INTERACTIONS OF FAMILY HISTORY OF BREAST CANCER WITH RADIOTHERAPY IN RELATION TO THE RISK OF BREAST CANCER RECURRENCE IN A POPULATION BASED BREAST CANCER REGISTRY By DANMENG LI A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2016
2016 Danmeng Li
4 ACKNOWLEDGMENTS Foremost, I would like to express my sincere gratitude to my advisor Professor Lusine Yaghjyan for the continuous support of my study and research, for her patience, motivation, enthusiasm, and immense knowledge. Her guidance helped me in all the time of research and writing of this thesis. I could not have imagined having a better advisor and mentor for my master study. Besides my advisor, I would like to thank the rest of my thesis committee: Professor Volker Mai and Professor Travis Gerke, for their encouragement, insightful comments, and hard questions. I would like to acknowledge The B reast Cancer Registry of Greater Cincinnati (BCRGC), which is supported by funding from NIEHS (P30 ES006096). We thank the many members of the BCRGC for providing t he data used in this analysis. Last but not the least, I would like to thank my family: my husband Peng Shi and my parents Weigang Li and Jinxia Wang, for their love and support throughout my life
5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 6 LIST OF FIGURES ................................ ................................ ................................ .......... 7 ABSTRACT ................................ ................................ ................................ ..................... 8 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 10 2 PATIENTS AND METHODS ................................ ................................ ................... 12 Study Population and Data Collection ................................ ................................ .... 12 Radiotherapy and Family History ................................ ................................ ............ 13 Covariates ................................ ................................ ................................ ............... 13 Statistical Analysis ................................ ................................ ................................ .. 14 3 RESULTS ................................ ................................ ................................ ............... 17 4 DISCUSSION ................................ ................................ ................................ ......... 23 LIST OF REFERENC ES ................................ ................................ ............................... 29 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 34
6 LIST OF TABLES Table page 3 1 Characteristics of study participants by radiotherapy status and breast cancer recurrence ................................ ................................ ................................ .......... 19 3 2 HRs for recurrence according to family history by radiotherapy status ............ 22 4 1 Summary of previous studies on the association between a family history of breast cancer and the risk of breast cancer recurrence ................................ ...... 27
7 LIST OF FIGURES Figure page 2 1 Subject selection diagram ................................ ................................ .................. 16 3 1 Cumulative survival in relation to the total number of relatives with breast cancer, by the status of radiotherapy ................................ ................................ .. 22
8 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science INTERACTIONS OF FAMILY HISTORY OF BREAST CANCER WITH RADIOTHERAPY IN RELATION TO THE RISK OF BREAST CANCER RECURRENCE IN A POPULATION BASED BREAST CANCER REGISTRY By Danmeng Li May 2016 Chair : Lusine Yaghjyan Major : Epidemiology Radiation therapy is a common therapeutic approach for breast cancer that reduces the risk of breast cancer recurrence. However, ionizing radiation is a known breast cancer risk factor. Individuals with a family history of breast cancer could represent individuals with impaired DNA repair capacity who are more susceptible to the effects of radiation. Whether a family history of breast cancer differentially affects the risk of breast cancer recurrence in women with and without radiotherapy is poorly understood. We examined the int eraction between radiotherapy and a family history of breast cancer in relation to the risk of breast cancer recurrence Participants (n=2,440) were selected from women enrolled in the Breast Cancer Registry of Greater Cincinnati (BCRGC), an established po pulation based breast cancer registry with more than 15 years of follow up. Information on breast cancer risk factors, including a detailed family history of breast cancer, characteristics of the primary breast cancer diagnosis, treatment history, and recu rrence status were collected at baseline and via updates thereafter. Associations of the family history of breast cancer with the risk of breast cancer recurrence were examined separately in women with and without
9 radiotherapy using survival analysis, whil e adjusting for age and body mass index at diagnosis and a history of breast surgery. A ssociations were assessed for the family history of breast cancer in the first degree relatives and in all relatives combined. Over an average follow up time of 8.78 ye ars in this study population, no associations were found between the family history of breast cancer and the risk of breast cancer recurrence among women with a history of radiotherapy (Hazard Ratio [HR]=0.96, 95% CI 0.75 1.23). Among women without a histo ry of radiotherapy, the total number of relatives with breast cancer was positively associated with breast cancer recurrence risk (HR=1.21, 95% CI 1.00 1.47). A formal test of the interaction effect in multivariable survival models did not reach significan ce for any of the family history variables (p interaction >0.05 for all). The findings of this study do not support a hypothesis that radiotherapy for a primary breast cancer in women with a family history of breast cancer increases the risk of breast can cer recurrence. However, given a significant association of the family history with the recurrence risk in women without radiotherapy, future studies are warranted to explore possible reasons for these association patterns.
