Relationship Between Anthropometric Factors and Risk of Second Breast Cancer Among Women With a History of Ductal Carcinoma In Situ

Relationship Between Anthropometric Factors and Risk of Second Breast Cancer Among Women With a... Background: Women with ductal carcinoma in situ (DCIS) have an elevated risk of a second breast cancer, but few data are available regarding the impact of modifiable lifestyle factors on this risk. Methods: In a population-based case–control patient study of women with a history of DCIS in western Washington diag- nosed between 1996 and 2013, 497 patients diagnosed with DCIS and a second ipsilateral or contralateral invasive or in situ breast cancer were enrolled. There were 965 matched control patients with one DCIS diagnosis. Associations between anthro- pometric factors and risk of an invasive or in situ second breast cancer event were evaluated using conditional logistic regres- sion. Statistical tests were two-sided. Results: Obesity (body mass index [BMI]  30 kg/m ) at initial DCIS diagnosis was associated with a 1.6-fold (95% confidence interval [CI] ¼ 1.2 to 2.2) increased risk of any second breast cancer and a 2.2-fold increased risk of a contralateral second breast cancer (95% CI ¼ 1.4 to 3.3) compared with normal weight women (BMI < 25 kg/m ). BMI and weight, both at initial DCIS diagnosis and at the time of the second breast cancer diagnosis, were positively associated with risk of any second and second invasive breast cancers (odds ratio ¼ 1.01–1.04, all P  .03). Conclusions: Although additional confirmatory studies are needed, obesity appears to be an important contributor to the risk of second breast cancers within the growing population of women with DCIS. This has potential clinical relevance with respect to identifying which women with a history of DCIS may require more careful monitoring and who may benefit from lifestyle modifications. The incidence of ductal carcinoma in situ (DCIS) has increased Previous studies have identified demographic, mammo- in parallel with the rise in screening mammography, such that graphic, treatment, and clinical/pathologic characteristics asso- nearly one-third of all newly diagnosed breast cancer case ciated with second breast cancer events among women with a patients in the United States are DCIS (1,2). Although the history of DCIS (6–16). Adjuvant radiation and endocrine ther- 10-year breast cancer–specific mortality rate after treatment of apy decrease the risk of local recurrence and contralateral sec- DCIS is approximately 2%–3% (3,4), up to 30% of patients will ex- ond breast cancer events after DCIS by 50% (11,12,17,18), but perience a subsequent DCIS or invasive breast cancer event (5). relatively little is known about the impact of potentially modifi- For clinicians to provide individualized treatment recommenda- able lifestyle factors. In particular, the role of obesity in breast tions, it is imperative to be able to stratify patients according to cancer is of increasing interest (19). Obese patients with inva- their risk of experiencing a second breast cancer event. sive cancer are more likely to experience a second breast cancer Received: April 10, 2018; Accepted: April 13, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 1of 8 by Ed 'DeepDyve' Gillespie user on 21 June 2018 2of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 or die from breast cancer compared with women who are nor- diagnosis for case patients; for control patients, this was the mal or underweight (20–24). Three previous cohort studies have date corresponding to the interval between the first DCIS and evaluated the association of body mass index (BMI) and second second breast cancer diagnosis of the case patient they were breast events in DCIS patients with inconsistent results (25–27). matched to. Height was collected at the same time points. Data One study demonstrated increased risk of ipsilateral second from medical record review were used as the primary source for breast cancer events in obese patients at initial diagnosis (27), anthropometric measures, and when unavailable, interview- another showed no overall association (25), and a third found based data were used (24%). that the relationship was modified by menopausal status (26). A key limitation of these three studies was small sample sizes, Characterization of Exposures with the number of second breast cancer events ranging from 76 to 162. The 49 case patients and 103 control patients with missing BMI Given the growing population of DCIS survivors, the rising (kg/m ) data were excluded, leaving a final analytic data set epidemic of obesity in the United States (28), and the paucity of consisting of 448 case patients and 862 control patients. Results studies that have evaluated the relationship between anthropo- from this case patient–complete analysis were not appreciably metric factors and risk of developing a second breast cancer, different from those completed on the entire study population. further investigation is warranted. We examined the relation- Height and weight were evaluated as continuous variables. BMI ship between BMI, height, and weight and the risk of second was categorized as a continuous variable and as a categorical breast cancers in a large population-based study of women with variable using the modified Centers for Disease Control (CDC) a history of DCIS. The identification of potentially modifiable classification system (underweight and normal [<25 kg/m ], factors that impact this risk could guide and motivate changes 2 2 overweight [25 to 29.9 kg/m ], and obese [30 kg/m ]). Changes in health behaviors. in BMI and weight between the initial DCIS diagnosis and refer- ence date were also evaluated. Methods Statistical Analysis Study Population For the primary analysis, control patients were compared with We conducted a population-based nested case–control patient three case patient groups: any second breast event, invasive study from an underlying cohort of 4157 women age 30–79 years second breast event, in situ second breast event. Associations diagnosed with DCIS in the Seattle–Puget Sound region between between anthropometric factors and these outcomes were esti- January 1, 1996, and June 30, 2013 (Supplementary Figure 1, mated using conditional logistic regression given our use of a available online). Study participants were identified through the matched case–control patient design (31). Odds ratios (ORs) and Cancer Surveillance System, a cancer registry serving 13 coun- Wald-type 95% confidence intervals were calculated as esti- ties in western Washington State. Patients who underwent bi- mates of relative risks. Effect modification by menopausal sta- lateral mastectomy were excluded (29,30), as were women who tus at initial diagnosis, change in menopausal status between developed nonbreast cancers as treatment could impact the initial diagnosis and second breast event/reference date, and re- risk of a second breast cancer event. Cases were classified as ceipt of adjuvant endocrine therapy were assessed based on patients with a second invasive or in situ breast cancer event at likelihood ratio testing. Because there were no statistically sig- least six months following initial diagnosis. Of the 705 eligible nificant interactions with any of the main effects assessed at case patients, 497 were enrolled (70.5% response rate). Control the prespecified P value of less than .1, no effect modifiers were patients were those diagnosed with DCIS who did not have a included in the final models. second breast cancer event during the study period. Controls Associations between BMI at initial diagnosis with ipsilateral were individually matched to case patients on age and year of or contralateral second breast cancers were examined in a sec- initial diagnosis (þ/-2 years), county of residence, surgical and ondary analysis. One patient with bilateral second breast can- radiation treatment, histology, grade, and disease-free survival cers was excluded. For the analysis of ipsilateral events, time. All potentially eligible control patients who met matching patients who underwent a unilateral mastectomy for their ini- criteria for a given case patient were assigned a random number tial procedure were excluded. and placed in numerical order. Proceeding down the list, two to A sensitivity analysis was performed to assess for significant three control patients per case patient were contacted. Of the differences in risk estimates using data from medical record re- 1695 eligible matched control patients, 965 were enrolled (57% view and interview-based data for our primary exposures. Risk response rate). Written, informed consent was obtained from estimates changed less than 10% when analyses were restricted study participants, and the