# Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Karin Kast, Esther M John, John L Hopper, Nadine Andrieu, Catherine Noguès, Emmanuelle Mouret-Fourme, Christine Lasset, Jean-Pierre Fricker, Pascaline Berthet, Véronique Mari, et al.

► To cite this version:

Karin Kast, Esther M John, John L Hopper, Nadine Andrieu, Catherine Noguès, et al. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium. Breast Cancer Research, 2023, 25 (1), pp.72. 10.1186/s13058-023-01673-w. inserm-04546076

HAL Id: inserm-04546076

https://inserm.hal.science/inserm-04546076

Submitted on 15 Apr 2024

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# Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

Karin Kast, Esther M John, John L Hopper, Nadine Andrieu, Catherine Noguès, Emmanuelle Mouret-Fourme, Christine Lasset, Jean-Pierre Fricker, Pascaline Berthet, Véronique Mari, et al.

► To cite this version:

Karin Kast, Esther M John, John L Hopper, Nadine Andrieu, Catherine Noguès, et al. Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium. Breast Cancer Research, 2023, 25 (1), pp.72. 10.1186/s13058-023-01673-w. inserm-04546076

HAL Id: inserm-04546076

https://inserm.hal.science/inserm-04546076v1

Submitted on 15 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
RESEARCH

Open Access

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# Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in *BRCA1* or *BRCA2*: the *BRCA1* and *BRCA2* Cohort Consortium

Karin Kast¹*, Esther M. John²,³, John L. Hopper⁴, Nadine Andrieu⁵,⁶,⁷,⁸, Catherine Noguès⁹,¹⁰, Emmanuel Mouret-Fourme⁶, Christine Lasset¹¹, Jean-Pierre Fricker¹², Pascaline Berthet¹³, Véronique Mari¹⁴, Lucie Salle¹⁵, Marjanka K. Schmidt¹⁶, Margreet G. E. M. Ausems¹⁷, Encarnacion B. Gomez Garcia¹⁸, Irma van de Beek¹⁹, Marijke R. Wevers²⁰, D. Gareth Evans²¹,²²,²³, Marc Tischkowitz²⁴, Fiona Lalloo²⁵, Jackie Cook²⁶, Louise Izatt²⁷, Vishakha Tripathi²⁸, Katie Snape²⁹, Hannah Musgrave³⁰, Saba Sharif³¹, Jennie Murray³²,³³,³⁰,³¹, EMBRACE Collaborators³⁴, Sarah V. Colonna³⁵, Irene L. Andrulis³⁶,³⁷, Mary B. Daly³⁸, Melissa C. Southey³⁹,⁴⁰, Miguel de la Hoya⁴¹, Ana Osorio⁴², Lenka Foretova⁴³, Dita Berkova⁴³, Anne-Marie Gerdes⁴⁴, Edith Olah⁴⁵, Anna Jakubowska⁴⁶,⁴⁷, Christian F. Singer⁴⁸, Yen Tan⁴⁸, Annelie Augustinsson⁴⁹, Johanna Rantala⁵⁰, Jacques Simard⁵¹, Rita K. Schmutzler¹, Roger L. Milne⁴,⁵²,⁵³, Kelly-Anne Phillips⁵⁴,⁵⁵, Mary Beth Terry⁵⁶, David Goldgar⁵⁷, Flora E. van Leeuwen⁵⁸, Thea M. Mooij⁵⁸, Antonis C. Antoniou⁵⁹, Douglas F. Easton³⁴,⁵⁹, Matti A. Rookus⁵⁸ and Christoph Engel⁶⁰

**Abstract**

**Introduction** Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the *BRCA1* or *BRCA2* genes.

**Patients and methods** An international pooled cohort of 8091 *BRCA1/2* variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change.

**Results** In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for *BRCA2* variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04–1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both *BRCA1* (HR 0.75 per 5 kg/m², 95% CI 0.66–0.84) and *BRCA2* (HR 0.76, 95% CI 0.65–0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with

<footnote>*Correspondence:
Karin Kast
karin.kast@uk-koeln.de
Full list of author information is available at the end of the article</footnote>
RESEARCH

Open Access

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# Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in *BRCA1* or *BRCA2*: the *BRCA1* and *BRCA2* Cohort Consortium

Karin Kast¹*, Esther M. John²,³, John L. Hopper⁴, Nadine Andrieu⁵,⁶,⁷,⁸, Catherine Noguès⁹,¹⁰,
Emmanuelle Mouret-Fourme⁶, Christine Lasset¹¹, Jean-Pierre Fricker¹², Pascaline Berthet¹³, Véronique Mari¹⁴,
Lucie Salle¹⁵, Marjanka K. Schmidt¹⁶, Margreet G. E. M. Ausems¹⁷, Encarnacion B. Gomez Garcia¹⁸,
Irma van de Beek¹⁹, Marijke R. Wevers²⁰, D. Gareth Evans²¹,²²,²³, Marc Tischkowitz²⁴, Fiona Lalloo²⁵,
Jackie Cook²⁶, Louise Izatt²⁷, Vishakha Tripathi²⁸, Katie Snape²⁹, Hannah Musgrave³⁰, Saba Sharif³¹,
Jennie Murray³²,³³,³⁰,³¹, EMBRACE Collaborators³⁴, Sarah V. Colonna³⁵, Irene L. Andrulis³⁶,³⁷,
Mary B. Daly³⁸, Melissa C. Southey³⁹,⁴⁰, Miguel de la Hoya⁴¹, Ana Osorio⁴², Lenka Foretova⁴³,
Dita Berkova⁴³, Anne-Marie Gerdes⁴⁴, Edith Olah⁴⁵, Anna Jakubowska⁴⁶,⁴⁷, Christian F. Singer⁴⁸, Yen Tan⁴⁸,
Annelie Augustinsson⁴⁹, Johanna Rantala⁵⁰, Jacques Simard⁵¹, Rita K. Schmutzler¹, Roger L. Milne⁴,⁵²,⁵³,
Kelly-Anne Phillips⁵⁴,⁵⁵, Mary Beth Terry⁵⁶, David Goldgar⁵⁷, Flora E. van Leeuwen⁵⁸, Thea M. Mooij⁵⁸,
Antonis C. Antoniou⁵⁹, Douglas F. Easton³⁴,⁵⁹, Matti A. Rookus⁵⁸ and Christoph Engel⁶⁰

**Abstract**

**Introduction** Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the *BRCA1* or *BRCA2* genes.

**Patients and methods** An international pooled cohort of 8091 *BRCA1/2* variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change.

**Results** In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for *BRCA2* variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04–1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both *BRCA1* (HR 0.75 per 5 kg/m², 95% CI 0.66–0.84) and *BRCA2* (HR 0.76, 95% CI 0.65–0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with

<footnote>*Correspondence:
Karin Kast
karin.kast@uk-koeln.de
Full list of author information is available at the end of the article</footnote>
higher postmenopausal breast cancer risk for *BRCA1* carriers (HR 1.20 per 5 kg/m², 95% CI 1.02–1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01–1.19, respectively).

**Conclusion** Anthropometric measures are associated with breast cancer risk for *BRCA1* and *BRCA2* variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

**Introduction**

Taller height and higher postmenopausal body mass index (BMI) are well-established risk factors for breast cancer [1-5]. While weight gain in adulthood increases the risk of postmenopausal breast cancer, higher weight in adolescence and early adulthood has been associated with decreased risk of pre- and postmenopausal breast cancer [3, 6-8]. The latter may be due in part to the fact that the differentiation of the mammary glands is promoted under higher estrogen levels in obese adolescents and young adults [4, 9-12].

Carriers of germline pathogenic variants in the *BRCA1* or *BRCA2* breast cancer predisposition genes have high breast cancer risks [13]. However, the extent to which these risks are modified by anthropometric factors is unknown. Most previous studies have been retrospective, some of them with limited sample sizes, and their results have generally been inconclusive [14-21]. Three previous studies examined the association of height with breast cancer risk in pathogenic variant carriers [17, 18, 20]. While two studies reported a positive association between height and breast cancer risk [17, 20], one did not observe an association [18]. These studies also analyzed body weight and breast cancer risk by menopausal status. Manders et al. found an association of higher current weight with post-menopausal breast cancer risk in a cohort of 299 carriers of pathogenic variants in *BRCA1* or *BRCA2* [17]. They also found weak evidence of a positive association between weight gain and postmenopausal breast cancer [17]. The retrospective study by Qian et al. reported an inverse association for higher BMI at age 18 years and risk of premenopausal breast cancer in a cohort of 14,676 carriers of pathogenic variants in *BRCA1* and 7912 in *BRCA2* [20]. Using a Mendelian randomization approach, they additionally showed a similar inverse association between genetically determined BMI and premenopausal breast cancer risk, consistent with that seen in the general population [3, 5-8]. The only prospective study on BMI and breast cancer risk in carriers of a pathogenic variant in *BRCA1* or *BRCA2* found weak evidence for an association of higher BMI at age 18 years with lower postmenopausal breast cancer risk, but no association of current BMI or weight change and breast cancer risk [18].

The identification of non-genetic risk factors for breast cancer in high-risk populations is important for developing more accurate risk prediction models and designing risk-adapted prevention strategies. In the present work, we evaluated the associations of height, BMI, and change in weight with pre- and postmenopausal breast cancer risk for carriers of a pathogenic variant in *BRCA1* or *BRCA2*, using data from the International *BRCA1* and *BRCA2* Cohort Consortium [22-25].

**Methods**

**Study sample**

We used pooled data from three large prospective cohort studies of *BRCA1* and *BRCA2* pathogenic variant carriers: the International *BRCA1/2* Carrier Cohort Study (IBCCS, consisting of 19 national multi- and single-center prospective cohort studies) [22], the Kathleen Cuningham Foundation Consortium for research into Familial Breast cancer (kConFab) [24, 26], and the Breast Cancer Family Registry (BCFR) [23, 25] (Additional file 1: Table S1). The study sample comprised women who were 18 to 80 years of age at recruitment and tested positive for a pathogenic germline variant in *BRCA1* or *BRCA2*. Women with pathogenic variants in both genes were excluded.

**Data collection**

Study participants completed a baseline questionnaire and one or more follow-up questionnaires. The questionnaires asked about risk factors for breast cancer, including height, young-adult weight (age 18 or 20 years), weight at questionnaire completion, reproductive and medical history, surgical interventions, and menstrual history (age at menarche, age at last menstruation, whether the woman had had any periods in the past year, the number of years/months since the last menstruation, and reason(s) for periods stopping) [27].

BMI was calculated as weight (kg) divided by height (m) squared. Weight change was calculated as the difference (in kg) between baseline weight and young-adult weight.

For women who indicated no periods in the past year, age at menopause was determined by adding one year to “age at last menstruation.” Women below the age of 60 years were considered premenopausal if they indicated
higher postmenopausal breast cancer risk for *BRCA1* carriers (HR 1.20 per 5 kg/m², 95% CI 1.02–1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01–1.19, respectively).

**Conclusion** Anthropometric measures are associated with breast cancer risk for *BRCA1* and *BRCA2* variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

**Introduction**

Taller height and higher postmenopausal body mass index (BMI) are well-established risk factors for breast cancer [1-5]. While weight gain in adulthood increases the risk of postmenopausal breast cancer, higher weight in adolescence and early adulthood has been associated with decreased risk of pre- and postmenopausal breast cancer [3, 6-8]. The latter may be due in part to the fact that the differentiation of the mammary glands is promoted under higher estrogen levels in obese adolescents and young adults [4, 9-12].

Carriers of germline pathogenic variants in the *BRCA1* or *BRCA2* breast cancer predisposition genes have high breast cancer risks [13]. However, the extent to which these risks are modified by anthropometric factors is unknown. Most previous studies have been retrospective, some of them with limited sample sizes, and their results have generally been inconclusive [14-21]. Three previous studies examined the association of height with breast cancer risk in pathogenic variant carriers [17, 18, 20]. While two studies reported a positive association between height and breast cancer risk [17, 20], one did not observe an association [18]. These studies also analyzed body weight and breast cancer risk by menopausal status. Manders et al. found an association of higher current weight with post-menopausal breast cancer risk in a cohort of 299 carriers of pathogenic variants in *BRCA1* or *BRCA2* [17]. They also found weak evidence of a positive association between weight gain and postmenopausal breast cancer [17]. The retrospective study by Qian et al. reported an inverse association for higher BMI at age 18 years and risk of premenopausal breast cancer in a cohort of 14,676 carriers of pathogenic variants in *BRCA1* and 7912 in *BRCA2* [20]. Using a Mendelian randomization approach, they additionally showed a similar inverse association between genetically determined BMI and premenopausal breast cancer risk, consistent with that seen in the general population [3, 5-8]. The only prospective study on BMI and breast cancer risk in carriers of a pathogenic variant in *BRCA1* or *BRCA2* found weak evidence for an association of higher BMI at age 18 years with lower postmenopausal breast cancer risk, but no association of current BMI or weight change and breast cancer risk [18].

The identification of non-genetic risk factors for breast cancer in high-risk populations is important for developing more accurate risk prediction models and designing risk-adapted prevention strategies. In the present work, we evaluated the associations of height, BMI, and change in weight with pre- and postmenopausal breast cancer risk for carriers of a pathogenic variant in *BRCA1* or *BRCA2*, using data from the International *BRCA1* and *BRCA2* Cohort Consortium [22-25].

**Methods**

**Study sample**

We used pooled data from three large prospective cohort studies of *BRCA1* and *BRCA2* pathogenic variant carriers: the International *BRCA1/2* Carrier Cohort Study (IBCCS, consisting of 19 national multi- and single-center prospective cohort studies) [22], the Kathleen Cuningham Foundation Consortium for research into Familial Breast cancer (kConFab) [24, 26], and the Breast Cancer Family Registry (BCFR) [23, 25] (Additional file 1: Table S1). The study sample comprised women who were 18 to 80 years of age at recruitment and tested positive for a pathogenic germline variant in *BRCA1* or *BRCA2*. Women with pathogenic variants in both genes were excluded.

**Data collection**

Study participants completed a baseline questionnaire and one or more follow-up questionnaires. The questionnaires asked about risk factors for breast cancer, including height, young-adult weight (age 18 or 20 years), weight at questionnaire completion, reproductive and medical history, surgical interventions, and menstrual history (age at menarche, age at last menstruation, whether the woman had had any periods in the past year, the number of years/months since the last menstruation, and reason(s) for periods stopping) [27].

BMI was calculated as weight (kg) divided by height (m) squared. Weight change was calculated as the difference (in kg) between baseline weight and young-adult weight.

For women who indicated no periods in the past year, age at menopause was determined by adding one year to “age at last menstruation.” Women below the age of 60 years were considered premenopausal if they indicated
that they had had a period in the past year, or if the “reason for periods stopping” was medication, oral contraceptive use, pregnancy, or breastfeeding. Women below the age of 60 years reporting risk-reducing salpingo-oophorectomy (RRSO) as the reason for menopause were considered premenopausal until RRSO. For women who reported a hysterectomy without bilateral oophorectomy, menopausal status was considered unknown. For women who were still menstruating when they started hormonal therapy and those who took hormonal contraceptives at older ages, age at menopause was classified as unknown.

Occurrence of breast cancer was derived from follow-up questionnaires and, for some studies, through linkage to cancer registries. Information on vital status was obtained from municipal or death registries, medical records, or family members. For details, see Kuchenbaecker et al. [13]. All study participants provided written informed consent, and each study was approved by the relevant ethics committee at each participating institution.