10 CHAPTER 1 INTRODUCTION A family history of breast cancer is a well established, strong risk factor for breast cancer [1 6] Some previous studies suggested that the family history of breast cancer also increases the risk of breast cancer recurrence and the risk of the second primary breast cancer [7 10] Previous studies report a 1.62 4.5 times increase in the risk of breast cancer recurrence in women with a family history of breast cancer [11 12 ] Other studies further focused on the relationship b etween genetic mutations contributing to the familial breast cancer and the risk of breast cancer recurrence [8, 13] A majority of these studies investigated the associations of mutations in BRCA 1 and BRCA 2 genes with breast cancer risk as well as the r isk of breast cancer recurrence [14 18] However, mutations in BRCA1 and BRCA2 are found only in about 25% of all breast cancer patients with a family history, suggesting that other genetic factors may contribute to the family history of breast cancer [8, 19] Among these factors, other DNA repair genes have received increasing attention  Impaired DNA repair capacity in individuals with selected genetic variations in DNA repair genes could result in slower rates of DNA damage repair caused by endogenou s and exogenous influences, thus increasing cancer risk [21 24] Among environmental risk factors inducing DNA damage, ionizing radiation has been long recognized as a breast cancer risk factor [25 28] Findings from studies in atomic bomb survivors indica ted a significant linear association between radiation dose and breast cancer risk [25, 26] Consistent results were reported by other studies [29 31] Moreover, some studies suggested that the association between ionizing radiation and breast cancer risk is stronger in women with a family history of breast cancer as
11 compared to women without a family history [32, 33] On the other hand, because of the sensitivity of malignant breast tissue to the effects of ionizing radiation, radiation has been widely use d for treatment of patients with breast cancer [18 34 ] However, some concerns were raised regarding the potential damaging effects of radiation therapy on the surrounding normal tissue and the tissue in unaffected breast. Recognizing this concern, a few s tudies investigated the association of radiation therapy with the risk of recurrence and the risk of contralateral breast cancer. Some of these studies found significant positive associations of radiotherapy with the risk of contralateral breast cancer [35 36] Further, a few reports suggested that radiotherapy could increase the risk of tumor initiation in patients with a family history of breast cancer [17, 37] The results of the previous studies on the association between radiotherapy and breast cance r risk among individuals with a family history of breast cancer are inconsistent. A retrospective study in 247 breast cancer patients showed that breast cancer patients with BRCA1/2 or CHEK2 mutation were more likely to develop contralateral breast cancer after radiotherapy as compared to non carriers  while another study found no difference in the risk of breast cancer recurrence after receiving radiotherapy in women with and without a family history  The purpose of the current study was to exam ine the association between a family history of breast cancer and the risk of breast cancer recurrence in women with and without radiation therapy in a large population based breast cancer registry.
