Available online http://breast-cancer-research.

com/content/11/3/R31

Research article
Vol 11 No 3

Open Access

Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors
Marilyn L Kwan1, Lawrence H Kushi1, Erin Weltzien1, Benjamin Maring1, Susan E Kutner2, Regan S Fulton3, Marion M Lee4, Christine B Ambrosone5 and Bette J Caan1
1Kaiser

Permanente, Division of Research, 2000 Broadway, First Floor, Oakland, CA 94612, USA Permanente, San Jose, 280 Hospital Parkway, San Jose, CA 95119, USA 3Kaiser Permanente, Regional Immunohistochemistry Laboratory, 350 St. Joseph's Street, San Francisco, CA 94115, USA 4Department of Epidemiology and Biostatistics, Box 0981, 185 Berry Street 6600, University of California, San Francisco, CA 94143-0981, USA 5Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
2Kaiser

Corresponding author: Marilyn L Kwan, marilyn.l.kwan@kp.org Received: 6 Jan 2009 Revisions requested: 23 Feb 2009 Revisions received: 23 Mar 2009 Accepted: 22 May 2009 Published: 22 May 2009 Breast Cancer Research 2009, 11:R31 (doi:10.1186/bcr2261) This article is online at: http://breast-cancer-research.com/content/11/3/R31 © 2009 Kwan et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Introduction The aim of this study was to describe breast tumor subtypes by common breast cancer risk factors and to determine correlates of subtypes using baseline data from two pooled prospective breast cancer studies within a large health maintenance organization. Methods Tumor data on 2544 invasive breast cancer cases subtyped by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (Her2) status were obtained (1868 luminal A tumors, 294 luminal B tumors, 288 triple-negative tumors and 94 Her2-overexpressing tumors). Demographic, reproductive and lifestyle information was collected either in person or by mailed questionnaires. Caseonly odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for age at diagnosis, race/ethnicity, and study origin. Results Compared with luminal A cases, luminal B cases were more likely to be younger at diagnosis (P = 0.0001) and were less likely to consume alcohol (OR = 0.74, 95% CI = 0.56 to 0.98), use hormone replacement therapy (HRT) (OR = 0.66, 95% CI = 0.46 to 0.94), and oral contraceptives (OR = 0.73, 95% CI = 0.55 to 0.96). Compared with luminal A cases, triplenegative cases tended to be younger at diagnosis (P  0.0001) and African American (OR = 3.14, 95% CI = 2.12 to 4.16), were more likely to have not breastfed if they had parity greater than or equal to three (OR = 1.68, 95% CI = 1.00 to 2.81), and were more likely to be overweight (OR = 1.82, 95% CI = 1.03 to 3.24) or obese (OR = 1.97, 95% CI = 1.03 to 3.77) if premenopausal. Her2-overexpressing cases were more likely to be younger at diagnosis (P = 0.03) and Hispanic (OR = 2.19, 95% CI = 1.16 to 4.13) or Asian (OR = 2.02, 95% CI = 1.05 to 3.88), and less likely to use HRT (OR = 0.45, 95% CI = 0.26 to 0.79).

Conclusions These observations suggest that investigators should consider tumor heterogeneity in associations with traditional breast cancer risk factors. Important modifiable lifestyle factors that may be related to the development of a specific tumor subtype, but not all subtypes, include obesity, breastfeeding, and alcohol consumption. Future work that will further categorize triple-negative cases into basal and non-basal tumors may help to elucidate these associations further.

Introduction
Among women in the USA, breast cancer remains the most commonly diagnosed cancer, excluding skin cancers, and the second leading cause of cancer-related death [1]. Breast can-

cer is characterized by its molecular and clinical heterogeneity. Studies using cDNA microarrays and immunohistochemical (IHC) markers [2-6] have classified breast cancers into five distinct subtypes: luminal A (estrogen receptor (ER) positive

