Citation
Interaction of Alcohol Consumption and Adjuvant Hormone Therapy in Relation to Breast Cancer Free Survival among Women with Primary Breast Cancer

Material Information

Title:
Interaction of Alcohol Consumption and Adjuvant Hormone Therapy in Relation to Breast Cancer Free Survival among Women with Primary Breast Cancer
Creator:
Kowalski, Allison
Publisher:
University of Florida
Publication Date:
Language:
English

Thesis/Dissertation Information

Degree:
Master's ( M.S.)
Degree Grantor:
University of Florida
Degree Disciplines:
Epidemiology
Committee Chair:
YAGHJYAN,LUSINE
Committee Co-Chair:
STRILEY,CATHERINE L
Committee Members:
VARMA,DEEPTHI SATHEESA

Subjects

Subjects / Keywords:
adjuvant
alcohol
breast-cancer
hormone
survival
therapy

Notes

General Note:
Alcohol consumption has been consistently associated with an increase in breast cancer risk in previous studies. However, the findings on the associations of alcohol consumption at the time of breast cancer diagnosis with breast cancer-free survival, have been inconsistent. Further, whether the association of alcohol consumption with breast cancer-free survival could differ in women with and without adjuvant hormone therapy is unknown. We examined interactions of alcohol consumption with adjuvant hormone therapy in relation to breast cancer-free survival among women with primary breast cancer diagnosis. This study utilized data collected by the Moffitt Cancer Center Health and Informatics that links Cancer Registry data with patient reported information. We identified women who were diagnosed with incident breast cancer and treated between 2007-2012, completed the patient survey prior to diagnosis, and had available data on alcohol consumption and important covariates (n=1,399). Alcohol consumption during the 12 months preceding diagnosis was assessed through a self-administered survey and categorized as never, occasional (less than or equal to drink/month), and current (greater than 1 drink/month) as well as a binary variable (drinker [greater than 1 drinks/month] vs. non-drinker [0 drinks/month]). Information on adjuvant hormone therapy was available from the treatment data. Cox proportional hazards models were used to describe the association between alcohol consumption and breast cancer-free survival after adjustment for age, body mass index, menopausal status, and relevant treatment. Overall, alcohol consumption was associated with better breast cancer-free survival (Hazard Ratio [HR]=0.77, 95% CI 0.65-0.92 for any vs. no drinking and HR=0.75, 95% CI 0.62-0.89 for current vs. no drinking). Among women without adjuvant therapy, alcohol consumption was not associated with breast cancer-free survival. Among women with adjuvant therapy, alcohol consumption was associated with better survival (current vs. no drinking: HR=0.68, 95% CI 0.55-0.85 and any vs. no drinking HR=0.71, 95% CI 0.57-0.88). There was no significant interaction between alcohol consumption and adjuvant therapy with either of the exposure modeling approaches (P-interaction>0.05). Associations of alcohol consumption with breast cancer-free survival are similar in women with and without adjuvant hormone therapy. Future studies are warranted to elucidate potential mechanisms behind the observed inverse associations.

Record Information

Source Institution:
UFRGP
Rights Management:
All applicable rights reserved by the source institution and holding location.
Embargo Date:
5/31/2019

Downloads

This item has the following downloads:


Full Text

PAGE 1

INTERACTION OF ALCOHOL CONSUMPTION AND ADJUVANT HORMONE THERAPY IN RELATION TO BREAST CANCER FREE SURVIVAL AMONG WOMEN WITH PRIMARY BREAST CANCER By ALLISON KOWALSKI 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 2017

PAGE 2

2017 Allison Kowalski

PAGE 3

To Robert Ward

PAGE 4

4 ACKNOWLEDGMENTS First off, I would like to express my gratitude to my advisor Dr. Lusine Yaghjyan for her motivation, knowledge, and patience through my thesis. Her continued guidance and support helped me through the writing of this thesis and was greatly appreciated. I would like to thank the other members of my committee: Drs. Catherine Striley a nd Professor Deepthi Varma, for their support and insight on this thesis. I would also like to thank Dr. Travis Gerke for his expertise in statistics. We would like to thank Dr. Kathleen Egan as well as other members of the Moffitt Cancer Center for provi ding the data from the Moffitt Cancer Center Data Warehouse that was used in this analysis. Last, I would like to thank my family: my mom Vicky Kowalski and my grandparents Robert and Joanne Ward for encouraging and supporting everything I have done thro ughout my life.

PAGE 5

5 TABLE OF CONTENTS page ACKNOWLED GMENTS ................................ ................................ ................................ ............... 4 LIST OF TABLES ................................ ................................ ................................ ........................... 6 LIST OF FIGURE S ................................ ................................ ................................ ......................... 7 ABSTRACT ................................ ................................ ................................ ................................ ..... 8 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .................. 10 2 METHODS ................................ ................................ ................................ ............................. 14 Study Population ................................ ................................ ................................ ..................... 14 Assessment of Alcohol Consumption ................................ ................................ ..................... 14 Covariates ................................ ................................ ................................ ............................... 15 Outcomes ................................ ................................ ................................ ................................ 15 Statistical Analysis ................................ ................................ ................................ .................. 16 3 RESULTS ................................ ................................ ................................ ............................... 19 4 DISCUSSION ................................ ................................ ................................ ......................... 26 APPENDIX: SECOND PRIMARY BREAST CANCER AND CHEMOTHERAPY CODES .... 29 LIST OF REFERENCES ................................ ................................ ................................ ............... 37 BI OLOGICAL SKETCH ................................ ................................ ................................ ............... 42

PAGE 6

6 LIST OF TABLES Table page 3 1 Characteristics of Study Participants by Breast Cancer Related Outcomes ...................... 22 3 2 Characteristics of Study Participants by Adjuvant Therapy and Breast Cancer Related Outcomes ................................ ................................ ................................ .............. 24 3 3 Hazard Ratios (HRs) of Second Primary Breast Cancer, Breast Cancer Recurrence, and Death from Breast Cancer by Alcohol Consumption and Adjuvant Therapy ............ 25 A 1 Second Primary Breast Cancer and Chemotherapy Codes ................................ ................ 29

PAGE 7

7 LIST OF FIGURES Figure page 2 1 Patient selection diagram ................................ ................................ ................................ ... 18

PAGE 8

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 INTERACTION OF ALCOHOL CONSUMPTION AND ADJUVANT HORMONE THERAPY IN RELATION TO BREAST CANCER FREE SURVIVAL AMONG WOMEN WITH PRIMARY BREAST CANCER By Allison Kowalski May 2017 Chair: Lusine Yaghjyan Major: Epidemiology Alcohol consumption has been consi stently associated with an increase in breast cancer risk in previous studies. However, t he findings on the associations of alcohol consumption at the time of breast cancer diagnosis with breast cancer free survival have been inconsistent. Further, whethe r the association of alcohol consumption with breast cancer free survival could differ in women with and without adjuvant hormone therapy is unknown. We examined interactions of alcohol consumption with adjuvant hormone therapy in relation to breast cancer free survival among women with primary breast cancer diagnosis. This study utilized data collected by the Moffitt Cancer Center Health and Informatics that links Cancer Registry data with patient reported information We identified women who were diagnos ed with incident breast cancer and treated between 2007 2012, completed the patient survey prior to diagnosis, and had available data on alcohol consumption and important covariates (n=1,399). Alcohol consumption during the 12 months preceding diagnosis wa s assessed through a self administered sur vey and categorized as never, drink/month), and current (>1 dri nk /month) as well as a binary variable (drinker [>1 drinks/month] vs. non drinker [0 drinks/month]). Information on adjuvant hormone the rapy was

PAGE 9

9 available from the treatment data. Cox proportional hazards models were used to describe the association between alcohol consumption and breast cancer free survival after adjustment for age, body mass index, menopausal status, and relevant treatme nt. Overall, alcohol consumption was associated with better breast cancer free survival (Hazard Ratio [HR]=0.77, 95% CI 0.65 0.92 for any vs. no drinking and HR=0.75, 95% CI 0.62 0.89 for current vs. no drinking). Among women without adjuvant therapy, a lcohol consumption was not associated with breast cancer free survival. Among women with adjuvant therapy, alcohol consumption was associated with better survival (current vs. no drinking: HR=0.68, 95% CI 0.55 0.85 and any vs. no drinking HR=0.71, 95% CI 0 .57 0.88). There was no significant interaction between alcohol consumption and adjuvant therapy with either of the exposure modeling approaches (P interaction>0.05). Associations of alcohol consumption with breast cancer free survival are similar in wome n with and without adjuvant hormone therapy. Future studies are warranted to elucidate potential mechanisms behind the observed inverse associations.