study was approved by the to participants with medical record data, and thus in our final Institutional Review Board at the Fred Hutchinson Cancer models we included all participants with available data, priori- Research Center. tizing medical record over interview data for anthropomorphic variables. All models were implicitly adjusted for the case/control Data Collection patient matching variables given our use of conditional logistic Patient demographic, epidemiologic, and clinical data were col- regression. Additionally, we adjusted for menopausal status at lected from structured telephone interviews and detailed medi- initial diagnosis and receipt of adjuvant endocrine therapy as cal record review. Tumor and treatment data were obtained via these have been shown to be potential confounders in previous medical records. Lifestyle factors such as tobacco and alcohol literature (25,26,32). The time period between initial diagnosis consumption, reproductive factors, menopausal status, and and second event (or reference date) varied among some case/ family history were obtained via interview. Data on weight were control patient pairs (case patients: median ¼ 61 months; con- collected at initial diagnosis and date of second breast cancer trol patients: median ¼ 58 months). Consequently, models for Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 M. R. Flanagan et al. | 3 of 8 Table 1. Patient, pathology, and treatment characteristics of women with and without a second breast cancer event after initial ductal carci- noma in situ diagnosis Any second Controls breast cancer Invasive* In situ† (n ¼ 862) (n ¼ 448) (n ¼ 303) (n ¼ 145) No. (%) No. (%) No. (%) No. (%) Patient demographics Age at initial diagnosis, y Median (IQR) 53 (47–61) 53 (47–61) 54 (47–63) 52 (47–59) 30–39 29 (3.4) 20 (4.5) 13 (4.3) 7 (4.8) 40–49 274 (31.8) 138 (30.8) 92 (30.4) 46 (31.7) 50–59 307 (35.6) 156 (34.8) 97 (32.0) 59 (40.7) 60–69 186 (21.6) 95 (21.2) 75 (24.8) 20 (13.8) 70þ 66 (7.7) 39 (8.7) 26 (8.6) 13 (9.0) Year of diagnosis 1995–2001 448 (52.0) 448 (52.0) 167 (55.1) 70 (48.3) 2002–2007 358 (41.5) 358 (41.5) 119 (39.3) 62 (42.8) 2008–2013 56 (6.5) 56 (6.5) 17 (5.6) 13 (9.0) Race/ethnicity Hispanic 15 (1.7) 11 (2.5) 8 (2.6) 3 (2.1) Non-Hispanic white 772 (89.6) 389 (86.8) 267 (88.1) 122 (84.1) Black 17 (2.0) 12 (2.7) 8 (2.6) 4 (2.8) Asian/Pacific Islander 45 (5.2) 26 (5.8) 12 (4.0) 14 (9.7) Native American 13 (1.5) 9 (2.0) 7 (2.3) 2 (1.4) Unknown 0 1 (0.2) 1 (0.3) 0 (0) First-degree family history No 620 (73.5) 300 (68.6) 202 (68.2) 98 (69.5) Yes 223 (26.5) 137 (31.4) 94 (31.8) 43 (30.5) Unknown 19 11 7 4 Reproductive characteristics No. of full-term pregnancies Nulliparous 179 (20.9) 101 (22.6) 66 (21.9) 35 (24.1) Parous 677 (79.1) 346 (77.4) 236 (78.1) 110 (75.9) Unknown 6 1 1 0 Age at first live birth‡, y <20 87 (10.5) 50 (14.9) 38 (16.5) 12 (11.4) 20–24 257 (30.9) 133 (39.6) 94 (40.7) 39 (37.1) 25–29 185 (22.2) 85 (25.3) 54 (23.4) 31 (29.5) 30–34 84 (10.1) 47 (24.0) 31 (13.4) 16 (15.2) 35 40 (4.8) 21 (6.3) 14 (6.1) 7 (6.1) Unknown 24 10 5 5 Menopausal status at initial DCIS diagnosis Pre- or perimenopausal 340 (40.8) 180 (41.3) 115 (39.1) 65 (45.8) Postmenopausal 493 (59.2) 256 (58.7) 179 (60.9) 77 (54.2) Unknown 29 12 9 3 Menopausal hormone replacement therapy Never 492 (57.4) 492 (57.4) 190 (63.1) 87 (60.0) Former (any type) 29 (3.4) 29 (3.4) 18 (6.0) 5 (3.4) Current estrogen only 182 (21.2) 182 (21.2) 56 (18.6) 29 (20.0) Current estrogen and progesterone 154 (18.0) 154 (18) 37 (12.3) 24 (16.6) Unknown 5 2 2 0 Tumor characteristics Histology of initial DCIS* Mixed 339 (39.3) 155 (34.6) 103 (34.0) 52 (35.9) NOS 210 (24.4) 88 (19.6) 63 (20.8) 25 (17.2) Comedo 104 (12.1) 67 (15.0) 47 (15.5) 20 (13.8) Cribriform 100 (11.6) 58 (12.9) 41 (13.5) 17 (11.7) Solid 73 (8.5) 55 (12.3) 35 (11.6) 20 (13.8) Other 36 (4.2) 25 (5.6) 14 (4.6) 11 (7.6) Grade of initial DCIS 1 20 (2.8) 20 (2.8) 13 (5.3) 4 (3.4) 2 210 (29.4) 210 (29.4) 63 (25.6) 30 (25.6) 3 223 (31.3) 223 (31.3) 70 (28.5) 41 (35.0) 4 259 (36.4) 259 (36.4) 100 (40.7) 42 (35.9) Unknown 150 85 57 28 (continued) Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 4of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 1. (continued) Any second Controls breast cancer Invasive* In situ† (n ¼ 862) (n ¼ 448) (n ¼ 303) (n ¼ 145) No. (%) No. (%) No. (%) No. (%) Size of initial DCIS, cm <2 541 (79.7) 541 (79.7) 197 (81.4) 83 (75.5) 2.1–5 116 (17.1) 116 (17.1) 32 (13.2) 20 (18.2) >5 22 (3.2) 22 (3.2) 13 (5.4) 7 (6.4) Unknown 183 96 61 35 Treatment characteristics Treatment for initial DCIS Biopsy only 7 (0.8) 6 (1.3) 4 (1.3) 2 (1.4) BCS with radiation 465 (53.9) 242 (54.0) 161 (53.1) 81 (55.9) BCS without radiation 203 (23.5) 105 (23.4) 79 (26.1) 26 (17.9) Mastectomy 187 (21.7) 95 (21.2) 59 (19.5) 36 (24.8) Adjuvant endocrine therapy No 542 (63) 321 (71.7) 218 (71.9) 103 (71) Yes 318 (37) 127 (28.3) 85 (28.1) 42 (29) Unknown 2 0 0 0 *Classified according to ICD-O-3 codes for invasive carcinomas: 8000/3, 8010/3, 8050/3, 8140/3, 8201/3, 8211/3, 8230/3, 8401/3, 8480/3, 8490/3, 8500/3, 8501/3, 8503/3, 8504/ 3, 8507/3, 8520/3, 8522/3, 8523/3, 8524/3, 8530/3, 8540/3, 8541/3, 8543/3, 8575/3. BCS ¼ breast conservation surgery; DCIS ¼ ductal carcinoma in situ; IQR ¼ interquartile range; NOS ¼ not otherwise specified. †Classified according to ICD-O-3 codes for subtypes of ductal carcinoma in situ: 8201/2, 8230/2, 8500/2, 8501/2, 8503/2, 8507/2, 8522/2, 8523/2. ‡Excludes nulliparous patients (n ¼ 280). change in BMI were adjusted for number of months between pronounced for invasive vs in situ second breast cancers; how- initial diagnosis and reference date. All other covariates in ever, the differences were not statistically significantly different Table 1 were assessed as potential confounders. None were (initial: P ¼ .61; second: P ¼ .38). Height was heterogeneity heterogeneity found to change odds ratios more than 10% for continuous or cat- not related to risk of second breast cancer. egorical weight, height, or BMI variables, so they were not added There were no statistically significant associations observed to the final multivariable models. To quantify the magnitude with gain or loss of BMI and second breast cancer event of the case patient–case differences, we calculated two-sided (Table 3). There was a suggestion of increased risk with BMI loss P values by excluding control patients and comparing of –3 kg/m or more for any, invasive, and in situ second breast heterogeneity different case patient groups. STATA/SE 12.1 (StataCorp LP, events, but this was not significant. College Station, TX) was used for all analyses. After exclusion of four unilateral mastectomy patients and one bilateral recurrence, there were 173 ipsilateral (39.0%) and 270 contralateral (60.8%) second breast cancers. Most ipsilat- Results eral (74.0%) and contralateral (63.3%) second breast events were invasive. There was no association between initial BMI Of the 448 case patients with a second breast cancer event, 303 and ipsilateral second breast cancer events among all women (67.6%) were invasive and 145 (32.4%) were in situ. The median (Table 4), or those with invasive second breast cancer events time between initial DCIS and second breast cancer event (data not shown). However, there was a 2.2-fold (95% CI ¼ 1.4 (range) was 68 (6–208) months for invasive and 49 (6–213) to 3.3) increased risk of a contralateral second breast cancer months for in situ events. Case and control patients groups associated with obese BMI at initial diagnosis, and there was had similar distributions of age, diagnosis year, race, parity, increased risk associated with both overweight and obese BMI and menopausal status (Table 1). Patients with invasive second at the second breast cancer event (overweight: OR ¼ 1.6, 95% CI breast cancer events were more likely to have used meno- ¼ 1.1 to 2.4;obese:OR ¼ 1.9, 95% CI ¼ 1.3 to 2.8). There was a pausal hormone therapy before initial diagnosis. Patients with statistically significantly elevated risk of a contralateral breast any or an invasive second breast cancer event were less likely cancer event associated with a decrease in BMI of 3 kg/m or to have received adjuvant endocrine therapy after their initial more (OR ¼ 2.0, 95% CI ¼ 1.1to 3.6), which was theonly statisti- diagnosis. cally significant risk difference between ipsilateral and contra- Body weight and BMI, both at the time of initial diagnosis lateral case patients (P ¼ .01). Among women with heterogeneity and at second diagnosis/reference date, were positively associ- invasive contralateral second breast cancer events, there was ated with risk of a second breast cancer event (odds ratio ¼ an approximately twofold increased risk associated with obe- 1.011.04, all P  .03) (Table 2). For each 1 mg/kg