Abstract
Background:
The impact of alcohol consumption on breast cancer (BC) prognosis remains unclear.
Methods:
We examined short-term alcohol intake in relation to recurrence and mortality in 3,659 women diagnosed with Stage I-IV BC from 2005–2013 in the Pathways Study. Alcohol drinking in the past 6 months was assessed at cohort entry (mean=2 months post-diagnosis) and 6 months later using a food frequency questionnaire. Study endpoints were recurrence and death due to BC, cardiovascular disease (CVD), and all causes. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models.
Results:
Over an average follow-up of 11.2 years, 524 recurrences and 834 deaths (369 BC-specific and 314 CVD-specific) occurred. Compared with non-drinkers (36.9%), drinkers were more likely younger, more educated, and current or past smokers. Overall, alcohol consumption was not associated with recurrence or mortality. However, women with higher body mass index (BMI≥30 kg/m2) had lower risk of overall mortality with increasing alcohol consumption for occasional (HR=0.71; 95% CI: 0.54–0.94) and regular drinking (HR=0.77; 95% CI: 0.56–1.08) around diagnosis, along with six months later, in a dose-response manner (p<.05). Women with lower BMI<30 kg/m2 were not at higher risk of mortality but possibly higher, yet non-significant, risk of recurrence for occasional (HR=1.29; 95% CI: 0.97–1.71) and regular drinking (HR=1.19; 95% CI: 0.88–1.62).
Conclusions:
Alcohol drinking around and up to six months after BC diagnosis was associated with lower risk of all-cause mortality in obese women. A possible higher risk of recurrence was observed in non-obese women.
Keywords: alcohol, ethanol, estrogen, breast cancer, recurrence, mortality, prognosis
Precis
Alcohol consumption around and up to six months after breast cancer diagnosis was associated with lower risk of all-cause mortality in women with obesity in the Pathways Study. A potential association of alcohol intake with increased risk of recurrence in women without obesity was suggested.
Introduction
Many women with a history of breast cancer are interested in how to improve their prognosis and survival by making lifestyle changes after diagnosis. Alcohol consumption is of high interest and generally recognized to increase risk of breast cancer.1–3 The most common hypothesized mechanisms for greater risk are increased alcohol metabolism resulting in high circulating levels of the carcinogen acetaldehyde, particularly in premenopausal women, and alcohol elevating endogenous estrogen levels and upregulating estrogen receptors under certain hormonal conditions in pre- and postmenopausal women.4–9
Current cancer prevention guidelines recommend avoiding alcohol intake or limiting consumption to no more than 1 drink per day for women.1,10 However, no specific guideline exists for cancer survivors, other than following the cancer prevention guidelines to reduce the risk of a second cancer.10 A modest number of studies have examined alcohol consumption (primarily before diagnosis) and outcomes after breast cancer diagnosis with inconclusive results. The most recent systematic review on this topic reported some evidence that alcohol intake increases the risk of breast cancer recurrence, specifically in postmenopausal women.11 Further, moderate alcohol intake has been associated with reduced risk of cardiovascular death, which is a major cause of mortality second to breast cancer in breast cancer survivors.12,13 Overall, studies of alcohol and breast cancer prognosis have suffered from methodological challenges, namely varied disease endpoints, narrow ranges of exposure to alcohol, pre-diagnosis rather than post-diagnosis exposure assessment, and failure to adjust for important prognostic factors.11,14,15
We conducted a comprehensive investigation of peri-diagnosis and early post-diagnosis alcohol consumption and breast cancer recurrence and mortality in 3,659 breast cancer survivors in the Pathways Study. This is the largest analysis from a single prospective cohort study of women with breast cancer on short-term alcohol intake and prognosis. We also examined potential effect modification by a priori estrogenic factors including menopausal status, estrogen receptor status, and obesity.
Materials and Methods
The Pathways Study
The Pathways Study is a prospective cohort study of 4,504 female breast cancer survivors diagnosed with invasive breast cancer from 2005 to 2013 at Kaiser Permanente Northern California (KPNC).16 Eligibility criteria included being female; aged 21 years or older at diagnosis; KPNC member; speaking English, Spanish, Cantonese, or Mandarin; living within a 65-mile radius of a field interviewer; diagnosis of first invasive breast cancer; and no prior history of other invasive cancers. The study was approved by the KPNC institutional review board, and written informed consent was obtained from study participants.