PAGE 10

10 CHAPTER 1 INTRODUCTION Breast cancer is the most common cancer in women and the second leading cause of cancer mortality in the US and Europe (1, 2) In 2016 in the US, the estimated incidence and mortality of breast cancer were 246,660 and 40,450, respectively (2) Recent advancements in breast cancer treatment have improved patient outcomes and survival (3) The rate of mortality has been falling each year from 2004 2013 in the US for breast cancer (2) indicating the improved effectiveness of treatments. Breast cancer survival and the risk of recurrence are associate d with clinical and morphological tumor characteristics, including stage (which incorporates information on tumor size and nodal involvement), differentiation grade, and receptor status (4, 5) Breast cancer survival worsens and the recurrence risk increases in tumor stages III and IV (6, 7) Survival rates for breast cancer stages are 96%, 85.6%, 59.2% and 25.5% for stage I, II, III, and IV respectively (6) while recurrence rates are 11.5 13.3%, 42.3 48.2%, 60.3 66.1%, 66.7 73.3%, respectively (3) Another study saw a 66% increase in the risk of recurrence per one centimeter increase in tumor size among women (8) Other studies showed that higher tumor grade in women with low tumor size and two positive lymph nodes have a lower 5 and 10 year survival (9) with the 10 year survival for grade 3 being 62% as compared to 86% for grade 1 (6, 9, 10) As with the other clinical tumor factors, studies show that estrogen, progesterone and HER2 receptor status affects survival of breast cancer (10) Survival for women with both estrogen receptor (ER) positive and progesterone receptor (PR) positive tumors is better as compared to ER negative an d PR negative tumors (10 12) Across all stages of breast cancer, women with triple negative breast cancer (estrogen receptor negative, progesterone receptor negative, and

PAGE 11

11 HER2 negative) have worse overall and breast cancer cause specific survival compared to women with non triple negative breast cancer (13) In previous studies, breast cancer survival has been associated with some epidemiologic risk factors for breast cancer. Women diagnosed at age younger than 36 years have a higher rate of recurrence and worse 5 year survival compared to women who are older than 36 years at diagnosis (14) Both breast cancer survival and the risk of recurr ence have been shown to be positively associated with body mass index (BMI) (15) The risk of breast cancer recurrence in women with BMI>30 is 43% higher than in women with BMI<30 (16) Alcohol is a well known breast cancer risk factor with consistent positive associations with breast cancer risk across the studies (17 19) Light alcohol consumption shows a positive association with about a 5% increase in breast cancer risk compared to nondrinkers (17) Moderate alcohol consumption of as little as 5g/day (1/2 drink/day) has a p ositive association with the risk of breast cancer in African Americans, Japanese Americans, Caucasians, and Latinas (20) High levels of alcohol consumption (>3 drinks/day) increases the risk of breast cancer by 40 50% (17) Alcohol consumption between first menarche and first term pregnancy is also positively associated with an increased risk of breast cancer with hormone re ceptor positive tumors at exposure level of 10g/day or 6 drinks/week (21) Alcohol intake overall increases the relative risk of breast cancer by 7% for each additional 10g of alcohol per day (22) Studies on the associations of alcohol and breast cancer outcomes such as recurrence, second primary, and mortality are inconsistent. Some studies have shown no association between recurrence and alcohol consumption while others have f ound a positive association. Breast cancer recurrence and alcohol consumption did not show a significant association among postmenopausal women but showed a nonlinear negative association with breast cancer mortality

PAGE 12

12 among postmenopausal women (23) One study found that consuming 3 4 drinks/week is associated with an increased risk of recurrence by 50% among postmenopausal women and 60% among obese or overweight women while only postmenopausal women showed a statistically significant increase in risk for breast cancer death post diagnosis (24) For second primary contralateral breast cancer, a positive association h as been seen with alcohol consumption of >7 drinks/week pre diagnosis with a 70% higher odds compared to nondrinkers (25) Adjuvant hormone therapy is used after breast cancer diagnosis and surgery to improve overall survival from recurrence and mortality. There is a higher risk of breast cancer recurrence in women that are not adherent to adjuvant hormone therapy (3) Adjuvant hormone therapy has also been shown to improve breast cancer free surv ival by reducing mortality and the risk of recurrence by 34% and 40%, respectively with a five year treatment (26) In previous studies, tamoxifen improved patient outcomes when taken for five years by reducing the risk of recurrence and mortality; the risk of recurrence also decreased after 10 years of treatment in women with ER positive breast cancer (2 7) Further, the com bination of chemotherapy and tamoxifen may reduce the risk of dying from breast cancer by 50% in women under the age of 50 years and a little less than 50% for women aged 50 69 years (26) Whether there is an interaction between alcohol consumption and adjuvant hormone therapy is po orly understood. Some previous studies show that concurrent alcohol consumption of >20g/day and postmenopausal hormone therapy increases breast cancer risk by two fold compared to women without alcohol consumption (28) In this case, there a re several biological mechanisms that may explain the potential interaction between alcohol consumption and adjuvant hormone therapy. A plausible biological mechanism is one of the criteria for establishing not just an interaction but a causal relationship according to Sir Bradford Hill. (29)

PAGE 13

13 For example, long term alcohol consumption may affect the xenobiotic metabolism by altering the metabolism of the drug resulting in higher toxicity and/or dangerous drug interactions (30) Certain drug metabolizing enzymes such as CYP450, glutathione S transferases, diphosphate glucuronosyl transferases are essential for the metabolism of xenobiotics including hormones for adjuvant hormo ne therapy (31) Long term alcohol consumption may have potential to influence the activity of these enzymes. CYP19 (aromatase), a crucial enzyme in estrogen metabolism (32) can be induced by alcohol (33) resulting in an altered hormonal environment during adjuvant therapy treatment. The potential interaction between alcohol use and adjuvant therapy has never been invest igated. This study aimed to assess the interaction between alcohol consumption and adjuvant hormone therapy in relation to breast cancer free survival in women with primary breast cancer diagnosis.

PAGE 14

14 CHAPTER 2 METHODS Study Population The current study ut ilizes the cancer registry data collected by the Moffitt Cancer Center (Tampa, FL) which provides cancer care to the population of Hillsborough and Pasco counties in Tampa Bay encompassing a population of nearly 3 million individuals. The Moffitt Cancer Ce nter has collected and stored data on patients diagnosed with any type of cancer and follow up information through the Health and Informatics (HRI) data warehouse. Through agreement collaboration with Dr. Egan, we were provided with de identified data subs et from the HRI for this study. The HRI links data from several clinical systems, a biobank and patient survey upon treatment, survival, tumor related characterist ics, and patient survey data. From HRI data, we identified all women who were diagnosed with incident breast cancer and treated between 2007 2012, completed the patient survey prior to diagnosis, and had available data on alcohol consumption (n=1,407). Fro m these, we excluded eight women missing adjuvant therapy or age at diagnosis. The final study population included 1,399 women. This study was approved by the University of Florida and Moffitt Cancer Center Institutional Review Boards (IRBs). Assessment o f Alcohol Consumption Alcohol consumption during 12 months preceding diagnosis was assessed through a self administered patient survey. Participants were asked to report frequency of alcohol consumption, the number of drinks typically consumed and the type of beverage. One drink was defined as one 12 oz. can or bottle of beer, one 5 ounce glass of wine, one can or bottle of a wine cooler, one cocktail or one shot of liquor. Alcohol consumption was categorized as never (0 drinks/month), month), and current (>1drinks/month) as well as a binary variable (drinker