BMI: body mass index; CBCS: Carolina Breast Cancer Study; CI: confidence interval; CK: cytokeratin; EGFR: epidermal growth factor receptor; ER: estrogen receptor; FISH: fluorescence in situ hybridization; Her2: human epidermal growth factor receptor 2; HRT: hormone replacement therapy; IHC: immunohistochemical; IRB: institutional review board; KPNC: Kaiser Permanente Northern California; LACE: Life After Cancer Epidemiology; OC: oral contraceptive; OR: odds ratio; PBCS: Polish Breast Cancer Study; PR: progesterone receptor; WS: Washington State. Page 1 of 13
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19]. luminal B (ER positive and/or PR positive.20.14. The mean time from diagnosis to enrollment is 1. typically at the time of the in-person baseline interview. 2280 eligible women completed baseline questionnaires via mail. kg/m2). Her2 overexpressing (ER negative. the peak risk of recurrence occurs within three years of diagnosis.26]. number of biological children. Her2 negative. Although many studies have examined associations between common breast cancer risk factors. Women are recruited as soon after diagnosis as possible (usually within two months).14.5.5.9 months).0 to 38. eligibility criteria included age between 18 and 70 years at enrollment. Approximately 70% of 'triplenegative' breast cancers (ER negative. cases are rapidly ascertained on a daily basis by automatic scanning of electronic pathology reports with subsequent verification of cancer diagnosis and patient notification by a medical record analyst. The study was approved by the institutional review boards (IRB) of KPNC and the University of Utah. household income. ability to speak English. Self-reported height and weight one year before diagnosis (LACE) and around diagnosis (Pathways) was obtained to calculate body mass index (BMI. and mortality rates are increased for five years after diagnosis [14.Breast Cancer Research Vol 11 No 3 Kwan et al. The present analysis includes data from 1821 KPNC breast cancer patients from the LACE Study with complete breast cancer subtype information. 2212 breast cancer patients have been enrolled via in-person interview. and demographics (age at breast cancer diagnosis. higher grade [2.19.19. Briefly. PR negative. II. resulting in the triple-negative subtype commonly being used as a surrogate marker for the basal-like subtype. or IIIA). Data collection Materials and methods LACE Study The Life After Cancer Epidemiology (LACE) Study consists of 2280 women diagnosed with invasive breast cancer between 1997 and 2000 and recruited primarily from the Kaiser Permanente Northern California (KPNC) Cancer Registry (82%) and the Utah Cancer Registry (12%). hormone replacement therapy (HRT)). race [30-36] and hormone receptor status [36-41]. PR negative.3. and no history of other cancers in the five years prior to enrollment. Luminal tumors have been associated with the most favorable prognoses. The subtype accounts for approximately 15% of invasive breast cancers [2.20-22]. Her2 positive). Between January 2000 and April 2002. as described elsewhere [45]. family history of breast cancer [27]. 2008. a diagnosis of early-stage primary breast cancer (stages I  1 cm. Therefore. Eligibility criteria include: current KPNC membership. free of recurrence.43] [see Additional data file 1]. including age at first fullterm pregnancy. Her2 negative) express basal markers [7-9]. II. we set out to describe breast tumor subtypes by race/ethnicity and common breast cancer risk factors and to determine correlates of breast cancer subtypes using baseline data from two large. Any missing values were supplemented by concurrent information from KPNC electronic medical records.27. For triple-negative tumors.17. The mean time Reproductive and lifestyle factors In the mailed baseline questionnaire of the LACE Study and during the in-person baseline interview of the Pathways Study. The study was approved by the IRB of KPNC and all collaborating sites.4.8 months (range = 11. race/ethnicity.6.20] and is commonly associated with African American race [2.24].17. alcohol use. breastfeeding.9. from diagnosis to enrollment was 22.11. and live within a 65-mile radius of a field interviewer. Recruitment is ongoing.17.25].42.24.21. at least 21 years of age at diagnosis.3 months). recent diagnosis of first primary invasive breast cancer (all stages). PR negative.28. Cantonese.10. Her2 positive). or IIIA breast cancer and having complete breast cancer subtype data. few studies have explored the relationship between common breast cancer risk factors and the molecular subtypes of breast cancer [22.11.22-24].11. more advanced stage [10. younger age at diagnosis [10. or their surrogate triple negative tumors.29]. Additional information was collected on smoking. enrollment between 11 and 39 months postdiagnosis. participants were asked detailed information on family history of cancer and reproductive history. have been associated with the worst prognoses [2. In addition.9 months (range = 0 to 7. Spanish. hormone use (oral contraceptives (OC). education). or Mandarin. human epidermal growth factor receptor 2 (Her2) negative). Page 2 of 13 (page number not for citation purposes) . Briefly.16.11. Further details on the LACE cohort have been previously reported [44]. Written informed consent is obtained from all participants before they are enrolled in the study.16. no prior history of any cancer. and BRCA1 mutations [23.10. and/or progesterone receptor (PR) positive. prospective breast cancer survivorship studies of 2544 invasive breast cancer cases.16. and menopausal status. In order to make these cases comparable with those from the LACE Study. the present analysis includes data from the first 723 women enrolled with a diagnosis of stages I  1 cm. basal-like (ER negative. having completed breast cancer treatment (except for adjuvant hormonal therapy). a passive consent is obtained from the patient's physician of record by an email notification stating our intention to contact the patient for study recruitment. while Her2-overexpressing and basal-like tumors. high mitotic indices [2. and as of 20 October.10-18]. Pathways Study The Pathways Study is a prospective cohort study actively recruiting women diagnosed with invasive breast cancer from the KPNC patient population since January 2006. cytokeratin (CK) 5/6 positive and/or epidermal growth factor receptor (EGFR) positive) and normal breast-like tumors.