increase in sity at both the first and second events, as well as with a BMI BMI at initial DCIS diagnosis, there was a 3% increase in the loss of 3 kg/m or more (data not shown). odds of any second breast cancer event (OR ¼ 1.03, 95% confi- dence interval [CI] ¼ 1.01 to 1.05). Women who were obese at initial diagnosis had a 1.6-fold (95% CI ¼ 1.2 to 2.2) higher risk of Discussion developing a second breast cancer compared with women with a normal BMI. Similar odds were seen for BMI at second diagno- The population of women with a history of DCIS has grown as sis (OR ¼ 1.01 to 1.04, all P  .03). These risks were more incidence rates have risen steadily over the past several Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 M. R. Flanagan et al. | 5 of 8 Table 2. Risk of second breast cancer event in relation to anthropometric factors at initial ductal carcinoma in situ diagnosis and reference date Any second breast cancer* Invasive* In situ* Controls (n ¼ 448) (n ¼ 303) (n ¼ 145) (n ¼ 862) No. (%) No. (%) OR (95% CI) No. (%) OR (95% CI) No. (%) OR (95% CI) Initial diagnosis BMI, mean (SD), kg/m 26.1 (6.13) 27.1 (6.49) 1.03 (1.01 to 1.1)† 27.2 (6.41) 1.04 (1.01 to 1.1)† 26.8 (6.69) 1.01 (0.9 to 1.05) P (per 1 kg/m ) .007 .005 .491 trend BMI categories, kg/m <25.0 417 (48.4) 186 (41.5) 1.0 (ref) 124 (40.9) 1.0 (ref) 62 (42.8) 1.0 (ref) 25.0–29.9 255 (29.6) 133 (29.7) 1.2 (0.9 to 1.6) 89 (29.4) 1.3 (0.9 to 1.9) 44 (30.3) 0.9 (0.6 to 1.6) 30.0 190 (22.0) 129 (28.8) 1.6 (1.2 to 2.2)† 90 (29.7) 1.8 (1.2 to 2.6)† 39 (26.9) 1.3 (0.8 to 2.3) Height, mean (SD), cm 164 (6.8) 165 (6.8) 1.0 (0.9 to 1.03) 165 (6.8) 1.0 (0.9 to 1.04) 164 (7.0) 1.0 (0.9 to 1.1) P (per 1 cm) .123 .202 .389 trend Height, quartiles, m 130–160 278 (32.3) 139 (31) 1.0 (ref) 91 (30) 1.0 (ref) 48 (33.1) 1.0 (ref) 161–164 179 (20.8) 88 (19.6) 1.0 (0.7 to 1.4) 61 (20.1) 1.0 (0.7 to 1.5) 27 (18.6) 0.9 (0.5 to 1.7) 165–168 213 (24.7) 98 (21.9) 0.9 (0.7 to 1.3) 67 (22.1) 1.0 (0.6 to 1.5) 31 (21.4) 0.8 (0.5 to 1.5) 169–188 192 (22.3) 123 (27.5) 1.3 (0.9 to 1.9) 84 (27.7) 1.4 (0.9 to 2.1) 39 (26.9) 1.2 (0.7 to 2.2) Weight, mean (SD), kg 70.9 (16.7) 74.2 (18.2) 1.01 (1.00 to 1.02)† 74.5 (17.6) 1.01 (1.01 to 1.02)† 73.4 (19.5) 1.01 (0.99 to 1.02) P (per 1 kg) .002 .002 .349 trend Weight, quartiles, kg 37.2–59.9 231 (26.8) 96 (21.4) 1.0 (ref) 58 (19.1) 1.0 (ref) 38 (26.2) 1.0 (ref) 60.0–68.9 239 (27.7) 119 (26.6) 1.1 (0.8 to 1.6) 82 (27.1) 1.3 (0.9 to 2.0) 37 (25.5) 0.8 (0.5 to 1.4) 69.0–80.9 201 (23.3) 94 (21.0) 1.2 (0.8 to 1.7) 63 (20.8) 1.3 (0.8 to 2.1) 31 (21.4) 0.9 (0.5 to 1.8) 81.0–168.3 191 (22.2) 139 (31.0) 1.8 (1.3 to 2.6)† 100 (33.0) 2.2 (1.4 to 3.4)† 39 (26.9) 1.1 (0.6 to 2.1) Second breast event/reference date BMI, mean (SD), kg/m 26.5 (6.3) 27.4 (6.4) 1.03 (1.00 to 1.04)† 27.6 (6.3) 1.03 (1.01 to 1.06)† 27.1 (6.5) 1.01 (0.97 to 1.05) P (per 1 kg/m ) .028 .017 .698 trend BMI categories, kg/m <25.0 388 (45.0) 162 (36.2) 1.0 (ref) 106 (35.0) 1.0 (ref) 56 (38.6) 1.0 (ref) 25.0–29.9 263 (30.5) 154 (34.4) 1.4 (1.1 to 1.9)† 106 (35.0) 1.8 (1.3 to 2.7)† 48 (33.1) 0.9 (0.6 to 1.5) 30.0 211 (24.5) 132 (29.5) 1.5 (1.1 to 2.1)† 91 (30.0) 1.6 (1.1 to 2.3)† 41 (28.3) 1.3 (0.8 to 2.3) Weight, mean (SD), kg P (per 1 kg) 71.9 (17.5) 74.9 (17.8) 1.01 (1.00 to 1.02)† 75.4 (17.4) 1.01 (1.00 to 1.02)† 74.0 (18.7) 1.00 (0.90 to 1.02) trend Weight quartiles, kg .008 .006 .509 42.0–60.9 212 (24.6) 103 (23.0) 1.0 (ref) 63 (20.8) 1.0 (ref) 40 (27.6) 1.0 (ref) 61.0–69.0 248 (28.8) 87 (19.4) 0.7 (0.5 to 1.02) 57 (18.8) 0.8 (0.5 to 1.2) 30 (20.7) 0.6 (0.4 to 1.2) 69.1–81.9 211 (24.5) 126 (28.1) 1.3 (0.9 to 1.9) 93 (30.7) 1.7 (1.1 to 2.8)† 33 (22.8) 0.8 (0.4 to 1.4) 82.0–172.8 191 (22.2) 132 (29.5) 1.4 (0.9 to 2.0) 90 (29.7) 1.6 (1.04 to 2.6)† 42 (29.0) 1.1 (0.6 to 1.9) *Odds ratios and 95% confidence intervals were estimated using conditional logistic regression and were implicitly adjusted for matching variables (age and year of the initial DCIS diagnosis, county, histology, grade of initial DCIS lesion, surgical and radiation treatment, and survival time). All models were additionally adjusted for menopausal status at initial DCIS diagnosis and use of adjuvant endocrine therapy. BMI ¼ body mass index; CI ¼ confidence interval; OR ¼ odds ratio. †P < .05. decades. These women have an elevated risk of developing a increased risk of ipsilateral second breast cancer compared with subsequent breast cancer, but relatively little is known regard- women with a BMI of less than 22 kg/m . Kuerer et al. also com- ing how modifiable lifestyle factors influence this risk. Of partic- bined invasive and in situ events, but presented associations ular importance is obesity given the continued rise in obesity stratified by laterality. Consistent with our findings, but con- rates and previously established links between obesity and in- trasting those of Habel et al., they found no association with vasive breast cancer (20–24). Our results indicate that the rela- risk of an ipsilateral second breast cancer in a single-institution tionship between BMI and second primary breast events among cohort study (n ¼ 1885) with 40 ipsilateral events (25). A poten- DCIS survivors is complex, with variation across levels of BMI tial explanation for these differences is variation in DCIS treat- and possibly according to stage and laterality. ment. Receipt of radiation therapy is associated with decreased Few studies have evaluated the impact of anthropometric risk of ipsilateral second breast cancers (5). In the Kuerer et al. factors on second breast cancer events after DCIS, and they had study, 80% of patients received adjuvant radiation compared inconsistent results. In a population-based cohort study includ- with 55% in our study and 40% in Habel et al. Adjuvant tamoxi- ing 480 patients from 1980 to 1992, Habel et al. evaluated the fen therapy also decreases the risk of second breast cancer risk of invasive or in situ ipsilateral second breast cancers or events (17,33). This was used by approximately one-third of metastases among breast conservation patients (27). Based on patients in Kuerer et al. and our study but was not routinely 76 ipsilateral events, obesity was associated with a twofold used during the time frame of Habel et al. Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 6of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 3. Risk of second breast cancer event in relation to changes in body mass index and weight between initial ductal carcinoma in situ diag- nosis and reference date Any second breast cancer* Invasive* In situ* Controls (n ¼ 448) (n ¼ 303) (n ¼ 145) (n ¼ 862) No. (%) No. (%) OR (95% CI) No. (%) OR (95% CI) No. (%) OR (95% CI) Change in BMI, kg/m BMI loss 3 56 (6.5) 42 (9.4) 1.5 (0.95 to 2.4) 26 (8.6) 1.4 (0.8 to 2.5) 16 (11.0) 1.7 (0.8 to 3.8) BMI loss >1–<3 122 (14.2) 59 (13.2) 1.0 (0.6 to 1.4) 38 (12.5) 0.8 (0.5 to 1.4) 21 (14.5) 1.3 (0.6 to 2.5) BMI change þ/- 1 389 (45.1) 193 (43.1) 1.0 (ref) 124 (40.9) 1.0 (ref) 69 (47.6) 1.0 (ref) BMI gain >1–<3 203 (23.5) 103 (23.0) 1.0 (0.7 to 1.4) 80 (26.4) 1.1 (0.8 to 1.7) 23 (15.9) 0.7 (0.4 to 1.3) BMI gain 3 92 (10.7) 51 (11.4) 1.1 (0.7 to 1.6) 35 (11.6) 1.0 (0.6 to 1.7) 16 (11.0) 1.2 (0.5 to 2.5) P (2 kg/m ) .302 .572 .326 trend Change in weight, kg Loss 6 95 (11.0) 68 (15.2) 1.3 (0.9 to 2.0) 43 (14.2) 1.3 (0.8 to 2.1) 25 (17.2) 1.4 (0.7 to 2.8) Loss >2–5.9 146 (16.9) 67 (15.0) 0.9 (0.6 to 1.3) 47 (15.5) 0.9 (0.5 to 1.4) 20 (13.8) 0.9 (0.5 to 1.9) Gain or loss within 2 242 (28.1) 120 (26.8) 1.0 (ref) 79 (26.1) 1.0 (ref) 41 (28.3) 1.0 (ref) Gain >2–5.9 236 (27.4) 111 (24.8) 0.9 (0.6 to 1.2) 75 (24.8) 1.0 (0.6 to 1.5) 36 (24.8) 0.7 (0.4 to 1.3) Gain 6 143 (16.6) 82 (18.3) 1.0 (0.7 to 1.5) 59 (19.5) 1.1 (0.7 to 1.8) 23 (15.9) 0.8 (0.4 to 1.7) P (2 kg) .321 .477 .481 trend *Odds ratios and 95% confidence intervals were estimated using conditional logistic regression and were implicitly adjusted for matching variables (age and year of the initial ductal carcinoma in situ [DCIS] diagnosis, county, histology, grade of initial DCIS lesion, surgical and radiation treatment, and survival time). All models were additionally adjusted for menopausal status at initial DCIS diagnosis and use of adjuvant endocrine therapy. BMI ¼ body mass index; CI ¼ confidence interval; OR ¼ odds ratio. Table 4. Relationship of second breast cancer laterality and body mass index at initial ductal carcinoma in situ diagnosis, second breast can- cer/reference date, and change in BMI Ipsilateral* Contralateral Controls Cases Controls Cases (n ¼ 336) (n ¼ 173) (n ¼ 513) (n ¼ 270) No. (%) OR† (95% CI) No. (%) No. (%) OR† (95% CI) Initial diagnosis BMI categories, kg/m <25.0 165 (49.1) 77 (44.5) 1.0 (ref) 246 (48.0) 106 (39.3) 1.0 (ref) 25.0–29.9 93 (27.7) 52 (30.1) 1.2 (0.7 to 1.9) 158 (30.8) 79 (29.3) 1.2 (0.8 to 1.8) 