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Keywords:

  • ER-receptor;
  • PR-receptor;
  • breast cancer;
  • menarche;
  • height;
  • leg length;
  • sitting height

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.08–1.20]) had a stronger risk association than leg length (1.05[1.00–1.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (≤13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and −negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women.

Breast cancer is a complex and heterogeneous disease with a variety of histopathological and molecular subforms, diverse clinical outcomes and different relationships with established risk factors.1, 2 The routine identification of estrogen (ER) and progesterone (PR) receptors is one major subclassification of breast cancer and guides targeted therapies and provides important prognostic information.3 In addition to the clinical use of ER and PR, differences in the etiology of ER and PR expressing tumors are observed.2

Adult attained height, leg length, sitting height and an earlier age at menarche are established risk factors of breast cancer.4, 5 Standing height, leg length, sitting height and sexual maturation are considered as indicators of multiple attributes and influences, such as genetics and nutrition, during childhood6 stimulated by complex interactions of hormones and growth factors (such as insulin growth factor-1 [IGF-1], growth hormone [GH], estrogens, androgens and leptin7). Leg and trunk length make up final adult height and are associated with different growth processes during childhood and puberty.8 The majority of height gained during puberty occurs in the long bones and exposures during the growth spurt can be indirectly measured using leg length in adults.9 In addition, leg length remains constant throughout a person's life span.10 Axial and appendicular growth in women is slower after menarche owing to high levels of estrogens and cessation of growth in the long bones.6, 10 Nutritional and lifestyle influences during early childhood growth and after menarche have also been proposed to be reflected in the length of the torso or sitting height.5, 9

The average age at menarche for European women has decreased over the last century, whereas adult stature has increased,11 and both trends are believed to reflect significant changes of nutritional and other lifestyle factors during early childhood years.12 Early life and adolescence are critical times for maturation of the hypothalamic pituitary ovarian axis, which regulates the ovarian synthesis of estrogen and progesterone.13 Exposure to estrogens has a critical role in female development, particularly in mammary gland development.7 Puberty is the time of rapid development of mammary gland structures and growth.13 The period of preadolescence up to the first pregnancy may be a period in which the breast is more highly susceptible to carcinogenic influences.14

Risk associations of factors reflecting childhood and adolescent growth and reproductive development with the hormone receptor (HR)-negative (ER and/or PR) breast cancer subtype are unclear and inconsistent.15–22 For HR-negative malignancies, prospective studies had relatively smaller sample sizes inherent to this receptor expression pattern. To our knowledge, ours is the largest prospective study to report associations of leg length and sitting height with HR-defined malignancies.

The aim of this analysis is to examine the relationships of markers of childhood growth and sexual maturation (adult attained height, leg length, sitting height and age at menarche) and their interactions with risk of ER+PR+ and PR-PR- breast tumors. This analysis uses the latest (2010) follow-up data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which presently includes a total of almost 7,000 incident cases of breast cancer with information on ER and/or PR status and includes 990 ER-PR- tumors.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

EPIC is a multicenter prospective cohort study designed to investigate the relationships between diet, nutrition and metabolic factors and cancer.23 It consists of approximately 360,000 women and 150,000 men aged mostly between 25 and 70 years.24 All participants were enrolled between 1992 and 2000 from 23 regional and national research centers located in ten western European countries: Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, The Netherlands and the United Kingdom.

Extensive details about the standardized procedures for recruitment, measuring baseline anthropometry, questionnaires on current habitual diet, reproductive and menstrual history, exogenous hormone use (oral contraceptive and hormone replacement therapy use), medical history, lifetime smoking and alcohol consumption history, occupation, level of education and physical activity and biological sample collection at study centers have been reported previously.23, 24 All subjects gave written informed consent to use their questionnaire data and the Internal Review Boards (IRB) of IARC and all EPIC recruitment centers approved the analyses based on EPIC participants.

Study participants

Of the 367,903 female participants in EPIC, women were a priori excluded if they had a history of cancer prior to recruitment (n = 19,853) or were missing a diagnosis or censoring date (n = 2,892), and thus leaving 345,158 participants. Three EPIC study centers, Malmo (Sweden), Granada and Murcia (Spain), did not provide information on breast tumor receptor status and were excluded from this analysis (n = 26,091). Women were further excluded if it was unclear whether their breast cancer diagnosis was a primary incidence case (n = 3), did not contribute to the underlying time at risk variable (n = 3) and if they were missing questionnaire data (n = 526). This analysis excluded women who were missing data on standing and sitting height, weight as well as age at menarche (n = 220). In addition, we excluded from our analysis women who had their menarche at a nonphysiological age which was defined as ages of <8 years and above 18 years (n = 11,715). This left a total cohort of 306,600 women from ten countries for our analysis.