Alcohol Consumption
Alcohol consumption was collected from participants at enrollment into the cohort and six months later using an expanded version of the Block 2005 Food Frequency Questionnaire (FFQ) consisting of 139 food items.17 Women reported their average frequency of consumption over the past six months for wine, beer, and liquor. A medium serving size was defined as one 6-ounce (oz) glass, one 12-oz can or bottle, or one 1.5-oz shot. Baseline assessment captured the period just before and around the time of breast cancer diagnosis (peri-diagnosis), while the six-month assessment captured the early period after breast cancer diagnosis (post-diagnosis).
Servings per day of each alcoholic beverage were converted to grams (g) per day of alcohol (one standard drink in the U.S. is about 12.0–14.0 g of pure ethanol18), and respondents were categorized as non-drinker (<0.36 g/day), occasional drinker (0.36-<6.0 g/day), and regular drinker (≥6.0 g/day). Half a drink per day (6.0 g) represented the cutpoint for regular drinker, as the median level of intake among drinkers in the cohort was 5.5 g/day and the current cancer prevention guidelines advise no more than one drink per day for women with no history of cancer.2,10 Higher consumption categories were also created to examine dose response relationships in regular drinkers: regular low (6.0-<12.0 g/day), regular medium (12.0-<24.0 g/day), and regular high (≥24.0 g/day).
Covariates
Sociodemographic and lifestyle factors.
The baseline questionnaire included questions on self-reported race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Asian/Pacific Islander, Hispanic, American Indian/Alaska Native), education (high school or less, some college, college graduate, post-graduate), menopausal status at diagnosis (premenopausal, postmenopausal), nulliparity at diagnosis (no, yes), and smoking history at diagnosis (never, past, current). Moderate-vigorous physical activity in minutes per week in the past six months at baseline was determined from the validated Arizona Activity Frequency Questionnaire19 and classified as meeting or not meeting the 2018 Physical Activity Guidelines of at least 150 minutes per week or more of moderate-vigorous intensity aerobic activity.20 Body mass index (BMI) at diagnosis was determined from the electronic health record (EHR) and supplemented with baseline self-report if EHR data were not available (<5%). A census block group-level composite measure of neighborhood socioeconomic status (nSES) was derived.21,22
Clinical and treatment characteristics.
Data were obtained from the KPNC Cancer Registry and electronic databases including the Virtual Data Warehouse.23 Characteristics included age at cancer diagnosis (years), AJCC stage 7th edition (I, II, III, IV), estrogen receptor (ER)/progesterone receptor (PR) status (ER+/PR+, ER+/PR-, ER-/PR+, ER-/PR-), human epidermal growth factor receptor 2 (Her2) status (negative, positive), chemotherapy (no, yes), radiation therapy (no, yes), endocrine therapy (no, yes), surgery type (none, lumpectomy, mastectomy), comorbidity status (Charlson comorbidity index), and history of alcohol dependence at baseline (ICD-9 303, ICD-10 F10.2).
Study Outcomes
Study outcomes included breast cancer recurrence, breast cancer mortality, cardiovascular disease (CVD) mortality, and all-cause mortality. Recurrences were ascertained during follow-up interviews at 6, 12, 24, 48, 72, and 96 months, and biennially thereafter with participants, and from monthly algorithmic searches of KPNC electronic databases. All recurrences were confirmed by EHR chart review. Deaths and primary causes of death were identified from periodic linkages with vital statistics data from the state of California, the Social Security Administration, and the National Death Index. Death information was also obtained from KPNC sources and relatives of deceased participants during routine follow-up interviews, and then confirmed by EHR chart review.
Final Samples
For analyses of alcohol consumption peri-diagnosis, 845 women with a missing baseline FFQ were excluded from the full cohort, leaving a final sample size of 3,659 for analysis. For analyses of alcohol consumption during the six months post-diagnosis, 1,741 women with a missing six-month follow-up FFQ were excluded from the full cohort, leaving a final sample size of 2,763 for analysis. A total of 2,576 women were included in both analytic cohorts.
Statistical Analysis
Sociodemographic, lifestyle, and clinical characteristics, overall and by category of baseline alcohol intake, were summarized by frequency distributions for categorical variables and means with standard deviations (SD) for continuous variables.