7) 46 (23.2) 163 (86.8) 6 (3.4) 33 (16.7) < 0.8 (11.7 (12.9) 71 (38.9) 1.1) 5 (9.6) 104 (59.1) 87 (44.6) 28 (57.0) 45 (22.2) 73 (38.5) 116 (75.215 343 (17. reproductive.6) 578 (29.2) 37 (42.1) 0.1) 20 (37.4) 31 (15.1) 72 (40.9) < 0.3) 13 (6.7) 79 (40.7) 28 (51.3) 38 (24.3) 279 (14.1) 29 (53.8) 994 (76.4) 14 (25.0001 Page 3 of 13 (page number not for citation purposes) .3) 31 (16.7) 894 (46.2) 41 (75.9) 8 (4.7 (9.0) 80 (40.7) < 0.2) 675 (34.4) 19 (12.1) 77 (67.9) 675 (39.330 (75.5) 37 (32.7) 31 (57.0001 908 (47.503 (77.8) 22 (14.7) 1.4) 17 (11.2) 9 (16.2) 78 (67.2) 20 (10.4) 13 (24.7) 59.2) 73 (47.1) 25 (13.001 389 (20.9) 47 (45.2) 92 (59.7) 6 (11.7) 12 (22.6) 56 (54.3) 46 (24.4) 37 (32.8 (11.6) 133 (85.7) 54.8) 22 (40.8) 12 (34.9) 13 (27.4) 440 (22.2) 50 (26.8) 167 (84.5) 31 (15.0001 1.4) 55.6) 35 (72.4) 90 (71.0) 879 (45.5) 733 (38.Available online http://breast-cancer-research.3) 23 (65.6) 56.7) 19 (12.6) 113 (57.1) 0.3) 93 (49.6) 50 (25.0) 169 (8.5) 0.0) 10 (6.8) < 0.016 (60.6) 32 (20.2) 57.9) 117 (65.2) 8 (15.7) 80 (51.3) 43 (27.0001 343 (17.9) 17 (31.2) 66 (42.3) 82 (43.0) 269 (14.0) 706 (36.3) 22 (14.8) 563 (29.7) 61 (32.1) 21 (42.3) 113 (73.6) 430 (24.4) 62 (34.006 1.1) 148 (78.6) 46 (24.5) 54 (35.com/content/11/3/R31 Table 1 Distribution of demographic.3) 87 (46.3) 61 (32.3) 21 (38.1) 51 (57.2) 43 (27.7) 93 (62.6) 25 (47.0001 925 (48.0001 African American Total n = 155 n (%) Asian Total n = 189 n (%) Hispanic Total n = 197 n (%) Other Total n = 54 n (%) P valuea < 0.8) 91 (48.2 (10.5) 9 (16.4) 56 (37.2) 67 (43.8) 119 (60.9) < 0.0) 41 (21.0) 67 (34.9) 13 (24.4) 36 (28.2) 26 (13.9) 81 (44.8) 22 (14.8) 30 (15. and lifestyle risk factors by race/ethnicity in the combined LACE and Pathways Studies (n = 2544) White Total n = 1943 n (%) Age at diagnosis (years) < 50 50 to 64  65 mean (± standard deviation) Menopausal status Postmenopausal Premenopausal Family history No Yes Parity Nulliparous 1 to 2 children  3 children Age at first full-term pregnancy (years) Nulliparous < 26  26 Lifetime duration of lactation Never 0 to 3 months  4 months Alcohol use Never Ever Smoking history (years) Never  10 11 to 19  20 Hormone replacement therapy (postmenopausal women only) Never Ever Oral contraceptive use 310 (23.020 (52.

then the woman is classified as having Her2-negative tumor expression. and are obtained directly from the KPNC regional cytogenetics laboratory. then the woman is classified as having Her2positive tumor expression.0) 48 (31.05 were considered statistically significant.  4 months). lifetime duration of lactation (never. Asian. Table 1 (Continued) Distribution of demographic. yes).  30 kg/m2). and Her2 positive (luminal B). case-only odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression.5) 23 (12.0. We also examined whether the associations between parity and tumor subtype varied by breastfeeding and whether BMI and tumor subtype varied by menopausal status by first generating strata-specific estimates and then including an interaction term in the model to test for statistical significance.6%).2 years) and Asians (mean age = 54.0) 67 (34.1) 491 (25.7) 119 (62.47-51]. smoking duration (never.1%).Breast Cancer Research Vol 11 No 3 Kwan et al. PR negative. 11 to 19. and lifestyle characteristics by cohort study and race/ethnicity were conducted using Pearson chi-square tests. ever). Gene expression profiling studies have shown that IHC of paraffin sections is a reliable surrogate for molecular classification of invasive breast cancers [3. and lifestyle factors varied significantly by race/ethnicity in the combined studies (Table 1). post). For all breast surgical specimens. and Her2 positive (Her2-overexpressing). we did not have IHC data for CK5/6 and EGFR expression. Demographically.1) 72 (37. ever).5) 64 (33. Asians (59.8 years) were more likely to be diagnosed at a younger age although whites were more likely to be diagnosed at an older age (mean age = 59.3) 46 (24.8 years).5) 20 (37. Beginning in July 1999.  10. then the specimen is sent for fluorescence in situ hybridization (FISH) at the KPNC regional cytogenetics laboratory. and added to the KPNC Cancer Registry approximately four months after diagnosis to allow for the completion of treatment. and Her2 expression is determined by IHC at the KPNC regional IHC laboratory and has been reported to the KPNC Cancer Registry since January 2000.8) < 0. if the IHC staining for Her2 expression is equivocal (less than 30% strong staining. 1 to 2.  20 years).2) (Pathways). and lifestyle covariates of interest were classified as follows: age at diagnosis (< 50.6%) and other races/ethnicities (24.9) 20 (37. Hispanic. the tumor subtype groups in this analysis consisted of: ER positive and/or PR positive.00 or P < 0. and Her2 negative (luminal A). hormone replacement therapy (HRT) among post-menopausal women (never. Statistical analysis Comparisons of demographic.9%). for this analysis. The luminal A group was selected as the referent because the majority of invasive breast cancer cases are of this subtype. reproductive. race/ethnicity.2) 37 (69. parity (nulliparous. Considering this limitation. African Americans (71. Page 4 of 13 (page number not for citation purposes) . reproductive. if the FISH score is greater than 2. Using the combined sample size of 2544 breast cancer survivors. reproductive.0) 76 (49. Thus. ER positive and/or PR positive.2) 40 (26. African American.4) 600 (31. African Americans (mean age = 56. but more than 10% weak staining). If the FISH score (Her2: 17 cen) is less than 2.4%). Data are collected.  3 children). CIs not overlapping with 1. Results Demographic. A positive family history of breast cancer was more common among whites (22. ER negative.3) 100 (55. and Pathways/LACE study origin except when these covariates were the predictors of interest.1%) were less likely to be post-menopausal than whites (75.7) 110 (73. hormone receptor status. PR negative.0 [52]. OC use (never.  65 years). However. 25 to 29. age at first full-term pregnancy (nulliparous.0) 119 (63.  26 years).5) 31 (20. reproductive. than among the other groups.3) 16 (30. coded. and Her2 negative (triple negative). Outcome classification Although the presence of basal markers can significantly improve the prognostic value of the triple-negative phenotype [13]. 0 to 3. ever). b Body mass index one year pre-diagnosis (LACE) and around diagnosis Tumor characteristics Data on ER and PR status and Her2 expression were obtained from medical record review and the KPNC Cancer Registry [46] for LACE and from the KPNC Cancer Registry and other KPNC databases for Pathways. ER negative. < 26.9) 79 (44.0001 a From Pearson chi-square test across racial/ethnic categories.0) 14 (25. we were unable to further classify triple-negative cases into basal-like and non-basal-like breast tumors. Results from FISH analyses are not reported to the KPNC Cancer Registry. 50 to 64. menopausal status (pre. All models were adjusted for age at diagnosis. Covariate classification Demographic. and other races/ethnicities (72. alcohol use (never.252 (66.8) 1. family history of breast cancer (no. race/ethnicity (white.0) 638 (33. 63 (32. and lifestyle risk factors by race/ethnicity in the combined LACE and Pathways Studies (n = 2544) Never Ever Body mass index < 25 25 to 29  30 (kg/m2)b 835 (43. and BMI (< 25. other).