Classification of body measurements, menarcheal age and baseline variables

The details of standardized procedures for measuring height and baseline variables at EPIC study centers have been reported previously.25 With the exception of Norway, Umea and a large proportion of the EPIC cohort in France (69%), subjects had their standing and sitting height measured to the nearest centimeter and most subjects had their height measured in light clothing and without shoes by trained study researchers. Weight was measured to the nearest kilogram and body mass index (BMI) was constructed by dividing weight by height in meters squared (kg/m2). In Norway, Umea and the large proportion from France, subjects' height and weight were measured and self-reported by the cohort participants themselves, following detailed instructions.24, 25 In Oxford, subjects also self-reported their height and weight; however, a subset of these participants was also measured by study researchers to calibrate self-reported measurements of the Oxford cohort.26 Sitting height was measured in Denmark, Italy, Greece, Germany, the Netherlands and in the subset of France where height was measured by study researchers. Sitting height was measured from the head to the seat of the chair to the nearest 10 mm in France and Greece and nearest 1 mm in all other centers. Leg length was then estimated from total body height (leg length = height − sitting height). Age at menarche was obtained from the general lifestyle questionnaire and details have also been reported previously.11 Briefly, in Greece, Italy, the Netherlands, Sweden and the United Kingdom, age at menarche was asked in years. In the other countries, age at menarche was asked in defined categories (≤8, 9, 10,…,18, 19 or ≥20 years).

In addition, baseline information was recorded in all centers about menstrual history, exogenous hormone use and hysterectomy. Women were considered postmenopausal at recruitment if they had no menstrual cycles in the last 12 months, were older than 55 years (if the menstrual cycle history was missing) or had a bilateral oophorectomy. Women who were aged 46–55 years and had incomplete or were missing questionnaire data on menstrual history were classified with a peri/-or of unknown menopausal status. Women were deemed premenopausal if they reported regular menstrual cycles in the last 12 months or if they were younger than 46 years of age.

Prospective ascertainment of breast cancer cases and the coding of receptor status

In all countries (except for France, Germany and Greece), incident breast cancer cases were identified using record linkage with cancer and pathology registries. In France, Germany and Greece, cancer occurrence was prospectively ascertained through linkage with health insurance records and regular direct contact with participants and their next of kin, and all reported breast cancer cases were then systematically verified against clinical and pathological records. Mortality data were coded according to the 10th Revision of the International Statistical Classification of Diseases, Injuries and Causes of Death (ICD-10), and cancer incidence data were coded according to the International Classification of Diseases for Oncology (ICD-O-2). Invasive (primary, malignant) breast cancer was as per the International Classification of Diseases for Oncology (C50), second revision (ICD-O-2). Breast tumor receptor status was standardized across EPIC centers using the following criteria for a positive expression: ≥10% cells stained, any “plus-system” description, ≥20 fmol/mg, an Allred score of ≥3, an IRS ≥2 or an H-score of ≥10.27

Vital status was collected from regional or national mortality registries. The last updates of endpoint data for cancer incidence and vital status were between 2005 and 2010, depending on the center. Women were considered at risk from the time of recruitment until breast cancer diagnosis or censoring (age at death, loss to follow-up, end of follow-up or diagnosis of other cancer), respectively. A total of 9,307 invasive breast cancer cases were included for this analysis. A total of 6,977 breast cancer cases had information on ER status (5,620 ER positive and 1,357 ER negative) of which 5,775 had further information on PR status (3,524 ER+PR+, 1,061 ER+PR-, 200 ER-PR+ and 990 ER-PR-).

Statistical analysis

Correlations between standing and sitting height, leg length and age at menarche were assessed using Pearson's correlation adjusted for study center and birth year. Associations of standing height, leg length, sitting height and age at menarche with the risk of breast cancer subtype were evaluated using Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CIs). The outcomes of total incident breast cancer cases and breast cancer subtypes defined either as jointly classified ER+PR+, ER+PR-, ER-PR+ and ER-PR-, ER-positive versus ER-negative and PR-positive versus PR-negative subtypes were assessed. The underlying time variable started from age at recruitment to breast cancer diagnosis or censoring. All multivariate analyses were stratified by age in 1-year categories and by study center, to avoid violations of the proportional-hazard assumption. Trend tests across tertile levels of standing height, leg length and sitting height categories were performed using quantitative tertile scores of 1,2,3.