PAGE 15

15 [>1 drinks/month] vs non drinker [0 drinks/month]) (34, 35) Separate analyses were performed using both of these exposure variables. In a second analysis, alcoh ol consumption was assessed using frequency of drinks per heavy (>7 drinks/week) (36) Covariates The survey collected information on potential confounders such as demographics, menopausal status, reproductive history, fami ly history of breast cancer in first degree relatives, types of treatment, and tumor characteristics. Family history was categorized as having no family member with a history of breast cancer or having any first degree family member with breast cancer (inc luding mother, daughter, sister, father, brother, or son). BMI was calculated using height and weight available from the medical record or reported on the survey. For the majority of the women (n=982), information on BMI was available from within the year preceding the diagnosis. For women with missing BMI from within the year preceding the diagnosis, BMI was retrieved from within two years preceding date of diagnosis (n=27), within the year after diagnosis (n=1), or within two years after diagnosis (n=89). BMI was categorized as underweight/normal (<25kg/m 2 ), overweight (25 29.9 kg/m 2 ), obese (>30 kg/m 2 ), or unknown (n=300). Outcomes The history of a secondary malignant breast neoplasm and chemotherapy indicator codes from the cancer registry and patient b illing system were used to identify women with the outcomes of interest. This approach was similar to the previously described methods in Hassett et al (37) The primary outcomes of interest included second primary breast cancer, breast cancer recurrence, and death from breast cancer. Sec ond primary breast cancer was defined as having

PAGE 16

16 International Classification of Diseases Identification version 9 Clinical Modification code 198.81 after the primary breast cancer diagnosis. Recurrence was defined as having any of the relevant breast cance r related treatment that occurred at least 15 months from the date of original diagnosis, in the absence of any new cancer diagnosis for another site. The list of codes for each of the coding system used for recurrence definition is presented in the Append ix. Death from breast cancer was identified through the cancer registry. Women without an outcome of interest were censored at the time of death by other causes or the end of the study (7/31/2015). Out of all women in the study, 559 women had the outcome o f interest (85 second primary breast cancers, 439 recurrences, and 35 deaths), and 840 were censored. Statistical Analysis Baseline characteristics of women with and without the study outcome were compared with chi squared (categorical variables) and t tes ts (continuous variable) overall and by the status squared was not valid. Cox proportional hazard models were used to calculate hazards ratios (HRs) and corresponding 95% confidence intervals using follow up time as the time variable. Follow up for women with a study outcome was defined by the number of months from the date of diagnosis to the first occurring outcome of interest: breast cancer recurrence, second primary bre ast cancer, or death from breast cancer. Follow up for women without the outcome was defined as the number of months between primary breast cancer diagnosis and either date of death from other causes or the end of study (7/31/2015), which ever came first. The risk estimates were adjusted for potential confounders and the final model was selected with step wise model selection approach. BMI and age at diagnosis were forced into the final survival model as they have shown associations with breast cancer free survival in previous studies (15, 38) The final survival models included the following covariates: age at diagnosis (years), B MI (normal, overweight,

PAGE 17

17 obese, unknown), immunotherapy (yes, no), hormone therapy (yes, no), surgery (yes, no), chemotherapy (yes, no), and menopausal status (post, other). The interaction between alcohol consumption (modeled as binary as well as categori cal with three levels) and adjuvant therapy (yes, no) was evaluated by including an interaction term in the overall models. Next, the survival analysis was stratified by adjuvant therapy. Proportional hazards assumption was evaluated for each model. Chemo therapy was the only variable to violate the proportional hazards assumptions, in both models. To account for the nonproportionality we added an interaction term with chemotherapy and time (39) All the tests were two sided and significance of the effects was assessed at 0.05 significance level. All analyses were performed with SAS (SAS In stitute Inc. version 9.4). After looking at our findings, a second analysis was done to determine if the observed associations between alcohol and breast cancer free survival could be explained by the benefits of moderate drinking. Moderate drinking has b een shown to have protective effects on other chronic diseases (40, 41) In this analysis, alco hol consumption was categorized based on the number of drinks per week and the associations were examined overall and by the status of adjuvant therapy. We then conducted additional analysis that excluded women with immunotherapy or chemotherapy to exclude potential masking effects of immune and chemotherapy on survival. The associations were examined overall and by status of adjuvant therapy. Risk estimates in the models were adjusted for age at diagnosis, BMI, surgery, hormone therapy, adjuvant therapy ( except stratified), and menopausal status. The interactions between alcohol consumption and adjuvant therapy were assessed in both secondary analyses. Where needed an interaction term with chemotherapy and time was added to the models to account for nonpr oportionality.

PAGE 18

18 Figure 2 1. Patient selection diagram All women treated for breast cancer 2007 2012 N=4459 Women with no prior breast cancer N=1593 Women with alcohol consumption data N=1542 Women with survey done prior to date of diagnosis N=1407 Prior history of breast cancer N=2866 Missing alcohol data N=51 Survey taken after date of diagnosis N=135 Missing adjuvant therapy or age at diagnosis data N=8 Women without adjuvant hormone therapy N=462 Women with adjuvant hormone therapy N=937

PAGE 19

19 CHAPTER 3 RESULTS This study included 1,399 women with invasive breast cancer (462 women without adjuvant therapy and 937 with adjuvant therapy). Table 3 1 shows characteristics of the study participants by the study outcomes (having breast cancer recurrence, second primary breast cancer, or breast cancer related death). Women with the outcome were less likely to be drinkers (53.49% vs 59.52%, p=0.0293), more likely to have had chemotherapy (70.84% vs. 42.26%, p< 0.0001), more likely to have had immunotherapy (22.36% vs. 8.93%, p<0.0001), and less likely to have had surgery (94.28% vs. 97.98%, p=0.0004) compared to participants without the outcome. Characteristics of patients stratified by adjuvant therapy and outc ome are shown in table 3 2. Among women with adjuvant therapy, those with outcome were less likely to be current drinkers (47.57% vs. 55.91%, p=0.0258), less likely to have a progesterone receptor positive tumor (85.95% vs 90.30%, p=0.0335), more likely to have had chemotherapy (71.16% vs. 33.69%, p<0.0001), and more likely to have had immunotherapy (21.35% vs. 6.35%, p<0.0001). Among women without adjuvant therapy, those with the outcome were less likely to have had surgery (83.07% vs. 93.77%, p=0.0004), m ore likely to have had immunotherapy (24.34% vs. 14.29%, p=0.0088), and more likely to have had hormone therapy (16.93% vs. 5.86%, p=0.0002). Distributions of other characteristics were similar among women with and without the study outcome in both of the adjuvant therapy strata. Adjuvant therapy was inversely associated with the outcome in the overall model (HR=0.59, 95% CI 0.36 0.95). The results for the association of alcohol consumption with the outcome, overall as well as stratified by adjuvant therapy are summarized in table 3 3. Overall, alcohol consumption within preceding 12 months was inversely associated with the risk of the study outcomes with a 23% reduction in risk among women with any consumption as compared

PAGE 20

20 to no consumption (HR=0.77, 95% CI 0.65 0.92) and a 25% reduction in risk among current as compared to never drinkers (HR=0.75, 95% CI 0.62 0.89). Among women without adjuvant therapy, alcohol consumption was not associated with adverse breast cancer related outcomes after adjustment for the other covariates (occasional vs. no drinking: HR=0.97, 95% CI 0.55 1.70; current vs. no drinking: HR=0.83, 95% CI 0.60 1.13; and any consumption vs. none: HR= 0.85, 95% CI 0.63 1.14). Among women with adjuvant therapy, alcohol consumption was inverse ly associated with adverse breast cancer related outcomes with a 32% reduction in the risk of having the outcome among current as compared to never drinkers (HR=0.68, 95% CI 0.55 0.85) and a 29% reduction in the risk for individuals with any consumption as compared to none (HR=0.71, 95% CI 0.57 0.88). There was no significant interaction between alcohol consumption and adjuvant therapy with either of the exposure modeling approaches (p>0.05 for both). In secondary analysis among women without immunotherapy or chemotherapy, breast cancer free survival appeared to be better in women consuming alcohol though these associations no longer reached statistical significance due to a smaller sample size (n=639; current vs. no drinking: HR=0.82, 95% CI 0.57 1.16; any consumption vs. none: HR=0.89, 95% CI 0.64 1.25). Similar, though non significant results were observed in stratified analyses (among women without adjuvant therapy: current vs. no drinking: HR=1.26, 95% CI 0.67 2.37; any consumption vs. none: HR=1.30, 95% CI 0.70 2.38; and among women with adjuvant therapy: current vs. no drinking: HR=0.70, 95% CI 0.46 1.07; any consumption vs. none: HR=0.78, 95% CI 0.52 1.17). No interaction between alcohol consumpti on and adjuvant therapy

PAGE 21

21 was found (P interaction=0.22 and 0.27 for three level and binary alcohol consumption, respectively). In the models with alcohol consumption assessed as drinks per week, a better breast cancer free survival was observed in women con suming alcohol, both overall and by the status of adjuvant therapy (table 3 3). There was no interaction between alcohol consumption and adjuvant therapy (P interaction=0.42).