56 to 0.7%) as Her2-overexpressing. Her2-overexpressing cases were more likely to be Hispanic (OR = 2.26 to 0.74.4% and 60. reproductive.5) Other n (%) 37 (68. 288 (11. Her2+) n = 94 (3.4%).0) 30 (15.02. reproductive. Whites were more likely to have ever consumed alcohol (60. Asians 6. + = positive. while fewer Asians (44.03). The distribution of breast cancer subtypes by race/ethnicity in the combined studies is presented in Table 2. African Americans 3. All case-only ORs were adjusted for age.2) 7 (13.4) 13 (6.5) P valuea 0. Compared with luminal A cases.0%) followed by other races/ethnicities (37.3%.3) 21 (10.4) Asian n (%) 135 (71. race/ethnicity. Breastfeeding for at least four months was associated with being less likely to have a triple negative tumor. PR-.4%) were classified as luminal A. The distribution of race/ethnicity within each subtype compared with all other subtypes varied significantly (P < 0. The Her2-overexpressing subtype was least common among all races/ethnicities (whites 3.78. luminal B cases were more likely to be younger at diagnosis (OR for < 50 years = 1.= negative. likely to be due to differences in time periods of data collection. 95% CI = 0. and 94 (3. and OC (OR = 0.5%. Page 5 of 13 (page number not for citation purposes) . 95% CI = 2.16 to 4.99 to 3. Her2-) n = 288 (11. Hispanics (68. 95% CI = 1. The majority of the whites (75. Her2-overexpressing cases were more likely to be younger at diagnosis (P = 0. Compared with luminal A cases.05 to 3. yet non-similarities were apparent among reproductive and hormonal factors.6%) as luminal B. and Her2-overexpressing) compared with luminal A are shown in Tables 3 and 4.6) 3 (5.3%). Her2+) n = 294 (11.83.6) Triple negative (ER-. African Americans and Hispanics had more biological children (42.2%. 95% CI = 0.4) Luminal B (ER+ and/or PR+. triple negative cases tended to be younger at diagnosis (OR for < 50 years = 2. 1868 (73.49.4) Hispanic n (%) 135 (68.5%). African Americans had the highest prevalence of the triple negative subtype (28. and African Americans (59. The majority of the case-only ORs were in the same direction as observed in the combined analysis. similar to luminal B and triple negative cases. Among the hormonal factors. Her2-) n = 1868 (73. more whites had used HRT (76. PR = progesterone receptor.1%) had used OCs compared with the other races/ethnicities.1) 5 (3. Asians 6.16).5%). other 5.4%) compared with the other races/ethnicities (whites 10. 95% CI = 1.2%.0001 215 (11. the two study populations were similar demographically. Compared with luminal A cases.03 1943 (100) 155 (100) 189 (100) 197 (100) 54 (100) --- Pearson chi-square test across racial/ethnic categories.18 204 (10. P = 0. PR-. similar to luminal B cases.12 to 4.94). The associations between the risk factors and tumor subtypes for the individual studies are presented in Additional data files 3 and 4. Hispanics 10. and lifestyle factors within each subtype (luminal B. .2%) compared with the other races/ethnicities.05). Among the 2544 invasive breast cancer cases.59 to 1.78.32 to 2. and lifestyle factors in the LACE and Pathways Studies separately.0001 60 (3.79). except for the association between BMI and the triple-negative subtype. use HRT (OR = 0.0) 0. 95% CI = 0.1) 14 (9.7%. 95% CI = 1.6%. and less likely to use HRT (OR = 0. 95% CI = 0.0%).4%. ER = estrogen receptor.5) 44 (28.7) 7 (13. 294 (11. other 13.1%.98).0001) and were less likely to consume alcohol (OR = 0.14. other (68.3%) were more likely to have never smoked.13) and Asian (OR = 2. and Pathways/LACE study origin except when either age at diagnosis or race/ethnicity were the main predictors in the logistic regression model.5%). triple negative.3) Her2 overexpressing (ER-.1%) while Asians (78. Additional data file 2 shows the distribution of demographic.55 to 0.3%) as triple negative.6% and 44. In the LACE Study.03).com/content/11/3/R31 Reproductive history also differed markedly by race/ethnicity.5) 0.46 to 0.4) 12 (6. Asians (71. triple-negative cases were more likely to have higher Distribution of breast cancer tumor subtypes by race/ethnicity in the combined LACE and Pathways Studies (n = 2544) Tumor subtype Luminal A (ER+ and/or PR+.88).55. yet this association was of borderline significance (OR = 0.96). African Americans were more obese at diagnosis (49.73.0001) and African American (OR = 3.7) Total n = 2544 (100) a From White n (%) 1464 (75.0) < 0.19. respectively) and were younger during their first pregnancy (73. Overall.2) 12 (6. Table 2 The associations between various demographic.0%) and Hispanics (34.3) African American n (%) 92 (59.90. 95% CI = 1. 95% CI = 0.7%) compared with the other races/ethnicities.66.5%). Furthermore.4%) had the luminal A tumor subtype. Her2 = human epidermal growth receptor 2. Hispanics 6. P  0.9) 28 (14.Available online http://breast-cancer-research.