Age at menarche was categorized as ≤12, 13–14 and ≥15 years. Standing height, leg length and sitting height tertiles were created using cut-points based on the overall cohort distribution of body measurements (standing height tertile 1: ≤159 cm, standing height tertile 2: 159.1–164.9 cm, standing height tertile 3: ≥165 cm; leg length tertile 1: ≤73.6 cm, leg length tertile 2: 73.7–77.5 cm, leg length tertile 3: ≥77.6 cm; sitting height tertile 1: ≤84 cm, sitting height tertile 2: 84.1–87 cm, sitting height tertile 3: ≥87.1 cm). Categories of menarche and the tertiles of standing height were assessed for statistical interaction by including an interaction term and using the log likelihood ratio test.

Furthermore, adjustments for possible confounders of BMI (continuous), waist circumference (continuous), smoking status (current, former, never and missing), baseline alcohol consumption (nonconsumers, 0.1–6, 6.1–12,12.1–24, 24.1–60 g/day; missing, >60 g/day), baseline physical activity (inactive, moderately inactive, moderately active, active and missing26), education level (none, primary school, technical/professional school, secondary school, longer education including university degree and missing), age at first child birth (<20 years, 20–30 years, >30 years and missing), parity (nulliparous, one full-term birth, two full-term births or three or more full-term births and missing), history of breastfeeding (ever vs. never, missing), use of oral contraceptives (ever vs. never, missing), menopausal status (premenopausal, peri/unknown menopausal and postmenopausal), hormone replacement therapy use (ever vs. never, missing), age at menopause (in postmenopausal women only) and time since menopause (in postmenopausal women only) did not remarkably alter the results (by ≥5%28) for any anthropometric measurement or for age at menarche and therefore were not kept in the final model (data not shown). In addition, to examine whether the combination of leg length or sitting height was better markers of risk for overall breast cancer and HR-defined malignancies, a model using standing height (per 1 standard deviation score [SD] increase) was compared to a model that included both sitting height (per 1 SD increase) and leg length (per 1 SD increase). A log likelihood ratio test was used to assess goodness of fit.

To assess whether breast cancer subtype risk with standing height, leg length and sitting height changed across women of older ages after menopause, left and/or right side censoring was used to count person-years within defined age periods “≤49 years,” and “between 50 and 60 years,” and “>60 years.” As no differences were observed between risk estimates of age at menarche and breast cancer subtype risk across the age bands, we report results for all women combined.

Differences in risk estimates for standing height, leg length, sitting height indices and menarche by breast cancer subtype risks were analyzed using the data augmentation method as described by Lunn and McNeil,29 using a log likelihood ratio test to compare the model with and without interaction terms between the anthropometric variable and the breast cancer subtype. Women who developed the competing breast cancer subtype or were missing receptor status were censored at the time of occurrence.29

A sensitivity analysis that excluded all un-calibrated self-reported anthropometric measurements was also completed to assess the effect of including self-reported indices of anthropometry into the models. Risk estimates remained similar (data not shown). Therefore, both self-reported and measured standing height, leg length and sitting height were retained in the models. All statistical analyses were performed using the statistical analysis system (SAS) software package, version 9.2 (SAS Institute, Cary, NC).

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

A total cohort of 306,600 women was followed for a sum of 3,297,579 person-years. At the time of recruitment, 34.9% were premenopausal, 18.8% were of perimenopausal or of unknown menopausal status and 46.3% were postmenopausal. Baseline characteristics by age at diagnosis or censoring and by EPIC country of all women within this cohort are summarized in Table 1. The majority of breast cancer cases (87.6%) were diagnosed at the age of 50 years or older. Women who were in the range of ≤49 age band were on average slightly taller, had longer leg lengths and sitting heights in comparison women who were within the older age bands. Of the women who had a joint ER and PR receptor status, 990 (21.9%) were joint ER-PR- tumors. After adjustment for center and birth year, age at menarche was positively correlated with standing height (r = 0.08, p < 0.001) and leg length (r = 0.11, p < 0.001) but not with sitting height. Additionally, menarcheal age showed a weak inverse correlation with BMI (r = −0.12, p < 0.001). Height was strongly correlated with sitting height (r = 0.72, p < 0.001) and leg length (r = 0.84, p < 0.001). In addition, both leg length and sitting height were also weakly correlated (r = 0.23, p < 0.001).