PAGE 22

22 Table 3 1. Characteristics of Study Participants by Breast Cancer Related Outcomes Characteristic Without Outcome N=840 With Outcome N=559 P value Age at Diagnosis, mean (Standard Deviation) 58.32 (12.28) 56.38 (11.83) 0.3321 BMI n (%) Normal Overweight Obese Unknown 221 (26.31) 208 (24.76) 213 (25.36) 198 (23.57) 122 (21.82) 143 (25.58) 166 (29.70) 128 (22.90) 0.1550 Menopausal Status n (%) Other Post 477 (56.79) 363 (43.21) 300 (53.67) 259 (46.33) 0.2736 Drinking Status n (%) Occasional Never Current 55 (6.55) 340 (40.48) 445 (52.98) 49 (8.77) 260 (46.51) 250 (44.72) 0.0079 Drinker n (%) No Yes 340 (40.48) 500 (59.52) 260 (46.51) 299 (53.49) 0.0293 Family History n (%) Any None 148 (17.62) 692 (82.38) 84 (15.03) 475 (84.97) 0.2288 Progesterone Receptor n (%) PR PR+ Borderline Missing 229 (27.26) 596 (70.95) 0 15 (1.79) 169 (30.18) 386 (68.93) 1 (0.18) 4 (0.71) 0.2649 Adjuvant therapy n (%) Yes No 567 (67.50) 273 (32.50) 370 (66.19) 189 (33.81) 0.6510 Chemotherapy n (%) No Yes 485 (57.74) 355 (42.26) 163 (29.16) 396 (70.84) <0.0001 Surgery n (%) No Yes 17 (2.02) 823 (97.98) 32 (5.72) 527 (94.28) 0.0004 Radiation n (%) No Yes 332 (39.52) 508 (60.48) 220 (39.36) 339 (60.64) 0.9944

PAGE 23

23 Table 3 1. Continued Characteristic Without Outcome With Outcome P value Immunotherapy n (%) No Yes 765 (91.07) 75 (8.93) 434 (77.64) 125 (22.36) <0.0001 Hormone Therapy n (%) No Yes 263 (31.31) 57 (68.69) 160 (28.62) 399 (71.38) 0.3113

PAGE 24

24 Table 3 2. Characteristics of Study Participants by Adjuvant Therapy and Breast Cancer Related Outcomes Without Adjuvant Therapy P value With Adjuvant Therapy P value Characteristic Without Outcome n=273 With Outcome n=189 Without Outcome n=567 With Outcome n=370 Age at Diagnosis, mean (Standard Deviation) 58.31 (14.24) 57.65 (12.72) 0.0975 58.32 (11.23) 55.73 (11.31) 0.8869 BMI n (%) Normal Overweight Obese Unknown 82 (30.04) 55 (20.15) 64 (23.44) 72 (26.37) 39 (20.63) 50 (26.46) 50 (26.46) 50 (26.46) 0.1052 139 (24.51) 153 (26.98) 149 (26.28) 126 (22.22) 83 (22.43) 93 (25.14) 116 (31.35) 78 (21.08) 0.4117 Menopausal Status n (%) Other Post 142 (52.01) 131 (47.99) 101 (53.44) 88 (46.56) 0.8362 335 (59.08) 232 (40.92) 199 (53.78) 171 (46.22) 0.1250 Drinking Status n (%) Occasional Never Current 20 (7.33) 125 (45.79) 128 (46.89) 15 (7.94) 100 (52.91) 74 (39.15) 0.2534 35 (6.17) 215 (37.92) 317 (55.91) 34 (9.16) 160 (43.24) 176 (47.57) 0.0258 Drinker n (%) No Yes 125 (45.79) 148 (54.21) 100 (52.91) 89 (47.09) 0.1582 215 (37.92) 352 (62.08) 160 (43.24) 210 (56.76) 0.1193 Family History n (%) Any None 45 (16.48) 228 (83.52) 23 (12.17) 166 (87.83) 0.2488 103 (18.17) 464 (81.83) 61 (16.49) 309 (83.51) 0.5664 Progesterone Receptor n (%) PR PR+ Borderline Missing 175 (64.10) 84 (30.77) 0 14 (5.13) 118 (62.43) 68 (35.98) 0 3 (1.59) 0.4214 54 (9.52) 512 (90.30) 0 1 (0.18) 51 (13.78) 318 (85.95) 1 (0.27) 0 0.0335

PAGE 25

25 Table 3 2. Continued Without Adjuvant Therapy P value With Adjuvant Therapy P value Characteristic Without Outcome n=273 With Outcome n=189 Without Outcome n=567 With Outcome n=370 Chemotherapy n (%) No Yes 109 (39.93) 164 (60.07) 60 (31.75) 129 (68.25) 0.0898 376 (66.31) 191 (33.69) 103 (27.84) 267 (71.16) <0.0001 Surgery n (%) No Yes 17 (6.23) 256 (93.77) 32 (16.93) 157 (83.07) 0.0004 0 567 (100) 0 370 (100) Radiation n (%) No Yes 128 (46.89) 145 (53.11) 104 (55.03) 85 (44.97) 0.1040 204 (36.98) 363 (64.02) 116 (31.35) 254 (68.65) 0.1646 Immunotherapy n (%) No Yes 234 (85.71) 39 (14.29) 143 (75.66) 46 (24.34) 0.0088 531 (93.65) 36 (6.35) 291 (78.65) 79 (21.35) <0.0001 Hormone Therapy n (%) No Yes 257 (94.14) 16 (5.86) 157 (83.07) 32 (16.93) 0.0002 6 (1.06) 561 (98.94) 3 (0.81) 367 (99.19) 0.9705 Table 3 3. Hazard Ratios (HRs) of Second Primary Breast Cancer, Breast Cancer Recurrence, and Death from Breast Cancer by Alcohol Consumption and Adjuvant Therapy Alcohol consumption All women Women without adjuvant therapy Women with adjuvant therapy N Hazard Ratio (95% CI) a N Hazard Ratio (95% CI) b N Hazard Ratio (95% CI) b Never Occasional Current 442 96 554 1.0 0.96 (0.70,1.30) 0.75 (0.62,0.89) 156 34 155 1.0 0.97 (0.55,1.70) 0.83 (0.60,1.13) 286 62 399 1.0 0.87 (0.60,1.26) 0.68 (0.55,0.85) None Any Never Moderate Heavy 442 650 600 224 358 1.0 0.77 (0.65,0.92) 1.0 0.75 (0.58,0.97) 0.72 (0.58,0.89) 156 189 225 64 113 1.0 0.85 (0.63,1.14) 1.0 0.77 (0.47,1.26) 0.64 (0.43,0.95) 286 461 375 160 245 1.0 0.71 (0.57,0.88) 1.0 0.69 (0.51,0.94) 0.74 (0.58,0.96) Abbreviations: CI confidence interval a Adjusted for age at diagnosis, BMI, surgery, chemotherapy, adjuvant therapy, menopausal status, hormone therapy and immunotherapy. b Adjusted for age at diagnosis, BMI, surgery, chemotherapy, menopausal status, hormone therapy and immunotherapy.

