Dataset Information

Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

ABSTRACT:

Background

Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.

Methods

We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.

Results

In case-case analyses, of the epidemiological risk factors examined, early age at menarche (?12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ? 30 kg/m(2)) in younger women (?50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.

Conclusions

This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

SUBMITTER: Yang XR

PROVIDER: S-EPMC3107570 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Publications

Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

Yang Xiaohong R XR Chang-Claude Jenny J Goode Ellen L EL Couch Fergus J FJ Nevanlinna Heli H Milne Roger L RL Gaudet Mia M Schmidt Marjanka K MK Broeks Annegien A Cox Angela A Fasching Peter A PA Hein Rebecca R Spurdle Amanda B AB Blows Fiona F Driver Kristy K Flesch-Janys Dieter D Heinz Judith J Sinn Peter P Vrieling Alina A Heikkinen Tuomas T Aittomäki Kristiina K Heikkilä Päivi P Blomqvist Carl C Lissowska Jolanta J Peplonska Beata B Chanock Stephen S Figueroa Jonine J Brinton Louise L Hall Per P Czene Kamila K Humphreys Keith K Darabi Hatef H Liu Jianjun J Van 't Veer Laura J LJ van Leeuwen Flora E FE Andrulis Irene L IL Glendon Gord G Knight Julia A JA Mulligan Anna Marie AM O'Malley Frances P FP Weerasooriya Nayana N John Esther M EM Beckmann Matthias W MW Hartmann Arndt A Weihbrecht Sebastian B SB Wachter David L DL Jud Sebastian M SM Loehberg Christian R CR Baglietto Laura L English Dallas R DR Giles Graham G GG McLean Catriona A CA Severi Gianluca G Lambrechts Diether D Vandorpe Thijs T Weltens Caroline C Paridaens Robert R Smeets Ann A Neven Patrick P Wildiers Hans H Wang Xianshu X Olson Janet E JE Cafourek Victoria V Fredericksen Zachary Z Kosel Matthew M Vachon Celine C Cramp Helen E HE Connley Daniel D Cross Simon S SS Balasubramanian Sabapathy P SP Reed Malcolm W R MW Dörk Thilo T Bremer Michael M Meyer Andreas A Karstens Johann H JH Ay Aysun A Park-Simon Tjoung-Won TW Hillemanns Peter P Arias Pérez Jose Ignacio JI Menéndez Rodríguez Primitiva P Zamora Pilar P Benítez Javier J Ko Yon-Dschun YD Fischer Hans-Peter HP Hamann Ute U Pesch Beate B Brüning Thomas T Justenhoven Christina C Brauch Hiltrud H Eccles Diana M DM Tapper William J WJ Gerty Sue M SM Sawyer Elinor J EJ Tomlinson Ian P IP Jones Angela A Kerin Michael M Miller Nicola N McInerney Niall N Anton-Culver Hoda H Ziogas Argyrios A Shen Chen-Yang CY Hsiung Chia-Ni CN Wu Pei-Ei PE Yang Show-Lin SL Yu Jyh-Cherng JC Chen Shou-Tung ST Hsu Giu-Cheng GC Haiman Christopher A CA Henderson Brian E BE Le Marchand Loic L Kolonel Laurence N LN Lindblom Annika A Margolin Sara S Jakubowska Anna A Lubiński Jan J Huzarski Tomasz T Byrski Tomasz T Górski Bohdan B Gronwald Jacek J Hooning Maartje J MJ Hollestelle Antoinette A van den Ouweland Ans M W AM Jager Agnes A Kriege Mieke M Tilanus-Linthorst Madeleine M A MM Collée Margriet M Wang-Gohrke Shan S Pylkäs Katri K Jukkola-Vuorinen Arja A Mononen Kari K Grip Mervi M Hirvikoski Pasi P Winqvist Robert R Mannermaa Arto A Kosma Veli-Matti VM Kauppinen Jaana J Kataja Vesa V Auvinen Päivi P Soini Ylermi Y Sironen Reijo R Bojesen Stig E SE Ørsted David Dynnes DD Kaur-Knudsen Diljit D Flyger Henrik H Nordestgaard Børge G BG Holland Helene H Chenevix-Trench Georgia G Manoukian Siranoush S Barile Monica M Radice Paolo P Hankinson Susan E SE Hunter David J DJ Tamimi Rulla R Sangrajrang Suleeporn S Brennan Paul P McKay James J Odefrey Fabrice F Gaborieau Valerie V Devilee Peter P Huijts P E A PE Tollenaar R A E M RA Seynaeve C C Dite Gillian S GS Apicella Carmel C Hopper John L JL Hammet Fleur F Tsimiklis Helen H Smith Letitia D LD Southey Melissa C MC Humphreys Manjeet K MK Easton Douglas D Pharoah Paul P Sherman Mark E ME Garcia-Closas Montserrat M

Journal of the National Cancer Institute 20101229 3

<h4>Background</h4>Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.<h4>Methods</h4>We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological ris ...[more]

PMID: 21191117

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Project description:Background:Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors. Methods:Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status. Results:The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction?=?0.009), adult height (P-interaction?=?0.025) and current use of combined MHT (P-interaction?=?0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P?=?0.013 for global and 0.18 for tail-based tests). Conclusions:The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.

Project description:BackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Project description:The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

Dataset Information

Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

Background

Methods

Results

Conclusions

Publications

Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

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