30.0 78 (23.2) 44 (25.4) 1.1 (0.7 to 1.8) 109 (21.2) 85 (31.5) 2.2 (1.4 to 3.3)‡ P (per 1 kg/m ) .466 .008 trend Second breast event/reference date BMI categories, kg/m <25.0 146 (43.5) 66 (38.2) 1.0 (ref) 237 (46.2) 94 (34.8) 1.0 (ref) 25.0–29.9 100 (29.8) 57 (32.9) 1.6 (0.9 to 2.8) 157 (30.6) 94 (34.8) 1.6 (1.1 to 2.4)‡ 30.0 90 (26.8) 50 (28.9) 1.1 (0.6 to 2.1) 119 (23.2) 82 (30.4) 1.9 (1.3 to 2.8)‡ P (per 1 kg/m ) .572 .027 trend Change in exposure status Change in BMI, kg/m BMI loss 3 24 (7.1) 9 (5.2) 0.8 (0.4 to 1.9) 32 (6.2) 33 (12.2) 2.0 (1.1 to 3.6)‡ BMI loss >1–<3 44 (13.1) 24 (13.9) 1.1 (0.6 to 2.1) 76 (14.8) 34 (12.6) 0.8 (0.5 to 1.4) BMI change þ/- 1 145 (43.2) 74 (42.8) 1.0 (ref) 237 (46.2) 117 (43.3) 1.0 (ref) BMI gain >1–<3 83 (24.7) 41 (23.7) 1.0 (0.6 to 1.7) 117 (22.8) 61 (22.6) 1.0 (0.7 to 1.6) BMI gain 3 40 (11.9) 25 (14.5) 1.3 (0.7 to 2.4) 51 (9.9) 25 (9.3) 0.9 (0.5 to 1.6) P (2 kg/m ) .991 .198 trend *Excludes patients with previous unilateral mastectomy. BMI ¼ body mass index; CI ¼ confidence interval; OR ¼ odds ratio. †Odds ratios and 95% confidence intervals were estimated using conditional logistic regression and were implicitly adjusted for matching variables (age and year of the initial ductal carcinoma in situ [DCIS] diagnosis, county, histology, grade of initial DCIS lesion, surgical and radiation treatment, and survival time). All models were additionally adjusted for menopausal status at initial DCIS diagnosis and use of adjuvant endocrine therapy. ‡P < .05. Although Kuerer et al. found no statistically significant dif- cancers associated with overweight/obesity among women who ferences in the risk of ipsilateral second breast events according did not receive adjuvant tamoxifen therapy. No multivariable to BMI, a univariate analysis of their data revealed a borderline analysis was presented. In our analysis adjusted for adjuvant significantly (P ¼ .06) elevated risk of contralateral second breast endocrine therapy, there were no statistically significant Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 M. R. Flanagan et al. | 7 of 8 differences in risk of ipsilateral or contralateral second breast largely abstracted from medical records and not subject to recall cancers; however, there was a suggestion of increased contra- bias. For those patients missing BMI data, there may be bias lateral risk associated with obesity at both initial and second di- that we cannot account for in our models. There was no differ- agnosis. Both studies were likely underpowered to detect ence with respect to patient demographic, lifestyle, and tumor statistically significant associations, and further studies with characteristics compared with patients without missing data, longer follow-up and larger numbers of contralateral breast and the degree and direction of bias are unknown. An additional cancers are needed to confirm our finding of a possible associa- limitation is lack of data on other modifiable risk factors, partic- tion between obesity and contralateral breast cancer risk. ularly physical activity. However, data on this subject in DCIS McLaughlin et al. conducted the largest examination of BMI are lacking. However, data from a large meta-analysis including and second breast cancer events in a DCIS population (n ¼ 11 cohort and eight case–control patient studies found no differ- 1925). In contrast to our study, they did not observe increased ential effects of physical activity on invasive breast cancer risk risk of second breast cancer events associated with increasing according to BMI (47). Therefore, we would not expect physical BMI before initial diagnosis (HR ¼ 0.99, 95% CI ¼ 0.96 to 1.02) or activity to significantly confound or modify our findings. between initial and subsequent diagnosis (HR ¼ 1.03, 95% CI ¼ Participation bias is another potential concern, but we did 0.97 to 1.10) in the overall cohort. However, they found that achieve reasonable response rates for a study of this type, menopausal status at initial diagnosis modified the effect of which limits the impact of this bias. During the time frame in- obesity on the risk of second breast cancer events (26). cluding many of the initial DCIS diagnoses, hormone receptors Premenopausal women who were obese at diagnosis were 77% were not routinely tested. Therefore, there is a substantial less likely to develop any second breast cancer compared with amount of missing data for this variable, and we were unable to normal and underweight women, whereas a non-statistically include this as a matching variable, effect modifier, or con- significant trend toward increased risk associated with over- founder. Finally, although our results suggest that there may be weight and obesity was seen in postmenopausal women. We increased risk of invasive and contralateral second breast can- did not find evidence of effect modification according to meno- cer events associated with increasing BMI, the study lacked pausal status in our study, but in their analysis of premeno- power to show significant heterogeneity. Larger studies are pausal women, there were only four obese patients with second needed to confirm our findings. breast cancer events (compared with 39 in our study), limiting Few studies have evaluated the influence of potentially the statistical power and generalizability of their findings. modifiable lifestyle factors on the risk of subsequent breast can- One finding unique to our study was the increased risk of a cers among women with DCIS. Second breast cancers are an im- contralateral second breast cancer event associated with a sub- portant outcome for this population, as women with DCIS have stantial loss of BMI after initial diagnosis, but no increased risk a two to four times greater risk of developing a second breast associated with weight gain. McLaughlin et al. evaluated change cancer than women in the general population have of develop- in weight, and also did not observe an association between ing a first breast cancer. Additionally, a second invasive event is weight gain and risk of second breast cancer events (26). In con- associated with a 1.75-fold increased mortality risk (12). Our trast to our study, they also found no association with loss of findings suggest that obesity is positively related to second BMI. Although there is a dearth of information about weight breast cancer events, and possibly more strongly with invasive change after DCIS, a number of studies have investigated this and contralateral second cancers. Efforts to maintain a normal relationship after an invasive cancer diagnosis (34–43). These weight have well-known health benefits for a variety of dis- studies have shown conflicting results, with several reporting eases, and this may also extend to lowering risk of a second an increased risk of second breast cancers associated with breast cancer among women diagnosed with DCIS. Further re- weight gain (37,41), others demonstrating no association (35), search is needed on the types of exercise/dietary interventions and another offering evidence of a relationship between sub- that could be effective among DCIS survivors. stantial weight loss and increased risk of second breast cancer (43). Mechanisms explaining associations between weight loss Funding and second breast cancers are lacking but may involve compro- mised tumor–immune system interactions accompanying MRF was supported by T32 grant support from the National chronic undernutrition (44) or dysfunctional mammary adipo- Institutes of Health under award number CA009168. The cytes (45,46). Whether our results suggest that avoidance of ma- content is solely the responsibility of the authors and does jor weight loss subsequent to a DCIS diagnosis may be an not necessarily represent the official views of the National additional approach to reduce the risk of second breast cancer Institutes of Health. events or if this is merely a reflection of cachexia associated with a second breast cancer event is unclear and requires addi- tional study. Notes One of the strengths of our study is its population-based nested case–control patient design, which is well suited to Affiliations of authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (MRF, MTCT, studying rare diseases such as second cancer events that re- quire many years of follow-up for detection. This is only the MLB, PLP, KEM, CIL); Breast Service, Department of Surgery, fourth published study to assess the relationship between BMI Memorial Sloan Kettering Cancer Center, New York, NY (MRF). and risk of second breast cancer events after a diagnosis of There are no potential conflicts of interest. DCIS, and our sample size is appreciably larger than any of the prior studies. Further, the population-based nature of our study References makes it potentially more generalizable than single-institution 1. DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J series. Clin. 2014;64(1):52–62. The primary potential limitation of our study is recall bias. 2. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst However, data for our primary exposures of interest were Monogr. 2010;2010(41):139–141. 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Relationship Between Anthropometric Factors and Risk of Second Breast Cancer Among Women With a History of Ductal Carcinoma In Situ