PAGE 26

26 CHAPTER 4 DISCUSSION Our study, using data from the HRI database, looked at the interaction between prediagnostic alcohol consumption and adjuvant hormone therapy in relation to breast cancer free survival. Our findings suggest better breast cancer free survival in women consuming alcohol overall and among women with adjuvant hormone therapy. Findings on association s of alcohol consumption with breast cancer free survival from previous studies have been inconsistent (23, 42 44) Kwan et al. reported a 19% increase in risk of breast cancer recurrence in postmenopausal women consuming >3 drinks per week compared to nondrinkers (HR, 1.19, 95% CI, 1.01 1.40) in a cohort of 9,329 women with invasive breast cancer (45) In contrast, Reding et al. saw an inverse association of alcohol consumption in the 5 year period prior to diagnosis with breast cancer mortality among 1,286 women diagnosed before 45 years, with a 30% reduction i n risk among drinkers compared to non drinkers (HR=0.7, 95% CI 0.5 0.9) (46) Several other studies found no associations of alcohol consumption with breast cancer mortality, breast cancer recurrence, or second primary breast cancer (42, 47) The results from the secondary analysis showed an inverse association of alcohol consumption with the risk of breast cancer related outcomes in both models. The first model with the exclusion of women with chemotherapy or immunotherapy shows a n inverse association of alcohol consumption with adverse breast cancer outcomes even though the association is non significant. Since our results still show an inverse association, our findings are thus not influenced by potential masking effect of these two treatments. In the other model, among women with drinks per week, there was still an inverse association of alcohol consumption with adverse breast cancer outcomes, overall and stratified by adjuvant therapy. However, there was 217 (27%) women among dr inkers in the study that did not have data on the frequency of drinks

PAGE 27

27 per week resulting in a reduced number of women in the analysis. The results from the secondary analysis confirm moderate drinking is not a factor in better survival among drinkers and u nknown mechanisms or several mechanisms may be occurring. Also, the results add to the previous research of alcohol consumption and breast cancer survival. The mechanism for potential effect of alcohol consumption on survival after breast cancer diagnosis from previous studies is unclear but alcohol has been suggested to decrease breast cancer survival through the effects on estrogen metabolism (48) Adjuvant hormone therapy on the other hand, inhibits the action of estrogen on estrogen receptors. Alcohol can induce CYP19 causing an increase in estrogen levels (33) An increa se in estrogen levels can result in a change of the hormone environment effecting adjuvant hormone therapy treatment and negatively impacting breast cancer free survival. On the other hand, alcohol is able to induce enzymes in the P450 family that are invo lved in the metabolism of tamoxifen and other adjuvant therapy drugs (49) Some primary and secondary metabolites of tamoxifen have be tter antiestrogenic effects through higher affinity for estrogen receptors compared to tamoxifen such as endoxifen and 4 hydroxytamoxifen (50) The induction of enzymes in the P450 family by alcohol could accelerate the metabolism of tamoxifen resulting in an increase in concentrations of biologically active metabolites that inhibit action of estrogen on estrogen receptors potentially leading to better survival (51) The final net effect of the alcohol on breast cancer free survival would depend on relative contribution of these two potential mechanisms working in opposite directions. Our results suggest that better survival among drinkers could potentially be driven by the activation of CYP450 family rather than the effect o f alcohol on CYP19. One of the strengths of our study is utilizing hospital based cancer registry data with detailed information on tumor characteristics and treatment, and linkage with patient reported

PAGE 28

28 information. However, our study had a few limitations Information for demographics and alcohol consumption was self reported. Previous studies have shown high accuracy in recall of self reported alcohol consumption in men and women (52 54) However, misclassification of alcohol cannot be completely ruled out as it is always a concern when using a self re ported questionnaire. Another limitation is the inability to assess alcohol consumption as drinks per week as we only had drinks per month for all patients. For drinks per week, 73% of drinkers did not have data. In addition to the ICD 9 codes, our study second primary breast cancer and breast cancer recurrence. Even though this method demonstrated high validity in the previous studies, some misclassification of the breast cancer outcomes cannot be ruled out compl etely. Hassett et al. reported a specificity of 99% for using billing codes to define breast cancer recurrence. In a cohort of 2,726 women with breast cancer, the sensitivity for using billing codes for outcome definition was 79 81% for either breast cance r recurrence or second primary breast cancer (37) Our findings show a similar association of alcohol consumption with breast cancer free survival among women with and without adjuvant hormone therapy. Also, our results suggest an inverse association of alcohol consumption with breast cancer free survival among women with adjuvant hormone therapy. Future studies are needed to determine the interaction between alcohol consumption and adjuvant hormone therapy in relation to breast cancer free survival and elucidate potential mechanisms behind the observed ass ociations.

PAGE 29

29 APPENDIX SECOND PRIMARY BREAST CANCER AND CHEMOTHERAPY CODES Table A 1. Second Primary Breast Cancer and Chemotherapy Codes Secondary Malignant Neoplasm ICD 9 198.81 Second malig neo breast Chemotherapy ICD 9 00.10 Implantation of chemotherapy agent 17.70 intravenous infusion of clofarabine (17.70) 99.25 Injection or infusion of cancer chemotherapeutic substance 99.28 Injection or infusion of biological response modifier BRM¨ as an antineoplastic agent 99.29 Injection or in fusion of other therapeutic or prophylactic substance v58.1 Encounter for chemotherapy and immunotherapy for neoplastic conditions v58.11 Encounter for antineoplastic chemotherapy v58.12 Encounter for antineoplastic immunotherapy v66.2 Convalescence and palliative care Following chemotherapy v67.2 Follow up examination Following chemotherapy e930.7 Antineoplastic antibiotics (daunorubicin, mitomycin, etc.) e933.1 Primarily systemic agents Antineoplastics and immunosuppresive drugs Diagnosis related Groups 410 Chemotherapy w/o acute leukemia as secondary diagnosis 492 Chemotherapy w acute leukemia as secondary diagnosis Revenue Center 0331 Radiology therapeutic chemotherapy injected 0332 Radiology therapeutic chemotherapy oral 0335 Radiology therapeutic chemotherapy IV Berenson Eggers Type of Service O1D Chemotherapy Current Procedure Terminology 36260 Insertion of implantable intra arterial infusion pump 36640 Arterial catheterization for prolonged infusion therapy (chemotherapy), 36823 Insertion of arterial and venous cannula(s) for isolated extracorporeal circulation 61215 Insertion of subcutaneous reservoir, pump or continuous infusion system 61517 Implantation of brain intracavitary chemotherapy agent 62360 Implantation or replacement of device for intrathecal or epidural drug infusion;

PAGE 30

30 Table A 1 Continued Current Procedure Terminology 62361 Implantation or replacement of device for intrathecal or epidural drug infusion; 62362 Implantation or replacement of device for intrathecal or epidural drug infusion; 62365 90765 Intravenous infusion, for therapy, prophylaxis, or diagnosis 90766 Intravenous infusion, for therapy, prophylaxis, or diagnosis 90767 Intravenous infusion, for therapy, prophylaxis, or diagnosis 90768 Intravenous infusion, for therapy, prophylaxis, or diagnosis 90772 Therapeutic, prophylactic or diagnostic injection 90773 Therapeutic, prophylactic or diagnostic injection 90774 Therapeutic, prophylactic or diagnostic injection 90775 Therapeutic, prophylactic or diagnostic injection 90776 Therapeutic, prophylactic or diagnostic injection 90779 Unlisted therapeutic prophylactic or diagnostic intravenous or intra arterial 90780 IV INFUSION THERAPY/DX, GIVEN BY/UNDER DIRECTION, PHYSICIAN: UP TO 1 HR 90781 IV INFUSION THERAPY/DX, GIVEN BY/UNDER DIRECTION, PHYSICIAN: EACH ADDL HR 90782 THERAPEUTIC/PROPHYLACTIC/DX INJECTION (SPECIFY MATL INJECTED): SUBQ/IM 90783 THERAPEUTIC/PROPHYLACTIC/DX INJECTION (SPECIFY MATL INJECTED): INTRA ARTERIAL 90784 THERAPEUTIC/PROPHYLACTIC/DX INJECTION (SPECIFY MATL INJECTED): IV 90799 UNLISTED PROC, INJECTION, THERAPEUTIC/PROPHYLACTIC/DX 95990 Refilling and maintenance of implantable pump or reservoir for drug delivery 95991 Refilling and maintenance of implantable pump or reservoir for drug delivery 96365 Intravenous infusion, for therapy, prophylaxis, or di agnosis 96366 Intravenous infusion, for therapy, prophylaxis, or diagnosis 96367 Intravenous infusion, for therapy, prophylaxis, or diagnosis 96368 Intravenous infusion, for therapy, prophylaxis, or diagnosis 96379 Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra arterial 96400 CHEMOTHERAPY ADMINISTRATION, SUBQ/IM, W/WO LOCAL ANESTHESIA 96401 Chemotherapy administration, subcutaneous or intramuscular non hormonal anti neoplastic 96402 Chemotherapy administration, subcutaneous o r intramuscular hormonal anti neoplastic 96405 Chemotherapy administration: intralesional, up to and including 7 lesions 96406 Chemotherapy administration: intralesional, more than 7 lesions 96408 CHEMOTHERAPY ADMINISTRATION, IV: PUSH TECHNIQUE 96409 Chemotherapy administration: intravenous, push technique, single or initial substance 96410 CHEMOTHERAPY ADMINISTRATION, IV: INFUSION, UP TO 1 HR