## Statistical analysis

Associations with breast cancer risk were evaluated using Cox proportional hazards regression with age as the timescale, estimating hazard ratios (HR) and corresponding 95% confidence intervals (CI). Exposure variables analyzed were height, young-adult BMI, baseline BMI, and weight change between early adulthood and baseline. Each anthropometric variable was analyzed in a separate model. All analyses were stratified by year of birth (<1950, 1950–1959, 1960–1969, ≥1970) and study and were adjusted for age at menarche, number of full-term pregnancies, oral hormonal contraceptive use (ever/never), and hormone replacement therapy (ever/never), as reported in the baseline questionnaire. Robust variance estimation was used to account for familial clustering of study participants. Associations were examined separately for retrospective and prospective observation times, i.e., before and after baseline questionnaire, respectively, separately for *BRCA1* and *BRCA2* pathogenic variant carriers, and separately for pre- and post-menopausal women, resulting in eight sets of analyses.

## Retrospective analysis

Associations of breast cancer risk with height and young-adult BMI were analyzed. For premenopausal women, the observation time started at birth and ended at diagnosis of the first primary breast cancer (invasive or in situ) as the event of interest, or was censored at diagnosis of any other type of cancer, risk-reducing mastectomy (RRM), completion of baseline questionnaire, or menopause, whichever came first. For postmenopausal women, observation started at menopause (if menopause

occurred before baseline) and was censored at diagnosis of the first primary breast cancer (event), or at diagnosis of any other type of cancer, RRM, or baseline, whichever came first. Due to the non-random sampling of prevalent breast cancer cases, retrospective analyses were performed using the weighted retrospective cohort approach described by Antoniou et al. [28]. Individuals were weighted such that the observed breast cancer incidence rates in the pre- and postmenopausal cohorts were consistent with established age-specific risk estimates for *BRCA1* and *BRCA2* variant carriers [29].

## Prospective analysis

Associations of breast cancer risk with height, young-adult BMI, baseline BMI, and weight change between early adulthood and baseline were analyzed. For pre-menopausal women, observation time started at baseline questionnaire completion (if women were premenopausal at that time point) and ended at diagnosis of the first primary breast cancer as the event of interest. Observation time was censored at diagnosis of any other type of cancer, RRM, last follow-up, or menopause, whichever came first. For postmenopausal women, observation started at baseline or menopause, whichever came last, and ended at diagnosis of the first primary breast cancer, or at diagnosis of any other type of cancer, RRM, or last follow-up, whichever came first.

If a woman's prospective observation period had included both pre- and postmenopausal periods, then follow-up periods were assigned to the pre- and post-menopausal analyses, as appropriate.

All reported *P* values are two-sided. *P* values < 0.05 were considered statistically significant. Statistical analyses were conducted using R 4.1.1 for Windows (R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org) and IBM SPSS Statistics for Windows Version 26 (IBM Corp, Armonk, NY).

## Results

### Retrospective analysis

The retrospective analysis included 6858 pathogenic variant carriers (*BRCA1*: 4257; *BRCA2*: 2601). The mean age at the end of observation was 40.5 years (SD ± 10.6), see Table 1.

Taller height was associated with higher premenopausal breast cancer risk in *BRCA2* pathogenic variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04–1.38). A consistent HR estimate was seen among postmenopausal women (HR 1.30 per 10 cm increase, 95% CI 0.97–1.74), see Table 2 and Additional file 2: Table S2. No association was seen for *BRCA1* variant carriers, neither for pre- or
that they had had a period in the past year, or if the “reason for periods stopping” was medication, oral contraceptive use, pregnancy, or breastfeeding. Women below the age of 60 years reporting risk-reducing salpingo-oophorectomy (RRSO) as the reason for menopause were considered premenopausal until RRSO. For women who reported a hysterectomy without bilateral oophorectomy, menopausal status was considered unknown. For women who were still menstruating when they started hormonal therapy and those who took hormonal contraceptives at older ages, age at menopause was classified as unknown.

Occurrence of breast cancer was derived from follow-up questionnaires and, for some studies, through linkage to cancer registries. Information on vital status was obtained from municipal or death registries, medical records, or family members. For details, see Kuchen-baecker et al. [13]. All study participants provided written informed consent, and each study was approved by the relevant ethics committee at each participating institution.

## Statistical analysis

Associations with breast cancer risk were evaluated using Cox proportional hazards regression with age as the timescale, estimating hazard ratios (HR) and corresponding 95% confidence intervals (CI). Exposure variables analyzed were height, young-adult BMI, baseline BMI, and weight change between early adulthood and baseline. Each anthropometric variable was analyzed in a separate model. All analyses were stratified by year of birth (<1950, 1950–1959, 1960–1969, ≥1970) and study and were adjusted for age at menarche, number of full-term pregnancies, oral hormonal contraceptive use (ever/never), and hormone replacement therapy (ever/never), as reported in the baseline questionnaire. Robust variance estimation was used to account for familial clustering of study participants. Associations were examined separately for retrospective and prospective observation times, i.e., before and after baseline questionnaire, respectively, separately for *BRCA1* and *BRCA2* pathogenic variant carriers, and separately for pre- and post-menopausal women, resulting in eight sets of analyses.

## Retrospective analysis

Associations of breast cancer risk with height and young-adult BMI were analyzed. For premenopausal women, the observation time started at birth and ended at diagnosis of the first primary breast cancer (invasive or in situ) as the event of interest, or was censored at diagnosis of any other type of cancer, risk-reducing mastectomy (RRM), completion of baseline questionnaire, or menopause, whichever came first. For postmenopausal women, observation started at menopause (if menopause

occurred before baseline) and was censored at diagnosis of the first primary breast cancer (event), or at diagnosis of any other type of cancer, RRM, or baseline, whichever came first. Due to the non-random sampling of prevalent breast cancer cases, retrospective analyses were performed using the weighted retrospective cohort approach described by Antoniou et al. [28]. Individuals were weighted such that the observed breast cancer incidence rates in the pre- and postmenopausal cohorts were consistent with established age-specific risk estimates for *BRCA1* and *BRCA2* variant carriers [29].

## Prospective analysis

Associations of breast cancer risk with height, young-adult BMI, baseline BMI, and weight change between early adulthood and baseline were analyzed. For pre-menopausal women, observation time started at baseline questionnaire completion (if women were premenopausal at that time point) and ended at diagnosis of the first primary breast cancer as the event of interest. Observation time was censored at diagnosis of any other type of cancer, RRM, last follow-up, or menopause, whichever came first. For postmenopausal women, observation started at baseline or menopause, whichever came last, and ended at diagnosis of the first primary breast cancer, or at diagnosis of any other type of cancer, RRM, or last follow-up, whichever came first.

If a woman's prospective observation period had included both pre- and postmenopausal periods, then follow-up periods were assigned to the pre- and post-menopausal analyses, as appropriate.

All reported *P* values are two-sided. *P* values < 0.05 were considered statistically significant. Statistical analyses were conducted using R 4.1.1 for Windows (R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: https://www.R-project.org) and IBM SPSS Statistics for Windows Version 26 (IBM Corp, Armonk, NY).

## Results

### Retrospective analysis

The retrospective analysis included 6858 pathogenic variant carriers (*BRCA1*: 4257; *BRCA2*: 2601). The mean age at the end of observation was 40.5 years (SD ± 10.6), see Table 1.

Taller height was associated with higher premenopausal breast cancer risk in *BRCA2* pathogenic variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04–1.38). A consistent HR estimate was seen among postmenopausal women (HR 1.30 per 10 cm increase, 95% CI 0.97–1.74), see Table 2 and Additional file 2: Table S2. No association was seen for *BRCA1* variant carriers, neither for pre- or
<table><caption>**Table 1** Characteristics of women in the retrospective analysis, by menopausal status</caption><thead><tr><th rowspan="3">Menopausal status</th><th colspan="3">Premenopausal</th><th colspan="6">Postmenopausal</th><th colspan="3">Pre-/postmenopausal</th></tr><tr><th colspan="2">BRCA1</th><th rowspan="2">Total</th><th colspan="2">BRCA2</th><th rowspan="2">Total</th><th colspan="2">BRCA1</th><th rowspan="2">Total</th><th colspan="2">BRCA2</th><th rowspan="2">Total</th></tr><tr><th>Unaffected</th><th>Affected</th><th>Unaffected</th><th>Affected</th><th>Unaffected</th><th>Affected</th><th>Unaffected</th><th>Affected</th><th>Total</th><th>BRCA1/2</th></tr></thead><tbody><tr><td>Number</td><td>n=2729</td><td>n=1528</td><td>n=4257</td><td>n=1765</td><td>n=836</td><td>n=2601</td><td>n=451</td><td>n=199</td><td>n=650</td><td>n=327</td><td>n=179</td><td>n=506</td><td>n=6858</td></tr><tr><td>Age at Censoring</td><td>38.2±9.0</td><td>37.5±6.7</td><td>37.9±8.2</td><td>39.9±8.9</td><td>39.9±6.6</td><td>39.9±8.2</td><td>53.4±9.0</td><td>54.2±8.0</td><td>53.7±8.7</td><td>57.4±8.8</td><td>56.0±7.2</td><td>56.9±8.3</td><td>40.5±10.6</td></tr><tr><td>Year of Birth, no (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;1950</td><td>581 (21.3)</td><td>332 (21.7)</td><td>913 (21.4)</td><td>465 (26.3)</td><td>182 (21.8)</td><td>647 (24.9)</td><td>218 (48.3)</td><td>150 (75.4)</td><td>368 (56.6)</td><td>205 (62.7)</td><td>136 (76.0)</td><td>341 (67.4)</td><td>1560 (22.7)</td></tr><tr><td>1950-1959</td><td>552 (20.2)</td><td>529 (34.6)</td><td>1081 (25.4)</td><td>343 (19.4)</td><td>295 (35.3)</td><td>638 (24.5)</td><td>148 (32.8)</td><td>39 (19.6)</td><td>187 (28.8)</td><td>88 (26.9)</td><td>41 (22.9)</td><td>129 (25.5)</td><td>1719 (25.1)</td></tr><tr><td>1960-1969</td><td>748 (27.4)</td><td>487 (31.9)</td><td>1235 (29.0)</td><td>456 (25.8)</td><td>283 (33.9)</td><td>739 (28.4)</td><td>79 (17.5)</td><td>8 (4.0)</td><td>87 (13.4)</td><td>31 (9.5)</td><td>2 (1.1)</td><td>33 (6.5)</td><td>1974 (28.8)</td></tr><tr><td>≥1970</td><td>848 (31.1)</td><td>180 (11.8)</td><td>1028 (24.1)</td><td>501 (28.4)</td><td>76 (9.1)</td><td>577 (22.2)</td><td>6 (1.3)</td><td>2 (1.0)</td><td>8 (1.2)</td><td>3 (0.9)</td><td>0 (0.0)</td><td>3 (0.6)</td><td>1605 (23.4)</td></tr><tr><td>Height (cm)</td><td>164.9±6.9</td><td>164.6±6.6</td><td>164.8±6.8</td><td>164.3±6.8</td><td>164.6±7.0</td><td>164.4±6.8</td><td>163.6±6.9</td><td>162.1±6.6</td><td>163.1±6.8</td><td>162.6±6.7</td><td>162.3±6.3</td><td>162.5±6.5</td><td>164.2±6.6</td></tr><tr><td>Young adult*</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weight (kg)</td><td>57.5±8.9</td><td>56.1±7.9</td><td>57.0±8.6</td><td>57.9±9.8</td><td>56.6±7.9</td><td>57.5±9.2</td><td>56.8±8.2</td><td>56.1±8.3</td><td>56.6±8.2</td><td>57.9±11.4</td><td>55.8±8.5</td><td>57.2±10.5</td><td>57.2±8.8</td></tr><tr><td>BMI (kg/m²)</td><td>21.1±3.0</td><td>20.7±2.6</td><td>21.0±2.9</td><td>21.4±3.3</td><td>20.9±2.6</td><td>21.3±3.1</td><td>21.2±2.8</td><td>21.4±2.9</td><td>21.3±2.8</td><td>21.9±3.9</td><td>21.2±2.9</td><td>21.6±3.6</td><td>21.1±3.0</td></tr></tbody><tfoot><tr><td colspan="14">Numbers are means±SD unless otherwise specified</td></tr><tr><td colspan="14">*Age 18 or 20 years</td></tr></tfoot></table>
<table><caption>**Table 1** Characteristics of women in the retrospective analysis, by menopausal status</caption><thead><tr><th rowspan="3">Menopausal status</th><th colspan="3">Premenopausal</th><th colspan="6">Postmenopausal</th><th colspan="3">Pre-/postmenopausal</th></tr><tr><th colspan="2">BRCA1</th><th rowspan="2">Total</th><th colspan="2">BRCA2</th><th rowspan="2">Total</th><th colspan="2">BRCA1</th><th rowspan="2">Total</th><th colspan="2">BRCA2</th><th rowspan="2">Total</th></tr><tr><th>Unaffected</th><th>Affected</th><th>Unaffected</th><th>Affected</th><th>Unaffected</th><th>Affected</th><th>Unaffected</th><th>Affected</th><th>Total</th><th>BRCA1/2</th></tr></thead><tbody><tr><td>Number</td><td>n=2729</td><td>n=1528</td><td>n=4257</td><td>n=1765</td><td>n=836</td><td>n=2601</td><td>n=451</td><td>n=199</td><td>n=650</td><td>n=327</td><td>n=179</td><td>n=506</td><td>n=6858</td></tr><tr><td>Age at Censoring</td><td>38.2±9.0</td><td>37.5±6.7</td><td>37.9±8.2</td><td>39.9±8.9</td><td>39.9±6.6</td><td>39.9±8.2</td><td>53.4±9.0</td><td>54.2±8.0</td><td>53.7±8.7</td><td>57.4±8.8</td><td>56.0±7.2</td><td>56.9±8.3</td><td>40.5±10.6</td></tr><tr><td>Year of Birth, no (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;1950</td><td>581 (21.3)</td><td>332 (21.7)</td><td>913 (21.4)</td><td>465 (26.3)</td><td>182 (21.8)</td><td>647 (24.9)</td><td>218 (48.3)</td><td>150 (75.4)</td><td>368 (56.6)</td><td>205 (62.7)</td><td>136 (76.0)</td><td>341 (67.4)</td><td>1560 (22.7)</td></tr><tr><td>1950-1959</td><td>552 (20.2)</td><td>529 (34.6)</td><td>1081 (25.4)</td><td>343 (19.4)</td><td>295 (35.3)</td><td>638 (24.5)</td><td>148 (32.8)</td><td>39 (19.6)</td><td>187 (28.8)</td><td>88 (26.9)</td><td>41 (22.9)</td><td>129 (25.5)</td><td>1719 (25.1)</td></tr><tr><td>1960-1969</td><td>748 (27.4)</td><td>487 (31.9)</td><td>1235 (29.0)</td><td>456 (25.8)</td><td>283 (33.9)</td><td>739 (28.4)</td><td>79 (17.5)</td><td>8 (4.0)</td><td>87 (13.4)</td><td>31 (9.5)</td><td>2 (1.1)</td><td>33 (6.5)</td><td>1974 (28.8)</td></tr><tr><td>≥1970</td><td>848 (31.1)</td><td>180 (11.8)</td><td>1028 (24.1)</td><td>501 (28.4)</td><td>76 (9.1)</td><td>577 (22.2)</td><td>6 (1.3)</td><td>2 (1.0)</td><td>8 (1.2)</td><td>3 (0.9)</td><td>0 (0.0)</td><td>3 (0.6)</td><td>1605 (23.4)</td></tr><tr><td>Height (cm)</td><td>164.9±6.9</td><td>164.6±6.6</td><td>164.8±6.8</td><td>164.3±6.8</td><td>164.6±7.0</td><td>164.4±6.8</td><td>163.6±6.9</td><td>162.1±6.6</td><td>163.1±6.8</td><td>162.6±6.7</td><td>162.3±6.3</td><td>162.5±6.5</td><td>164.2±6.6</td></tr><tr><td>Young adult*</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weight (kg)</td><td>57.5±8.9</td><td>56.1±7.9</td><td>57.0±8.6</td><td>57.9±9.8</td><td>56.6±7.9</td><td>57.5±9.2</td><td>56.8±8.2</td><td>56.1±8.3</td><td>56.6±8.2</td><td>57.9±11.4</td><td>55.8±8.5</td><td>57.2±10.5</td><td>57.2±8.8</td></tr><tr><td>BMI (kg/m²)</td><td>21.1±3.0</td><td>20.7±2.6</td><td>21.0±2.9</td><td>21.4±3.3</td><td>20.9±2.6</td><td>21.3±3.1</td><td>21.2±2.8</td><td>21.4±2.9</td><td>21.3±2.8</td><td>21.9±3.9</td><td>21.2±2.9</td><td>21.6±3.6</td><td>21.1±3.0</td></tr></tbody><tfoot><tr><td colspan="14">Numbers are means±SD unless otherwise specified</td></tr><tr><td colspan="14">*Age 18 or 20 years</td></tr></tfoot></table>
<table><caption>**Table 2** Retrospective analysis of height, body mass index, and breast cancer risk, by menopausal status</caption><thead><tr><th rowspan="3">Menopausal status<br>BRCA status</th><th colspan="8">Premenopausal</th><th colspan="8">Postmenopausal</th></tr><tr><th colspan="4">BRCA1</th><th colspan="4">BRCA2</th><th colspan="4">BRCA1</th><th colspan="4">BRCA2</th></tr><tr><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th></tr></thead><tbody><tr><td>Height, per 10 cm</td><td>4257</td><td>1528</td><td>1.06</td><td>0.95-1.17</td><td>2601</td><td>836</td><td>1.20</td><td>1.04-1.38</td><td>650</td><td>199</td><td>0.87</td><td>0.69-1.10</td><td>506</td><td>179</td><td>1.30</td><td>0.97-1.74</td></tr><tr><td colspan="19">Young-adult BMI, kg/m² (categories)</td></tr><tr><td>&lt; 18.5</td><td>714</td><td>268</td><td>1.20</td><td>1.00-1.42</td><td>362</td><td>132</td><td>1.16</td><td>0.89-1.51</td><td>91</td><td>32</td><td>1.67</td><td>1.09-2.56</td><td>63</td><td>31</td><td>1.58</td><td>0.95-2.60</td></tr><tr><td>18.5 to &lt; 25 (reference)</td><td>3231</td><td>1177</td><td>1.0</td><td></td><td>2015</td><td>654</td><td>1.0</td><td></td><td>504</td><td>148</td><td>1.0</td><td></td><td>394</td><td>134</td><td>1.0</td><td></td></tr><tr><td>≥25</td><td>312</td><td>83</td><td>0.67</td><td>0.51-0.88</td><td>224</td><td>50</td><td>0.65</td><td>0.46-0.93</td><td>55</td><td>19</td><td>1.10</td><td>0.67-1.82</td><td>49</td><td>14</td><td>0.95</td><td>0.53-1.69</td></tr><tr><td>Young-adult BMI per<br>5 kg/m² (continuous)</td><td>4257</td><td>1528</td><td>0.75</td><td>0.66-0.84</td><td>2601</td><td>836</td><td>0.76</td><td>0.65-0.89</td><td>650</td><td>199</td><td>0.86</td><td>0.64-1.17</td><td>506</td><td>179</td><td>0.85</td><td>0.64-1.14</td></tr></tbody></table>