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Abstract

Background: Women with ductal carcinoma in situ (DCIS) have an elevated risk of a second breast cancer, but few data are available regarding the impact of modifiable lifestyle factors on this risk. Methods: In a population-based case–control patient study of women with a history of DCIS in western Washington diag- nosed between 1996 and 2013, 497 patients diagnosed with DCIS and a second ipsilateral or contralateral invasive or in situ breast cancer were enrolled. There were 965 matched control patients with one DCIS diagnosis. Associations between anthro- pometric factors and risk of an invasive or in situ second breast cancer event were evaluated using conditional logistic regres- sion. Statistical tests were two-sided. Results: Obesity (body mass index [BMI]  30 kg/m ) at initial DCIS diagnosis was associated with a 1.6-fold (95% confidence interval [CI] ¼ 1.2 to 2.2) increased risk of any second breast cancer and a 2.2-fold increased risk of a contralateral second breast cancer (95% CI ¼ 1.4 to 3.3) compared with normal weight women (BMI < 25 kg/m ). BMI and weight, both at initial DCIS diagnosis and at the time of the second breast cancer diagnosis, were positively associated with risk of any second and second invasive breast cancers (odds ratio ¼ 1.01–1.04, all P  .03). Conclusions: Although additional confirmatory studies are needed, obesity appears to be an important contributor to the risk of second breast cancers within the growing population of women with DCIS. This has potential clinical relevance with respect to identifying which women with a history of DCIS may require more careful monitoring and who may benefit from lifestyle modifications. The incidence of ductal carcinoma in situ (DCIS) has increased Previous studies have identified demographic, mammo- in parallel with the rise in screening mammography, such that graphic, treatment, and clinical/pathologic characteristics asso- nearly one-third of all newly diagnosed breast cancer case ciated with second breast cancer events among women with a patients in the United States are DCIS (1,2). Although the history of DCIS (6–16). Adjuvant radiation and endocrine ther- 10-year breast cancer–specific mortality rate after treatment of apy decrease the risk of local recurrence and contralateral sec- DCIS is approximately 2%–3% (3,4), up to 30% of patients will ex- ond breast cancer events after DCIS by 50% (11,12,17,18), but perience a subsequent DCIS or invasive breast cancer event (5). relatively little is known about the impact of potentially modifi- For clinicians to provide individualized treatment recommenda- able lifestyle factors. In particular, the role of obesity in breast tions, it is imperative to be able to stratify patients according to cancer is of increasing interest (19). Obese patients with inva- their risk of experiencing a second breast cancer event. sive cancer are more likely to experience a second breast cancer Received: April 10, 2018; Accepted: April 13, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 1of 8 by Ed 'DeepDyve' Gillespie user on 21 June 2018 2of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 or die from breast cancer compared with women who are nor- diagnosis for case patients; for control patients, this was the mal or underweight (20–24). Three previous cohort studies have date corresponding to the interval between the first DCIS and evaluated the association of body mass index (BMI) and second second breast cancer diagnosis of the case patient they were breast events in DCIS patients with inconsistent results (25–27). matched to. Height was collected at the same time points. Data One study demonstrated increased risk of ipsilateral second from medical record review were used as the primary source for breast cancer events in obese patients at initial diagnosis (27), anthropometric measures, and when unavailable, interview- another showed no overall association (25), and a third found based data were used (24%). that the relationship was modified by menopausal status (26). A key limitation of these three studies was small sample sizes, Characterization of Exposures with the number of second breast cancer events ranging from 76 to 162. The 49 case patients and 103 control patients with missing BMI Given the growing population of DCIS survivors, the rising (kg/m ) data were excluded, leaving a final analytic data set epidemic of obesity in the United States (28), and the paucity of consisting of 448 case patients and 862 control patients. Results studies that have evaluated the relationship between anthropo- from this case patient–complete analysis were not appreciably metric factors and risk of developing a second breast cancer, different from those completed on the entire study population. further investigation is warranted. We examined the relation- Height and weight were evaluated as continuous variables. BMI ship between BMI, height, and weight and the risk of second was categorized as a continuous variable and as a categorical breast cancers in a large population-based study of women with variable using the modified Centers for Disease Control (CDC) a history of DCIS. The identification of potentially modifiable classification system (underweight and normal [<25 kg/m ], factors that impact this risk could guide and motivate changes 2 2 overweight [25 to 29.9 kg/m ], and obese [30 kg/m ]). Changes in health behaviors. in BMI and weight between the initial DCIS diagnosis and refer- ence date were also evaluated. Methods Statistical Analysis Study Population For the primary analysis, control patients were compared with We conducted a population-based nested case–control patient three case patient groups: any second breast event, invasive study from an underlying cohort of 4157 women age 30–79 years second breast event, in situ second breast event. Associations diagnosed with DCIS in the Seattle–Puget Sound region between between anthropometric factors and these outcomes were esti- January 1, 1996, and June 30, 2013 (Supplementary Figure 1, mated using conditional logistic regression given our use of a available online). Study participants were identified through the matched case–control patient design (31). Odds ratios (ORs) and Cancer Surveillance System, a cancer registry serving 13 coun- Wald-type 95% confidence intervals were calculated as esti- ties in western Washington State. Patients who underwent bi- mates of relative risks. Effect modification by menopausal sta- lateral mastectomy were excluded (29,30), as were women who tus at initial diagnosis, change in menopausal status between developed nonbreast cancers as treatment could impact the initial diagnosis and second breast event/reference date, and re- risk of a second breast cancer event. Cases were classified as ceipt of adjuvant endocrine therapy were assessed based on patients with a second invasive or in situ breast cancer event at likelihood ratio testing. Because there were no statistically sig- least six months following initial diagnosis. Of the 705 eligible nificant interactions with any of the main effects assessed at case patients, 497 were enrolled (70.5% response rate). Control the prespecified P value of less than .1, no effect modifiers were patients were those diagnosed with DCIS who did not have a included in the final models. second breast cancer event during the study period. Controls Associations between BMI at initial diagnosis with ipsilateral were individually matched to case patients on age and year of or contralateral second breast cancers were examined in a sec- initial diagnosis (þ/-2 years), county of residence, surgical and ondary analysis. One patient with bilateral second breast can- radiation treatment, histology, grade, and disease-free survival cers was excluded. For the analysis of ipsilateral events, time. All potentially eligible control patients who met matching patients who underwent a unilateral mastectomy for their ini- criteria for a given case patient were assigned a random number tial procedure were excluded. and placed in numerical order. Proceeding down the list, two to A sensitivity analysis was performed to assess for significant three control patients per case patient were