0001 1464 92 135 135 37 215 14 28 30 7 Ref 0. 2.47 1.00 1453 410 245 49 Ref 0. 1. 1. 2.88.78 0.77) 321 326 224 Luminal Ba N OR 95% CI 637 871 355 82 124 88 Ref 1. 1.65.88 0. 2.72. 2.14 50 59 26 Ref 1. 1.56.45.04 0.88. 1.29 --0.24 1.58.03 --0.53.83 --0.74 --0.70. 2.32 0.85.25 1.13) (0. 1. 1.32 1.Breast Cancer Research Vol 11 No 3 Kwan et al.86 --0.74 0.50 871 255 711 135 50 100 Ref 1. 1.76 0. 2.94 --- 1283 406 173 95 Ref 1.90.32.90 --(0.12 0.04 --0.38 1. Table 3 Case-only odds ratios and 95% confidence intervals from logistic regression modelsa of associations between breast cancer tumor subtypes and demographic. and lifestyle risk factors.76) Page 6 of 13 (page number not for citation purposes) . 1.89.55 P = 0. combined LACE and Pathways Studies (n = 2544) Luminal A (comparison) n Age at diagnosis (years)  65 (Ref) 50 to 64 < 50 Test for trend Race/ethnicity White (Ref) African American Hispanic Asian Other Menopausal status Postmenopausal (Ref) Premenopausal Family history No (Ref) Yes Age at first full-term pregnancy (years) Nulliparous (Ref) < 26  26 Parity Nulliparous (Ref) 1 to 2 children  3 children Lifetime duration of breastfeeding Never (Ref) 0 to 3 months  4 months Parity among never breastfedb Nulliparous (Ref) 1 to 2 children  3 children Parity among 0 to 3 months 1 to 2 children (Ref)  3 children Parity among  4 months breastfedb breastfedb 144 108 33 17 Ref 0. reproductive.54.09 1. 1.02 335 959 567 51 158 85 Ref 1. 1.92.87.31 0.52 335 837 691 51 150 93 Ref 1.97 1.38 1.01 --(0.81.

yet the effect measures for Her2-overexpressing tumors were not Page 7 of 13 (page number not for citation purposes) . OR = odds ratio. 0. reproductive.32) < 25 (Ref) 25 to 29  30 BMI (kg/m2) among postmenopausalb < 25 (Ref) 25 to 29  30 a Adjusted 480 422 372 67 52 50 Ref 0.00 0.66 --0. parity of at least three children was associated with a statistically significant increased likelihood of having a triple-negative tumor (OR = 1. 1.68. although these effect measures were not statistically significant.51 0.05) in any tumor subtype model.96 314 943 55 114 Ref 0.com/content/11/3/R31 Table 3 (Continued) Case-only odds ratios and 95% confidence intervals from logistic regression modelsa of associations between breast cancer tumor subtypes and demographic. 1.51) at diagnosis.93 0. no differential associations of breastfeeding and parity were observed among luminal B cases.Available online http://breast-cancer-research.90 0. BMI while in the Pathways Study the opposite trend was observed.15.23) compared with luminal A. 1.03 --0.74 to 8.24 0. combined LACE and Pathways Studies (n = 2544) 1 to 2 children (Ref)  3 children Alcohol use Never (Ref) Ever Smoking history Never (Ref)  10 11 to 19  20 Hormone replacement therapy (postmenopausal only) Never (Ref) Ever Oral contraceptive use Never (Ref) Ever BMI (kg/m2)c < 25 (Ref) 25 to 29  30 BMI (kg/m2) among premenopausalb 223 99 81 50 21 24 Ref 1.27 to 7. Her2-overexpressing: OR = 2.51.03.56.07 785 563 500 134 79 77 Ref 0.75.33 0. For the subgroup analyses. In contrast.66.80 --0.77. premenopausal triple-negative and Her2overexpressing cases were more likely to be overweight (triple negative: OR = 1. b P for interaction not statistically significant (P > 0.94 921 251 147 531 163 39 22 68 Ref 0. As for the effect of BMI by menopausal status.09 709 880 131 119 Ref 0.41 647 1160 110 172 Ref 0.47 for age at diagnosis. among non-breastfeeding cases.46.61.57.03 to 3.97. 1.59. 1.03 to 3. c BMI = body mass index one year pre-diagnosis (LACE) and around diagnosis (Pathways). and Pathways/LACE study origin except in models with age at diagnosis or race/ethnicity as main predictors.00 to 2.55.84 --(0.98 358 352 56 44 Ref 0. race/ethnicity. 95% CI = 1. 0. All P values for interaction of parity by breastfeeding were not statistically significant. and lifestyle risk factors.67. 95% CI = 0.11 1.54. 95% CI = 1. 3.99 --0. 95% CI = 1.73 --0.68 --0. 0. 1. CI = confidence interval.74 --0. 1.81) and a Her2-overexpressing tumor (OR = 3.70 to 6.24.92 1.58) or obese (triple negative: OR = 1. 95% CI = 1. 95% CI = 0.59.92. Her2-overexpressing: OR = 2.82.86 0. 1.27 0.62. 2.