BC breast cancer, BMI body mass index, 1.0 = reference value

All analyses were adjusted for age at menarche, number of full-term pregnancies, oral hormonal contraceptive use, and hormone replacement therapy

menopausal women. Higher young-adult BMI was associated with lower risk of premenopausal breast cancer both in *BRCA1* (HR 0.75 per 5 kg/m², 95% CI 0.66–0.84) and *BRCA2* (HR 0.76 per 5 kg/m², 95% CI 0.65–0.89) variant carriers. Consistent inverse associations with premenopausal breast cancer risk were also seen when young-adult BMI was categorized. In postmenopausal women, high young-adult BMI was associated with reduced breast cancer risk in *BRCA1* carriers compared to women with a normal BMI, although statistical significance was only reached in the category of low compared to normal BMI (<18.5 kg/m² vs. 18.5 to <25 kg/m²: HR 1.67, 95% CI 1.09–2.56). A consistent, but not statistically significant result was observed for *BRCA2* variant carriers. Young-adult BMI, considered as a continuous variable, was not significantly associated with postmenopausal breast cancer risk.

## Prospective analysis

The prospective analysis was based on 3698 pathogenic variant carriers (*BRCA1*: 2167; *BRCA2*: 1531 with information on height and baseline weight. In total, 397 incident breast cancer cases were diagnosed (Table 3). The premenopausal cohort comprised 2527 carriers (*BRCA1*: 1516; *BRCA2*: 1011), and the postmenopausal cohort 1531 carriers (*BRCA1*: 905; *BRCA2*: 626), with a mean follow-up time of 5.3±3.5 years. Information on young-adult weight was available for a subgroup of 3100 (84%) carriers.

There was a suggestion for increased premenopausal breast cancer risk for taller *BRCA1* and *BRCA2* variant carriers, but the association was not significant (HR 1.19 per 10 cm increase, 95% CI 0.91–1.56 and HR 1.32, 95% CI 0.92–1.90, respectively). There was no evidence for an association with postmenopausal breast cancer (Table 4, Additional file 2: Table S2). HR estimates for

young-adult BMI (continuous measure) were less than 1 for premenopausal breast cancer risk in both *BRCA1* and *BRCA2* variant carriers, although the associations were not statistically significant. In contrast, higher baseline BMI was associated with an increased risk for postmenopausal breast cancer for *BRCA1* variant carriers (HR per 5 kg/m² increase 1.20, 95% CI 1.02–1.42). However, there was no association between higher baseline BMI and risk for *BRCA2* carriers (HR 0.97, 95% CI 0.81–1.17).

Between early adulthood and baseline premenopausal *BRCA1* variant carriers gained a mean of 6.5±9.9 kg and postmenopausal *BRCA1* variant carriers gained 11.3±11.9 kg. Similarly premenopausal *BRCA2* variant carriers gained a mean of 7.2±10.5 kg and postmenopausal *BRCA2* variant carriers gained 11.4±12.1 kg. In *BRCA1* variant carriers, weight gain was associated with increased risk of postmenopausal breast cancer (HR per kg gain 1.10, 95% CI 1.01–1.19); however, no significant association was found for *BRCA2* variant carriers (HR 0.99, 95% CI 0.88–1.11). For premenopausal breast cancer, no associations with weight change were observed in carriers of pathogenic variants in either gene.

These results were unchanged after adjustment for use of hormonal contraception and postmenopausal hormone therapy (Additional file 3: Table S3 and Additional file 4: Table S4). To find out if absolute weight was the better explanatory variable compared to BMI, we performed a sensitivity analysis and examined associations with baseline weight and young-adult weight separately. No large differences in association with breast cancer compared to baseline BMI and young-adult BMI were found (Additional file 5: Table S5). To question if the inverse association of young-adult BMI was related to lower height in adolescence or young
<table><caption>**Table 2** Retrospective analysis of height, body mass index, and breast cancer risk, by menopausal status</caption><thead><tr><th rowspan="3">Menopausal status<br>BRCA status</th><th colspan="8">Premenopausal</th><th colspan="8">Postmenopausal</th></tr><tr><th colspan="4">BRCA1</th><th colspan="4">BRCA2</th><th colspan="4">BRCA1</th><th colspan="4">BRCA2</th></tr><tr><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th></tr></thead><tbody><tr><td>Height, per 10 cm</td><td>4257</td><td>1528</td><td>1.06</td><td>0.95-1.17</td><td>2601</td><td>836</td><td>1.20</td><td>1.04-1.38</td><td>650</td><td>199</td><td>0.87</td><td>0.69-1.10</td><td>506</td><td>179</td><td>1.30</td><td>0.97-1.74</td></tr><tr><td colspan="19">Young-adult BMI, kg/m² (categories)</td></tr><tr><td>&lt; 18.5</td><td>714</td><td>268</td><td>1.20</td><td>1.00-1.42</td><td>362</td><td>132</td><td>1.16</td><td>0.89-1.51</td><td>91</td><td>32</td><td>1.67</td><td>1.09-2.56</td><td>63</td><td>31</td><td>1.58</td><td>0.95-2.60</td></tr><tr><td>18.5 to &lt; 25 (reference)</td><td>3231</td><td>1177</td><td>1.0</td><td></td><td>2015</td><td>654</td><td>1.0</td><td></td><td>504</td><td>148</td><td>1.0</td><td></td><td>394</td><td>134</td><td>1.0</td><td></td></tr><tr><td>≥25</td><td>312</td><td>83</td><td>0.67</td><td>0.51-0.88</td><td>224</td><td>50</td><td>0.65</td><td>0.46-0.93</td><td>55</td><td>19</td><td>1.10</td><td>0.67-1.82</td><td>49</td><td>14</td><td>0.95</td><td>0.53-1.69</td></tr><tr><td>Young-adult BMI per<br>5 kg/m² (continuous)</td><td>4257</td><td>1528</td><td>0.75</td><td>0.66-0.84</td><td>2601</td><td>836</td><td>0.76</td><td>0.65-0.89</td><td>650</td><td>199</td><td>0.86</td><td>0.64-1.17</td><td>506</td><td>179</td><td>0.85</td><td>0.64-1.14</td></tr></tbody></table>

BC breast cancer, BMI body mass index, 1.0 = reference value

All analyses were adjusted for age at menarche, number of full-term pregnancies, oral hormonal contraceptive use, and hormone replacement therapy

menopausal women. Higher young-adult BMI was associated with lower risk of premenopausal breast cancer both in *BRCA1* (HR 0.75 per 5 kg/m², 95% CI 0.66–0.84) and *BRCA2* (HR 0.76 per 5 kg/m², 95% CI 0.65–0.89) variant carriers. Consistent inverse associations with premenopausal breast cancer risk were also seen when young-adult BMI was categorized. In postmenopausal women, high young-adult BMI was associated with reduced breast cancer risk in *BRCA1* carriers compared to women with a normal BMI, although statistical significance was only reached in the category of low compared to normal BMI (<18.5 kg/m² vs. 18.5 to <25 kg/m²: HR 1.67, 95% CI 1.09–2.56). A consistent, but not statistically significant result was observed for *BRCA2* variant carriers. Young-adult BMI, considered as a continuous variable, was not significantly associated with postmenopausal breast cancer risk.

## Prospective analysis

The prospective analysis was based on 3698 pathogenic variant carriers (*BRCA1*: 2167; *BRCA2*: 1531 with information on height and baseline weight. In total, 397 incident breast cancer cases were diagnosed (Table 3). The premenopausal cohort comprised 2527 carriers (*BRCA1*: 1516; *BRCA2*: 1011), and the postmenopausal cohort 1531 carriers (*BRCA1*: 905; *BRCA2*: 626), with a mean follow-up time of 5.3 ± 3.5 years. Information on young-adult weight was available for a subgroup of 3100 (84%) carriers.

There was a suggestion for increased premenopausal breast cancer risk for taller *BRCA1* and *BRCA2* variant carriers, but the association was not significant (HR 1.19 per 10 cm increase, 95% CI 0.91–1.56 and HR 1.32, 95% CI 0.92–1.90, respectively). There was no evidence for an association with postmenopausal breast cancer (Table 4, Additional file 2: Table S2). HR estimates for

young-adult BMI (continuous measure) were less than 1 for premenopausal breast cancer risk in both *BRCA1* and *BRCA2* variant carriers, although the associations were not statistically significant. In contrast, higher baseline BMI was associated with an increased risk for postmenopausal breast cancer for *BRCA1* variant carriers (HR per 5 kg/m² increase 1.20, 95% CI 1.02–1.42). However, there was no association between higher baseline BMI and risk for *BRCA2* carriers (HR 0.97, 95% CI 0.81–1.17).

Between early adulthood and baseline premenopausal *BRCA1* variant carriers gained a mean of 6.5 ± 9.9 kg and postmenopausal *BRCA1* variant carriers gained 11.3 ± 11.9 kg. Similarly premenopausal *BRCA2* variant carriers gained a mean of 7.2 ± 10.5 kg and postmenopausal *BRCA2* variant carriers gained 11.4 ± 12.1 kg. In *BRCA1* variant carriers, weight gain was associated with increased risk of postmenopausal breast cancer (HR per kg gain 1.10, 95% CI 1.01–1.19); however, no significant association was found for *BRCA2* variant carriers (HR 0.99, 95% CI 0.88–1.11). For premenopausal breast cancer, no associations with weight change were observed in carriers of pathogenic variants in either gene.