PAGE 31

31 Table A 1 Continued Current Procedure Terminology 96411 Chemotherapy administration: intravenous, push technique, each additional substance 96412 CHEMOTHERAPY, IV: INFUSION, 1 8 HR, ADDL HR 96413 Chemotherapy administration, intravenous infusion technique: up to 1 hour, single 96413 Chemotherapy administration, intravenous infusion technique: up to 1 hour, single 96414 CHEMOTHERAPY, IV: INFUSION, > 8 HR W/PORTABLE/IMPLANTABLE PUMP 96415 Chemotherapy administration, intravenous infusion technique: each additional hour 96416 Chemotherapy administration, intravenous infusion technique: initiation of pr olonged 96417 Chemotherapy administration, intravenous infusion technique: each additional 96420 Chemotherapy administration, intra arterial: push technique 96422 Chemotherapy administration, intra arterial: infusion technique, up to one hour 96423 Chemotherapy administration, intra arterial: infusion technique, each additional 96425 Chemotherapy administration, intra arterial: infusion technique 96440 Chemotherapy administration into pleural cavity 96445 Chemotherapy administration into peritoneal cavity 96446 Chemotherapy administration into peritoneal cavity via indwelling port or catheter 96450 Chemotherapy administration, into CNS (eg, intrathecal) 96520 REFILLING & MAINTENANCE, PORTABLE PUMP 96521 Refilling and maintenance of por table pump 96522 Refilling and maintenance of implantable pump or reservoir for drug delivery 96523 Irrigation of implanted venous access device for drug delivery systems 96530 REFILLING & MAINTENANCE, IMPLANTABLE PUMP/RESERVOIR DRUG DELIVERY, SYSTEMIC 96542 Chemotherapy injection, subarachnoid or intraventricular via subcutaneous reservoir 96545 PROVISION, CHEMOTHERAPY AGENT 96549 Unlisted chemotherapy procedure 96567 Photodynamic therapy by external application of light to destroy premalignant and/or malignant lesions 96570 Photodynamic therapy by endoscopic application of light to ablate abnormal tissue 96571 Photodynamic therapy by endoscopic application of light to ablate abnormal tissue 96910 Photochemotherapy; tar and ultraviolet B (Goec kerman treatment) or petrolatum and ultraviolet B 96912 Photochemotherapy; psoralens and ultraviolet A (PUVA) 99601 Home infusion/specialty drug administration, per visit (up to 2 hours): 99602 Home infusion/specialty drug administration, per visit (up to 2 hours): each additional 0169T Stereotactic placement of infusion catheter(s) in the brain for delivery of therapy 0519F Planned chemotherapy regimen, including at a minimum: drug(s) prescribed, dose, 4180F Adjuvant chemotherapy referred, prescribed or previously received for Stage III

PAGE 32

32 Table A 1 Continued Healthcare Common Procedure Coding System C1084 Denileukin diftitox, 300 mcg C1086 Temozolomide, 5 mg C1166 INJECTION, CYTARABINE LIPOSOME, PER 10 MG C1167 INJECTION, EPIRUBICIN HYDROCHLORIDE, 2 MG C1178 INJECTION BUSULFAN PER 6 MG C8953 CHEMOTHERAPY ADMIN IV, PU C8954 CHEMO ADMIN IV, INFUS UP C8955 CHEMO ADMN IV, INFUS EA A C9004 Gemtuzumab ozogamicin inj,5m C9012 Injection, arsenic trioxide C9110 INJECTION, ALEMTUZUMAB, PER 10 MG/ ML C9205 INJECTION, OXALIPLATIN, PER 5 MG C9207 INJECTION, BORTEZOMIB, PER 3.5 MG C9213 INJECTION, PEMETREXED, PER 10 MG C9214 INJECTION, BEVACIZUMAB, PER 10 MG C9215 INJECTION, CETUXIMAB, PER 10 MG C9216 INJECTION, ABARELIX FOR INJECTABLE SUSPENSION, PER 10 MG C9235 Injection, panitumumab, 10 mg C9257 Injection, bevacizumab, 0.25 mg C9262 Fludarabine phosphate, oral, 1 mg C9414 ETOPOSIDE, ORAL, BRAND NAME, 50 MG C9415 DOXORUBICIN HCL, BRAND NAME, 10 MG C9417 BLEOMYCIN SULFATE, BRAND NAME, 15 UNITS C9418 CISPLATIN, POWDER OR S0LUTION, BRAND NAME, PER 10 MG C9419 INJECTION, CLADRIBINE, BRAND NAME, PER 1 MG C9420 CYCLOPHOSPHAMIDE, BRAND NAME, 100 MG C9421 CYCLOPHOSPHAMIDE, LYOPHILIZED, BRAND NAME, 100 MG C9422 CYTARABINE, BRAND NAME 100 MG C9423 DACARBAZINE, BRAND NAME, 100 MG C9424 DAUNORUBICIN, BRAND NAME, 10 MG C9425 ETOPOSIDE, BRAND NAME, 10 MG C9426 FLOXURIDINE, BRAND NAME, 500 MG C9427 IFOSFAMIDE, BRAND NAME, 1 GM C9429 IDARUBICIN HYDROCHLORIDE, BRAND NAME, 5 MG C9431 PACLITAXEL, BRAND NAME, 30 MG C9432 MITOMYCIN, BRAND NAME, 5 MG C9433 THIOTEPA, BRAND NAME, 15 MG C9434 Gallium ga 67, brand C9436 AZATHIOPRINE, PARENTERAL, BRAND NAME, PER 100 MG C9437 CARMUSTINE, BRAND NAME, 100 MG C9438 CYCLOSPORINE, ORAL, BRAND NAME, 100 MG C9440 VINORELBINE TARTRATE, BRAND NAME, PER 10 MG G0355 CHEMO SQ/IM NONHORMONL AN

PAGE 33

33 Table A 1. Continued Healthcare Common Procedure Coding System G0357 CHEMOTHERAPY IV PUSH, SINGLE/INITIAL DRUG G0358 CHEMOTHERAPY ADMINSTRATION OF EACH ADD. PUSHED CHEMO DRUG G0359 CHEMO IV INFUS,UP TO 1 HR G0360 CHEMO ADMIN IV INFUS, EA G0361 INIT PROLNG CHEMO INFUS R G0362 CHEMOTHERAPY ADMINSTRATION OF EACH INFUSED CHEMO DRUG, UP TO 1 HR G8372 CHEMO DOC RECV STAGE III G8373 CHEMO PLAN DOC PRIOR CHEM G8374 CHEMO PLAN NOT DOC PRIOR G9021 CHEMO ASSESS NV LEVL 1: N G9022 CHEMO ASSESS NV LEVL 2: L G9023 CHEMO ASSESS NV LEVL 3: Q G9024 CHEMO ASSESS NV LEVL 4: V G9025 CHEMO ASSESS PAIN LVL 1: G9026 CHEMO ASSESS PAIN LVL 2: G9027 CHEMO ASSESS PAIN LVL 3: G9028 CHEMO ASSESS PAIN LVL 4: G9029 CHEMO ASSESS FATIGUE 1: N G9030 CHEMO ASSESS FATIGUE LVL G9031 CHEMO ASSESS FATIGUE 3: Q G9032 CHEMO ASSESS FATIGUE LVL J0207 INJECTION, AMIFOSTINE, 500 MG J0594 Injection, busulfan, 1 mg J0640 INJECTION, LEUCOVORIN CALCIUM, PER 50 MG J0641 INJECTION, LEVOLEUCOVORIN CALCIUM, 0.5 MG J0894 INJECTION, DECITABINE, 1 MG J1190 INJECTION, DEXRAZOXANE HYDROCHLORIDE, PER 250 MG J7150 Prescription Oral Chemo Drug J8510 Busulfan: oral, 2 mg J8520 Capecitabine, oral, 150 mg J8521 Capecitabine, oral, 500 mg J8530 Cyclophosphamide: oral, 25 mg J8560 Etoposide; oral, 50 mg J8565 Gefitinib, oral, 250 mg J8600 Melphalan: oral, 2 mg J8610 Methotrexate: oral, 2.5 mg J8700 Temozolomide, oral, 5 mg J8705 TOPOTECAN, ORAL, 0.25 MG J8999 Prescription drug, oral, chemotherapeutic, NOS J9000 Doxorubicin HCl, 10 mg J9001 Doxorubicin HCl, all lipid formulations, 10 mg