12 CHAPTER 2 PATIENTS AND METHODS Study Population and Dat a Collection The Breast Cancer Registry of Greater Cincinnati (BCRGC), which was established by the University of Cincinnati, Department of Environmental Health in 2003, aimed to collect information on breast cancer cases in the Greater Cincinnati area and explore the risk factors for breast cancer in this population. M en and women living in the Greater Cincinnati area and diagnosed with breast cancer were recruited through the local oncology practices, media, and community outreach events. Demographic info rmation, clinical characteristics of the tumor, treatment information, reproductive history and detailed family history of cancer were collected via the baseline self administered questionnaire. The data on recurrence of the tumor and updated information on breast cancer risk factors were collected in 2006, 2011 and 2013. Out of the 5,725 women in the BCRGC, we excluded women with missing diagnosis data ( n =125) and prior history of breast cancer recurrence at enrollment or missing recurrence date at the ba seline ( n =618) To be eligible for the study, women were required to have at least one update completed during the follow up and to know the history of their biological family (n= 2,503). We further excluded women with missing radiotherapy history informati on ( n =63). The final study sample included 2,440 women (42.62% of all participants in BCRGC) of which 1,486 had a history of radiotherapy and 954 women did not receive radiotherapy (Figure 2 1). This study was approved by the University of Florida and Uni versity of Cincinnati IRB s
13 Radiotherapy and Family History Information about radiation therapy for the initial breast cancer diagnosis was collected at baseline. Detailed information on the family history of breast cancer in the first (mother, sister and daughter) and second degree relatives (paternal and maternal grandmothers and aunts) was collected at baseline and updated at each follow up cycle. For these analyses, the family history of breast cancer was defined in sev eral ways: (1) having any first d egree relative with breast cancer diagnosis (any or n one); (2) total number of first degree relatives with breast cancer; (3) total number of relatives with breast cancer; and (4) a total family history score which was calculated as the sum of the number o f first degree relative with breast cancer a nd second degree relatives with breast cancer multiplied by 0.5. Covariates Several patient characteristics were considered as potential confounders including age (years) and BMI(kg/m 2 ) at the time of diagnosis, menopausal status and postmenopausal hormone use (premenopausal, postmenopausal and never used hormones, postmenopausal with hormone use history, and postmenopausal with unknown hormone use status), receptor status ( positive or negative for each of the est rogen, progesterone and human epidermal growth factor receptor 2), history of benign breast biopsies (yes/no), parity and the age at first birth (nulliparous, any years), a history of surgery (yes/no), chemotherapy (yes/no), or adjuvant therapy (yes/no), nodal involvement (positive/negative), a history of alcohol consumption (any/none), and smoking (yes/no). The missing indicator method was used for covariates with missingness in the survival analysis
14 Statistical Analysis Distribution s of baseline characteristics in women with and without a history of radiotherapy were compared using t test (for continuous variables) and Chi square (for categorical variables). Cox proportional hazards models with time since diagnosis in months as the underlying time variable were used to calculate hazards ratios (HRs) and the corresponding 95% c onfidence i ntervals (95% CI) The primary endpoint, breast cancer recurrence, was defined as an episode of recurrence self reported on any of the update questionnaires For individuals with breast cancer recurrence, follow up begins at the time of the breast cancer diagnosis and ends at the date of breast cancer recurrence. If the exact date o f recurrence was not specified, the mid point between the previous contact and the date of the update when the recurrence was reported was used as the estimated date of recurrence (n=16). For women without breast cancer recurrence, the follow up begins at the time of diagnosis and ends at the time of the last contact or the end of the study (December 31, 2014), whichever occurred first. The survival analysis was stratified by the history of radiotherapy. We used multivaria ble model s to adjust for potential confounders As age and BMI have shown significant associations with breast cancer free survival in the previous studies [ 7 39] both of these variables were forced into the survival models. The best fitting model was selected using step wise model select ion approach and only covariates that met statistical significance at 0.05 level were kept in the final models The survival models were run separately in women with and without radiation therapy. Proportional hazards assumption was tested for the surviv al models within each of the radiotherapy strata. In the models for women without radiotherapy, the test was significant for the total number of first degree relatives with breast cancer (p=0.030), the
15 total number of relatives with breast cancer (p=0.021) and the total Score (p=0.023) among the non radiotherapy group. Plots of scaled Schoenfeld residuals were not perfectly flat, but substantial time trends were not observed and the results were likely influenced by a small number of outliers. We further p erformed Supremu m tests for proportional hazards assumptions and the results were not significant, suggesting no assumption violations. Hence, we proceeded with the Cox proportional hazards models for the survival analysis. The differences in the associati ons of each of the family history variables with the risk of breast cancer recurrence in women with and without radiotherapy were tested by including an interaction term in the survival model for the entire study sample. All the tests were two sided and si gnificance of the effects was assessed at 0.05 level. All analyses were preformed using SAS statistical software (SAS institute Inc., Version 9.4).