These results were unchanged after adjustment for use of hormonal contraception and postmenopausal hormone therapy (Additional file 3: Table S3 and Additional file 4: Table S4). To find out if absolute weight was the better explanatory variable compared to BMI, we performed a sensitivity analysis and examined associations with baseline weight and young-adult weight separately. No large differences in association with breast cancer compared to baseline BMI and young-adult BMI were found (Additional file 5: Table S5). To question if the inverse association of young-adult BMI was related to lower height in adolescence or young
<table><caption>**Table 3** Characteristics of women in the prospective analysis, by menopausal status</caption><thead><tr><th rowspan="2">Menopausal status</th><th colspan="3">Premenopausal</th><th colspan="3">Postmenopausal</th><th colspan="3">Pre-/postmenopausal</th></tr><tr><th>BRCA status</th><th>Unaffected</th><th>Affected</th><th>Total</th><th>Unaffected</th><th>Affected</th><th>Total</th><th>Unaffected</th><th>Affected</th><th>Total</th></tr></thead><tbody><tr><td>Breast cancer</td><td>BRCA1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Number</td><td>n = 1401</td><td>n = 115</td><td>n = 1516</td><td>n = 960</td><td>n = 51</td><td>n = 1011</td><td>n = 793</td><td>n = 112</td><td>n = 905</td><td>n = 626</td><td>n = 3698</td></tr><tr><td>Age at Start</td><td>32.4 ± 7.8</td><td>33.3 ± 6.0</td><td>32.5 ± 7.7</td><td>33.9 ± 8.1</td><td>37.0 ± 6.4</td><td>34.1 ± 8.1</td><td>47.8 ± 9.5</td><td>48.0 ± 9.0</td><td>47.8 ± 9.5</td><td>51.4 ± 9.8</td><td>52.9 ± 8.4</td><td>51.6 (9.7)</td><td>38.9 ± 12.0</td></tr><tr><td>Age at Censoring</td><td>36.7 ± 7.1</td><td>37.0 ± 5.5</td><td>36.7 ± 7.0</td><td>37.8 ± 7.7</td><td>39.8 ± 6.0</td><td>37.9 ± 7.6</td><td>52.7 ± 10.4</td><td>51.7 ± 9.4</td><td>52.6 ± 10.3</td><td>55.9 ± 10.4</td><td>55.9 ± 8.8</td><td>55.9 ± 10.3</td><td>44.0 ± 12.3</td></tr><tr><td>Follow-up time (years)</td><td>4.3 ± 3.2</td><td>3.6 ± 2.9</td><td>4.2 ± 3.2</td><td>3.9 ± 2.9</td><td>2.8 ± 2.5</td><td>3.8 ± 2.8</td><td>4.9 ± 3.3</td><td>3.7 ± 3.1</td><td>4.8 ± 3.3</td><td>4.5 ± 3.3</td><td>3.1 ± 2.7</td><td>4.4 ± 3.0</td><td>5.2 ± 3.5</td></tr><tr><td>Year of Birth</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;1950</td><td>11 (0.8)</td><td>1 (0.9)</td><td>12 (0.8)</td><td>7 (0.7)</td><td>1 (2.0)</td><td>8 (0.8)</td><td>184 (23.2)</td><td>29 (25.9)</td><td>213 (23.5)</td><td>185 (33.1)</td><td>33 (49.3)</td><td>218 (34.8)</td><td>449 (12.1)</td></tr><tr><td>1950-1959</td><td>140 (10.0)</td><td>10 (8.7)</td><td>150 (9.9)</td><td>112 (11.7)</td><td>9 (17.6)</td><td>121 (12.0)</td><td>265 (33.4)</td><td>40 (35.7)</td><td>305 (33.7)</td><td>181 (32.4)</td><td>21 (31.3)</td><td>202 (32.3)</td><td>679 (18.4)</td></tr><tr><td>1960-1969</td><td>435 (31.0)</td><td>55 (47.8)</td><td>490 (32.2)</td><td>309 (32.2)</td><td>27 (52.9)</td><td>336 (33.2)</td><td>284 (35.8)</td><td>41 (36.6)</td><td>325 (29.9)</td><td>167 (29.9)</td><td>13 (19.4)</td><td>180 (28.8)</td><td>1128 (30.5)</td></tr><tr><td>≥1970</td><td>815 (58.2)</td><td>49 (42.6)</td><td>864 (57.0)</td><td>532 (55.4)</td><td>14 (27.5)</td><td>546 (54.0)</td><td>60 (7.6)</td><td>2 (1.8)</td><td>62 (4.7)</td><td>26 (4.7)</td><td>0 (0.0)</td><td>26 (4.2)</td><td>1442 (39.0)</td></tr><tr><td>Height (cm)</td><td>165.7 ± 6.8</td><td>160.4 ± 7.0</td><td>165.7 ± 6.8</td><td>165.2 ± 6.6</td><td>166.4 ± 6.5</td><td>165.3 ± 6.3</td><td>164.3 ± 6.8</td><td>164.5 ± 7.0</td><td>164.3 ± 6.8</td><td>163.5 ± 6.8</td><td>162.4 ± 6.6</td><td>163.4 ± 6.8</td><td>164.9 ± 6.9</td></tr><tr><td>Weight at baseline (kg)</td><td>65.1 ± 13.7</td><td>65.2 ± 9.9</td><td>65.1 ± 13.4</td><td>66.4 ± 13.8</td><td>66.5 ± 13.6</td><td>66.5 ± 13.8</td><td>68.0 ± 14.4</td><td>71.0 ± 18.7</td><td>68.4 (15)</td><td>68.9 ± 15.3</td><td>70.6 ± 14.8</td><td>69.1 ± 15.2</td><td>67.0 ± 14.4</td></tr><tr><td>BMI at baseline (kg/m²)</td><td>23.7 ± 4.8</td><td>23.6 ± 3.9</td><td>23.7 ± 4.7</td><td>24.3 ± 4.9</td><td>24.0 ± 4.5</td><td>24.3 ± 4.8</td><td>25.2 ± 5.2</td><td>26.2 ± 6.5</td><td>25.3 ± 5.4</td><td>25.8 ± 5.5</td><td>26.7 ± 5.3</td><td>25.9 ± 5.5</td><td>24.7 ± 5.2</td></tr><tr><td>Breast cancer</td><td>BRCA1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Number</td><td>n = 1146</td><td>n = 96</td><td>n = 1242</td><td>n = 789</td><td>n = 40</td><td>n = 829</td><td>n = 640</td><td>n = 89</td><td>n = 729</td><td>n = 453</td><td>n = 56</td><td>n = 509</td><td>n = 3100</td></tr><tr><td>Young adult*</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weight (kg)</td><td>58.5 ± 9.9</td><td>57.7 ± 9.4</td><td>58.5 ± 9.9</td><td>59.5 ± 10.1</td><td>58.3 ± 8.4</td><td>59.5 ± 10.0</td><td>56.9 ± 8.7</td><td>56.9 ± 9.0</td><td>56.9 ± 8.7</td><td>57.7 ± 10.6</td><td>58.6 ± 12.3</td><td>57.8 ± 10.8</td><td>58.4 ± 10.0</td></tr><tr><td>BMI (kg/m²)</td><td>21.3 ± 3.4</td><td>20.8 ± 3.2</td><td>21.3 ± 3.4</td><td>21.8 ± 3.4</td><td>21.2 ± 2.6</td><td>21.7 ± 3.4</td><td>21.1 ± 3.0</td><td>21.0 ± 2.8</td><td>21.1 ± 2.9</td><td>21.6 ± 3.7</td><td>22.2 ± 4.3</td><td>21.7 ± 3.8</td><td>21.5 ± 3.4</td></tr><tr><td>Weight change total (kg)</td><td>6.4 ± 9.8</td><td>7.7 ± 10.2</td><td>6.5 ± 9.9</td><td>7.1 ± 10.5</td><td>9.2 ± 10.4</td><td>7.2 ± 10.5</td><td>11.0 ± 11.3</td><td>13.9 ± 15.2</td><td>11.3 ± 11.9</td><td>11.2 ± 11.8</td><td>12.7 ± 14.1</td><td>11.4 ± 12.1</td><td>8.6 ± 11.1</td></tr><tr><td>Weight change</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≥5 kg loss</td><td>87 (7.6)</td><td>6 (6.3)</td><td>93 (7.5)</td><td>50 (6.3)</td><td>2 (5.0)</td><td>52 (6.3)</td><td>24 (3.8)</td><td>4 (4.5)</td><td>28 (3.8)</td><td>23 (5.1)</td><td>6 (10.7)</td><td>29 (5.7)</td><td>190 (6.3)</td></tr><tr><td>&lt;5 kg loss to &lt;5 kg gain</td><td>472 (41.2)</td><td>34 (35.4)</td><td>506 (40.7)</td><td>313 (39.7)</td><td>11 (27.5)</td><td>324 (39.1)</td><td>165 (25.8)</td><td>18 (20.2)</td><td>183 (25.1)</td><td>114 (25.2)</td><td>7 (12.5)</td><td>121 (23.8)</td><td>1035 (34.1)</td></tr><tr><td>≥ +5 kg to 15 kg gain</td><td>404 (35.3)</td><td>34 (35.4)</td><td>438 (35.3)</td><td>282 (35.7)</td><td>19 (47.5)</td><td>301 (36.3)</td><td>254 (39.7)</td><td>34 (38.2)</td><td>288 (39.5)</td><td>167 (36.9)</td><td>27 (48.2)</td><td>194 (38.1)</td><td>1122 (36.9)</td></tr><tr><td>≥15 kg gain</td><td>183 (16.0)</td><td>22 (22.9)</td><td>205 (16.5)</td><td>144 (18.3)</td><td>8 (20.0)</td><td>152 (18.3)</td><td>197 (30.8)</td><td>33 (37.1)</td><td>230 (31.6)</td><td>149 (32.9)</td><td>16 (28.6)</td><td>165 (32.4)</td><td>692 (22.8)</td></tr></tbody></table>

Numbers are means±SD unless otherwise specified, * age 18 or 20 years
<table><caption>**Table 3** Characteristics of women in the prospective analysis, by menopausal status</caption><thead><tr><th rowspan="2">Menopausal status</th><th colspan="3">Premenopausal</th><th colspan="3">Postmenopausal</th><th colspan="3">Pre-/postmenopausal</th></tr><tr><th>BRCA status</th><th>Unaffected</th><th>Affected</th><th>Total</th><th>Unaffected</th><th>Affected</th><th>Total</th><th>Unaffected</th><th>Affected</th><th>Total</th></tr></thead><tbody><tr><td>Breast cancer</td><td>BRCA1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Number</td><td>n = 1401</td><td>n = 115</td><td>n = 1516</td><td>n = 960</td><td>n = 51</td><td>n = 1011</td><td>n = 793</td><td>n = 112</td><td>n = 905</td><td>n = 626</td><td>n = 3698</td></tr><tr><td>Age at Start</td><td>32.4 ± 7.8</td><td>33.3 ± 6.0</td><td>32.5 ± 7.7</td><td>33.9 ± 8.1</td><td>37.0 ± 6.4</td><td>34.1 ± 8.1</td><td>47.8 ± 9.5</td><td>48.0 ± 9.0</td><td>47.8 ± 9.5</td><td>51.4 ± 9.8</td><td>52.9 ± 8.4</td><td>51.6 (9.7)</td><td>38.9 ± 12.0</td></tr><tr><td>Age at Censoring</td><td>36.7 ± 7.1</td><td>37.0 ± 5.5</td><td>36.7 ± 7.0</td><td>37.8 ± 7.7</td><td>39.8 ± 6.0</td><td>37.9 ± 7.6</td><td>52.7 ± 10.4</td><td>51.7 ± 9.4</td><td>52.6 ± 10.3</td><td>55.9 ± 10.4</td><td>55.9 ± 8.8</td><td>55.9 ± 10.3</td><td>44.0 ± 12.3</td></tr><tr><td>Follow-up time (years)</td><td>4.3 ± 3.2</td><td>3.6 ± 2.9</td><td>4.2 ± 3.2</td><td>3.9 ± 2.9</td><td>2.8 ± 2.5</td><td>3.8 ± 2.8</td><td>4.9 ± 3.3</td><td>3.7 ± 3.1</td><td>4.8 ± 3.3</td><td>4.5 ± 3.3</td><td>3.1 ± 2.7</td><td>4.4 ± 3.0</td><td>5.2 ± 3.5</td></tr><tr><td>Year of Birth</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;1950</td><td>11 (0.8)</td><td>1 (0.9)</td><td>12 (0.8)</td><td>7 (0.7)</td><td>1 (2.0)</td><td>8 (0.8)</td><td>184 (23.2)</td><td>29 (25.9)</td><td>213 (23.5)</td><td>185 (33.1)</td><td>33 (49.3)</td><td>218 (34.8)</td><td>449 (12.1)</td></tr><tr><td>1950-1959</td><td>140 (10.0)</td><td>10 (8.7)</td><td>150 (9.9)</td><td>112 (11.7)</td><td>9 (17.6)</td><td>121 (12.0)</td><td>265 (33.4)</td><td>40 (35.7)</td><td>305 (33.7)</td><td>181 (32.4)</td><td>21 (31.3)</td><td>202 (32.3)</td><td>679 (18.4)</td></tr><tr><td>1960-1969</td><td>435 (31.0)</td><td>55 (47.8)</td><td>490 (32.2)</td><td>309 (32.2)</td><td>27 (52.9)</td><td>336 (33.2)</td><td>284 (35.8)</td><td>41 (36.6)</td><td>325 (29.9)</td><td>167 (29.9)</td><td>13 (19.4)</td><td>180 (28.8)</td><td>1128 (30.5)</td></tr><tr><td>≥1970</td><td>815 (58.2)</td><td>49 (42.6)</td><td>864 (57.0)</td><td>532 (55.4)</td><td>14 (27.5)</td><td>546 (54.0)</td><td>60 (7.6)</td><td>2 (1.8)</td><td>62 (4.7)</td><td>26 (4.7)</td><td>0 (0.0)</td><td>26 (4.2)</td><td>1442 (39.0)</td></tr><tr><td>Height (cm)</td><td>165.7 ± 6.8</td><td>160.4 ± 7.0</td><td>165.7 ± 6.8</td><td>165.2 ± 6.6</td><td>166.4 ± 6.5</td><td>165.3 ± 6.3</td><td>164.3 ± 6.8</td><td>164.5 ± 7.0</td><td>164.3 ± 6.8</td><td>163.5 ± 6.8</td><td>162.4 ± 6.6</td><td>163.4 ± 6.8</td><td>164.9 ± 6.9</td></tr><tr><td>Weight at baseline (kg)</td><td>65.1 ± 13.7</td><td>65.2 ± 9.9</td><td>65.1 ± 13.4</td><td>66.4 ± 13.8</td><td>66.5 ± 13.6</td><td>66.5 ± 13.8</td><td>68.0 ± 14.4</td><td>71.0 ± 18.7</td><td>68.4 (15)</td><td>68.9 ± 15.3</td><td>70.6 ± 14.8</td><td>69.1 ± 15.2</td><td>67.0 ± 14.4</td></tr><tr><td>BMI at baseline (kg/m²)</td><td>23.7 ± 4.8</td><td>23.6 ± 3.9</td><td>23.7 ± 4.7</td><td>24.3 ± 4.9</td><td>24.0 ± 4.5</td><td>24.3 ± 4.8</td><td>25.2 ± 5.2</td><td>26.2 ± 6.5</td><td>25.3 ± 5.4</td><td>25.8 ± 5.5</td><td>26.7 ± 5.3</td><td>25.9 ± 5.5</td><td>24.7 ± 5.2</td></tr><tr><td>Breast cancer</td><td>BRCA1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Number</td><td>n = 1146</td><td>n = 96</td><td>n = 1242</td><td>n = 789</td><td>n = 40</td><td>n = 829</td><td>n = 640</td><td>n = 89</td><td>n = 729</td><td>n = 453</td><td>n = 56</td><td>n = 509</td><td>n = 3100</td></tr><tr><td>Young adult*</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Weight (kg)</td><td>58.5 ± 9.9</td><td>57.7 ± 9.4</td><td>58.5 ± 9.9</td><td>59.5 ± 10.1</td><td>58.3 ± 8.4</td><td>59.5 ± 10.0</td><td>56.9 ± 8.7</td><td>56.9 ± 9.0</td><td>56.9 ± 8.7</td><td>57.7 ± 10.6</td><td>58.6 ± 12.3</td><td>57.8 ± 10.8</td><td>58.4 ± 10.0</td></tr><tr><td>BMI (kg/m²)</td><td>21.3 ± 3.4</td><td>20.8 ± 3.2</td><td>21.3 ± 3.4</td><td>21.8 ± 3.4</td><td>21.2 ± 2.6</td><td>21.7 ± 3.4</td><td>21.1 ± 3.0</td><td>21.0 ± 2.8</td><td>21.1 ± 2.9</td><td>21.6 ± 3.7</td><td>22.2 ± 4.3</td><td>21.7 ± 3.8</td><td>21.5 ± 3.4</td></tr><tr><td>Weight change total (kg)</td><td>6.4 ± 9.8</td><td>7.7 ± 10.2</td><td>6.5 ± 9.9</td><td>7.1 ± 10.5</td><td>9.2 ± 10.4</td><td>7.2 ± 10.5</td><td>11.0 ± 11.3</td><td>13.9 ± 15.2</td><td>11.3 ± 11.9</td><td>11.2 ± 11.8</td><td>12.7 ± 14.1</td><td>11.4 ± 12.1</td><td>8.6 ± 11.1</td></tr><tr><td>Weight change</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≥5 kg loss</td><td>87 (7.6)</td><td>6 (6.3)</td><td>93 (7.5)</td><td>50 (6.3)</td><td>2 (5.0)</td><td>52 (6.3)</td><td>24 (3.8)</td><td>4 (4.5)</td><td>28 (3.8)</td><td>23 (5.1)</td><td>6 (10.7)</td><td>29 (5.7)</td><td>190 (6.3)</td></tr><tr><td>&lt;5 kg loss to &lt;5 kg gain</td><td>472 (41.2)</td><td>34 (35.4)</td><td>506 (40.7)</td><td>313 (39.7)</td><td>11 (27.5)</td><td>324 (39.1)</td><td>165 (25.8)</td><td>18 (20.2)</td><td>183 (25.1)</td><td>114 (25.2)</td><td>7 (12.5)</td><td>121 (23.8)</td><td>1035 (34.1)</td></tr><tr><td>≥ +5 kg to 15 kg gain</td><td>404 (35.3)</td><td>34 (35.4)</td><td>438 (35.3)</td><td>282 (35.7)</td><td>19 (47.5)</td><td>301 (36.3)</td><td>254 (39.7)</td><td>34 (38.2)</td><td>288 (39.5)</td><td>167 (36.9)</td><td>27 (48.2)</td><td>194 (38.1)</td><td>1122 (36.9)</td></tr><tr><td>≥15 kg gain</td><td>183 (16.0)</td><td>22 (22.9)</td><td>205 (16.5)</td><td>144 (18.3)</td><td>8 (20.0)</td><td>152 (18.3)</td><td>197 (30.8)</td><td>33 (37.1)</td><td>230 (31.6)</td><td>149 (32.9)</td><td>16 (28.6)</td><td>165 (32.4)</td><td>692 (22.8)</td></tr></tbody></table>