Table 1. Mean and standard deviations of age at menarche, height, sitting height and leg length of all women and breast cancer cases in the EPIC cohort
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For all incident breast cancers (n = 9,307), Cox regression models showed a positive association with an increase in standing height, leg length and sitting height, per SD increase as well as per tertile increase (Fig. 1). A similar positive association was observed for both joint ER+PR+ (n = 3,524) and ER-PR- (n = 990) breast cancer for every SD increase with standing height and leg length. Standing and sitting height risk estimates tended to be stronger for ER+PR+ breast cancer than for ER-PR- tumors although statistical heterogeneity was not observed. Relative risk estimates for standing height, leg length and sitting height with the discordant ER+PR- breast cancer subtype were similar to the ER+PR+ breast tumor subtype, whereas the discordant ER-/PR+ tumors showed no distinct associations (Supporting Information Table 1).

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Figure 1. Hazard ratios and 95% CI for increases in standing height, leg length, sitting height and age at menarche for all incident and joint ER and PR breast cancer subtypes, stratified by center and age at recruitment. Log likelihood ratio test for heterogeneity between ER+PR+ and ER-PR- breast cancer subtypes. Standing height: tertile 1: ≤159 cm, tertile 2: 159.1–164.9 cm, tertile 3: ≥165 cm. Leg length tertile 1: ≤73.6 cm, tertile 2: 73.7–77.5 cm, tertile 3: ≥77.6 cm. Sitting height tertile 1: ≤84 cm, tertile 2: 84.1–87 cm, tertile 3: ≥87.1 cm.

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Women in the upper tertile of standing height had a 26% increased risk of ER+PR+ disease in comparison to women within the first tertile (HR: 1.26 [95% CI: 1.15–1.38]; ptrend < 0.001). ER-PR- breast tumors showed a somewhat weaker risk estimate pattern for women within the upper tertile (HR: 1.08 [95% CI: 0.91–1.28]; ptrend = 0.37). However, the heterogeneity between ER+PR+ and ER-PR- was not statistically significant. On a continuous scale, leg length and sitting height showed similar risk associations with ER+PR+ (for leg length HR: 1.09 [95% CI: 1.04–1.14], ptrend < 0.001; for sitting height HR: 1.15 [95% CI: 1.09–1.21], ptrend < 0.001) and ER-PR- tumors (for leg length HR: 1.11 [95% CI: 1.01–1.22], ptrend = 0.04, pheterogeneity = 0.75; for sitting height HR: 1.07 [95% CI: 0.97–1.18], ptrend < 0.001, pheterogeneity = 0.18). However, with each tertile increase of leg length, the risk association with ER+PR+ tumors was restricted to the third tertile (HR: 1.12 [95% CI: 1.00–1.26], ptrend < 0.001). For ER-PR- disease, women within the second and third tertile showed an increased risk association. Risk increases with each tertile of sitting height followed similar patterns to those for standing height for both ER+PR+ and ER-PR- subtypes.

Further adjustments for either BMI or age at menarche did not change any of the anthropometric risk estimates by breast cancer subtypes (data not shown). Increased standing height, leg length and sitting height showed similar relative risk patterns when analyses were restricted to ER-positive and ER-negative breast cancer subtypes ignoring PR status, or to PR-positive and PR-negative ignoring ER status (Supporting Information Table 2).

The weak correlation of leg length and sitting height justified the separation of height into the combination of leg length and sitting height. To determine the stronger predictor of breast cancer risk, a model containing standing height was compared to a model containing both leg length and sitting height (Table 2). Although leg length (HR: 1.07[95% CI: 1.04–1.11]) and sitting height (HR: 1.09 [95%CI: 1.05–1.13]) showed similar associations to standing height with overall breast cancer (HR: 1.13 [95% CI: 1.10–1.17]), sitting height showed a stronger risk estimate for ER+PR+ breast tumors (HR: 1.14 [95% CI: 1.08–1.20]) than leg length (HR: 1.05 [95% CI: 1.00–1.11] pequality = 0.03). Although for ER-PR- tumors sitting height and leg length showed similar indications of a positive risk association, the heterogeneity between the two subtypes was not statistically significant (sitting height: pheterogeneity = 0.18; leg length: pheterogeneity = 0.75).