81. 7.58 0.79 335 837 691 52 137 99 Ref 1.13 335 959 567 52 163 72 Ref 1.53 0. 4. 3.15 P = 0.23) Page 8 of 13 (page number not for citation purposes) .32 0.80) 321 326 224 Triple negativea n OR 95% CI HER2-overexpressinga n OR 95% CI 637 871 355 68 115 105 Ref 1. combined LACE and Pathways Studies (n = 2544) Luminal A (comparison) n Age at diagnosis (years)  65 (Ref) 50 to 64 < 50 Test for trend Race/ethnicity White (Ref) African American Hispanic Asian Other Menopausal status Postmenopausal (Ref) Premenopausal Family history No (Ref) Yes Age at first full-term pregnancy (years) Nulliparous (Ref) < 26  26 Parity Nulliparous (Ref) 1 to 2 children  3 children Lifetime duration of breastfeeding Never (Ref) 0 to 3 months  4 months Parity among never breastfedb Nulliparous (Ref) 1 to 2 children  3 children Parity among 0 to 3 months 1 to 2 children (Ref)  3 children Parity among  4 months breastfedb breastfedb 144 108 25 16 Ref 1.58. 2. 3.81) 12 15 16 Ref 1.88 0.39 1.93 0. 1. 1.68. 1.34 1. 2. reproductive.71.54.47 0. 3.90 P  0.02 1.56.69.19 2.53 1.62 --0.34.12.52 1283 406 163 91 Ref 0. 3.57.78 --0.83. 1. 1. 3.99. 1. 1.14 0. 1.38 13 61 18 Ref 2.29 80 13 Ref 0.05.78 --0.38 50 59 39 Ref 1.18 --0.0001 23 45 25 Ref 1.95 --0.53.Breast Cancer Research Vol 11 No 3 Kwan et al.86 --1.84 --0. 2.08) (1.21 1.02 0.82 0.62 1.85.03 1464 92 135 135 37 204 44 21 12 7 Ref 3. 1.95 --0. 1. 1.33 1453 410 229 59 Ref 0.41) (1.53 871 255 711 148 41 97 Ref 1.55.29 0.30 1. Table 4 Case-only odds ratios and 95% confidence intervals from logistic regression modelsa of associations between breast cancer tumor subtypes and demographic.86 --0.07. 1.68 --(0. 3.68.82 --0.90.16. 2. 1. 3.94 60 5 13 12 3 Ref 1.72 13 40 40 Ref 1.65 --0.99 2. 6.82 --(0.16 --(0.57.66 0.93 --0. 1.75 --0.04 0. 4. 2.28.00.28 0.25 2.52 3.78.11 1.35 0.87.28 --2.27.97 0.13 1.80 0.03 43 16 32 Ref 1. 2. 5. and lifestyle risk factors.49. 0.56) 9 7 Ref 1.94.31.97.42.63.71.03 --(0.52 0.27 57 21 Ref 0.59. 2.

63.58 0.72.46.89 0.99 --(0.05) in any tumor subtype model.51 1. 0.57.45 --0.54. 1. 6. 8. body mass statistically significant.97 --1. All P values for interaction of BMI by menopausal status were not statistically significant.17 1.51 for age at diagnosis. these associations were not observed.56 0.50 358 352 52 44 Ref 0.98 --0.76 --0.45 39 31 23 Ref 1. 2.17 25 18 14 Ref 0.30 39 40 Ref 0.05 --0.65. 1. and lifestyle risk factors.15 2.21 1. reproductive.08 0.78 647 1160 80 202 Ref 0. 1. and were more likely to not breastfeed if they had at least three children.26. use HRT.03.51 --0. Among luminal A cases. 1.Available online http://breast-cancer-research.31 29 63 Ref 1. and lifestyle factors were examined. and less likely to use HRT.51 785 563 500 110 99 77 Ref 1.75.20 24 33 Ref 0.83 314 943 50 112 Ref 0. 1. not statistically significant (P > 0. 1. We Page 9 of 13 (page number not for citation purposes) .54.86 0. Women with triple-negative tumors were also less likely to breastfeed for longer periods. Her2overexpressing cases were more likely to be younger at diagnosis and Hispanic or Asian. 1. 1.98. 1.83 --0.33 1.24 1.04 --0.98 --0. index one year pre-diagnosis (LACE) and around diagnosis (Pathways).97 --0.23.49. 3.12 --0. reproductive.com/content/11/3/R31 Table 4 (Continued) Case-only odds ratios and 95% confidence intervals from logistic regression modelsa of associations between breast cancer tumor subtypes and demographic. Discussion In a pooled analysis of 2544 breast cancer cases using data from two prospective cohort studies housed within a large health maintenance organization. OR = odds ratio.74. 1. associations between breast cancer subtypes and various demographic.34 51 7 8 26 Ref 0.61 0. 1.63. race/ethnicity. luminal B cases were more likely to be younger at diagnosis and were less likely to consume alcohol.99 0.70.40 0.03.95 0.57. HER2 = human epidermal growth receptor 2. 1. 1. 2.23 --(0.72. and were more likely to be overweight and/or obese at diagnosis if premenopausal. b P for interaction c BMI.73. 1. combined LACE and Pathways Studies (n = 2544) 1 to 2 children (Ref)  3 children Alcohol use Never (Ref) Ever Smoking history Never (Ref)  10 11 to 19  20 Hormone replacement therapy (postmenopausal only) Never (Ref) Ever Oral contraceptive use Never (Ref) Ever BMI (kg/m2)c < 25 (Ref) 25 to 29  30 BMI (kg/m2) among premenopausalb 223 99 81 39 28 23 Ref 1. 1.76 --0.81 0.94 --0.66) < 25 (Ref) 25 to 29  30 BMI (kg/m2) among postmenopausalb < 25 (Ref) 25 to 29  30 a Adjusted 480 422 372 59 60 43 Ref 1. 1.69.03 --0.59. 1. Triple-negative cases tended to be younger at diagnosis and African American. 3.73 709 880 110 129 Ref 0.38. In case-case analyses with the luminal A cases as the reference group. 1.14 0.73.55) 14 17 Ref 1. 1.59.77 7 7 7 Ref 2.79 921 251 147 531 146 41 21 78 Ref 0.82 1. and Pathways/LACE study origin except in models with age at diagnosis or race/ethnicity as main predictors. CI = confidence interval.74.59 0. and OCs.47 0.