Numbers are means ± SD unless otherwise specified, * age 18 or 20 years
<table><caption>**Table 4** Prospective analysis of height, body mass index, weight change, and breast cancer risk, by menopausal status</caption><thead><tr><th rowspan="3">Menopausal status<br>BRCA status</th><th colspan="4">Premenopausal</th><th colspan="4">Postmenopausal</th></tr><tr><th colspan="2">BRCA1</th><th colspan="2">BRCA2</th><th colspan="2">BRCA1</th><th colspan="2">BRCA2</th></tr><tr><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th></tr></thead><tbody><tr><td>Height, per 10 cm</td><td>1516</td><td>115</td><td>1.19</td><td>0.91-1.56</td><td>1011</td><td>51</td><td>1.32</td><td>0.92-1.90</td><td>905</td><td>112</td><td>0.97</td><td>0.73-1.30</td><td>626</td><td>67</td><td>0.95</td><td>0.68-1.31</td></tr><tr><td>Young-adult BMI per 5 kg/m² (continuous)</td><td>1242</td><td>96</td><td>0.78</td><td>0.52-1.16</td><td>829</td><td>40</td><td>0.82</td><td>0.49-1.36</td><td>729</td><td>89</td><td>1.06</td><td>0.73-1.53</td><td>509</td><td>56</td><td>1.00</td><td>0.76-1.30</td></tr><tr><td>Baseline BMI, kg/m² (categories)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 18.5</td><td>96</td><td>2</td><td>0.25</td><td>0.58-1.08</td><td>33</td><td>1</td><td>0.71</td><td>0.11-4.46</td><td>25</td><td>3</td><td>0.95</td><td>0.30-3.06</td><td>9</td><td>1</td><td>1.15</td><td>0.16-8.50</td></tr><tr><td>18.5 to &lt; 25 (reference)</td><td>986</td><td>83</td><td>1.0</td><td></td><td>656</td><td>38</td><td>1.0</td><td></td><td>489</td><td>56</td><td>1.0</td><td></td><td>331</td><td>29</td><td>1.0</td><td></td></tr><tr><td>≥25</td><td>434</td><td>30</td><td>0.89</td><td>0.57-1.39</td><td>322</td><td>12</td><td>0.59</td><td>0.30-1.15</td><td>391</td><td>53</td><td>1.21</td><td>0.81-1.82</td><td>286</td><td>37</td><td>1.13</td><td>0.68-1.89</td></tr><tr><td>Baseline BMI per 5 kg/m² (continuous)</td><td>1516</td><td>115</td><td>1.00</td><td>0.84-1.20</td><td>1011</td><td>51</td><td>0.92</td><td>0.66-1.28</td><td>905</td><td>112</td><td>1.20</td><td>1.02-1.42</td><td>626</td><td>67</td><td>0.97</td><td>0.81-1.17</td></tr><tr><td>Weight change (categories)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≥5 kg loss</td><td>93</td><td>6</td><td>0.76</td><td>0.34-1.75</td><td>52</td><td>2</td><td>1.40</td><td>0.23-8.65</td><td>28</td><td>4</td><td>1.67</td><td>0.61-4.61</td><td>29</td><td>6</td><td>2.53</td><td>0.97-6.58</td></tr><tr><td>&lt; 5 kg loss to &lt; 5 kg gain (reference)</td><td>506</td><td>34</td><td>1.0</td><td></td><td>324</td><td>11</td><td>1.0</td><td></td><td>183</td><td>18</td><td>1.0</td><td></td><td>121</td><td>7</td><td>1.0</td><td></td></tr><tr><td>≥5 kg gain to &lt; 15 kg gain</td><td>438</td><td>34</td><td>1.07</td><td>0.65-1.75</td><td>301</td><td>19</td><td>2.16</td><td>0.96-4.88</td><td>288</td><td>34</td><td>1.21</td><td>0.67-2.20</td><td>194</td><td>27</td><td>1.89</td><td>0.85-4.19</td></tr><tr><td>≥15 kg gain</td><td>205</td><td>22</td><td>1.43</td><td>0.80-2.54</td><td>152</td><td>8</td><td>1.14</td><td>0.46-2.82</td><td>230</td><td>33</td><td>1.63</td><td>0.88-3.04</td><td>165</td><td>16</td><td>1.18</td><td>0.46-3.05</td></tr><tr><td>Weight change*, per kg (continuous)</td><td>1242</td><td>96</td><td>1.04</td><td>0.94-1.16</td><td>829</td><td>40</td><td>1.07</td><td>0.92-1.24</td><td>729</td><td>89</td><td>1.10</td><td>1.01-1.19</td><td>509</td><td>56</td><td>0.99</td><td>0.88-1.11</td></tr></tbody></table>

All analyses were adjusted for age at menarche, number of full-term pregnancies, oral hormonal contraceptive use, and hormone replacement therapy

BC breast cancer, BMI body mass index, 1.0 = reference value

*Positive values mean weight gain and negative values mean weight loss
<table><caption>**Table 4** Prospective analysis of height, body mass index, weight change, and breast cancer risk, by menopausal status</caption><thead><tr><th rowspan="3">Menopausal status<br>BRCA status</th><th colspan="4">Premenopausal</th><th colspan="4">Postmenopausal</th></tr><tr><th colspan="2">BRCA1</th><th colspan="2">BRCA2</th><th colspan="2">BRCA1</th><th colspan="2">BRCA2</th></tr><tr><th>n</th><th>BC</th><th>HR</th><th>95% CI</th><th>n</th><th>BC</th><th>HR</th><th>95% CI</th></tr></thead><tbody><tr><td>Height, per 10 cm</td><td>1516</td><td>115</td><td>1.19</td><td>0.91-1.56</td><td>1011</td><td>51</td><td>1.32</td><td>0.92-1.90</td><td>905</td><td>112</td><td>0.97</td><td>0.73-1.30</td><td>626</td><td>67</td><td>0.95</td><td>0.68-1.31</td></tr><tr><td>Young-adult BMI per 5 kg/m² (continuous)</td><td>1242</td><td>96</td><td>0.78</td><td>0.52-1.16</td><td>829</td><td>40</td><td>0.82</td><td>0.49-1.36</td><td>729</td><td>89</td><td>1.06</td><td>0.73-1.53</td><td>509</td><td>56</td><td>1.00</td><td>0.76-1.30</td></tr><tr><td>Baseline BMI, kg/m² (categories)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 18.5</td><td>96</td><td>2</td><td>0.25</td><td>0.58-1.08</td><td>33</td><td>1</td><td>0.71</td><td>0.11-4.46</td><td>25</td><td>3</td><td>0.95</td><td>0.30-3.06</td><td>9</td><td>1</td><td>1.15</td><td>0.16-8.50</td></tr><tr><td>18.5 to &lt; 25 (reference)</td><td>986</td><td>83</td><td>1.0</td><td></td><td>656</td><td>38</td><td>1.0</td><td></td><td>489</td><td>56</td><td>1.0</td><td></td><td>331</td><td>29</td><td>1.0</td><td></td></tr><tr><td>≥25</td><td>434</td><td>30</td><td>0.89</td><td>0.57-1.39</td><td>322</td><td>12</td><td>0.59</td><td>0.30-1.15</td><td>391</td><td>53</td><td>1.21</td><td>0.81-1.82</td><td>286</td><td>37</td><td>1.13</td><td>0.68-1.89</td></tr><tr><td>Baseline BMI per 5 kg/m² (continuous)</td><td>1516</td><td>115</td><td>1.00</td><td>0.84-1.20</td><td>1011</td><td>51</td><td>0.92</td><td>0.66-1.28</td><td>905</td><td>112</td><td>1.20</td><td>1.02-1.42</td><td>626</td><td>67</td><td>0.97</td><td>0.81-1.17</td></tr><tr><td>Weight change (categories)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≥5 kg loss</td><td>93</td><td>6</td><td>0.76</td><td>0.34-1.75</td><td>52</td><td>2</td><td>1.40</td><td>0.23-8.65</td><td>28</td><td>4</td><td>1.67</td><td>0.61-4.61</td><td>29</td><td>6</td><td>2.53</td><td>0.97-6.58</td></tr><tr><td>&lt; 5 kg loss to &lt; 5 kg gain (reference)</td><td>506</td><td>34</td><td>1.0</td><td></td><td>324</td><td>11</td><td>1.0</td><td></td><td>183</td><td>18</td><td>1.0</td><td></td><td>121</td><td>7</td><td>1.0</td><td></td></tr><tr><td>≥5 kg gain to &lt; 15 kg gain</td><td>438</td><td>34</td><td>1.07</td><td>0.65-1.75</td><td>301</td><td>19</td><td>2.16</td><td>0.96-4.88</td><td>288</td><td>34</td><td>1.21</td><td>0.67-2.20</td><td>194</td><td>27</td><td>1.89</td><td>0.85-4.19</td></tr><tr><td>≥15 kg gain</td><td>205</td><td>22</td><td>1.43</td><td>0.80-2.54</td><td>152</td><td>8</td><td>1.14</td><td>0.46-2.82</td><td>230</td><td>33</td><td>1.63</td><td>0.88-3.04</td><td>165</td><td>16</td><td>1.18</td><td>0.46-3.05</td></tr><tr><td>Weight change*, per kg (continuous)</td><td>1242</td><td>96</td><td>1.04</td><td>0.94-1.16</td><td>829</td><td>40</td><td>1.07</td><td>0.92-1.24</td><td>729</td><td>89</td><td>1.10</td><td>1.01-1.19</td><td>509</td><td>56</td><td>0.99</td><td>0.88-1.11</td></tr></tbody></table>

All analyses were adjusted for age at menarche, number of full-term pregnancies, oral hormonal contraceptive use, and hormone replacement therapy

BC breast cancer, BMI body mass index, 1.0 = reference value

*Positive values mean weight gain and negative values mean weight loss
adulthood, we performed an additional analysis of
young-adult BMI, adjusting for height. The results
remained similar (Additional file 5: Table S5).

Discussion

In this large cohort of women carrying a pathogenic vari-
ant in *BRCA1* or *BRCA2*, we found associations of height,
BMI, and weight gain with breast cancer risk in pre- and
postmenopausal women, which were generally consistent
in direction and magnitude with those described in the
general population. This is the first study with a large pro-
spective component to analyze the association anthropo-
metric measures with breast cancer risk by menopausal
status for *BRCA1* and *BRCA2* variant carriers separately.

Height as a risk factor for pre- and postmenopausal
breast cancer has been described in prospective cohort
studies, and in meta-analyses for the general population
[1, 2]. We found positive associations for *BRCA2* variant
carriers between height and risks of pre- and postmeno-
pausal breast cancer in the retrospective analyses, and
with premenopausal breast cancer risk in the prospec-
tive analysis; no associations with height were observed
for *BRCA1* variant carriers, although the 95% CI include
a 20% increased risk per 10 cm for all analyses except the
retrospective analysis of premenopausal women. Height
as a breast cancer risk factor for *BRCA2*, but not for
*BRCA1* variant carriers, was also found in a retrospective
study by Qian et al. [20]. The difference in the association
between *BRCA1* and *BRCA2* carriers may be explained
by the difference in proportions of estrogen receptor
(ER)-positive breast cancer (22% for *BRCA1*, 77% for
*BRCA2*) [27]. Zhang et al. showed, both in prospective
studies and using Mendelian randomization, that height
was a risk factor for hormone receptor positive breast
cancer, and a weak or no association for receptor nega-
tive disease [2].

We found that higher young-adult BMI is associated
with lower premenopausal breast cancer risk in both
*BRCA1* and *BRCA2* variant carriers in the retrospective
analysis, with consistent, although not statistically signifi-
cant, risk estimates in the prospective analysis. This is in
line with the associations seen in the general population,
Mendelian randomization studies, and earlier retrospec-
tive studies by Manders et al. [17] and Qian et al. [20] for
*BRCA1* and *BRCA2* variant carriers, the data of which
partially overlapped with the retrospective data of the
present study. The reasons for the inverse association of
high young-adult BMI with breast cancer risk are unclear,
but might be mediated through early breast tissue dif-
ferentiation [4, 9]. In particular, childhood adiposity has
been linked to a lower risk of benign breast disease and
lower mammographic density which are risk factors for
breast cancer [10, 11, 30]. Understanding the biological

mechanism underlying the inverse association of higher
young-adult BMI and lower premenopausal breast cancer
risk could potentially identify modifiable pathways and
provide new insights for prevention in the future.

Higher young-adult BMI is also associated with a lower
risk of postmenopausal breast cancer in the general pop-
ulation [3, 5]. We found no association of higher young-
adult BMI with postmenopausal breast cancer risk,
which is also consistent with the findings by Qian et al.
[20]. However, the retrospective cohort for postmeno-
pausal women was much smaller than the premenopausal
cohort and the HR estimates did not differ significantly.

In the prospective analysis of *BRCA1* pathogenic vari-
ant carriers, we found that higher baseline BMI and adult
weight gain were associated with higher risk of postmen-
opausal breast cancer, but not with risk of premenopausal
breast cancer. This is in line with the finding by Manders
et al. for *BRCA1/2* variant carriers and with the find-
ings in the general population [17, 31, 32]. However, for
*BRCA2* variant carriers, we found no evidence of asso-
ciation, although a HR of similar magnitude compared to
*BRCA1* variant carriers cannot be excluded, because of
the wide confidence intervals.

A recent study has suggested that weight may be more
predictive of postmenopausal breast cancer risk than
BMI [33]. We analyzed the variables baseline weight and
young-adult weight separately and found no large dif-
ferences in association with breast cancer compared to
baseline BMI and young-adult BMI (Additional file 4:
Table S4).

Two biological explanations for our findings of high
baseline BMI and of weight change and higher breast
cancer risk in the postmenopausal cohort of carriers of
*BRCA1* can be considered. A similar pattern (with an
association for *BRCA1*- but not *BRCA2*-associated breast
cancer) has been observed for oral contraceptive use [34].
Both findings were unexpected, since hormonal exposure
is known to especially promote the ER-positive breast
cancer subtype. However, in the general population, a
weak association between elevated BMI and hormone
receptor negative postmenopausal breast cancer and an
association of oral contraception use with early onset
triple negative breast cancer was reported [35-38]. One
explanation for hormone-induced triple negative breast
cancer might be the activation of the paracrine pathway
via the receptor activator of nuclear factor kB (RANK)
[39-46]. The pathway seems to be more relevant for carri-
ers of variants in *BRCA1* compared to *BRCA2* or *PALB2*
[47].