Table 2. Hazard ratios (95% CI) of overall breast cancer and ER+PR+ versus ER-PR- breast cancer subtypes comparing a single model with overall height to a joint model with leg length sitting height in one model for all women
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Across the age bands, Cox regression models showed that the association for standing height and sitting height with risk of ER+PR+ increased steadily in magnitude (for standing height ≤49 years HR: 1.06 [95% CI: 0.80–1.39], between 50 and 60 years HR: 1.21 [95% CI: 1.05–1.39] and >60 years HR: 1.36 [95% CI: 1.20–1.55]; for sitting height ≤49 years HR: 0.96 [95% CI: 0.65–1.40], between 50 and 60 years HR: 1.22 [95% CI: 1.00–1.50] and >60 years HR: 1.42 [95% CI: 1.21–1.68]) (Fig. 2). Leg length was associated only with an increased risk of ER+PR+ tumors within women aged >60 years (HR: 1.27 [95% CI: 1.08–1.49]). In contrast, for ER-PR- tumors, no significant risk associations for standing height, leg length and sitting height were observed across the age bands; however, a trend for an increased relative risk was observed among women aged between 50 and 60 years with all measures of height. Statistical tests for heterogeneity between the tumor subtypes were not significant for standing height, leg length or sitting height. Further adjustment for BMI, ever HRT use and time since menopause (in postmenopausal women) did not remarkably change the risk estimates with ER+PR+ tumors across the age bands (data not shown).

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Figure 2. Hazard ratios of ER+PR+ and ER-PR- tumors of women within the third tertiles of standing height, leg length and sitting height across women diagnosed ≤49, between 50 and 60 and >60 years. All models are stratified by center and age at recruitment and adjusted for menopausal status at baseline recruitment.

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The inverse risk association for increasing age at menarche with all incident breast cancer cases (per 1 year increase HR: 0.97 [95% CI: 0.95–0.99]; ptrend < 0.001) was again mirrored in both ER+PR+ (per 1 year increase HR: 0.95 [95% CI: 0.92–0.98]; ptrend < 0.001) and ER-PR- breast cancer (per 1 year increase 0.96 [95% CI: 0.92–1.00]; ptrend = 0.04; pheterogeneity = 0.95). In comparison to women who had menarche before the age of 13, menarche at or after the age of 15 was associated with a 24% decreased risk of ER+PR+ tumors (HR: 0.76 [95% CI: 0.68–0.85]), and a 16% decreased risk association for ER-PR- tumors (HR: 0.84 [95% CI: 0.69–1.03]; pheterogeneity = 0.47). Adjusting for either BMI or standing height did not change the risk association of age at menarche with any breast cancer subtype (data not shown).

With regard to the combined risk categories of height and menarcheal age, a joint classification of tertiles of standing height and age at menarche (≤12 years, 13–14 years, ≥15 years) was created. Using the shortest women who had menarche at or after the age of 15 years as the reference category, women who were within the upper tertile and had menarche before 13 years showed an almost twofold increase in risk for ER+PR+ breast cancer (HR: 1.95 [95% CI: 1.55–2.45]) (Fig. 3 and Table 3). Examining the relative risks for increasing age at menarche within separate strata of standing height tertiles, the inverse risk for association of menarcheal age at or after 15 years was the strongest among women who were within the lowest tertile (HR: 0.65 [95% CI: 0.52–0.81). This inverse association progressively weakened with increasing height tertile (tertile 2: (HR: 0.72 [95% CI: 0.60–0.87; tertile 3 (HR: 0.86 [95% CI: 0.72–1.03]; pinteraction = 0.038). For both leg length and sitting height, risk estimates for ER+PR+ disease showed similar patterns as shown by standing height; however, no significant interaction was observed. For ER-PR- tumors, low numbers of cases limited a clear interpretation of observed risk estimates between standing height, leg length or sitting height and age at menarche.

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Figure 3. Hazard ratio and 95% CI estimates of ER+PR+ breast cancer according to tertiles of height and age at menarche. Standing height tertile 1 and age at menarche ≥15 years is used as the reference category.