Future research should focus on refinement of tumor subtypes into more homogenous subgroups in order to best elucidate how risk factors may vary by subtype. However. The CBCS and PBCS were able to classify their triplenegative cases into basal-like and unclassified using CK5/6 and EGFR IHC expression data while the WS study did not do so. both studies observed a strong positive association for triple-negative cases (basal-like cases for CBCS) among women who had higher parity and never breastfed.4% Asian.9 (95% CI = 1. and the WS study did not examine luminal tumors separately by luminal A and luminal B subtype. These varying associations by subtype lend further support to the growing evidence base that breast cancer is a heterogeneous disease defined by ER. we were unable to further examine risk factors by white and African American race/ethnicity due to limited numbers.8% Hispanic. we observed that Her2-overexpressing cases were more likely to be women who had at least three children and had not breastfed. Casecase analyses among tumor subtypes are a useful exploratory tool to examine etiologic heterogeneity between the subtypes [53]. Similarly. Finally. limitations of our study should be discussed. yet we did not see any such association in our study. our results are in agreement with those of the CBCS that luminal B and Her2-overexpressing cases tended to be younger than luminal A cases.4) compared with luminal A cases. also found that these cases were more likely to be women with at least three children and no history of breastfeeding.1% other) than other studies that have examined breast cancer risk factors among tumor subtypes. Finally. the latter of which found no association. In fact. but not African American. 3. although our large study population of 2544 women diagnosed with invasive breast cancer was more ethnically diverse (76. As previously mentioned. The PBCS (case-control analysis) did not present data on the impact of breastfeeding on tumor subtypes. and a pooled study of two Washington State (WS) case-control studies (n = 1023 invasive cases) [42. especially the high-risk African American group.Breast Cancer Research Vol 11 No 3 Kwan et al. with additional funding.1% African American. These case-case observations suggest that heterogeneity in associations with traditional breast cancer risk factors exists by tumor subtype. and Her2-overexpressing). and it must be emphasized that the associations reported here are all in reference to risk of having a luminal A tumor subtype and should not be extended to risk of having invasive breast cancer. Although our results tend to be in agreement with those of other studies. the CBCS reported a caseonly OR for parity of at least three children and no breastfeeding as 1. triple negative. n = 1424 in situ and invasive cases) [22]. Only case-case comparisons were conducted. we have no data on CK5/6 and EGFR tumor markers to further classify triple-negative tumors into basal-like and unclassified. 2.6% white. as there were a limited number of Her2overexpressing tumors (n = 94. 7. including the Carolina Breast Cancer Study (CBCS. results concerning this subtype should be interpreted with caution. both the CBCS (case-case analysis) and our study found suggestive associations of shorter duration of breastfeeding (less than four months) with being more likely to have a triple-negative tumor. The WS study (casecontrol analysis) also reported that breastfeeding for at least six months was related to a reduced risk of triple-negative tumors [43]. unlike the CBCS. Furthermore. our triple-negative cases were more likely to be younger at diagnosis and African American. especially those regarding Hispanic and Asian differences.43] [see Additional data file 1]. we plan to conduct these additional IHC assays in triple negative cases. and Her2 expression with distinct etiologic pathways and prognoses. 6.7%). Also. should be replicated in other population-based studies. Conclusions In summary. we observed that these cases were less likely to use HRT although luminal B cases were less likely to consume alcohol. Several studies have assessed risk factor profiles of tumor subtypes. yet no clear modifiable risk factor profile was apparent for Her2-overexpressing subtypes due to a limited sample size. Page 10 of 13 (page number not for citation purposes) . Although we were unable to further classify triple-negative cases into basal-like and unclassified. The CBCS performed case-case and case-control analyses while the PBCS and WS study conducted case-control analyses only. the CBCS. public health programs aimed towards achieving a healthy weight and promoting breastfeeding might reduce the number of poor prognostic triple negative tumors among all breast cancer cases. similar to the results of the CBCS (case-case analysis) and PBCS (case-control analysis) for basal-like cases. luminal B. reported that Her2-overexpressing cases were slightly more likely to be African American. 804 invasive cases) [27]. We found that Her2-overexpressing cases were more likely to be Hispanic or Asian. using a case-case analysis to assess the associations between traditional breast cancer risk factors and breast cancer subtypes (luminal A. As for luminal B and Her2-overexpressing cases. No associations with these factors were observed in the PBCS.1 to 3. Important modifiable factors that may be related to the development of specific tumor subtypes include obesity and possibly breastfeeding (triple negative) and alcohol consumption (luminal B). Interestingly. comprised of only whites and African Americans. In contrast to the CBCS results. Our findings. the Polish Breast Cancer Study (PBCS. an observation which was not seen in any of the other studies. we observed significant heterogeneity of associations by tumor subtype. 7. which was in agreement with the basal-like cases in the CBCS but not the PBCS. the WS study (case-control analysis) reported a suggestive increased risk of triple-negative tumors with increasing BMI among women currently using hormone therapy [42]. PR. Given this information. We also observed that premenopausal triple-negative cases tended to have higher BMI. an association not seen in the CBCS.