Cox proportional hazards regression models estimated cause-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with time since diagnosis as the time scale.24 The entry date was the date of Pathways Study enrollment (signified by completion of the baseline interview). For recurrence, censoring was first of health plan disenrollment or study drop-out, death, or end of study (12/31/2021). Women with Stage IV breast cancer were not at risk of recurrence and thus excluded (n=56). For breast cancer mortality, censoring was on first of health plan disenrollment or study drop-out, death from other causes, or end of study. For CVD mortality, censoring was on first of death from other causes or end of study. For all-cause mortality, censoring was at end of study. The proportional hazards assumption was assessed by Schoenfeld residuals. Tests for linear trend were performed by modeling the continuous alcohol intake variable. Statistical significance was considered as p<.05 or 95% CI not overlapping with 1.0.
Covariates were chosen a priori from literature review. Age at diagnosis, AJCC stage, race and ethnicity, education, nSES, menopausal status at diagnosis, nulliparity at diagnosis, ER/PR status, surgery, treatment (radiation therapy, chemotherapy, endocrine therapy), smoking history at diagnosis, physical activity at diagnosis, BMI at diagnosis, comorbidity at diagnosis, and alcohol dependence at diagnosis were retained.
Possible a priori effect modification was evaluated in associations of alcohol consumption (3-level alcohol variable) with recurrence and all-cause mortality by menopausal status (premenopausal vs. postmenopausal), ER status (ER+ vs. ER-), and obesity (obese vs. non-obese) in stratified analyses. Statistical significance of multiplicative interaction terms was assessed by a Wald test of the cross-product terms between the main exposure (3-level alcohol variable) and the potential effect modifier (dichotomous variable described above) in the Cox models. Statistical significance was considered as p<.10.
Results
Over a mean follow-up of 11.2 years, 524 recurrences and 834 deaths (369 breast cancer-specific and 314 CVD-specific) were confirmed. Mean time (range) from breast cancer diagnosis was 4.9 (0.5–15.3) years to recurrence and 6.9 (0.3–15.0) years to death. Alcohol consumption was assessed at baseline, on average 2.3 months post-diagnosis (range: 0.7–18.7), and at six-month follow-up, on average 8.4 months post-diagnosis (range: 6.1–23.9). The time difference between these two assessments was mean 6.1 (range: 2.9–12.0) months.
Cohort characteristics by categories of alcohol consumption (g/day) of non-drinkers, occasional drinkers, and regular drinkers are shown in Table 1. Mean age at breast cancer diagnosis was 59.7 years, and 71.1% were postmenopausal at diagnosis. The racial and ethnic distribution was 68.1% non-Hispanic white, 6.6% non-Hispanic Black, 13.0% Asian/Pacific Islander, 10.3% Hispanic, and 2.1% American Indian/Alaska Native. Most women (85.0%) had at least some college education, 89.1% were diagnosed with Stage I or II tumors, and 84.2% of the tumors were ER+ and/or PR+. Compared with non-drinkers (36.9%), drinkers were more likely to be younger and premenopausal, more educated, diagnosed with earlier stage, hormone receptor positive breast cancer, and received radiation therapy or endocrine therapy. Drinkers also tended to be current or past smokers, more physically active, leaner, and with fewer comorbidities.
Table 1.