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Table 3. Hazard ratios of ER+PR+ and ER-PR- tumors for tertiles of standing height, sitting height and leg length1 within categories of menarcheal age2
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Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

Our analyses showed that adult attained height, leg length and an earlier age at menarche were associated with an increased risk of breast cancer overall as well as both ER+PR+ and ER-PR- disease. When leg length and sitting height were analyzed simultaneously, sitting height showed a stronger risk association than leg length with risk of ER+PR+ breast tumors. Additionally, across the age bands, the risk associations for standing and sitting height with ER+PR+ tumors progressively increased in magnitude. Although the difference between ER+PR+ and ER-PR- tumors was not statistically heterogeneous, no significant association of standing height, leg length and sitting height with risk of ER-PR- malignancies was observed across the age bands. The combination of tall stature and an early menarche, in comparison to a late menarche and short stature, was associated with an almost twofold increase in risk of ER+PR+ breast cancer. The low numbers of ER-PR- cases limited the ability to detect a similar interaction within the ER-PR- group.

Previous studies investigating the association of height with receptor-defined breast cancer subtypes have shown no clear patterns.15–18, 21, 22 In a recent population-based case–control study, height was related more strongly to risk of ER+PR+ than of ER-PR- breast cancer17; however, as in this study, the difference in the strength of the associations was not statistically significant. In a recent cohort study,16 leg length was associated with ER-positive tumors in postmenopausal women and sitting height was inversely associated with ER-negative tumors in premenopausal women. In this analysis, both leg length and sitting height were associated with ER+PR+ tumors and leg length was also associated with ER-PR- tumors. In addition, the associations of both leg length and sitting height with ER+PR+ tumors were stronger among women diagnosed after the age of 60 years and older. The inverse relationship of a later age at menarche with the increased risk of ER+PR+ breast cancer in our study was in line with the well-established inverse risk association of a later age at menarche generally seen for breast cancers overall.20 However, the association of menarcheal age with ER-PR- breast cancer has been less consistent.20, 30 Our study provides further evidence of a similar inverse relationship for ER-PR- breast disease as for ER+PR+ disease.

Leg length and sitting height were weakly correlated with each other and their associations with HR-defined breast cancer were independent of each other. Adult leg length is particularly sensitive to environmental factors and diet during childhood and early puberty because this is the period of most rapid leg growth, whereas rapid growth in the axial skeleton occurs after infancy but before puberty.9, 31 Although leg length remains constant throughout adult life, the sitting height can change.10 As women age, height loss can occur. After menopause, the decline of circulating estrogens leads to bone loss in the vertebrae10 and indeed, osteoporotic bone fractures after menopause have been found to be inversely associated with breast cancer risk.32 With an 8-cm difference between the top and the bottom means of sitting height within the tertiles, and, the progressively stronger positive association with ER+PR+ breast cancer across age bands, an increased sitting height could be a reflection of higher postmenopausal blood levels of estrogens, independently of BMI, HRT use and time since menopause. However, whether the risk association of sitting height is restricted to HR-positive tumors is uncertain. The numbers of ER-PR- tumors may have been insufficient to detect an equivalent or more precise risk association. Further, the hypothesis that sitting height could reflect higher postmenopausal estrogen levels cannot be assessed without taking into account early-life estrogen levels and any changes of estrogen levels over a woman's life course. We do not have multiple measurements for standing and sitting height across different periods of life and therefore cannot directly assess the association of height and loss of height with breast cancer subtype risk as women age.

Adult attained height and sexual maturation are used as markers of multiple attributes and influences during childhood, and hence the interpretation of both height and menarche with breast cancer risk remains speculative. Young girls reach their peak height velocity on average 1 year before menarche and growth slows after this; thus these two markers are entwined. The highest relative risk was observed in the tallest women who experienced an early menarche and appeared to be restricted to ER+PR+ tumors. This indicates a possible contribution of growth velocity and growth promoters prompted by complex interactions of hormones and growth factors (e.g., IGF-1, GH, androgens and leptin6, 7) during the pubertal growth spurt with endocrine-sensitive tumors. For example, levels of IGF-1 are positively associated with height in childhood; however, adult levels of IGF-1 are not strongly correlated to overall height.33 IGF-I has been reported to have a positive association with breast cancer33 by stimulating mitosis and inhibition of apoptosis34 and initial studies have observed the association of IGF-1 to be restricted to HR-positive disease.33 Therefore, the risk association of standing height and menarcheal age with these tumors may reflect input of the GH/IGF axis in long-term breast cancer carcinogenesis or the early establishment of an increased risk profile. However, an earlier pubertal onset has been associated with adverse adult metabolic profiles, such as obesity, type-2 diabetes and cardiovascular disease.35 Furthermore, there is an emerging epidemiological evidence for a link between the metabolic syndrome and the triple-negative breast cancer (ER-PR- and HER2- [human epidermal growth factor receptor-2]).36 In our data, however, we did not observe an association with HR-negative disease.