Early surgical menopause may lead to use of hormone
therapy, usually a combination of estrogen and progestin.
If BRCA1-deficient breast cells are particularly sensitive
to hormonal treatment, this could lead to a significantly
adulthood, we performed an additional analysis of
young-adult BMI, adjusting for height. The results
remained similar (Additional file 5: Table S5).

Discussion

In this large cohort of women carrying a pathogenic vari-
ant in *BRCA1* or *BRCA2*, we found associations of height,
BMI, and weight gain with breast cancer risk in pre- and
postmenopausal women, which were generally consistent
in direction and magnitude with those described in the
general population. This is the first study with a large pro-
spective component to analyze the association anthropo-
metric measures with breast cancer risk by menopausal
status for *BRCA1* and *BRCA2* variant carriers separately.

Height as a risk factor for pre- and postmenopausal
breast cancer has been described in prospective cohort
studies, and in meta-analyses for the general population
[1, 2]. We found positive associations for *BRCA2* variant
carriers between height and risks of pre- and postmeno-
pausal breast cancer in the retrospective analyses, and
with premenopausal breast cancer risk in the prospec-
tive analysis; no associations with height were observed
for *BRCA1* variant carriers, although the 95% CI include
a 20% increased risk per 10 cm for all analyses except the
retrospective analysis of premenopausal women. Height
as a breast cancer risk factor for *BRCA2*, but not for
*BRCA1* variant carriers, was also found in a retrospective
study by Qian et al. [20]. The difference in the association
between *BRCA1* and *BRCA2* carriers may be explained
by the difference in proportions of estrogen receptor
(ER)-positive breast cancer (22% for *BRCA1*, 77% for
*BRCA2*) [27]. Zhang et al. showed, both in prospective
studies and using Mendelian randomization, that height
was a risk factor for hormone receptor positive breast
cancer, and a weak or no association for receptor nega-
tive disease [2].

We found that higher young-adult BMI is associated
with lower premenopausal breast cancer risk in both
*BRCA1* and *BRCA2* variant carriers in the retrospective
analysis, with consistent, although not statistically signifi-
cant, risk estimates in the prospective analysis. This is in
line with the associations seen in the general population,
Mendelian randomization studies, and earlier retrospec-
tive studies by Manders et al. [17] and Qian et al. [20] for
*BRCA1* and *BRCA2* variant carriers, the data of which
partially overlapped with the retrospective data of the
present study. The reasons for the inverse association of
high young-adult BMI with breast cancer risk are unclear,
but might be mediated through early breast tissue dif-
ferentiation [4, 9]. In particular, childhood adiposity has
been linked to a lower risk of benign breast disease and
lower mammographic density which are risk factors for
breast cancer [10, 11, 30]. Understanding the biological

mechanism underlying the inverse association of higher
young-adult BMI and lower premenopausal breast cancer
risk could potentially identify modifiable pathways and
provide new insights for prevention in the future.

Higher young-adult BMI is also associated with a lower
risk of postmenopausal breast cancer in the general pop-
ulation [3, 5]. We found no association of higher young-
adult BMI with postmenopausal breast cancer risk,
which is also consistent with the findings by Qian et al.
[20]. However, the retrospective cohort for postmeno-
pausal women was much smaller than the premenopausal
cohort and the HR estimates did not differ significantly.

In the prospective analysis of *BRCA1* pathogenic vari-
ant carriers, we found that higher baseline BMI and adult
weight gain were associated with higher risk of postmen-
opausal breast cancer, but not with risk of premenopausal
breast cancer. This is in line with the finding by Manders
et al. for *BRCA1/2* variant carriers and with the find-
ings in the general population [17, 31, 32]. However, for
*BRCA2* variant carriers, we found no evidence of asso-
ciation, although a HR of similar magnitude compared to
*BRCA1* variant carriers cannot be excluded, because of
the wide confidence intervals.

A recent study has suggested that weight may be more
predictive of postmenopausal breast cancer risk than
BMI [33]. We analyzed the variables baseline weight and
young-adult weight separately and found no large dif-
ferences in association with breast cancer compared to
baseline BMI and young-adult BMI (Additional file 4:
Table S4).

Two biological explanations for our findings of high
baseline BMI and of weight change and higher breast
cancer risk in the postmenopausal cohort of carriers of
*BRCA1* can be considered. A similar pattern (with an
association for *BRCA1*- but not *BRCA2*-associated breast
cancer) has been observed for oral contraceptive use [34].
Both findings were unexpected, since hormonal exposure
is known to especially promote the ER-positive breast
cancer subtype. However, in the general population, a
weak association between elevated BMI and hormone
receptor negative postmenopausal breast cancer and an
association of oral contraception use with early onset
triple negative breast cancer was reported [35-38]. One
explanation for hormone-induced triple negative breast
cancer might be the activation of the paracrine pathway
via the receptor activator of nuclear factor kB (RANK)
[39-46]. The pathway seems to be more relevant for carri-
ers of variants in *BRCA1* compared to *BRCA2* or *PALB2*
[47].

Early surgical menopause may lead to use of hormone
therapy, usually a combination of estrogen and progestin.
If BRCA1-deficient breast cells are particularly sensitive
to hormonal treatment, this could lead to a significantly
higher risk of breast cancer compared with *BRCA2* variant carriers associated with very early menopause and hormonal contraception use. In our study, however, the comparison of analysis with and without adjustment for use of hormonal contraception and postmenopausal hormone therapy did not support this hypothesis, since an association of high baseline BMI and weight gain with postmenopausal breast cancer risk was consistently seen in carriers of a pathogenic variant in *BRCA1*, but not in *BRCA2*.

Another mechanism of action promoting *BRCA1*-associated postmenopausal breast cancer may be the lack of suppression of aromatase. *BRCA1* is known to be an inhibitor of aromatase (CYP19) transcription and also interferes with transcriptional activation mediated by the estrogen receptor alpha (ERα) [47]. High BMI and weight gain might therefore lead to higher estradiol levels due to increased aromatase activity and consecutively to postmenopausal *BRCA1*-associated breast cancer. Interestingly, after menopause the percentage of ER-positive *BRCA1*-associated breast cancer increases [48].

Avoiding over- and underweight is important for both pathogenic variant carriers and non-carriers. Even if the relative risks for anthropometric measures and breast cancer in *BRCA1* and *BRCA2* variant carriers are similar to those found in the general population, the absolute excess risks will be higher for *BRCA1* and *BRCA2* variant carriers because of the higher background breast cancer risk. Additionally, as shown by Hopper et al., the post-menopausal elevation of breast cancer risk by far outweighs the premenopausal protection associated with high BMI [49].

Variant carriers may be highly motivated to attempt to modify their breast cancer risk through a healthy lifestyle [50, 51]. Healthy behavior change might include better nutrition and weight loss, although a persistent change in lifestyle is hard to achieve, especially after menopause [51]. Our retrospective results of low BMI and higher premenopausal breast cancer risk imply that underweight and unhealthy weight loss should be discouraged in premenopausal women. But further research on a larger dataset is necessary. The first intervention study on nutrition and physical activity for *BRCA1/2*-pathogenic variant carriers (the LIBRE trial in Germany) is currently recruiting [52]. It aims to show that physical fitness and maintaining a healthy body weight are key to good quality of life and—in the long run—prevent breast cancer in both affected and unaffected carriers.

Anthropometric measures are included in cancer risk prediction models such as BOADICEA [53]. In BOADICEA, the relative risks for height and BMI among variant carriers are assumed to be the same as those for the general population. The present analyses suggest that, for

height, this is a reasonable assumption for *BRCA2*, but some adjustment may be needed for *BRCA1*. The association effect sizes for BMI are generally consistent with the general population estimates, at least for young-adult BMI [53].

The study has some limitations. Despite the large size of the cohort, the number of incident cases was still limited and the confidence limits were correspondingly wide, especially in subgroup analyses, such as postmenopausal high young-adult BMI. Thus, the results are still heavily dependent on the retrospective data, which are potentially subject to more bias. Much larger prospective cohorts with a broader age range and a longer follow-up are therefore needed.

A general challenge is the definition of menopausal status. Ideally, this would be defined by taking a detailed menstrual history and, in many cases, a blood test—but this is not feasible in large epidemiological studies, which rely on self-reporting. This may have led to some misclassification of postmenopausal women as premenopausal women, diluting the difference between the two groups.

A known limitation of retrospective studies is the potential for survival bias introduced by including prevalent cancer cases. There is evidence in the general population that higher BMI is associated with advanced tumor stage and a worse prognosis [54]. If the same is true for variant carriers, the inverse association with high BMI might be overestimated [55]. Some studies have addressed this by defining a pseudoincident cohort, which includes breast cancer cases only if they occurred within the last 5 years to avoid survival bias [34]. We did not utilize this approach, which would have substantially reduced the sample size. However, the retrospective and prospective findings were broadly consistent, though some associations (e.g., the inverse association with young-adult BMI in premenopausal women) were not statistically significant in the prospective analysis. Again, larger prospective analyses are needed.

This is the first prospective study to analyze the association of breast cancer risk with anthropometric measures by menopausal status, separately for *BRCA1* and *BRCA2* variant carriers. Height was a risk factor for premenopausal breast cancer in *BRCA2* variant carriers, but not *BRCA1* carriers. High young-adult BMI was associated with decreased risk of premenopausal breast cancer, but not for postmenopausal breast cancer. Higher BMI and weight gain in adult life were risk factors for postmenopausal breast cancer in *BRCA1* variant carriers.

In conclusion, our findings indicate that the associations of height, BMI and weight gain with breast cancer risk in *BRCA1* and *BRCA2* variant carriers are broadly similar to those reported in the general population when taking into account menopausal status. This research is
higher risk of breast cancer compared with *BRCA2* variant carriers associated with very early menopause and hormonal contraception use. In our study, however, the comparison of analysis with and without adjustment for use of hormonal contraception and postmenopausal hormone therapy did not support this hypothesis, since an association of high baseline BMI and weight gain with postmenopausal breast cancer risk was consistently seen in carriers of a pathogenic variant in *BRCA1*, but not in *BRCA2*.

Another mechanism of action promoting *BRCA1*-associated postmenopausal breast cancer may be the lack of suppression of aromatase. *BRCA1* is known to be an inhibitor of aromatase (CYP19) transcription and also interferes with transcriptional activation mediated by the estrogen receptor alpha (ERα) [47]. High BMI and weight gain might therefore lead to higher estradiol levels due to increased aromatase activity and consecutively to postmenopausal *BRCA1*-associated breast cancer. Interestingly, after menopause the percentage of ER-positive *BRCA1*-associated breast cancer increases [48].

Avoiding over- and underweight is important for both pathogenic variant carriers and non-carriers. Even if the relative risks for anthropometric measures and breast cancer in *BRCA1* and *BRCA2* variant carriers are similar to those found in the general population, the absolute excess risks will be higher for *BRCA1* and *BRCA2* variant carriers because of the higher background breast cancer risk. Additionally, as shown by Hopper et al., the post-menopausal elevation of breast cancer risk by far outweighs the premenopausal protection associated with high BMI [49].

Variant carriers may be highly motivated to attempt to modify their breast cancer risk through a healthy lifestyle [50, 51]. Healthy behavior change might include better nutrition and weight loss, although a persistent change in lifestyle is hard to achieve, especially after menopause [51]. Our retrospective results of low BMI and higher premenopausal breast cancer risk imply that underweight and unhealthy weight loss should be discouraged in premenopausal women. But further research on a larger dataset is necessary. The first intervention study on nutrition and physical activity for *BRCA1/2*-pathogenic variant carriers (the LIBRE trial in Germany) is currently recruiting [52]. It aims to show that physical fitness and maintaining a healthy body weight are key to good quality of life and—in the long run—prevent breast cancer in both affected and unaffected carriers.

Anthropometric measures are included in cancer risk prediction models such as BOADICEA [53]. In BOADICEA, the relative risks for height and BMI among variant carriers are assumed to be the same as those for the general population. The present analyses suggest that, for

height, this is a reasonable assumption for *BRCA2*, but some adjustment may be needed for *BRCA1*. The association effect sizes for BMI are generally consistent with the general population estimates, at least for young-adult BMI [53].

The study has some limitations. Despite the large size of the cohort, the number of incident cases was still limited and the confidence limits were correspondingly wide, especially in subgroup analyses, such as postmenopausal high young-adult BMI. Thus, the results are still heavily dependent on the retrospective data, which are potentially subject to more bias. Much larger prospective cohorts with a broader age range and a longer follow-up are therefore needed.

A general challenge is the definition of menopausal status. Ideally, this would be defined by taking a detailed menstrual history and, in many cases, a blood test—but this is not feasible in large epidemiological studies, which rely on self-reporting. This may have led to some misclassification of postmenopausal women as premenopausal women, diluting the difference between the two groups.

A known limitation of retrospective studies is the potential for survival bias introduced by including prevalent cancer cases. There is evidence in the general population that higher BMI is associated with advanced tumor stage and a worse prognosis [54]. If the same is true for variant carriers, the inverse association with high BMI might be overestimated [55]. Some studies have addressed this by defining a pseudoincident cohort, which includes breast cancer cases only if they occurred within the last 5 years to avoid survival bias [34]. We did not utilize this approach, which would have substantially reduced the sample size. However, the retrospective and prospective findings were broadly consistent, though some associations (e.g., the inverse association with young-adult BMI in premenopausal women) were not statistically significant in the prospective analysis. Again, larger prospective analyses are needed.

This is the first prospective study to analyze the association of breast cancer risk with anthropometric measures by menopausal status, separately for *BRCA1* and *BRCA2* variant carriers. Height was a risk factor for premenopausal breast cancer in *BRCA2* variant carriers, but not *BRCA1* carriers. High young-adult BMI was associated with decreased risk of premenopausal breast cancer, but not for postmenopausal breast cancer. Higher BMI and weight gain in adult life were risk factors for postmenopausal breast cancer in *BRCA1* variant carriers.

In conclusion, our findings indicate that the associations of height, BMI and weight gain with breast cancer risk in *BRCA1* and *BRCA2* variant carriers are broadly similar to those reported in the general population when taking into account menopausal status. This research is
not only important to inform carriers about age-specific
cancer risks, it might also open up new risk reduction
strategies by elucidating yet unknown signaling pathways.

**Supplementary Information**

The online version contains supplementary material available at https://doi.org/10.1186/s13058-023-01673-w.

**Additional file 1: Table S1.** Overview of the studies contributing to the retrospective and prospective analyses.

**Additional file 2: Table S2.** Retrospective and prospective analysis of height in quintiles and breast cancer risk, by menopausal status.

**Additional file 3: Table S3.** Retrospective analysis of height, body mass index, weight change and breast cancer risk, by menopausal status.

**Additional file 4: Table S4.** Prospective analysis of associations between height, body mass index, weight change and breast cancer risk, by menopausal status.

**Additional file 5: Table S5.** Weight versus body mass index and breast cancer risk in *BRCA1* and *BRCA2* variant carriers, by menopausal status.