Baseline characteristics of the Pathways Study (n=3659) by alcohol consumption around breast cancer diagnosis
| Overall | Non-drinker (<0.36 g/day) |
Occasional (0.36-<6 g/day) |
Regular (≥6 g/day) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| n=3659 | n=1352 | n=1211 | n=1096 | ||||||||
| Age at diagnosis, years (mean, SD) | 59.68 (11.9) | 60.30 (12.2) | 59.02 (11.9) | 59.65 (11.5) | |||||||
| BMI at diagnosis, kg/m2 (mean, SD) | 28.46 (6.7) | 29.31 (7.2) | 28.89 (6.8) | 26.94 (5.7) | |||||||
|
Total folate intake, mcg/day
(median, range) |
329.96 (1215.2) | 316 (1215.2) | 337.75 (1060.3) | 339.53 (975.0) | |||||||
| n | (%) | n | (%) | n | (%) | n | (%) | ||||
| Race/Ethnicity | |||||||||||
| Non-Hispanic White | 2490 | (68.1) | 757 | (56) | 805 | (66.5) | 928 | (84.7) | |||
| Non-Hispanic Black | 240 | (6.6) | 114 | (8.4) | 83 | (6.9) | 43 | (3.9) | |||
| Asian/Pacific Islander | 475 | (13.0) | 287 | (21.2) | 141 | (11.6) | 47 | (4.3) | |||
| Hispanic | 378 | (10.3) | 161 | (11.9) | 154 | (12.7) | 63 | (5.8) | |||
| American Indian/Alaska Native | 76 | (2.1) | 33 | (2.4) | 28 | (2.3) | 15 | (1.4) | |||
| Education | |||||||||||
| High school or less | 547 | (15.0) | 278 | (20.6) | 160 | (13.2) | 109 | (10.0) | |||
| Some college | 1244 | (34.0) | 463 | (34.3) | 431 | (35.6) | 350 | (32.0) | |||
| College grad | 1024 | (28.0) | 381 | (28.2) | 337 | (27.9) | 306 | (28.0) | |||
| Post grad | 842 | (23.0) | 230 | (17.0) | 282 | (23.3) | 330 | (30.1) | |||
| Neighborhood SES a | |||||||||||
| Quintile 1 | 148 | (4.2) | 74 | (5.7) | 51 | (4.3) | 23 | (2.2) | |||
| Quintile 2 | 409 | (11.6) | 189 | (14.4) | 141 | (12.0) | 79 | (7.5) | |||
| Quintile 3 | 717 | (20.3) | 282 | (21.5) | 242 | (20.6) | 193 | (18.3) | |||
| Quintile 4 | 1043 | (29.5) | 387 | (29.6) | 340 | (28.9) | 316 | (30.0) | |||
| Quintile 5 | 1222 | (34.5) | 377 | (28.8) | 402 | (34.2) | 443 | (42.0) | |||
| Menopausal Status at Diagnosis | |||||||||||
| Premenopausal | 1059 | (28.9) | 388 | (28.7) | 355 | (29.3) | 316 | (28.8) | |||
| Postmenopausal | 2600 | (71.1) | 964 | (71.3) | 856 | (70.7) | 780 | (71.2) | |||
| Nulliparity at Diagnosis | |||||||||||
| No | 2944 | (80.5) | 1135 | (84.0) | 1000 | (82.6) | 809 | (73.9) | |||
| Yes | 713 | (19.5) | 217 | (16.1) | 210 | (17.4) | 286 | (26.1) | |||
| AJCC Stage 7th Edition | |||||||||||
| I | 2007 | (54.9) | 714 | (52.8) | 656 | (54.2) | 637 | (58.1) | |||
| II | 1250 | (34.2) | 471 | (34.8) | 428 | (35.3) | 351 | (32.0) | |||
| III | 346 | (9.5) | 145 | (10.7) | 106 | (8.8) | 95 | (8.7) | |||
| IV | 56 | (1.5) | 22 | (1.6) | 21 | (1.7) | 13 | (1.2) | |||
| Hormone Receptor Status | |||||||||||
| ER+/PR+ | 2341 | (64.1) | 841 | (62.4) | 761 | (62.8) | 739 | (67.4) | |||
| ER+/PR- | 729 | (20.0) | 281 | (20.9) | 243 | (20.1) | 205 | (18.7) | |||
| ER-/PR+ | 6 | (0.2) | 1 | (0.1) | 2 | (0.2) | 3 | (0.3) | |||
| ER-/PR- | 579 | (15.8) | 225 | (16.7) | 205 | (16.9) | 149 | (13.6) | |||
| Chemotherapy | |||||||||||
| No | 1940 | (53.2) | 716 | (53.0) | 616 | (51.0) | 608 | (55.8) | |||
| Yes | 1708 | (46.8) | 634 | (47.0) | 592 | (49.0) | 482 | (44.2) | |||
| Radiation Therapy | |||||||||||
| No | 1940 | (53.2) | 716 | (53.0) | 616 | (51.0) | 608 | (55.8) | |||
| Yes | 1708 | (46.8) | 634 | (47.0) | 592 | (49.0) | 482 | (44.2) | |||
| Endocrine Therapy | |||||||||||
| No | 2038 | (55.7) | 802 | (59.3) | 683 | (56.4) | 553 | (50.5) | |||