contacted. Of the differences in risk estimates using data from medical record re- 1695 eligible matched control patients, 965 were enrolled (57% view and interview-based data for our primary exposures. Risk response rate). Written, informed consent was obtained from estimates changed less than 10% when analyses were restricted study participants, and the study was approved by the to participants with medical record data, and thus in our final Institutional Review Board at the Fred Hutchinson Cancer models we included all participants with available data, priori- Research Center. tizing medical record over interview data for anthropomorphic variables. All models were implicitly adjusted for the case/control Data Collection patient matching variables given our use of conditional logistic Patient demographic, epidemiologic, and clinical data were col- regression. Additionally, we adjusted for menopausal status at lected from structured telephone interviews and detailed medi- initial diagnosis and receipt of adjuvant endocrine therapy as cal record review. Tumor and treatment data were obtained via these have been shown to be potential confounders in previous medical records. Lifestyle factors such as tobacco and alcohol literature (25,26,32). The time period between initial diagnosis consumption, reproductive factors, menopausal status, and and second event (or reference date) varied among some case/ family history were obtained via interview. Data on weight were control patient pairs (case patients: median ¼ 61 months; con- collected at initial diagnosis and date of second breast cancer trol patients: median ¼ 58 months). Consequently, models for Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 M. R. Flanagan et al. | 3 of 8 Table 1. Patient, pathology, and treatment characteristics of women with and without a second breast cancer event after initial ductal carci- noma in situ diagnosis Any second Controls breast cancer Invasive* In situ† (n ¼ 862) (n ¼ 448) (n ¼ 303) (n ¼ 145) No. (%) No. (%) No. (%) No. (%) Patient demographics Age at initial diagnosis, y Median (IQR) 53 (47–61) 53 (47–61) 54 (47–63) 52 (47–59) 30–39 29 (3.4) 20 (4.5) 13 (4.3) 7 (4.8) 40–49 274 (31.8) 138 (30.8) 92 (30.4) 46 (31.7) 50–59 307 (35.6) 156 (34.8) 97 (32.0) 59 (40.7) 60–69 186 (21.6) 95 (21.2) 75 (24.8) 20 (13.8) 70þ 66 (7.7) 39 (8.7) 26 (8.6) 13 (9.0) Year of diagnosis 1995–2001 448 (52.0) 448 (52.0) 167 (55.1) 70 (48.3) 2002–2007 358 (41.5) 358 (41.5) 119 (39.3) 62 (42.8) 2008–2013 56 (6.5) 56 (6.5) 17 (5.6) 13 (9.0) Race/ethnicity Hispanic 15 (1.7) 11 (2.5) 8 (2.6) 3 (2.1) Non-Hispanic white 772 (89.6) 389 (86.8) 267 (88.1) 122 (84.1) Black 17 (2.0) 12 (2.7) 8 (2.6) 4 (2.8) Asian/Pacific Islander 45 (5.2) 26 (5.8) 12 (4.0) 14 (9.7) Native American 13 (1.5) 9 (2.0) 7 (2.3) 2 (1.4) Unknown 0 1 (0.2) 1 (0.3) 0 (0) First-degree family history No 620 (73.5) 300 (68.6) 202 (68.2) 98 (69.5) Yes 223 (26.5) 137 (31.4) 94 (31.8) 43 (30.5) Unknown 19 11 7 4 Reproductive characteristics No. of full-term pregnancies Nulliparous 179 (20.9) 101 (22.6) 66 (21.9) 35 (24.1) Parous 677 (79.1) 346 (77.4) 236 (78.1) 110 (75.9) Unknown 6 1 1 0 Age at first live birth‡, y <20 87 (10.5) 50 (14.9) 38 (16.5) 12 (11.4) 20–24 257 (30.9) 133 (39.6) 94 (40.7) 39 (37.1) 25–29 185 (22.2) 85 (25.3) 54 (23.4) 31 (29.5) 30–34 84 (10.1) 47 (24.0) 31 (13.4) 16 (15.2) 35 40 (4.8) 21 (6.3) 14 (6.1) 7 (6.1) Unknown 24 10 5 5 Menopausal status at initial DCIS diagnosis Pre- or perimenopausal 340 (40.8) 180 (41.3) 115 (39.1) 65 (45.8) Postmenopausal 493 (59.2) 256 (58.7) 179 (60.9) 77 (54.2) Unknown 29 12 9 3 Menopausal hormone replacement therapy Never 492 (57.4) 492 (57.4) 190 (63.1) 87 (60.0) Former (any type) 29 (3.4) 29 (3.4) 18 (6.0) 5 (3.4) Current estrogen only 182 (21.2) 182 (21.2) 56 (18.6) 29 (20.0) Current estrogen and progesterone 154 (18.0) 154 (18) 37 (12.3) 24 (16.6) Unknown 5 2 2 0 Tumor characteristics Histology of initial DCIS* Mixed 339 (39.3) 155 (34.6) 103 (34.0) 52 (35.9) NOS 210 (24.4) 88 (19.6) 63 (20.8) 25 (17.2) Comedo 104 (12.1) 67 (15.0) 47 (15.5) 20 (13.8) Cribriform 100 (11.6) 58 (12.9) 41 (13.5) 17 (11.7) Solid 73 (8.5) 55 (12.3) 35 (11.6) 20 (13.8) Other 36 (4.2) 25 (5.6) 14 (4.6) 11 (7.6) Grade of initial DCIS 1 20 (2.8) 20 (2.8) 13 (5.3) 4 (3.4) 2 210 (29.4) 210 (29.4) 63 (25.6) 30 (25.6) 3 223 (31.3) 223 (31.3) 70 (28.5) 41 (35.0) 4 259 (36.4) 259 (36.4) 100 (40.7) 42 (35.9) Unknown 150 85 57 28 (continued) Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 4of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 1. (continued) Any second Controls breast cancer Invasive* In situ† (n ¼ 862) (n ¼ 448) (n ¼ 303) (n ¼ 145) No. (%) No. (%) No. (%) No. (%) Size of initial DCIS, cm <2 541 (79.7) 541 (79.7) 197 (81.4) 83 (75.5) 2.1–5 116 (17.1) 116 (17.1) 32 (13.2) 20 (18.2) >5 22 (3.2) 22 (3.2) 13 (5.4) 7 (6.4) Unknown 183 96 61 35 Treatment characteristics Treatment for initial DCIS Biopsy only 7 (0.8) 6 (1.3) 4 (1.3) 2 (1.4) BCS with radiation 465 (53.9) 242 (54.0) 161 (53.1) 81 (55.9) BCS without radiation 203 (23.5) 105 (23.4) 79 (26.1) 26 (17.9) Mastectomy 187 (21.7) 95 (21.2) 59 (19.5) 36 (24.8) Adjuvant endocrine therapy No 542 (63) 321 (71.7) 218 (71.9) 103 (71) Yes 318 (37) 127 (28.3) 85 (28.1) 42 (29) Unknown 2 0 0 0 *Classified according to ICD-O-3 codes for invasive carcinomas: 8000/3, 8010/3, 8050/3, 8140/3, 8201/3, 8211/3, 8230/3, 8401/3, 8480/3, 8490/3, 8500/3, 8501/3, 8503/3, 8504/ 3, 8507/3, 8520/3, 8522/3, 8523/3, 8524/3, 8530/3, 8540/3, 8541/3, 8543/3, 8575/3. BCS ¼ breast conservation surgery; DCIS ¼ ductal carcinoma in situ; IQR ¼ interquartile range; NOS ¼ not otherwise specified. †Classified according to ICD-O-3 codes for subtypes of ductal carcinoma in situ: 8201/2, 8230/2, 8500/2, 8501/2, 8503/2, 8507/2, 8522/2, 8523/2. ‡Excludes nulliparous patients (n ¼ 280). change in BMI were adjusted for number of months between pronounced for invasive vs in situ second breast cancers; how- initial diagnosis and reference date. All other covariates in ever, the differences were not statistically significantly different Table 1 were assessed as potential confounders. None were (initial: P ¼ .61; second: P ¼ .38). Height was heterogeneity heterogeneity found to change odds ratios more than 10% for continuous or cat- not related to risk of second breast cancer. egorical weight, height, or BMI variables, so they were not added There were no statistically significant associations observed to the final multivariable models. To quantify the magnitude with gain or loss of BMI and second breast cancer event of the case patient–case differences, we calculated two-sided (Table 3). There was a suggestion of increased risk with BMI loss P values by excluding control patients and comparing of –3 kg/m or more for any, invasive, and in situ second breast heterogeneity different case patient groups. STATA/SE 12.1 (StataCorp LP, events, but this was not significant. College Station, TX) was used for all analyses. After exclusion of four unilateral mastectomy patients and one bilateral recurrence, there were 173 ipsilateral (39.0%) and 270 contralateral (60.8%) second breast cancers. Most ipsilat- Results eral (74.0%) and contralateral (63.3%) second breast events were invasive. There was no association between initial BMI Of the 448 case patients with a second breast cancer event, 303 and ipsilateral second breast cancer events among all women (67.6%) were invasive and 145 (32.4%) were in situ. The median (Table 4), or those with invasive second breast cancer events time between initial DCIS and second breast cancer event (data not shown). However, there was a 2.2-fold (95% CI ¼ 1.4 (range) was 68 (6–208) months for invasive and 49 (6–213) to 3.3) increased risk of a contralateral second breast cancer months for in situ events. Case and control patients groups associated with obese BMI at initial diagnosis, and there was had similar distributions of age, diagnosis year, race, parity, increased risk associated with both overweight and obese BMI and menopausal status (Table 1). Patients with invasive second at the second breast cancer event (overweight: OR ¼ 1.6, 95% CI breast cancer events were more likely to have used meno- ¼ 1.1 to 2.4;obese:OR ¼ 1.9, 95% CI ¼ 1.3 to 2.8). There was a pausal hormone therapy before initial diagnosis. Patients with statistically significantly elevated risk of a contralateral breast any or an invasive second breast cancer event were less likely cancer event associated with a decrease in BMI of 3 kg/m or to have received adjuvant endocrine therapy after their initial more (OR ¼ 2.0, 95% CI ¼ 1.1to 3.6), which was theonly statisti- diagnosis. cally significant risk difference between ipsilateral and contra- Body weight and BMI, both at the time of initial diagnosis lateral