PAGE 34

34 Table A 1. Continued Healthcare Common Procedure Coding System J9010 Alemtuzumab, 10 mg J9015 Aldesleukin, per single use vial J9017 Arsenic trioxide, 1 mg J9020 Asparaginase, 10,000 units J9025 Injection, azacitidine, 1 mg J9027 Injection, clofarabine, 1 mg J9033 INJECTION, BENDAMUSTINE HCL, 1 MG J9035 Injection, bevacizumab, 10 mg J9040 Bleomycin sulfate, 15 units J9041 Injection, bortezomib, 0.1 mg J9045 Carboplatin, 50 mg J9050 Carmustine, 100 mg J9055 Injection, cetuximab, 10 mg J9060 Cisplatin, powder or solution, per 10 mg J9062 Cisplatin, 50 mg J9065 Injection, cladribine, per 1 mg J9070 Cyclophosphamide, 100 mg J9080 Cyclophosphamide, 200 mg J9090 Cyclophosphamide, 500 mg J9091 Cyclophosphamide, 1 g J9092 Cyclophosphamide, 2 g J9093 Cyclophosphamide, lyophilized, 100 mg J9094 Cyclophosphamide, lyophilized, 200 mg J9095 Cyclophosphamide, lyophilized, 500 mg J9096 Cyclophosphamide, lyophilized, 1 g J9097 Cyclophosphamide, lyophilized, 2 g J9098 Cytarabine liposome, 10 mg J9100 Cytarabine, 100 mg J9110 Cytarabine, 500 mg J9120 Dactinomycin, 0.5 mg J9130 Dacarbazine, 100 mg J9140 Dacarbazine, 200 mg J9150 Daunorubicin, 10 mg J9151 Daunorubicin citrate, liposomal formulation, 10 mg J9160 Denileukin diftitox, 300 mcg J9170 Docetaxel, 20 mg J9171 Injection, docetaxel, 1 mg J9178 Injection, epirubicin HCl, 2 mg J9180 EPIRUBICIN HYDROCHLORIDE, 50 MG J9181 Etoposide, 10 mg J9182 Etoposide, 100 mg J9185 Fludarabine phosphate, 50 mg J9190 Fluorouracil, 500 mg

PAGE 35

35 Tab le A 1 Continued Healthcare Common Procedure Coding System J9200 Floxuridine, 500 mg J9201 Gemcitabine HCl, 200 mg J9206 Irinotecan, 20 mg J9207 INJECTION, IXABEPILONE, 1 MG J9208 Ifosfamide, per 1 g J9209 Mesna, 200 mg J9211 Idarubicin HCl 5 mg J9230 Mechlorethamine HCl, (nitrogen mustard), 10 mg J9245 Injection, melphalan HCl, 50 mg J9250 Methotrexate sodium, 5 mg J9260 Methotrexate sodium, 50 mg J9261 Injection, nelarabine, 50 mg J9263 Injection, oxaliplatin, 0.5 mg J9264 Injection, paclitaxel protein bound particles, 1 mg J9265 Paclitaxel, 30 mg J9266 Pegaspargase, per single dose vial J9268 Pentostatin, per 10 mg J9270 Plicamycin, 2.5 mg J9280 Mitomycin, 5 mg J9290 Mitomycin, 20 mg J9291 Mitomycin, 40 mg J9293 Injection, mitoxantrone HCl, per 5 mg J9300 Gemtuzumab ozogamicin, 5 mg J9302 Injection, ofatumumab, 10 mg J9303 Injection, panitumumab, 10 mg J9305 Injection, pemetrexed, 10 mg J9310 Rituximab, 100 mg J9320 Streptozocin, 1 g J9330 INJECTION, TEMSIROLIMUS, 1 MG J9340 Thiotepa, 15 mg J9350 Topotecan, 4 mg J9355 Trastuzumab, 10 mg J9357 Valrubicin, intravesical, 200 mg J9360 Vinblastine sulfate, 1 mg J9370 Vincristine sulfate, 1 mg J9375 Vincristine sulfate, 2 mg J9380 Vincristine sulfate, 5 mg J9390 Vinorelbine tartrate, per 10 mg J9600 Injection, porfimer sodium, 75 mg J9999 NOC, antineoplastic drug Q0083 Chemotherapy administration by other than infusion technique only Q0084 Chemotherapy administration by infusion technique only, per visit Q0085 Chemotherapy administration by both infusion technique and other technique(s)

PAGE 36

36 Table A 1 Continued Healthcare Common Procedure Coding System Q2017 INJECTION, TENIPOSIDE, 50 MG Q2024 Injection, bevacizumab, 0.25 mg S0087 Alemtuzumab injection, 30 mg S0088 Imatinib injection, 100 mg S0115 BORTEZOMIB, 3.5 MG S0116 BEVACIZUMAB 100 MG S0172 CHLORAMBUCIL, ORAL, 2MG S0176 HYDROXYUREA, ORAL, 500MG S0178 LOMUSTINE, ORAL, 10MG S0182 PROCARBAZINE HYDROCHLORIDE, ORAL, 50MG S5019 Chemotherapy admin supplies S5020 Chemotherapy admin supplies S9329 Home infusion therapy, chemotherapy infusion: administrative services S9330 Home infusion therapy, continuous (24 hours or more) chemotherapy infusion: S9331 Home infusion therapy, intermittent (less than 24 hours) chemotherapy infusion:

PAGE 37

37 LIST OF REFERENCES 1. Ferlay J SI, Soerjomataram I, Ervik M Dikshit R et al. GLOBOCAN 2012 Cancer Incidence and Mortality Worldwide. International Agency for Researc h on Cancer. Lyon, France; 2013. 2. Cancer Stat Facts: Female Breast Cancer: National Cancer Institute. Bethesda, MD 3. Xuan Q, Gao K, Song Y, Zhao S, et al. Adherence to Needed Adjuvant Therapy Could Decrease Recurrence Rates for Rural Patients With Early Breast Cancer. Clin Breast Cancer 2016. 4. Michaelson JS, Silverstein M, Sgroi D, Cheongsiatmoy JA, et al. The effect of tumor size and lymph node status on breast carcino ma lethality. Cancer 2003;98 :2133 43. 5. Shek LL, Godolphin W. Model for breast cancer survival: relative prognostic roles of axillary nodal status, TNM stage, estrogen receptor concentration, and tumor necr osis. Cancer Research 1988;48 :5565 9. 6. Ugnat AM, Xie L, Morriss J, Semenciw R, Mao Y. Survival of women with breast cancer in Ottawa, Canada: variation with age, stage, histology, grade and t reatment. Br J Cancer 2004;90 :1138 43. 7. Kmmel A, Kmmel S, Barinoff J, Heitz F, et al. Prognostic Factors for Local, Loco regional and Systemic Recurrence in Early stage Breast Cancer. Geburtshilf e und Frauenheilkunde 2015;75 :710 8. 8. Lertsithichai P, Sakulchairungreung B, Chirappapha P, Suvikapakornkul R, et al. Effect of young age, positive margins, and triple negative status on disease recurrence after breast conservi ng therapy. Gland Surgery 2016;5 :15 23. 9. Schwartz AM, Henson DE, Chen D, Rajamarthandan S. Histologic grade remains a prognostic factor for breast cancer regardless of the number of positive lymph nodes and tumor size: a study of 161 708 cases of breast cancer from the SEER Program. Archives of pathology & laboratory medicine 2014;138 :1048 52. 10. lvarez Bauelos MT, Rosado Alcocer LM. Prognostic Factors Associated with Survival in Women with Breast Cancer from Veracruz, Mexico. Journal of Canc er Scien ce & Therapy 2016;8 11. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Resear ch 2007;9: 6. 12. Chen L, Linden HM, Anderson BO, Li CI. Trends in 5 year survival rates among breast cancer patients by hormone receptor status and stage. Bre ast Cancer Res Treat 2014;147 :609 16.