16 Fi gure 2 1. Subject selection diagram Missing breast cancer diagnosis date N=125 Breast cancer recurrence reported at enrollment or missing recurrence date N=618 No updates since enrollment N=2,230 Unknown biological family history N=55 All women in the registry N=5,725 Women with known diagnosis date N=5,600 Women who did not have BC recurrence at the time of enrollment N=4,788 Women who completed at least one update since enrollment N= 2,558 Women with known biological family history N=2,503 Missing radiotherapy data N=63 Women who received radiotherapy N=1,486 Women who did not received radiotherapy N=954
17 CHAPTER 3 RESULTS This study included 2,440 women with breast cancer. The average follow up time was 8.78 years with the average of 8.42 years for women with radiotherapy (range 0.33 48.86) and 9.51 years for women without radiotherapy (range 0.17 46.95). During the follow up, there were 109 reported recurrence s ( 69 in women with radiotherapy and 40 in women wi thout radiotherapy ) The distribution of selected characteristics among study participants by the status of radiotherapy and recurrence are presented in the Table 3 1. Compared to the participants without radiotherapy cases who received radiotherapy were older (55.94 vs. 54.11 years, p<0.001), had shorter follow up period (83.04 vs. 101.90 months, p=0.006), had greater BMI (27.36 vs. 26.30, p<0.001) at the time of breast cancer diagnosis, were less likely to have any first degree relative with breast cance r (24.24% vs. 26.81%, p=0.025) or total number of relatives with breast cancer (0.27 vs. 0.32, p=0.003), and were less likely to have a history of chemotherapy (51.48% vs.61.74%, p<0.001). There was also a significant difference menopausal statu s and postmenopausal hormone use between the two groups (p<0.001) ; w omen who received radiotherapy were more likely to be postmenopausal and to have a history of postmenopausal hormone use. Among participants with a history of radiotherapy, women with a re currence were more likely to have greater BMI (29.8 vs. 27.24, p=0.002) less likely to have a history of adjuvant therapy (53.12% vs. 72.12%, p=0.002) and less likely to have estrogen receptor negative or progesterone receptor negative tumors (65.31% vs. 83.00%, p=0.002 and 33.33% vs. 57.77%, p=0.019, respectively). The distribution of other demographic characteristics treatment history, and tumor characteristics were similar in women with and without a recurren ce
18 in this stratum. Among women with no his tory of radiotherapy, those with recurrence were less likely to have a history of alcohol consumption (52.63% vs.68.05%, p=0.005), and more likely to be nulliparous (25% vs. 13.46%, p=0.018) and smoking (48.72% vs. 42.00% p=0.041) (Table 3 1). Table 3 2 s ummarizes the results of survival analysis in women with and without a history of radiotherapy. Among women with a history of radiotherapy, breast cancer recurrence was not associated with any of the variables for the family history after adjustment for ag e and BMI at diagnosis and a history of surgery (any first degree relative with breast cancer: HR=0.98, 95% CI 0.58 1.68; total first degree relatives with breast cancer: HR=0.89, 95% CI 0.57 1.39; total number of relatives with breast cancer: HR=0.96, 95% CI 0.75 1.23; total family history score: HR=0.92, 95% CI 0.65 1.32.) Among women without a history of radiotherapy, the total number of relatives with breast cancer was positively associated with breast cancer recurrence with approximately 21% increase i n the risk of recurrence per any additional family member with breast cancer (HR= 1.21, 95% CI 1.00 1.47). Corresponding Kaplan Merier survival curves for breast cancer specific survival in relation to total number of relatives who had breast cancer histor y in women with and without radiotherapy are shown in the Figure 3 1. None of the other family history variables were associated with the risk of breast cancer recurrence in women without radiotherapy. There were no interactions of any of the family history variables with radiotherapy (p interaction for all>0.05).The results were similar when we incorporated interaction terms for radiotherapy with each of the covariates in the full model.