| Yes | 1621 | (44.3) | 550 | (40.7) | 528 | (43.6) | 543 | (49.5) | |||
| Surgery Type | |||||||||||
| None | 118 | (3.2) | 45 | (3.3) | 54 | (4.5) | 19 | (1.7) | |||
| Lumpectomy | 2177 | (59.5) | 747 | (55.3) | 712 | (58.8) | 718 | (65.5) | |||
| Mastectomy | 1362 | (37.2) | 558 | (41.3) | 445 | (36.8) | 359 | (32.8) | |||
| Smoking History | |||||||||||
| Never | 2091 | (57.2) | 885 | (65.5) | 725 | (60.0) | 481 | (44.0) | |||
| Past | 1408 | (38.5) | 414 | (30.6) | 441 | (36.5) | 553 | (50.6) | |||
| Current | 154 | (4.2) | 53 | (3.9) | 42 | (3.5) | 59 | (5.4) | |||
| Any Comorbidity at Diagnosis | |||||||||||
| No | 3283 | (89.7) | 1166 | (86.2) | 1098 | (90.7) | 1019 | (93.0) | |||
| Yes | 376 | (10.3) | 186 | (13.8) | 113 | (9.3) | 77 | (7.0) | |||
| History of Alcohol Dependence at Diagnosis | |||||||||||
| No | 3620 | (98.9) | 1337 | (98.9) | 1203 | (99.3) | 1080 | (98.5) | |||
| Yes | 39 | (1.1) | 15 | (1.1) | 8 | (0.7) | 16 | (1.5) | |||
| Met 2018 Physical Activity Guidelines for Americans at Diagnosis | |||||||||||
| No | 1149 | (31.4) | 551 | (40.8) | 363 | (30.0) | 235 | (21.5) | |||
| Yes | 2506 | (68.6) | 800 | (59.2) | 848 | (70.0) | 858 | (78.5) | |||
NOTE: Missing values for covariates were as follows: race/ethnicity (n=0), education (n=2), neighborhood SES (n=120), menopausal status (n=0), nulliparity (n=2), AJCC stage (n=0), hormone receptor status (n=4), chemotherapy (n=11), radiation therapy (n=0), hormonal therapy (n=25), surgery type (n=2), smoking history (n=6), any comorbidity (n=0), history of alcohol dependence (n=0), and met 2018 Physical Activity Guidelines for Americans of 150 minutes per week of moderate-vigorous physical activity (n=4)
NOTE: 0.36 g/day and 6 g/day of ethanol are approximately 0.25 drinks/week and 3.5 drinks/week, respectively
The mean (SD) g/day of alcohol (ethanol) consumption at baseline was 7.1 (12.8) while the median was 1.0 (interquartile [IQ] range: 168.1) (Supplemental Table 1). The distribution of alcohol consumption was skewed by a small proportion of heavy drinkers. Among the drinkers (≥0.36 g/day), the mean (SD) consumption for occasional drinkers was 2.0 (1.6) g/day (median 1.3; IQ range: 5.6) and regular drinkers was 21.4 (15.9) g/day (median 16.7; IQ range: 162.1). At the six-month follow-up, drinking levels were lower. The mean (SD) was 5.7 (11.1) g/day. Among the drinkers (≥0.36 g/day), the mean (SD) consumption for occasional drinkers was 1.8 (1.5) g/day and regular drinkers was 20.1 (14.1) g/day.
Table 2 shows the associations between alcohol consumption peri-diagnosis and post-diagnosis and study endpoints of recurrence, all-cause mortality, breast cancer mortality, and CVD mortality. For peri-diagnosis consumption, compared with no consumption, occasional (0.36-<0.6 g/day) and regular consumption of alcohol (≥6.0 g/day) were not associated with any outcomes. No significant dose-response effect for increasing consumption was found. For alcohol drinking post-diagnosis, all the associations were non-significant, including for all-cause mortality, with no significant dose-response effects observed. Across all models, type of alcohol, including wine, beer, and liquor, was not associated with any outcome, except for beer consumed at follow-up was associated with higher risk of breast cancer mortality (HR=1.47; 95% CI: 1.06–2.03).
Table 2.