case patients (P ¼ .01). Among women with heterogeneity and at second diagnosis/reference date, were positively associ- invasive contralateral second breast cancer events, there was ated with risk of a second breast cancer event (odds ratio ¼ an approximately twofold increased risk associated with obe- 1.011.04, all P  .03) (Table 2). For each 1 mg/kg increase in sity at both the first and second events, as well as with a BMI BMI at initial DCIS diagnosis, there was a 3% increase in the loss of 3 kg/m or more (data not shown). odds of any second breast cancer event (OR ¼ 1.03, 95% confi- dence interval [CI] ¼ 1.01 to 1.05). Women who were obese at initial diagnosis had a 1.6-fold (95% CI ¼ 1.2 to 2.2) higher risk of Discussion developing a second breast cancer compared with women with a normal BMI. Similar odds were seen for BMI at second diagno- The population of women with a history of DCIS has grown as sis (OR ¼ 1.01 to 1.04, all P  .03). These risks were more incidence rates have risen steadily over the past several Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 M. R. Flanagan et al. | 5 of 8 Table 2. Risk of second breast cancer event in relation to anthropometric factors at initial ductal carcinoma in situ diagnosis and reference date Any second breast cancer* Invasive* In situ* Controls (n ¼ 448) (n ¼ 303) (n ¼ 145) (n ¼ 862) No. (%) No. (%) OR (95% CI) No. (%) OR (95% CI) No. (%) OR (95% CI) Initial diagnosis BMI, mean (SD), kg/m 26.1 (6.13) 27.1 (6.49) 1.03 (1.01 to 1.1)† 27.2 (6.41) 1.04 (1.01 to 1.1)† 26.8 (6.69) 1.01 (0.9 to 1.05) P (per 1 kg/m ) .007 .005 .491 trend BMI categories, kg/m <25.0 417 (48.4) 186 (41.5) 1.0 (ref) 124 (40.9) 1.0 (ref) 62 (42.8) 1.0 (ref) 25.0–29.9 255 (29.6) 133 (29.7) 1.2 (0.9 to 1.6) 89 (29.4) 1.3 (0.9 to 1.9) 44 (30.3) 0.9 (0.6 to 1.6) 30.0 190 (22.0) 129 (28.8) 1.6 (1.2 to 2.2)† 90 (29.7) 1.8 (1.2 to 2.6)† 39 (26.9) 1.3 (0.8 to 2.3) Height, mean (SD), cm 164 (6.8) 165 (6.8) 1.0 (0.9 to 1.03) 165 (6.8) 1.0 (0.9 to 1.04) 164 (7.0) 1.0 (0.9 to 1.1) P (per 1 cm) .123 .202 .389 trend Height, quartiles, m 130–160 278 (32.3) 139 (31) 1.0 (ref) 91 (30) 1.0 (ref) 48 (33.1) 1.0 (ref) 161–164 179 (20.8) 88 (19.6) 1.0 (0.7 to 1.4) 61 (20.1) 1.0 (0.7 to 1.5) 27 (18.6) 0.9 (0.5 to 1.7) 165–168 213 (24.7) 98 (21.9) 0.9 (0.7 to 1.3) 67 (22.1) 1.0 (0.6 to 1.5) 31 (21.4) 0.8 (0.5 to 1.5) 169–188 192 (22.3) 123 (27.5) 1.3 (0.9 to 1.9) 84 (27.7) 1.4 (0.9 to 2.1) 39 (26.9) 1.2 (0.7 to 2.2) Weight, mean (SD), kg 70.9 (16.7) 74.2 (18.2) 1.01 (1.00 to 1.02)† 74.5 (17.6) 1.01 (1.01 to 1.02)† 73.4 (19.5) 1.01 (0.99 to 1.02) P (per 1 kg) .002 .002 .349 trend Weight, quartiles, kg 37.2–59.9 231 (26.8) 96 (21.4) 1.0 (ref) 58 (19.1) 1.0 (ref) 38 (26.2) 1.0 (ref) 60.0–68.9 239 (27.7) 119 (26.6) 1.1 (0.8 to 1.6) 82 (27.1) 1.3 (0.9 to 2.0) 37 (25.5) 0.8 (0.5 to 1.4) 69.0–80.9 201 (23.3) 94 (21.0) 1.2 (0.8 to 1.7) 63 (20.8) 1.3 (0.8 to 2.1) 31 (21.4) 0.9 (0.5 to 1.8) 81.0–168.3 191 (22.2) 139 (31.0) 1.8 (1.3 to 2.6)† 100 (33.0) 2.2 (1.4 to 3.4)† 39 (26.9) 1.1 (0.6 to 2.1) Second breast event/reference date BMI, mean (SD), kg/m 26.5 (6.3) 27.4 (6.4) 1.03 (1.00 to 1.04)† 27.6 (6.3) 1.03 (1.01 to 1.06)† 27.1 (6.5) 1.01 (0.97 to 1.05) P (per 1 kg/m ) .028 .017 .698 trend BMI categories, kg/m <25.0 388 (45.0) 162 (36.2) 1.0 (ref) 106 (35.0) 1.0 (ref) 56 (38.6) 1.0 (ref) 25.0–29.9 263 (30.5) 154 (34.4) 1.4 (1.1 to 1.9)† 106 (35.0) 1.8 (1.3 to 2.7)† 48 (33.1) 0.9 (0.6 to 1.5) 30.0 211 (24.5) 132 (29.5) 1.5 (1.1 to 2.1)† 91 (30.0) 1.6 (1.1 to 2.3)† 41 (28.3) 1.3 (0.8 to 2.3) Weight, mean (SD), kg P (per 1 kg) 71.9 (17.5) 74.9 (17.8) 1.01 (1.00 to 1.02)† 75.4 (17.4) 1.01 (1.00 to 1.02)† 74.0 (18.7) 1.00 (0.90 to 1.02) trend Weight quartiles, kg .008 .006 .509 42.0–60.9 212 (24.6) 103 (23.0) 1.0 (ref) 63 (20.8) 1.0 (ref) 40 (27.6) 1.0 (ref) 61.0–69.0 248 (28.8) 87 (19.4) 0.7 (0.5 to 1.02) 57 (18.8) 0.8 (0.5 to 1.2) 30 (20.7) 0.6 (0.4 to 1.2) 69.1–81.9 211 (24.5) 126 (28.1) 1.3 (0.9 to 1.9) 93 (30.7) 1.7 (1.1 to 2.8)† 33 (22.8) 0.8 (0.4 to 1.4) 82.0–172.8 191 (22.2) 132 (29.5) 1.4 (0.9 to 2.0) 90 (29.7) 1.6 (1.04 to 2.6)† 42 (29.0) 1.1 (0.6 to 1.9) *Odds ratios and 95% confidence intervals were estimated using conditional logistic regression and were implicitly adjusted for matching variables (age and year of the initial DCIS diagnosis, county, histology, grade of initial DCIS lesion, surgical and radiation treatment, and survival time). All models were additionally adjusted for menopausal status at initial DCIS diagnosis and use of adjuvant endocrine therapy. BMI ¼ body mass index; CI ¼ confidence interval; OR ¼ odds ratio. †P < .05. decades. These women have an elevated risk of developing a increased risk of ipsilateral second breast cancer compared with subsequent breast cancer, but relatively little is known regard- women with a BMI of less than 22 kg/m . Kuerer et al. also com- ing how modifiable lifestyle factors influence this risk. Of partic- bined invasive and in situ events, but presented associations ular importance is obesity given the continued rise in obesity stratified by laterality. Consistent with our findings, but con- rates and previously established links between obesity and in- trasting those of Habel et al., they found no association with vasive breast cancer (20–24). Our results indicate that the rela- risk of an ipsilateral second breast cancer in a single-institution tionship between BMI and second primary breast events among cohort study (n ¼ 1885) with 40 ipsilateral events (25). A poten- DCIS survivors is complex, with variation across levels of BMI tial explanation for these differences is variation in DCIS treat- and possibly according to stage and laterality. ment. Receipt of radiation therapy is associated with decreased Few studies have evaluated the impact of anthropometric risk of ipsilateral second breast cancers (5). In the Kuerer et al. factors on second breast cancer events after DCIS, and they had study, 80% of patients received adjuvant radiation compared inconsistent results. In a population-based cohort study includ- with 55% in our study and 40% in Habel et al. Adjuvant tamoxi- ing 480 patients from 1980 to 1992, Habel et al. evaluated the fen therapy also decreases the risk of second breast cancer risk of invasive or in situ ipsilateral second breast cancers or events (17,33). This was used by approximately one-third of metastases among breast conservation patients (27). Based on patients in Kuerer et al. and our study but was not routinely 76 ipsilateral events, obesity was associated with a twofold used during the time frame of Habel et al. Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 6of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 3. Risk of second breast cancer event in relation to changes in body mass index and weight between initial ductal carcinoma in situ diag- nosis and reference date Any second breast cancer* Invasive* In situ* Controls (n ¼ 448) (n ¼ 303) (n ¼ 145) (n ¼ 862) No. (%) No. (%) OR (95% CI) No. (%) OR (95% CI) No. (%) OR (95% CI) Change in BMI, kg/m BMI loss 3 56 (6.5) 42 (9.4) 1.5 (0.95 to 2.4) 26 (8.6) 1.4 (0.8 to 2.5) 16 (11.0) 1.7 (0.8 to 3.8) BMI loss >1–<3 122 (14.2) 59 (13.2) 1.0 (0.6 to 1.4) 38 (12.5) 0.8 (0.5 to 1.4) 21 (14.5) 1.3 (0.6 to 2.5) BMI change þ/- 1 389 (45.1) 193 (43.1) 1.0 (ref) 124 (40.9) 1.0 (ref) 69 (47.6) 1.0 (ref) BMI gain >1–<3 203 (23.5) 103 (23.0) 1.0 (0.7 to 1.4) 80 (26.4) 1.1 (0.8 to 1.7) 23 (15.9) 0.7 (0.4 to 1.3) BMI gain 3 92 (10.7) 51 (11.4) 1.1 (0.7 to 1.6) 35 (11.6) 1.0 (0.6 to 1.7) 16 (11.0) 1.2 (0.5 to 2.5) P (2 kg/m ) .302 .572 .326 trend Change in weight, kg Loss 6 95 (11.0) 68 (15.2) 1.3 (0.9 to 2.0) 43 (14.2) 1.3 (0.8 to 2.1) 25 (17.2) 1.4 (0.7 to 2.8) Loss >2–5.9 146 (16.9) 67 (15.0) 0.9 (0.6 to 1.3) 47 (15.5) 0.9 (0.5 to 1.4) 20 (13.8) 0.9 (0.5 to 1.9) Gain or loss within 2 242 (28.1) 120 (26.8) 1.0 (ref) 79 (26.1) 1.0 (ref) 41 (28.3) 1.0 (ref) Gain >2–5.9 236 (27.4) 111 (24.8) 0.9 (0.6 to 1.2) 75 (24.8) 1.0 (0.6 to 1.5) 36 (24.8) 0.7 (0.4 to 1.3) Gain 6 143 (16.6) 82 (18.3) 1.0 (0.7 to 1.5) 59 (19.5) 1.1 (0.7 to 1.8) 23 (15.9) 0.8 (0.4 to 1.7) P (2 kg) .321 .477 .481 trend *Odds ratios and 95% confidence intervals were estimated using conditional logistic regression and were implicitly adjusted for matching variables (age and year of the initial ductal carcinoma in situ [DCIS] diagnosis, county, histology, grade of initial DCIS lesion, surgical and radiation treatment, and survival time). All models were additionally adjusted for menopausal status at initial DCIS diagnosis and use of adjuvant endocrine therapy. BMI ¼ body mass index; CI ¼ confidence interval; OR ¼ odds ratio. Table 4. Relationship of second breast cancer laterality and body mass index at initial ductal carcinoma in situ diagnosis, second breast can- cer/reference date, and