19 Table 3 1. Characteristics of study participants by radiotherap y status and breast cancer recurrence Characteristic Women with Radiotherapy (n=1,486) Women without Radiotherapy (n=954) All Recurrence (n=69) No recurrence (n=1417) All Recurrence (n=40) No recurrence (n=914) Mean (Standard Deviation) Age at diagnosis, years 55.94(10.94) 53.97(11.05) 56.03(10.93) 54.11(11.49) 52.56(13.74) 54.17(11.39) Length of follow up, months 100.98(70.48) 83.04(52.41) 101.85 (71.14) 114.07(83.40) 101.40(88.77) 114.37 (83.17) Body Mass Index at diagnosis, kg/m 2 27.36(6.31) 29.80(6.73) 27.24(6.27) 26.30(5.56) 26.82(5.83) 26.28(5.56) Age at menarche, years 12.57(3.53) 12.35(1.25) 12.58(3.60) 12.57(1.50) 12.55(1.48) 12.57(1.50) Age at natural menopause, years 47.14(7.29) 48.35(8.62) 47.09(7.22) 46.81(7.20) 46.97(7.79) 46.80(7.19) Total number of first degree relative s with breast cancer 0.27 (0.53) 0.29(0.49) 0.27(0.54) 0.32(0.59) 0.40(0.84) 0.32(0.57) Total number of relative s with breast cancer 0.65(0.93) 0.72(0.87) 0.65(0.94) 0.78(1.11) 1.15(0.66) 0.77(1.08) Total family history score 0.46(0.67) 0.51(0.61) 0.46(0.68) 0.55(0.77) 0.78(1.12) 0.54(0.76) Number (%) Race/ethnicity Caucasian 1322(88.96) 64(92.75) 1258(88.78) 829(86.90) 33(82.50) 796(87.09) African American 44(2.96) 1(1.45) 43(3.03) 36(3.77) 1(2.50) 35(3.83) Other race 120(8.08) 4(5.80) 116(8.19) 89(9.33) 6(15.00) 83(9.08) Benign breast biopsies (yes) 393(27.07) 19(28.36) 374(27.00) 269(29.05) 7(18.42) 262(29.50) Alcohol use (ever) 1019(69.94) 49(74.24) 970(69.73) 627(67.42) 20(52.63) 607(68.05) Smoking status (ever) 648(44.32) 33(48.53) 615(44.12) 397(42.28) 19(48.72) 378(42.00) Any first degree relative with breast cancer(yes) 342(23.01) 19(27.54) 323(22.79) 256(26.83) 11(27.50) 245(26.81)
20 Table 3 1. Continued Characteristic Women with Radiotherapy (n=1,486) Women without Radiotherapy (n=954) All Recurrence (n=69) No recurrence (n=1417) All Recurrence (n=40) No recurrence (n=914) Parity and age at first Nulliparous 234(15.75) 12(17.39) 222(15.67) 133(13.94) 10(25.00) 123(13.46) Any children with age at first birth <25 years 703(47.31) 31(44.93) 672(47.42) 451(47.27) 22(55.00) 429(46.94) Any children with age at 549(36.94) 26(37.68) 523(36.91) 370(38.78) 8(20.00) 362(39.61) Menopausal status/PMH history Premenopausal 112(7.54) 10(14.49) 102(7.20) 135(14.15) 6(15.00) 129(14.11) Postmenopausal, never used hormones 696(46.84) 33(47.83) 663(46.79) 459(48.11) 19(47.50) 440(48.14) Postmenopausal, with hormone use history 639(43.00) 24(34.78) 615(43.70) 338(35.43) 13(32.50) 325(35.56) Postmenopausal, unknown hormone use status 32(2.15) 2(2.90) 30(2.12) 18(1.89) 2(5.00) 16(1.75) Breast cancer diagnosis related Breast surgery (yes) 1399(94.34) 63(91.30) 1336(94.48) 886 (93.17) 37(92.50) 849(93.19) Chemotherapy (yes) 764(51.48) 39(56.52) 725(51.24) 589(61.74) 28(70.00) 561(61.38) Adjuvant therapy (yes) 1059(71.27) 37(53.62) 1022(72.12) 564(59.12) 23(57.50) 541(59.19)
21 Table 3 1. Continued Abbreviations: PMH postmenopausal hormone use Percentages calculated for women with non missing data on receptor status Characteristic Women with Radiotherapy (n=1,486) Women without Radiotherapy (n=954) All Recurrence (n=69) No recurrence (n=1417) All Recurrence (n=40) No recurrence (n=914) Nodal involvement (positive) 967(65.07) 49(71.01) 918(64.78) 592(62.05) 19(47.50) 573(62.69) Estrogen receptor status (positive) 828(82.14) 32(65.31) 796(83.00) 487(75.50) 17(62.96) 470(76.05) Progesterone receptor status (positive) 257(56.48) 8(33.33) 249(57.77) 168(51.38) 10(52.63) 158(51.30) HER2 receptor status (positive) 47(29.01) 0(0.00) 47(29.56) 49(35.00) 0(0.00) 49(36.03)
22 Table 3 2. HRs for recurrence according to family history by radiotherapy status Family H istory V ariables Women with radiotherapy Women without radiotherapy Any first degree relative with breast cancer 0.98 (0. 58 1.68 ) 0. 86 (0.4 2 1. 73 ) Total first degree relative(s) with breast cancer 0.89 (0. 57 1. 39 ) 1. 05 (0.6 6 1. 68 ) Total number of relative(s) with breast cancer 0.9 6 (0.7 5 1.2 3 ) 1.2 1 (1.00, 1.4 7 ) Total family history score 0.92(0.6 5 1.3 2 ) 1.2 6 (0.9 2 1.7 3 ) Adjusted for age and b ody mass index at diagnosis and a history of surgery Figure 3 1. Cumulative survival in relation to the total number of relatives with breast cancer, by the status of radiotherapy