**Acknowledgements**

The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL: M.K. Schmidt, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, D.J. Stommel-Jenner, R. de Groot, L. Hordijk; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, I. Geurts-Giele, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL: C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Medical Center Nijmegen, NL: M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, Univ of Amsterdam, NL: K.Y. van Spaendonck; Amsterdam UMC, Vrije Universiteit Amsterdam, NL: K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL: E.B. Gómez Garcia, M.J. Blok, M. de Boer; University of Groningen, NL: L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL): S. Siesling, J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA): Q.J.M. Voorham. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. We acknowledge the GENEPSO Centers: the Coordinating Center: Institut Paoli-Calmettes, Marseille: Catherine Nogues, Emmanuel Breysse, Pauline Pontois, Lilian Laborde, and the Collaborating Centers: Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars; Bruno Buecher, Institut Gustave Roussy, Villejuif; Olivier Caron; Hôpital René Huguenin/Institut Curie, Saint Cloud: Emmanuelle Fourme-Mouret; Centre Paul Strauss, Strasbourg: Jean-Pierre Fricker; Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona; Hôtel Dieu -Centre Hospitalier, Chambery: Sandra Fert-Ferrer; Centre François Baclesse, Caen: Pascaline Berthet; CHRU Dupuytren, Limoges: Laurence Venat-Bouvet; CHU La Milétrie, Poitiers: Brigitte Gilbert-Dussardier; Hôpital d'Enfants CHU Dijon -Centre Georges François Leclerc, Dijon: Laurence Faivre; Centre Alexis Vautrin, Vandoeuvre-les-Nancy: Elisabeth Luporsi; Institut Claudius Regaud, Toulouse: Laurence Gladieff; Réseau Oncogénétique Poitou Charente, Niort: Paul Gesta; Institut Paoli-Calmettes, Marseille: Catherine Nogès, Hagay Sobol, François Eisinger; Institut Bergonié, Bordeaux: Michel Longy, Centre Eugène Marquis, Rennes: Catherine Dugast†; GH Pitié Salpetrière, Paris: Chrystelle Colas, Florent Soubrier; CHU Arnaud de Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol, Carole Corsini; Centres Paul Papin, and Catherine de Sienne, Angers, Nantes: Alain Lortholary; Centre Oscar Lambret, Lille: Philippe Vennin†, Claude Adenis; Institut Jean Godinot, Reims: Tan Dat Nguyen; Institut Jean-Godinot and ICC Courlancy, Reims: Clotilde Penet; Centre René Gauducheau, Nantes: Capucine Delnatte; Centre Henri Becquerel, Rouen: Julie Tinat, Isabelle Tennevet; Hôpital Civil, Strasbourg: Jean-Marc Limacher; Christine Maugard; Polyclinique Courlancy, Reims: Liliane Demange†; Clinique Sainte Catherine, Avignon: Hélène Dreyfus; Hôpital Saint-Louis, Paris: Odile Cohen-Haguenauer; Couple-Enfant-CHU de Grenoble: Dominique Leroux; Hôpital de la Timone, Marseille: Hélène Zattara-Cannoni; CHU Fort de France, Fort de France: Odile Bera. In grateful memory of Hakan Olsson, MD PhD, Professor, Oncology, Clinical Sciences in Lund,

University Hospital, Lund, Sweden. We thank kConFab participants, kConFab investigators and all the kConFab coordinators, research nurses, interviewers, and data management staff, and the heads, and staff of the participating Family Cancer Clinics. We thank GC-HBOC participants, GC-HBOC investigators and staff of the participating GC-HBOC Centers of the University Hospital of Cologne and University Hospital of Dresden, Germany. Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT BRCAs): We would like to thank Dr Martine Dumont and Martine Tranchant (Cancer Genomics Laboratory, CRCHUQ) for sample management.

**Author contributions**

KK, CE, NA, MAR, TMM, FEv, DFE, ACA, KP, JH, RM, DG, EJ, and MBT contributed to the conception and design and analysis and interpretation of data, and KK, CE, MAR, JH, and EJ drafted an revised the article. All authors contributed to data acquisition and interpretation of the data. All authors read, revised, and approved the final manuscript.

**Funding**

Open Access funding enabled and organized by Projekt DEAL. The HEBON study is supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, NKI2007-3756, NKI 12535, the Netherlands Organisation of Scientific Research Grant NWO 91109024, the Pink Ribbon Grants 110005 and 2014-187.WO76, the BBMRI Grant NWO 184.021.007/CP46, and the Transcan Grant JTC 2012 Cancer 12-054. The EMBRACE study is supported by Cancer Research-UK Grants: PRCPJT-Nov21\100004, C1287/A23382 and C1287/A26886. MT is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014 and NIHR203312). DGE was supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France, the Ligue Nationale Contre le Cancer, by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008) and is being supported by Institut National du Cancer-DGOS, Grant PRT-K22-076 and by the "Programmes labelisés (PGA) 2022" of the Fondation ARC (N°ARCPGA202201000441_4863). The Breast Cancer Family Registry (BCFR) is supported by Grant U01 CA164920 from the USA National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. A.O. is partially funded by FIS P119/00640 supported by FEDER funds and the Spanish Network on Rare Diseases (CIBERER). The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) and the kConFab Follow-Up Study have been supported by grants from Cancer Australia (809195 and 1100868), the Australian National Breast Cancer Foundation (IF 17 kConFab), the National Health and Medical Research Council (454508, 288704, and 145684), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. K-AP is a National Health and Medical Research Council Leadership Fellow (Australia) (1195294). The GC-HBOC is supported by the German Cancer Aid (Grant No. 110837 and Grant No. 70114178, coordinator: Rita K. Schmutzler, Cologne) and the Federal Ministry of Education and Research (BMBF), Germany (Grant No. 01GY1901). Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT BRCAs) was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and by the Canadian Breast Cancer Research Alliance-Grant #019511. LF and DB supported by MH CZ-DRO (MMCI, 00209805). Role of the funders: The funding organizations had no role in the design and conduct of the study.

**Availability of data and materials**

The dataset supporting the conclusions of this article is available upon reasonable request. Requests should be made to Dr. Karin Kast (University Hospital Cologne, karin.kast@uk-koeln.de).

**Declarations**

**Ethics approval and consent to participate**

All procedures performed in studies involving human participants were in accordance with the ethical standards of the local institutional research committee and with the 1064 Helsinki declaration and its later amendments or
not only important to inform carriers about age-specific
cancer risks, it might also open up new risk reduction
strategies by elucidating yet unknown signaling pathways.

**Supplementary Information**

The online version contains supplementary material available at https://doi.org/10.1186/s13058-023-01673-w.

**Additional file 1: Table S1.** Overview of the studies contributing to the retrospective and prospective analyses.

**Additional file 2: Table S2.** Retrospective and prospective analysis of height in quintiles and breast cancer risk, by menopausal status.

**Additional file 3: Table S3.** Retrospective analysis of height, body mass index, weight change and breast cancer risk, by menopausal status.

**Additional file 4: Table S4.** Prospective analysis of associations between height, body mass index, weight change and breast cancer risk, by menopausal status.

**Additional file 5: Table S5.** Weight versus body mass index and breast cancer risk in *BRCA1* and *BRCA2* variant carriers, by menopausal status.

**Acknowledgements**

The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute (coordinating center), Amsterdam, NL; M.K. Schmidt, F.B.L. Hogervorst, F.E. van Leeuwen, M.A. Adank, D.J. Stommel-Jenner, R. de Groot, L. Hordijk; Erasmus Medical Center, Rotterdam, NL; J.M. Collée, I. Geurts-Giele, M.J. Hooning, I.A. Boere; Leiden University Medical Center, NL; C.J. van Asperen, P. Devilee, R.B. van der Luijt, T.C.T.E.F. van Cronenburg; Radboud University Medical Center Nijmegen, NL; M.R. Wevers, A.R. Mensenkamp; University Medical Center Utrecht, NL; M.G.E.M. Ausems, M.J. Koudijs; Amsterdam UMC, Univ of Amsterdam, NL; K.Y. van Spaendonck; Amsterdam UMC, Vrije Universiteit Amsterdam, NL; K. van Engelen, J.J.P. Gille; Maastricht University Medical Center, NL; E.B. Gómez García, M.J. Blok, M. de Boer; University of Groningen, NL; L.P.V. Berger, A.H. van der Hout, M.J.E. Mourits, G.H. de Bock; The Netherlands Comprehensive Cancer Organisation (IKNL); S. Siesling, J. Verloop; The nationwide network and registry of histo- and cytopathology in The Netherlands (PALGA); Q.J.M. Voorham. HEBON thanks the study participants and the registration teams of IKNL and PALGA for part of the data collection. We acknowledge the GENEPSO Centers: the Coordinating Center: Institut Paoli-Calmettes, Marseille: Catherine Nogues, Emmanuel Breysse, Pauline Pontois, Lilian Laborde, and the Collaborating Centers: Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars; Bruno Buecher, Institut Gustave Roussy, Villejuif; Olivier Caron; Hôpital René Huguenin/Institut Curie, Saint Cloud: Emmanuelle Fourme-Mouret; Centre Paul Strauss, Strasbourg; Jean-Pierre Fricker; Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona; Hôtel Dieu -Centre Hospitalier, Chambery: Sandra Fert-Ferrer; Centre François Baclesse, Caen: Pascaline Berthet; CHRU Dupuytren, Limoges: Laurence Venat-Bouvet; CHU La Milétrie, Poitiers: Brigitte Gilbert-Dussardier; Hôpital d'Enfants CHU Dijon -Centre Georges François Leclerc, Dijon: Laurence Faivre; Centre Alexis Vautrin, Vandoeuvre-les-Nancy: Elisabeth Luporsi; Institut Claudius Regaud, Toulouse: Laurence Gladieff; Réseau Oncogénétique Poitou Charente, Niort: Paul Gesta; Institut Paoli-Calmettes, Marseille: Catherine Nogès, Hagay Sobol, François Eisinger; Institut Bergonié, Bordeaux: Michel Longy, Centre Eugène Marquis, Rennes: Catherine Dugast†; GH Pitié Salpetrière, Paris: Chrystelle Colas, Florent Soubrier; CHU Arnaud de Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol, Carole Corsini; Centres Paul Papin, and Catherine de Sienne, Angers, Nantes: Alain Lortholary; Centre Oscar Lambret, Lille: Philippe Vennin†, Claude Adenis; Institut Jean Godinot, Reims: Tan Dat Nguyen; Institut Jean-Godinot and ICC Courlancy, Reims: Clotilde Penet; Centre René Gauducheau, Nantes: Capucine Delnatte; Centre Henri Becquerel, Rouen: Julie Tinat, Isabelle Tennevet; Hôpital Civil, Strasbourg: Jean-Marc Limacher; Christine Maugard; Polyclinique Courlancy, Reims: Liliane Demange†; Clinique Sainte Catherine, Avignon: Hélène Dreyfus; Hôpital Saint-Louis, Paris: Odile Cohen-Haguenauer; Couple-Enfant-CHU de Grenoble: Dominique Leroux; Hôpital de la Timone, Marseille: Hélène Zattara-Cannoni; CHU Fort de France, Fort de France: Odile Bera. In grateful memory of Hakan Olsson, MD PhD, Professor, Oncology, Clinical Sciences in Lund,

University Hospital, Lund, Sweden. We thank kConFab participants, kConFab investigators and all the kConFab coordinators, research nurses, interviewers, and data management staff, and the heads, and staff of the participating Family Cancer Clinics. We thank GC-HBOC participants, GC-HBOC investigators and staff of the participating GC-HBOC Centers of the University Hospital of Cologne and University Hospital of Dresden, Germany. Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT BRCAs): We would like to thank Dr Martine Dumont and Martine Tranchant (Cancer Genomics Laboratory, CRCHUQ) for sample management.

**Author contributions**

KK, CE, NA, MAR, TMM, FEv, DFE, ACA, KP, JH, RM, DG, EJ, and MBT contributed to the conception and design and analysis and interpretation of data, and KK, CE, MAR, JH, and EJ drafted an revised the article. All authors contributed to data acquisition and interpretation of the data. All authors read, revised, and approved the final manuscript.

**Funding**

Open Access funding enabled and organized by Projekt DEAL. The HEBON study is supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, NKI2007-3756, NKI 12535, the Netherlands Organisation of Scientific Research Grant NWO 91109024, the Pink Ribbon Grants 110005 and 2014-187.WO76, the BBMRI Grant NWO 184.021.007/CP46, and the Transcan Grant JTC 2012 Cancer 12-054. The EMBRACE study is supported by Cancer Research-UK Grants: PRCPJT-Nov21\100004, C1287/A23382 and C1287/A26886. MT is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014 and NIHR203312). DGE was supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France, the Ligue Nationale Contre le Cancer, by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008) and is being supported by Institut National du Cancer-DGOS, Grant PRT-K22-076 and by the "Programmes labelisés (PGA) 2022" of the Fondation ARC (N°ARCPGA202201000441_4863). The Breast Cancer Family Registry (BCFR) is supported by Grant U01 CA164920 from the USA National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. A.O. is partially funded by FIS P119/00640 supported by FEDER funds and the Spanish Network on Rare Diseases (CIBERER). The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) and the kConFab Follow-Up Study have been supported by grants from Cancer Australia (809195 and 1100868), the Australian National Breast Cancer Foundation (IF 17 kConFab), the National Health and Medical Research Council (454508, 288704, and 145684), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. K-AP is a National Health and Medical Research Council Leadership Fellow (Australia) (1195294). The GC-HBOC is supported by the German Cancer Aid (Grant No. 110837 and Grant No. 70114178, coordinator: Rita K. Schmutzler, Cologne) and the Federal Ministry of Education and Research (BMBF), Germany (Grant No. 01GY1901). Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT BRCAs) was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and by the Canadian Breast Cancer Research Alliance-Grant #019511. LF and DB supported by MH CZ-DRO (MMCI, 00209805). Role of the funders: The funding organizations had no role in the design and conduct of the study.

**Availability of data and materials**

The dataset supporting the conclusions of this article is available upon reasonable request. Requests should be made to Dr. Karin Kast (University Hospital Cologne, karin.kast@uk-koeln.de).

**Declarations**

**Ethics approval and consent to participate**

All procedures performed in studies involving human participants were in accordance with the ethical standards of the local institutional research committee and with the 1064 Helsinki declaration and its later amendments or
comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

## Competing interests

The authors declare that they have no competing interests.

## Author details

¹Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany. ²Department of Epidemiology & Population Health and of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA, USA. ³Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. ⁴Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia. ⁵INSERM U900, Paris, France. ⁶Institut Curie, Paris, France. ⁷ Mines Paris Tech, Fontainebleau, France. ⁸PSL Research University, Paris, France. ⁹Aix Marseille Université, INSERM, IRD, SESSTIM, Marseille, France. ¹⁰Département d'Anticipation et de Suivi Des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France. ¹¹Centre Léon Bérard, Lyon, France. ¹²CRLCC Paul Strauss, Strasbourg, France. ¹³Centre François Baclesse, Caen, France. ¹⁴Centre Antoine Lacassagne, Nice, France. ¹⁵Oncogénétique Poitou-Charentes, Niort, France. ¹⁶Division of Molecular Pathology, Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands. ¹⁷Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. ¹⁸Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands. ¹⁹Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

²⁰Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. ²¹The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK. ²²Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK. ²³Manchester Breast Centre, Oglesby Cancer Research Centre, The Christie, University of Manchester, Manchester, UK. ²⁴Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK. ²⁵Clinical Genetics Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.

²⁶Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.

²⁷Department of Clinical Genetics, Guy's and St Thomas's NHS Foundation Trust, London, UK. ²⁸Clinical Genetics Service, Guy's and St Thomas's NHS Foundation Trust, London, UK. ²⁹Department of Clinical Genetics, St George's University Hospitals NHS Foundation Trust, London, UK. ³⁰Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK. ³¹West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK. ³²South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK. ³³MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. ³⁴Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ³⁵Department of Medicine and Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA. ³⁶Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.