The inverse association of menarcheal age with increased breast cancer risk is thought to be resultant of a longer exposure to estrogens during a women's reproductive life.2 The inverse risk association of menarcheal age with both ER+PR+ and ER-PR- breast cancer subtypes suggests complex hormonal pathways mediating the risk association. Although epidemiologic, clinical and experimental evidence has established a late-stage growth-promoting effect of estrogens especially on estrogen sensitive tumors,37 there is evidence suggesting that estrogens also play an important role in earlier evolutionary stages of the development of both ER-positive and −negative tumor types.38 Mammary stem cells have also been shown to be responsive to sex steroid hormones despite not having a clear expression of an ER or PR.39 In the EPIC cohort, prediagnostic levels of estrogens were found to be associated with both HR-positive and HR-negative postmenopausal breast cancer.27

Exposure to estrogens has a critical role in female development, particularly in mammary gland development. They also regulate longitudinal growth by the initiation and cessation of longitudinal growth and in addition are involved in the maturation of the hypothalamic pituitary ovarian axis.7 With European secular trends of an earlier menarche having slowed or stopped11, 40 and with a continuing trend of an older age at first full-term pregnancy in Europe,41 the risk association could be more a reflection of a longer exposure to ovarian estrogens until a woman's first full-term pregnancy. It is during this time window that the breast tissue is the most undifferentiated and the most susceptible to carcinogenic influences.42 An earlier menarcheal age is also associated with a higher BMI in later life43 and persistent increases in estradiol levels and decreases in sex hormone-binding globulin during the follicular phase of menstrual cycling throughout reproductive life.44 Therefore, the association with both ER+PR+ and ER-PR- tumors may reflect a physiological response established or already existent during pubertal years by a more intensive and increased exposure to estrogen.44

Major strengths of this study are its prospective design and large number of incident cases with receptor information. To our knowledge, we are the first to report on a significant interaction between height and age at menarche with ER+PR+ breast cancer. Further, we are the first to report on the increased risk association of standing height, leg length and sitting height with ER+PR+ tumors particularly among women older than 60 years. However, our study does have its limitations. Although a number of studies have shown that the classification of ER and PR expression in tumors is relatively robust,45 the accuracy of classifying an ER- or PR-negative tumor remains controversial.46 Proportions of ER- and PR-positive and −negative tumors in the EPIC cohort are in line with the previously published reports.47, 48 Furthermore, the inclusion of PR provides an indication of a functional estrogen pathway2 and thus a joint ER-PR- may be more reflective of a genuine ER-negative tumor. At the time of our study, more detailed molecular subclassifications of breast cancer using HER2 could not be completed because of insufficient information on HER2. However, because routine assessment of HER2 is relatively more recent than ER and PR assessment, future cohort analyses will be able to include HER2.

Conclusions

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

In summary, our study showed the positive association of standing height and leg length and the inverse association of menarcheal age were associated with both ER+PR+ and ER-PR- breast tumor types, indicating that exposures during rapid growth periods are reflected in risk association for both breast cancer subtypes. Exposures during childhood promoting faster growth and sexual maturation may establish longer-term risk profiles for both HR-positive and −negative malignancies. The difference in the risk estimates of leg length and sitting height with ER+PR+ tumors indicates height should be assessed as a separate risk factors and that sitting height may be a stronger predictor of ER+PR+ breast cancer risk. The stronger risk association of all components of height with ER+PR+ disease in older women suggests a possible hormonal and or metabolic link that could be more specific for postmenopausal women and could be independent of risk patterns established during childhood.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

The authors thank Sabine Rohrmann, Jutta Schmitt and Jutta Kneisel for their assistance during the collection of hormone receptor status data, and the authors thank all the EPIC cohort participants for their contributions to data collection at baseline recruitment and during follow-up. Finally, the in-depth comments from the two anonymous reviewers are also greatly acknowledged.

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  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Supporting Information

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