change in BMI Ipsilateral* Contralateral Controls Cases Controls Cases (n ¼ 336) (n ¼ 173) (n ¼ 513) (n ¼ 270) No. (%) OR† (95% CI) No. (%) No. (%) OR† (95% CI) Initial diagnosis BMI categories, kg/m <25.0 165 (49.1) 77 (44.5) 1.0 (ref) 246 (48.0) 106 (39.3) 1.0 (ref) 25.0–29.9 93 (27.7) 52 (30.1) 1.2 (0.7 to 1.9) 158 (30.8) 79 (29.3) 1.2 (0.8 to 1.8) 30.0 78 (23.2) 44 (25.4) 1.1 (0.7 to 1.8) 109 (21.2) 85 (31.5) 2.2 (1.4 to 3.3)‡ P (per 1 kg/m ) .466 .008 trend Second breast event/reference date BMI categories, kg/m <25.0 146 (43.5) 66 (38.2) 1.0 (ref) 237 (46.2) 94 (34.8) 1.0 (ref) 25.0–29.9 100 (29.8) 57 (32.9) 1.6 (0.9 to 2.8) 157 (30.6) 94 (34.8) 1.6 (1.1 to 2.4)‡ 30.0 90 (26.8) 50 (28.9) 1.1 (0.6 to 2.1) 119 (23.2) 82 (30.4) 1.9 (1.3 to 2.8)‡ P (per 1 kg/m ) .572 .027 trend Change in exposure status Change in BMI, kg/m BMI loss 3 24 (7.1) 9 (5.2) 0.8 (0.4 to 1.9) 32 (6.2) 33 (12.2) 2.0 (1.1 to 3.6)‡ BMI loss >1–<3 44 (13.1) 24 (13.9) 1.1 (0.6 to 2.1) 76 (14.8) 34 (12.6) 0.8 (0.5 to 1.4) BMI change þ/- 1 145 (43.2) 74 (42.8) 1.0 (ref) 237 (46.2) 117 (43.3) 1.0 (ref) BMI gain >1–<3 83 (24.7) 41 (23.7) 1.0 (0.6 to 1.7) 117 (22.8) 61 (22.6) 1.0 (0.7 to 1.6) BMI gain 3 40 (11.9) 25 (14.5) 1.3 (0.7 to 2.4) 51 (9.9) 25 (9.3) 0.9 (0.5 to 1.6) P (2 kg/m ) .991 .198 trend *Excludes patients with previous unilateral mastectomy. BMI ¼ body mass index; CI ¼ confidence interval; OR ¼ odds ratio. †Odds ratios and 95% confidence intervals were estimated using conditional logistic regression and were implicitly adjusted for matching variables (age and year of the initial ductal carcinoma in situ [DCIS] diagnosis, county, histology, grade of initial DCIS lesion, surgical and radiation treatment, and survival time). All models were additionally adjusted for menopausal status at initial DCIS diagnosis and use of adjuvant endocrine therapy. ‡P < .05. Although Kuerer et al. found no statistically significant dif- cancers associated with overweight/obesity among women who ferences in the risk of ipsilateral second breast events according did not receive adjuvant tamoxifen therapy. No multivariable to BMI, a univariate analysis of their data revealed a borderline analysis was presented. In our analysis adjusted for adjuvant significantly (P ¼ .06) elevated risk of contralateral second breast endocrine therapy, there were no statistically significant Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky020/5025851 by Ed 'DeepDyve' Gillespie user on 21 June 2018 M. R. Flanagan et al. | 7 of 8 differences in risk of ipsilateral or contralateral second breast largely abstracted from medical records and not subject to recall cancers; however, there was a suggestion of increased contra- bias. For those patients missing BMI data, there may be bias lateral risk associated with obesity at both initial and second di- that we cannot account for in our models. There was no differ- agnosis. Both studies were likely underpowered to detect ence with respect to patient demographic, lifestyle, and tumor statistically significant associations, and further studies with characteristics compared with patients without missing data, longer follow-up and larger numbers of contralateral breast and the degree and direction of bias are unknown. An additional cancers are needed to confirm our finding of a possible associa- limitation is lack of data on other modifiable risk factors, partic- tion between obesity and contralateral breast cancer risk. ularly physical activity. However, data on this subject in DCIS McLaughlin et al. conducted the largest examination of BMI are lacking. However, data from a large meta-analysis including and second breast cancer events in a DCIS population (n ¼ 11 cohort and eight case–control patient studies found no differ- 1925). In contrast to our study, they did not observe increased ential effects of physical activity on invasive breast cancer risk risk of second breast cancer events associated with increasing according to BMI (47). Therefore, we would not expect physical BMI before initial diagnosis (HR ¼ 0.99, 95% CI ¼ 0.96 to 1.02) or activity to significantly confound or modify our findings. between initial and subsequent diagnosis (HR ¼ 1.03, 95% CI ¼ Participation bias is another potential concern, but we did 0.97 to 1.10) in the overall cohort. However, they found that achieve reasonable response rates for a study of this type, menopausal status at initial diagnosis modified the effect of which limits the impact of this bias. During the time frame in- obesity on the risk of second breast cancer events (26). cluding many of the initial DCIS diagnoses, hormone receptors Premenopausal women who were obese at diagnosis were 77% were not routinely tested. Therefore, there is a substantial less likely to develop any second breast cancer compared with amount of missing data for this variable, and we were unable to normal and underweight women, whereas a non-statistically include this as a matching variable, effect modifier, or con- significant trend toward increased risk associated with over- founder. Finally, although our results suggest that there may be weight and obesity was seen in postmenopausal women. We increased risk of invasive and contralateral second breast can- did not find evidence of effect modification according to meno- cer events associated with increasing BMI, the study lacked pausal status in our study, but in their analysis of premeno- power to show significant heterogeneity. Larger studies are pausal women, there were only four obese patients with second needed to confirm our findings. breast cancer events (compared with 39 in our study), limiting Few studies have evaluated the influence of potentially the statistical power and generalizability of their findings. modifiable lifestyle factors on the risk of subsequent breast can- One finding unique to our study was the increased risk of a cers among women with DCIS. Second breast cancers are an im- contralateral second breast cancer event associated with a sub- portant outcome for this population, as women with DCIS have stantial loss of BMI after initial diagnosis, but no increased risk a two to four times greater risk of developing a second breast associated with weight gain. McLaughlin et al. evaluated change cancer than women in the general population have of develop- in weight, and also did not observe an association between ing a first breast cancer. Additionally, a second invasive event is weight gain and risk of second breast cancer events (26). In con- associated with a 1.75-fold increased mortality risk (12). Our trast to our study, they also found no association with loss of findings suggest that obesity is positively related to second BMI. Although there is a dearth of information about weight breast cancer events, and possibly more strongly with invasive change after DCIS, a number of studies have investigated this and contralateral second cancers. Efforts to maintain a normal relationship after an invasive cancer diagnosis (34–43). These weight have well-known health benefits for a variety of dis- studies have shown conflicting results, with several reporting eases, and this may also extend to lowering risk of a second an increased risk of second breast cancers associated with breast cancer among women diagnosed with DCIS. Further re- weight gain (37,41), others demonstrating no association (35), search is needed on the types of exercise/dietary interventions and another offering evidence of a relationship between sub- that could be effective among DCIS survivors. stantial weight loss and increased risk of second breast cancer (43). Mechanisms explaining associations between weight loss Funding and second breast cancers are lacking but may involve compro- mised tumor–immune system interactions accompanying MRF was supported by T32 grant support from the National chronic undernutrition (44) or dysfunctional mammary adipo- Institutes of Health under award number CA009168. The cytes (45,46). Whether our results suggest that avoidance of ma- content is solely the responsibility of the authors and does jor weight loss subsequent to a DCIS diagnosis may be an not necessarily represent the official views of the National additional approach to reduce the risk of second breast cancer Institutes of Health. events or if this is merely a reflection of cachexia associated with a second breast cancer event is unclear and requires addi- tional study. Notes One of the strengths of our study is its population-based nested case–control patient design, which is well suited to Affiliations of authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (MRF, MTCT, studying rare diseases such as second cancer events that re- quire many years of follow-up for detection. 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