PAGE 38

38 13. Li X, Yang J, Peng L, Sahin AA, et al. Triple negative breast cancer has worse overall survival and cause specific survival than non triple negative breast cancer. Breast Cancer Re search and Treatment 2017;161 :279 87. 14. Gajdos C, Tartter PI, Bleiweiss IJ, Bodian C, Brower ST. Stage 0 to stage III breast cancer in young women. Journal of the American College of Surgeons 2000;190 :523 9. 15. Chan DS, Vieira AR, Aune D, Bandera EV, et al. Body mass index and survival in women with breast cancer systematic literature review and meta analysis of 82 follow up studies. Annals of Oncology : Official Journal of the European Society for Medical Oncology 2014;25 :1901 14. 16. Imkampe AK, Bates T. Impact of a raised body mass index on breast cancer survival in relation to age and disease extent at diagnosis. The Breast journal 20 10;16 :156 61. 17. Seitz HK, Peluc chi C, Bagnardi V, Vecchia CL. Epidemiology and Pathophysiology of Alcohol and Breast Cancer: Update 2012. A lcohol and Alcoholism 2012;47 :204 12. 18. Dam MK, Hvidtfeldt UA, Tjnneland A, Overvad K, Grnbk M, Tolstrup JS. Five year change in alcohol intak e and risk of breast cancer and coronary heart disease among postmenopausal women: prospective cohort study. BMJ 2016;353. 19. Singletary KW, Gapstur SM. Alcohol and breast cancer: review of epidemiologic and experimental evidence and potenti al mechanisms Jama 2001;286 :2143 51. 20. Park SY, Kolonel LN, Lim U, White KK, Henderson BE, Wilkens LR. Alcohol consumption and breast cancer risk among women from five ethnic groups with light to moderate intakes: the Multiethnic Cohort Study. Internation al Journal of Cancer 2014;134 :1504 10. 21. Liu Y, Colditz GA, Rosner B, Berkey CS, et al. Alcohol intake between menarche and first pregnancy: a prospective study of breast cancer risk. J Natl Cancer Inst 2013;105 :1571 8. 22. Alcohol, tobacco and breast cancer c ollaborative reanalysis of individual data from 53 the disease. Briti sh Journal of Cancer 2002;87 :1234 45. 23. Vrieling A, Buck K, Heinz J, Obi N, et al. Pre diagn ostic alcohol consumption and postmenopausal breast cancer survival: a prospective patient cohort study. Bre ast Cancer Res Treat 2012;136 :195 207. 24. Kwan ML, Kushi LH, Weltzien E, Tam EK, et al. Alcohol consumption and breast cancer recurrence and survi val among women with early stage breast cancer: the life after cancer epidemiology study. J Clin Oncol 2010;28 :4410 6.

PAGE 39

39 25. Li CI, Daling JR, Porter PL, Tang MT, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second pr imary contralateral breast cancer among women diagnosed with estrogen receptor positive invasive breast cance r. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009;27 :5312 8. 26. Clarke M. Meta analyses of adju vant therapies for women with early breast cancer: the Early Breast Cancer Trialists' Collaborative Gro up overview. Annals of oncology : official journal of the European Society for Medical Oncology 2006;17 Suppl 10:59 62. 27. Davies C, Pan H, Godwin J, Gray R, et al. Long term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor positive breast cancer: ATLAS, a randomi sed trial. Lancet 2013;381 :805 16. 28. Horn Ross PL, Canchola AJ, Bernstein L, Clarke CA, et al. Alcohol consumption and breast cancer risk among postmenopausal women following the cessation of hormone therapy use: the California Teachers Study. Cancer Epide miol Biomarkers Prev 2012;21 :2006 13. 29. Hill AB. The Environment and Disease: Association or Causation? Proceedings of the Roya l Society of Medicine 1965;58 :295 300. 30. Kim SK, Novak RF. The role of intracellular signaling in insulin mediated regulation of drug metabolizing enzyme gene a nd protein expression. Pharmac ology & Therapeutics 2007;113 :88 120. 31. Bosch TM, Meijerman I, Beijnen JH, Schellens JH. Genetic poly morphisms of drug metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. Clinical Pharmac okinetics 2006;45 :253 85. 32. Chumsri S, Howes T, Bao T, Sabnis G, Brodie A. Aromatase, Aromatase Inhibitors, and Breast Cancer. The Journal of Steroid Biochemistry and Molecular Biology 2011;125 :13 22. 33. Purohit V. Can alcohol promote aromatization of androgens to estroge ns? A review. Alcohol 2000;22 :123 7. 34. Kim S, Sandler DP, Carswell G, De Roo LA, et al. Telomere length in peripheral blood and breast cancer risk in a prospective case cohort analysis: results from the Sister Study. Cancer Causes Control 2011; 22 :1061 6. 35. Schoenborn CAaA, Patricia F. Alcohol Use Among Adults: United States, 1997 98. CDC Advance Data From Vital and Health Statistics 200 36. U.S. Department of Health and Human Services and U.S. Department of Agriculture Dietary Guidelines for Americans, 2005. 6th Edition. Washington, DC: U.S. Government Printing Office; 2005.

PAGE 40

40 37. Hass ett MJ, Ritzwoller DP, Taback N Carroll N, et al. Validating billing/encounter codes as indicators of lung, colorectal, breast, and prostate cancer recurrence using 2 large contemporary c ohorts. Medical Care 2014;52: 65 73. 38. Gnerlich JL, Deshpande AD, Jeffe DB, Sweet A, White N, Margenthaler JA. Elevated Breast Cancer Mortality in Women Younger than Age 40 Years Compared with Older Women Is Attributed to Poorer Survival in Early Stage Disease. Journal of the American College of Surgeons 2009;208 :341 7. 39. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Mod el. New York: Springer 2000; 140 52. 40. Newcomb PA, Kampman E, T rentham Dietz A, Egan KM, et al. Alcohol consumption before and after breast cancer diagnosis: associations with survival from breast cancer, cardiovascular disease, and other causes. J Clin Oncol 2013;31 :1939 46. 41. Behrens G, Leitzmann MF, Sandin S, Lo f M, et al. The association between alcohol consumption and mortality: the Swedish women's lifestyle and health study. European Jo urnal of Epidemiology 2011;26 :81 90. 42. Flatt SW, Thomson CA, Gold EB, Natarajan L, et al. Low to moderate alcohol intake is not associated with increased mortality after breast cancer. Cancer Epid emiol Biomarkers Prev 2010;19 :681 8. 43. Trentham Dietz A, Newcomb PA, Nichols HB, Hampton JM. Breast cancer risk factors and second primary malignancies among women with breast canc er. Breast Cancer Re s Treat 2007;105 :195 207. 44. Allemani C, Berrino F, Krogh V, Sieri S, et al. Do pre diagnostic drinking habits influence breast ca ncer survival? Tumori 2011;97 :142 8. 45. Kwan ML, Chen WY, Flatt SW, Weltzien EK, et al. Postdiagnosis alcohol consumption and breast cancer prognosis in the after breast cancer pooling project. Cancer Epidemi ology Biomarkers Prev 2013;22 :32 41. 46. Reding KW, Daling JR, Doody DR, O'Brien CA, Porter PL, Malone KE. Effect of prediagnostic alcohol consumptio n on survival after breast cancer in young women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2008;17 :1988 96. 47. Barnett GC, Sha h M, Redman K, Easton DF, Ponder BAJ, Pharoah PDP. Risk Factors for the Incidence of Breast Cancer: Do They Affect Survival From the Disease? Journal of Clinical Oncology 2008;26 :3310 6.

PAGE 41

41 48. Dumitrescu RG, Shields PG. The etiology of alcohol induced b reast cancer. Alcohol 2005;35 :213 25. 49. Meskar A, Plee Gautier E, Amet Y, Berthou F, Lucas D. Alcohol xenobiotic interactions. Role of cytochrome P450 2E1 Pathologie biologie 2001;49 :696 702. 50. Daniel J. Klein, Caroline F. Thorn, Zeruesenay Desta, D avid A. Flockhart, Russ B. Altman, Klein. TE. PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenetics and genomics 2013. 51. Weathermon R, Crabb DW. Alcohol and medication interactions. Alcohol research & health : the Journal of the Nation al Institute on Alcohol Abuse an d Alcoholism 1999;23 :40 54. 52. Del Boca FK, Darkes J. The validity of self reports of alcohol consumption: state of the science and challenges for research. Addiction 2003;98:1 12. 53. Feunekes GI, van 't Veer P, van Stav eren WA, Kok FJ. Alcohol intake assessment: the sober facts. AmericanJjou rnal of Epidemiology 1999;150 :105 12. 54. Glovannucci E, Colditz G, Stampfer MJ, Rimm EB et al. The Assessment of Alcohol Consumption by a Simple Self administered Questionnaire. Am erican Jou rnal of Epidemiology 1991;133 :810 7.

PAGE 42

42 BIOLOGICAL SKETCH University. She began her study at the University of Florida in the fall of 2015. She received her Master of Science in epidemiology fro m the University of Florida in s pring 2017