23 CHAPTER 4 DISCUSSION Using data from a population based prospective breast cancer registry, we examined the interactions between radiotherapy and a family history of breast cancer in relation to the risk of breast cancer recurrence Our finding s suggest that there is no difference in the associations of the family history of breast canc er with the risk of breast cancer recurrence by the status of radiotherapy. Consistent with previous reports, we found no association of the family history of breast cancer with the risk of breast cancer recurrence among women receiving radiotherapy. Chab ner et al examined the association of a family history of breast cancer in the first degree relatives with the risk of the local recurrence in women receiving radiotherapy [ 38 ] In this cohort study of 201 women diagnosed with stage I or II invasive breas t cancer, no difference was found between patients with or without positive family history of breast cancer in regard to the risk of recurrence We found a significant association of the total number of relatives with breast cancer with the risk of breast cancer recurrence among women who did not receive radiotherapy. The results of the previous studies on the family history of breast cancer and the risk of recurrence are inconsistent. Table 4 1 summarizes the results of the previous studies on the associat ion between a family history of breast cancer and the risk of breast cancer recurrence. Four studies have found significant positive associations. A retrospective study by Turkoz, et al. reported an increased recurrence risk among family history positive breast cancer cases with young age or triple negative breast cancer (HR=1.62 and 1.82, respectively)  Similarly, Jobsen et al. found a positive association between a family history of breast cancer and the risk of local
24 recurrence among young breast c 40 y ears old)  Some studies included both breast cancer and/or ovarian cancer (BOC) in the definition of family history of breast cancer. A case control study conducted in China suggested a significantly higher risk of recurrence i n breast cancer patients with a family history of BOC (P=0.04)  However, three cohort studies found no association between family history of BOC and the risk of breast cancer recurrence [43 45] Eccles, et al. only reported a non significant trend tow ards higher breast cancer recurrence risk among patients with family history of breast cancer compared to those without a family history  In a previous case control study by Harold et al. [47 ] 52 women with local breast cancer recurrence after lumpectomy and radiotherapy were compared to 52 matched controls who remained cancer free. The study found no associations of the family history of breast cancer with the recurrence risk. Our study utilized an established population based cohort with more than 15 years of follow up. Information on breast cancer risk factors, tumor characteristics, treatment history, and breast cancer recurrence status was self reported. Previous studies suggest a high accurac y of self reported cancer history [ 48 50 ] The prospective data collection also minimizes the possibility of misclassification Our study population appears to be representative of breast cancer cases reported by SEER registries in terms of the distributio ns of the receptor statuses [ 51,52 ] However, the Registry did not collect the information on breast cancer stage and tumor size. As treatment regimens are based on these tumor features and as we examined the effect of the treatment history in our analysis (surgery, adjuvant therapy and chemotherapy) it is very unlikely that the absence of the information on tumor stage influences our findings. Unlike
25 previous studies, we defined a family history of breast cancer using various approaches which allowed us t o examine separately the effects of the family history in first degree relatives, a family h istory in both first and second degree relatives as well as a total score that accounts for the nature of these familial relationships. It is possible, however, tha t some of the effects were not detected due to the relatively small number of recurrences in this cohort. Finally, misclassification of recurrence cannot be excluded completely. However, a previous study suggested high accuracy in self reported recurrence status and recall of the relevant medical data among breast cancer patients [ 53 ] After comparison of the self reported data (recall time 1.6 9 years, mean 3.2 years) with the medical records, the agreement between two data sources was 99% for a history o f radiotherapy and 97% for the breast cancer recurrence status. Some p revious stud ies suggested that breast cancer patients with a positive family history of breast cancer tend to undergo cancer screen ing more frequently and from younger age [15, 16 ] Hig her dose and early age at exposure to ionizing radiation have been linked to breast cancer risk in previous studies [29, 30, 32 ] Mammography represents a source of medical ionizing radiation in women and it is possible that the cumulative exposure to this radiation in women with a family history of breast cancer might contribute to the higher risk of breast cancer recurrence. I nformation on the number of prior mammograms however, was not collected by the Registry and could not be controlled for in this analysis. Future studies would benefit from inclusion of this cumulative exposure to ionizing radiation.