Jeffrey SS. Marchio C. R01 CA124924).doc 3. Bertucci F. Smith IE. Lee AH. Rijn M van de. MML contributed to analysis and interpretation of data. and survival in the Carolina Breast Cancer Study. Botstein D. Brown PO. Borresen-Dale AL. with additional support from the State of Utah Department of Health. Andre F: Does triple-negative phenotype accurately identify basal-like tumour? An immunohistochemical analysis based on 143 'triple-negative' breast cancers. Johnsen H. See http://www. Breast Cancer Res Treat 2008. Cowan D. All authors read and approved the final manuscript. Geisler S. Additional files The following Additional files are available online: References 1. and lifestyle risk factors. Rakha EA. Rijn M van de. and revised the manuscript critically for important intellectual content. Nielsen TO. Botstein D: Molecular portraits of human breast tumours. and revised the manuscript critically for important intellectual content. Edmiston S. Paish C. Perou CM: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Troester MA. Fluge O.biomedcentral. Eur J Cancer 2006. Macmillan D. reproductive. Viens P. Thorsen T. Livasy C. Pergamenschikov A. Ellis IO: Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. and the American Cancer Society (RSG-06-209-01-LR). See http://www. Finetti P. reproductive.com/content/11/3/R31 Competing interests The authors declare that they have no competing interests. Lonning PE. Cervera N. and revised the manuscript critically for important intellectual content. Carey LA. Bidard FC. EW contributed to analysis and interpretation of data. BM contributed to study conception and design. Eystein Lonning P. Cowan D. Johnsen H. Aas T. and interpretation of data. and acquisition. analysis. Karaca G. Additional file 4 A word file containing a table that shows case-only odds ratios and 95% confidence intervals from logistic regression models of associations between breast cancer tumor subtypes and demographic. Division of Research. 98:10869-10874. Zhu SX. Hermitte F. Green AR. Esterni B. Deming SL. CBA contributed to analysis and interpretation of data. 2. Livasy CA. Perou CM. Reis-Filho JS: Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Clin Cancer Res 2004. Hu Z. Dressler LG. Akslen LA. American Cancer Society: Cancer facts and figures 2008. We thank all LACE and Pathways Study participants. Ann Oncol 2007. LACE study (n = 1821).doc 7.doc 4. Eisen MB. SEK contributed to analysis and interpretation of data. Proc Natl Acad Sci USA 2001. El-Rehim DA. and revised the manuscript critically for important intellectual content. Millikan RC: Race. Hastie T. Boulet T.Available online http://breast-cancer-research.biomedcentral. We acknowledge the technical assistance of Dr Xu Li of the KPNC Cytogenetics Laboratory and the programming assistance of Isaac Joshua Ergas at Kaiser Permanente. Sorlie T. Perou CM. Nature 2000. Jensen K.biomedcentral.com/content/ supplementary/bcr2261-S4. Dressler L. 9. Cheang M. Blamey RW. Gown AM. 5. reproductive. and lifestyle risk factors in the LACE and Pathways studies individually and combined (n = 2544).com/content/ supplementary/bcr2261-S1. 42:3149-3156. JAMA 2006. 10:5367-5374. Akslen LA. Jeffrey SS. Sorlie T. and revised the manuscript critically for important intellectual content. See http://www. See http://www. Perou CM. RSF contributed to acquisition of data. and acquisition. Pollack JR. and drafted and revised the manuscript critically for important intellectual content. Conforti R. Geradts J. Rees CA. Savage K. and lifestyle risk factors. and interpretation of data. The Pathways Study was funded by the National Cancer Institute (R01 CA105274. Quist H. 406:747-752. Cheang MC. 123:236-240. Tse CK. Ragaz J.com/content/ supplementary/bcr2261-S2. Karaca G. Tan DS. Hernandez-Boussard T. Tibshirani R. Michiels S. LHK and BJC contributed to study conception and design. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies. Acknowledgements The LACE Study was funded by the National Cancer Institute (R01 CA80027) and by the Utah Cancer Registry (N01 PC67000). the Department of Defense (BC043120). Atlanta: American Cancer Society. 111:27-44. Conway K. and revised the manuscript critically for important intellectual content. Matese JC. Rijn M van de. Additional file 2 A word file containing a table that lists the distribution of demographic. Eisen MB. Gilks CB. Page 11 of 13 (page number not for citation purposes) . Brown PO. and revised the manuscript critically for important intellectual content.doc Authors' contributions MLK contributed to study conception and design. Birnbaum D: How basal are triple-negative breast cancers? Int J Cancer 2008. breast cancer subtypes. Dowsett M. 295:2492-2502. BorresenDale AL: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.biomedcentral. Earp HS. Hsu FD. Additional file 1 A word file containing a table that lists previous studies that have examined associations between common breast cancer risk factors and breast cancer tumor subtypes. Robertson JF. Nielsen TO. 18:1285-1286. Delaloge S. Pathways study (n = 723). analysis. Additional file 3 A word file containing a table that lists case-only odds ratios and 95% confidence intervals from logistic regression models of associations between breast cancer tumor subtypes and demographic. Moorman PG.com/content/ supplementary/bcr2261-S3. 2008. 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