³⁷Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. ³⁸Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA. ³⁹Precision Medicine, School of Clinical Sciences at, Monash Health Monash University, Clayton, VIC, Australia. ⁴⁰Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia. ⁴¹Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain. ⁴²Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO) and Spanish Network On Rare Diseases (CIBERER), Madrid, Spain. ⁴³Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. ⁴⁴Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. ⁴⁵Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. ⁴⁶Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. ⁴⁷Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. ⁴⁸Department of OB/GYN and Comprehensive Cancer Center, Medical

University of Vienna, Vienna, Austria. ⁴⁹Department of Oncology, Clinical Sciences in Lund, Lund University Hospital, Lund, Sweden. ⁵⁰Clinical Genetics, Karolinska Institutet, Stockholm, Sweden. ⁵¹Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Quebec City, QC, Canada. ⁵²Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia. ⁵³Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia. ⁵⁴The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.

⁵⁵Department of Medical Oncology, Peter MacCallum Cancer Centre, Victoria, Australia. ⁵⁶Department of Epidemiology, Mailman School of Public Health and the Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. ⁵⁷Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA. ⁵⁸Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

⁵⁹Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. ⁶⁰Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany.

Received: 16 December 2022 Accepted: 10 June 2023

Published online: 20 June 2023

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3. Chan DSM, Abar L, Cariolou M, Nanu N, Greenwood DC, Bandera EV, McTiernan A, Norat T. World Cancer Research Fund International: Continuous Update Project-systematic literature review and meta-analysis of observational cohort studies on physical activity, sedentary behavior, adiposity, and weight change and breast cancer risk. Cancer Causes Control. 2019;30(11):1183-200.

4. Premenopausal Breast Cancer Collaborative G, Schoemaker MJ, Nichols HB, Wright LB, Brook MN, Jones ME, O'Brien KM, Adami HO, Baglietto L, Bernstein L, et al. Association of body mass index and age with subsequent breast cancer risk in premenopausal women. JAMA Oncol. 2018;4(11):e181771.

5. van den Brandt PA, Ziegler RG, Wang M, Hou T, Li R, Adami HO, Agnoli C, Bernstein L, Buring JE, Chen Y, et al. Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies. Eur J Epidemiol. 2021;36(1):37-55.

6. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569-78.

7. Xue F, Rosner B, Eliassen H, Michels KB. Body fatness throughout the life course and the incidence of premenopausal breast cancer. Int J Epidemiol. 2016;45(4):1103-12.

8. Schoemaker MJ, Nichols HB, Wright LB, Brook MN, Jones ME, O'Brien KM, Adami HO, Baglietto L, Bernstein L, Bertrand KA, et al. Adult weight change and premenopausal breast cancer risk: a prospective pooled analysis of data from 628,463 women. Int J Cancer. 2020;147(5):1306-14.

9. Hilakivi-Clarke L, Forsen T, Eriksson JG, Luoto R, Tuomilehto J, Osmond C, Barker DJ. Tallness and overweight during childhood have opposing effects on breast cancer risk. Br J Cancer. 2001;85(11):1680-4.

10. Yochum L, Tamimi RM, Hankinson SE. Birthweight, early life body size and adult mammographic density: a review of epidemiologic studies. Cancer Causes Control. 2014;25(10):1247-59.

11. Schoemaker MJ, Jones ME, Allen S, Hoare J, Ashworth A, Dowsett M, Swerdlow AJ. Childhood body size and pubertal timing in relation to adult mammographic density phenotype. Breast Cancer Res. 2017;19(1):13.

12. Grodstein F, Goldman MB, Cramer DW. Body mass index and ovulatory infertility. Epidemiology. 1994;5(2):247-50.
comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

## Competing interests

The authors declare that they have no competing interests.

## Author details

¹Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany. ²Department of Epidemiology & Population Health and of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA, USA. ³Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. ⁴Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia. ⁵INSERM U900, Paris, France. ⁶Institut Curie, Paris, France. ⁷Mines Paris Tech, Fontainebleau, France. ⁸PSL Research University, Paris, France. ⁹Aix Marseille Université, INSERM, IRD, SESSTIM, Marseille, France. ¹⁰Département d'Anticipation et de Suivi Des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France. ¹¹Centre Léon Bérard, Lyon, France. ¹²CRLCC Paul Strauss, Strasbourg, France. ¹³Centre François Baclesse, Caen, France. ¹⁴Centre Antoine Lacassagne, Nice, France. ¹⁵Oncogénétique Poitou-Charentes, Niort, France. ¹⁶Division of Molecular Pathology, Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, Amsterdam, The Netherlands. ¹⁷Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. ¹⁸Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands. ¹⁹Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

²⁰Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. ²¹The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK. ²²Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK. ²³Manchester Breast Centre, Oglesby Cancer Research Centre, The Christie, University of Manchester, Manchester, UK. ²⁴Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK. ²⁵Clinical Genetics Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.

²⁶Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK. ²⁷Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK. ²⁸Clinical Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK. ²⁹Department of Clinical Genetics, St George's University Hospitals NHS Foundation Trust, London, UK. ³⁰Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK. ³¹West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK. ³²South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK. ³³MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK. ³⁴Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ³⁵Department of Medicine and Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, USA. ³⁶Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.

³⁷Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. ³⁸Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA. ³⁹Precision Medicine, School of Clinical Sciences at, Monash Health Monash University, Clayton, VIC, Australia. ⁴⁰Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia. ⁴¹Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain. ⁴²Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO) and Spanish Network On Rare Diseases (CIBERER), Madrid, Spain. ⁴³Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. ⁴⁴Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. ⁴⁵Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. ⁴⁶Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. ⁴⁷Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. ⁴⁸Department of OB/GYN and Comprehensive Cancer Center, Medical

University of Vienna, Vienna, Austria. ⁴⁹Department of Oncology, Clinical Sciences in Lund, Lund University Hospital, Lund, Sweden. ⁵⁰Clinical Genetics, Karolinska Institutet, Stockholm, Sweden. ⁵¹Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Quebec City, QC, Canada. ⁵²Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia. ⁵³Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia. ⁵⁴The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.

⁵⁵Department of Medical Oncology, Peter MacCallum Cancer Centre, Victoria, Australia. ⁵⁶Department of Epidemiology, Mailman School of Public Health and the Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. ⁵⁷Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT, USA. ⁵⁸Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

⁵⁹Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. ⁶⁰Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany.

Received: 16 December 2022 Accepted: 10 June 2023

Published online: 20 June 2023

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14. Chang-Claude J, Becher H, Eby N, Bastert G, Wahrendorf J, Hamann U. Modifying effect of reproductive risk factors on the age at onset of breast cancer for German BRCA1 mutation carriers. J Cancer Res Clin Oncol. 1997;123(5):272–9.

15. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302(5645):643–6.

16. Kotsopoulos J, Olopado OI, Ghadirian P, Lubinski J, Lynch HT, Isaacs C, Weber B, Kim-Sing C, Ainsworth P, Foulkes WD, et al. Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2005;7(5):R833-843.

17. Manders P, Piwijpe A, Hooning MJ, Kluijst I, Vasen HF, Hoogerbrugge N, van Asperen CJ, Meijers-Heijboer H, Ausems MG, van Os TA, et al. Body weight and risk of breast cancer in BRCA1/2 mutation carriers. Breast Cancer Res Treat. 2011;126(1):193–202.

18. Kim SJ, Huzarski T, Gronwald J, Singer CF, Moller P, Lynch HT, Armel S, Karlan BY, Foulkes WD, Neuhausen SL, et al. Prospective evaluation of body size and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Int J Epidemiol. 2018;47:987–97.

19. Pettapiece-Phillips R, Narod SA, Kotsopoulos J. The role of body size and physical activity on the risk of breast cancer in BRCA mutation carriers. Cancer Causes Control. 2015;26(3):333–44.

20. Qian F, Wang S, Mitchell J, McGuffog L, Barrowdale D, Leslie G, Oosterwijk JC, Chung WK, Evans DG, Engel C, et al. Height and Body mass index as modifiers of breast cancer risk in BRCA1/2 mutation carriers: a Mendelian randomization study. J Natl Cancer Inst. 2019;111(4):350–64.

21. Lecarpentier J, Nogues C, Mouret-Fourme E, Buecher B, Gauthier-Villars M, Stoppa-Lyonnet D, Bonadona V, Fricker JP, Berthet P, Caron O, et al. Breast cancer risk associated with estrogen exposure and truncating mutation location in BRCA1/2 carriers. Cancer Epidemiol Biomark Prev. 2015;24(4):698–707.

22. Goldgar D, Bonnardel C, Renard H, Yaqoubi O. The international BRCA1/2 carrier cohort study: purpose, rationale, and study design. Breast Cancer Res. 2000;2(6):E010.

23. John EM, Hopper JL, Beck JC, Knight JA, Neuhausen SL, Senie RT, Ziogas A, Andrulis IL, Anton-Culver H, Boyd N, et al. The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Res. 2004;6(R375-389).

24. Phillips KA, Butow PN, Stewart AE, Chang MJ, Weideman PC, Price MA, McLachlan SA, Lindeman GJ, McKay MJ, Friedlander ML, et al. Predictors of participation in clinical and psychosocial follow-up of the kConFab breast cancer family cohort. Fam Cancer. 2005;4(2):105–13.

25. Terry MB, Phillips KA, Daly MB, John EM, Andrulis IL, Buys SS, Goldgar DE, Knight JA, Whittemore AS, Chung WK, et al. Cohort profile: the breast cancer prospective family study cohort (ProF-SC). Int J Epidemiol. 2016;45(3):683–92.

26. Thorne H, Mitchell G, Fox S. kConFab c: kConFab: a familial breast cancer consortium facilitating research and translational oncology. J Natl Cancer Inst Monogr. 2011;2011(43):79–81.

27. Mavaddat N, Antoniou AC, Mooij TM, Hooning MJ, Heemskerk-Gerritsen BA, Genepso, Nogues C, Gauthier-Villars M, Caron O, Gesta P *et al.* Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers. *Breast Cancer Res* 2020;22(1):8.

28. Antoniou AC, Goldgar DE, Andrieu N, Chang-Claude J, Brohet R, Rookus MA, Easton DF. A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol. 2005;29(1):1–11.

29. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117–30.

30. Berkey CS, Rosner B, Tamimi RM, Willett WC, Hickey M, Toriola A, Frazier AL, Colditz GA. Body size from birth through adolescence in relation to risk of benign breast disease in young women. Breast Cancer Res Treat. 2017;162(1):139–49.

31. Rosner B, Eliassen AH, Toriola AT, Chen WY, Hankinson SE, Willett WC, Berkey CS, Colditz GA. Weight and weight changes in early adulthood and later breast cancer risk. Int J Cancer. 2017;140(9):2003–14.

32. Guo W, Key TJ, Reeves GK. Adiposity and breast cancer risk in postmenopausal women: results from the UK Biobank prospective cohort. Int J Cancer. 2018;143(5):1037–46.

33. Ye Z, Li S, Dite GS, Nguyen TL, MacInnis RJ, Andrulis IL, Buys SS, Daly MB, John EM, Kurian AW *et al.* Weight is more informative than body mass index for predicting post-menopausal breast cancer risk: Prospective Family Study Cohort (ProF-SC). *Cancer Prevention Research (Philadelphia, PA)* 2021.

34. Schrijver LH, Olsson H, Phillips KA, Terry MB, Goldgar DE, Kast K, Engel C, Mooij TM, Adlard J, Barrowdale D, et al. Oral contraceptive use and breast cancer risk: retrospective and prospective analyses from a BRCA1 and BRCA2 mutation carrier cohort study. JNCI Cancer Spectr. 2018;2(2):pky023.

35. Ritte R, Lukanova A, Berrino F, Dossus L, Tjonneland A, Olsen A, Overvad TF, Overvad K, Clavel-Chapelon F, Fournier A, et al. Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study. Breast Cancer Res. 2012;14(3):R76.

36. Phipps AI, Chlebowski RT, Prentice R, McTiernan A, Stefanick ML, Wactawski-Wende J, Kuller LH, Adams-Campbell LL, Lane D, Vitolins M, et al. Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer. Cancer Epidemiol Biomark Prev. 2011;20(3):454–63.

37. Phipps AI, Malone KE, Porter PL, Daling JR, Li CI. Body size and risk of luminal, HER2-overexpressing, and triple-negative breast cancer in postmenopausal women. Cancer Epidemiol Biomark Prev. 2008;17(8):2078–86.

38. Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, Malone KE. Risk factors for triple-negative breast cancer in women under the age of 45 years. Cancer Epidemiol Biomark Prev. 2009;18(4):1157–66.

39. Nolan E, Lindeman GJ, Visvader JE. Out-RANKing BRCA1 in mutation carriers. Can Res. 2017;77(3):595–600.

40. Hilton HN, Patterson McDonald LJ, Santucci N, van der Bent FR, Silvestri A, Graham JD, Clarke CL. BRCA1 attenuates progesterone effects on proliferation and NFkappaB activation in normal human mammary epithelial cells. J Mammary Gland Biol Neoplasia. 2019;24(3):257–70.

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53. Lee A, Mavaddat N, Wilcox AN, Cunningham AP, Carver T, Hartley S, Babb de Villiers C, Izquierdo A, Simard J, Schmidt MK, et al. BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors. Genet Med. 2019;21:1462.

54. Loi S, Milne RL, Friedlander ML, McCredie MR, Giles GG, Hopper JL, Phillips KA. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomark Prev. 2005;14(7):1686-91.

55. Chan DSM, Vieira AR, Aune D, Bandera EV, Greenwood DC, McTiernan A, Navarro Rosenblatt D, Thune I, Vieira R, Norat T. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014;25(10):1901-14.

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<figure><img src="image_3.png" /></figure>
by body mass index and familial risk: prospective family study cohort (ProF-SC). Breast Cancer Res. 2018;20(1):132.

50. Grill S, Yahiaoui-Doktor M, Dukatz R, Lammert J, Ullrich M, Engel C, Pfeifer K, Basrai M, Siniatchkin M, Schmidt T, et al. Smoking and physical inactivity increase cancer prevalence in BRCA-1 and BRCA-2 mutation carriers: results from a retrospective observational analysis. Arch Gynecol Obstet. 2017;296(6):1135-44.

51. Spector D. Lifestyle behaviors in women with a BRCA1 or BRCA2 genetic mutation: an exploratory study guided by concepts derived from the Health Belief Model. Cancer Nurs. 2007;30(1):E1-10.

52. Kiechle M, Engel C, Berling A, Hebestreit K, Bischoff S, Dukatz R, Gerber WD, Siniatchkin M, Pfeifer K, Grill S, et al. Lifestyle intervention in BRCA1/2 mutation carriers: study protocol for a prospective, randomized, controlled clinical feasibility trial (LIBRE-1 study). Pilot Feasibility Stud. 2016;2:74.

53. Lee A, Mavaddat N, Wilcox AN, Cunningham AP, Carver T, Hartley S, Babb de Villiers C, Izquierdo A, Simard J, Schmidt MK, et al. BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors. Genet Med. 2019;21:1462.

54. Loi S, Milne RL, Friedlander ML, McCredie MR, Giles GG, Hopper JL, Phillips KA. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomark Prev. 2005;14(7):1686-91.

55. Chan DSM, Vieira AR, Aune D, Bandera EV, Greenwood DC, McTiernan A, Navarro Rosenblatt D, Thune I, Vieira R, Norat T. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014;25(10):1901-14.

**Publisher's Note**

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ready to submit your research? Choose BMC and benefit from:

* fast, convenient online submission

* thorough peer review by experienced researchers in your field

* rapid publication on acceptance

* support for research data, including large and complex data types

* gold Open Access which fosters wider collaboration and increased citations

* maximum visibility for your research: over 100M website views per year

At BMC, research is always in progress.

Learn more biomedcentral.com/submissions

<figure><img src="image_3.png" /></figure>