when a woman is suspected to have
breast cancer on the basis of mammography or clinical examination, pathologic confirmation is required
to recommend treatment. After pathologic confirmation, breast‐conserving surgeries and adjuvant
treatment with chemotherapy or tamoxifen are routine therapy regimes (29). Prolonged survival has
been observed as a result of mammography screening and adjuvant systemic treatment following
primary surgery (98). One study analysing survival experiences of 834 women diagnosed with recurrent
breast cancer reported improvements in prognosis between 1974 and 2000 (99). For metastatic breast
cancer, newer, targeted therapies may be having a favourable impact on survival (100‐102).
Improvements in clinical medicine would not have been made possible without the accumulating
scientific knowledge‐base that arose during the 20th century and continuing today. As stated by Powles,
“In general, knowing what to do has been powerfully permissive of it (ultimately) being done” (90).
Advances in knowing what to do in epidemiologic enquiry have underpinned advances in knowing how
to improve clinical treatment of breast cancer. An important contributor and pioneer of epidemiologic
enquiry is Janet Lane‐Claypon. Her 1926 UK study marked the beginning of a new era of mounting
aetiologic knowledge, and epidemiologic methodologies to ascertain such information.
70
6. Acknowledgements
I am grateful to my academic supervisors and mentors:
Dr. Paul Pharoah, for providing the choice of topics, the historical studies to re‐analyse,
statistical methodologies and interpretation, and routinely supportive feedback. Without Dr.
Pharoah’s guidance and positive support, this report would not have been possible.
Dr. John Powles, for tireless dedication to the MPhil Public Health program and to his students.
Dr. Leslie Bernstein, my former academic/professional mentor, for training and for inspiration.
I appreciate Ms. Laura‐Jo Ayling, for critical appraisal and motivation.
I thank my parents, Sarah and Michael Press, for constant encouragement, support, and love.
Finally, I dedicate this report to my father, Dr. Michael F. Press, who has enthusiastically spent his
professional career endeavouring to understand and cure breast cancer.
71
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8. Appendix
Historical Figure 1 [1926]: Questionnaire from 1926 UK study
80
Historical Figure 2 [1926]: Table of Contents from 1926 UK study
Historic
Historic
cal Table 1a
cal Table 1 [1
[1931]: Nati
1926]: Natio
ionality in 19
onality in 192
81
931 US study
26 UK study
y
Historiccal Table 1c [1931]: Natiionality in 19
82
931 US studyy
Historiccal Table 2 [11926]: Age in 1926 UK st
83
tudy
Historic
Historic
cal Table 2d
cal Table 2 [1
[1931]: Age
1931]: Age i
in 1931 US
n 1931 US st
84
study
tudy
Historic
Historic
cal Table 3 [1
cal Table 3 [1
1931]: Civil s
1926]: Civil s
status in 193
status in 192
85
31 US study
26 UK study
Historiccal Table 4 [11926]: Occupation in 19
86
926 UK studyy (cases)
Historiccal Table 5 [11926]: Occupation in 19
87
926 UK studyy (controls)
Historic
Historic
cal Table 8 [1
cal Table 4 [1
1926]: Death
1931]: Occu
hs among ch
pation in 19
88
hildren in 19
931 US study
26 UK study
y
y
Historiccal Table 8 [11931]: Deathhs among ch
89
hildren in 1931 US study
y
Historic
Historic
cal Table 9 [1
cal Table 9 [
1926]: Age a
1931]: Age a
at menarche
at menarche
90
e in 1926 UK
e in 1931 US
study
study
Historic
Historic
cal Table 10
cal Table 10
[1931]: Age
[1926]: Age
at menopau
at menopau
91
use in 1931
use in 1926
US study
UK study
Historiccal Table 22 [1926]: Age at marriage
92
e in 1926 UK study
Historiccal Table 22 [1931]: Age at marriage
93
e in 1931 US study
Historiccal Table 25:: Parity in 19926 UK study
94
y
Historiccal Table 25 [1931]: Parity in 1931 U
95
US study
Historiccal Table 32 [1926]: Duraation of lact
96
tation in 19226 UK study (
(cases)
Historiccal Table 32 [1931]: Duraation of lact
97
tation in 19331 US study (
(cases)
Historiccal Table 33 [1926]: Duraation of lact
98
tation in 19226 UK study (
(controls)
Historic
Historic
cal Table 33g
cal Table 33
g [1931]: Du
[1931]: Dura
uration of lac
ation of lact
99
ctation in 19
tation in 193
931 US study
31 US study (
y
(controls)
top related