26 In conclusion, o ur findings do not support a hypothesis that r adiotherapy in breast cancer cases with a family history of breast cancer might increase the risk of breast cancer recurrence. Future studies are warranted to systematically examine these associations in larger population based studies with complete inform ation on other sources of ionizing radiation.
27 Table 4 1 Summary of previous studies on the association between a family history of breast cancer and the risk of breast cancer recurrence Author, year, place Study design Sample size Follow up time (mean, range) Definition of positive family history Type of breast cancer cases Covariates used in adjustment Main findings Turkoz et al. 2012, Turkey Retrospective cohort study 1,987 27 months (range 1 400) FDR, SDR and TDF of BOC Not specifically mentioned Age, tumor size and nodal status 1+ relative with BC years: HR 1.62; 95% CI 1.15 2.27; p=0.006) A mong triple negative cases : HR= 1.82; 95% CI 1.44 2.29; p<0.0001 Buist et al., 2010, US C ohort study 17,286 5 years Any FDR with BC DCIS or early stage (I/II) invasive breast cancer Stage, adjuvant therapy, age at diagnosis, and registry Women with a FH of BC had higher rates of second primaries but not recurrences Cao et al. 2011, China Case control 693 (Case: 348 Control: 345) 55.7 month (range: 6 120) BOC Females without distant metastasis at initial diagnosis, and with infiltrative carcinoma Age, stage, HER2 status, chemother apy, radiothera py, hormone therapy FH of BOC had higher risk of recurrence/metasatsis (log rank p=0.04), HR=0.012, 95% CI 0.02 0.57) in the HR(ER or PR)+ population
28 Table 4 1. Continued Author, year, place Study design Sample size Follow up time (mean, range) Definition of positive family history Type of breast cancer cases Covariates used in adjustment Main findings Figueriredo JC et al., 2006, Canada Prospective population based cohort 967 Not reported FDR of BOC All cases Tumor characteris tic and adjuvant treatment N o association s Eccles D, et al., 2001, UK Retrospective cohort study 304 7 years (range: 0 47) Significant FH (1+ FDR < 60 years old or 1+ paternal SDR <60) or BRCA 1 mutation Not reported Not reported No associations Harris, et al., 2000, US Prospective cohort study 146 7.8 years (range: <1 20) FDR or any other relative with BOC DCIS Not reported No associations Jobson, et al. 2000, Netherland Prospective cohort study 1,204 70 month (range: 2 175) First degree relative Early BC (T1, T2<=3cm) Not reported A significant positive relationship between LR and FH in young BC patients 40 years Szelei Stevens, et al. 2000, US Prospective cohort study 128 8.7 years (Median; range: 2.0 16.1) FDR and SDR with BC DCIS Not reported FH significantly increased the local recurrence rate (p=0.05) Abbreviations : BC breast cancer; DCIS ductal carcinoma in situ; FH family history; LR local recurrenc e; RR regional recurrence; OS overall survival; FDR first deg ree relative; SDR second degree relati ve; TDR third degree relative ; BOC breast and/or ovarian cancer ; HR hormone receptor; ER estrogen receptor ; PR progesterone receptor
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34 BIOGRAPHICAL SKETCH Clinical Medicine in 2009 and graduated with a Mast er of Science in Discipline of psychiatry and mental h ealth in 2012 from Peking University in China. During 2012 and 2014, she worked as a t herapeutic a rea p hysician in Department of Research and an Janssen Pharmaceutical Ltd. i n Beijing, C h ina. In the fall 2014 she b egan her study in College of Public Health and Health Professions at University of Florida. She received her Master of Sc ience in e pidemiology from the University of Florida in Spring 2016.