Associations of alcohol consumption around breast cancer diagnosis and 6 months post-breast cancer diagnosis and recurrence and mortality in the Pathways Study
| Alcohol Consumption Around Breast Cancer Diagnosis | Alcohol Consumption 6 months Post-Breast Cancer Diagnosis | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Recurrence | n=3659 (524 events) | n=2763 (372 events) | |||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 1352 | 186 | Ref | Ref | Ref | 1183 | 168 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 191 | 1.14 | 0.92 | 1.42 | 878 | 112 | 1.06 | 0.81 | 1.39 | |
| Regular (≥6g/day) | 1096 | 147 | 1.07 | 0.84 | 1.36 | 702 | 92 | 1.26 | 0.94 | 1.69 | |
| p for trend | .52 | .13 | |||||||||
| Non-drinker (<0.36 g/day) | 1352 | 186 | Ref | Ref | Ref | 1183 | 168 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 191 | 1.14 | 0.92 | 1.42 | 878 | 112 | 1.06 | 0.81 | 1.39 | |
| Regular low (6-<12 g/day) | 356 | 51 | 1.05 | 0.76 | 1.47 | 259 | 37 | 1.35 | 0.91 | 2.00 | |
| Regular medium (12-<24 g/day) | 414 | 55 | 1.11 | 0.80 | 1.54 | 241 | 29 | 1.09 | 0.70 | 1.69 | |
| Regular high (≥24 g/day) | 326 | 41 | 1.04 | 0.73 | 1.50 | 202 | 26 | 1.35 | 0.87 | 2.11 | |
| p for trend | .71 | .15 | |||||||||
| Continuous 6 g/day | 3659 | 524 | 1.00 | 0.99 | 1.01 | 2763 | 372 | 1.01 | 1.00 | 1.02 | |
| Wine | |||||||||||
| No | 1273 | 188 | Ref | Ref | Ref | 1099 | 149 | Ref | Ref | Ref | |
| Yes | 2386 | 336 | 0.91 | 0.73 | 1.14 | 1664 | 223 | 1.11 | 0.85 | 1.45 | |
| Beer | |||||||||||
| No | 2356 | 333 | Ref | Ref | Ref | 1924 | 254 | Ref | Ref | Ref | |
| Yes | 1303 | 191 | 1.09 | 0.88 | 1.35 | 839 | 118 | 1.24 | 0.96 | 1.62 | |
| Liquor | |||||||||||
| No | 2724 | 395 | Ref | Ref | Ref | 1771 | 241 | Ref | Ref | Ref | |
| Yes | 935 | 129 | 1.05 | 0.84 | 1.30 | 992 | 131 | 1.04 | 0.81 | 1.34 | |
| All-Cause Mortality | n=3659 (834 events) | n=2763 (594 events) | |||||||||
| n | events | HRa,c | 95% CI | n | events | HRa,c | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 1352 | 342 | Ref | Ref | Ref | 1183 | 287 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 268 | 0.97 | 0.82 | 1.15 | 878 | 163 | 0.89 | 0.72 | 1.10 | |
| Regular (≥6g/day) | 1096 | 224 | 0.89 | 0.74 | 1.08 | 702 | 144 | 0.95 | 0.76 | 1.19 | |
| p for trend | .25 | .54 | |||||||||
| Non-drinker (<0.36 g/day) | 1352 | 342 | Ref | Ref | Ref | 1183 | 287 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 268 | 0.97 | 0.82 | 1.15 | 878 | 163 | 0.89 | 0.72 | 1.10 | |
| Regular low (6-<12 g/day) | 356 | 69 | 0.87 | 0.66 | 1.15 | 259 | 52 | 0.97 | 0.69 | 1.35 | |
| Regular medium (12-<24 g/day) | 414 | 89 | 1.02 | 0.79 | 1.31 | 241 | 47 | 0.85 | 0.61 | 1.19 | |
| Regular high (≥24 g/day) | 326 | 66 | 0.78 | 0.58 | 1.03 | 202 | 45 | 1.05 | 0.75 | 1.48 | |
| p for trend | .18 | .78 | |||||||||
| Continuous 6 g/day | 3659 | 834 | 1.00 | 0.99 | 1.00 | 2763 | 594 | 1.00 | 1.00 | 1.01 | |
| Wine | |||||||||||
| No | 1273 | 326 | Ref | Ref | Ref | 1099 | 257 | Ref | Ref | Ref | |
| Yes | 2386 | 508 | 0.96 | 0.82 | 1.14 | 1664 | 337 | 1.00 | 0.82 | 1.23 | |
| Beer | |||||||||||
| No | 2356 | 569 | Ref | Ref | Ref | 1924 | 442 | Ref | Ref | Ref | |
| Yes | 1303 | 265 | 1.00 | 0.84 | 1.18 | 839 | 152 | 1.01 | 0.81 | 1.26 | |
| Liquor | |||||||||||
| No | 2724 | 661 | Ref | Ref | Ref | 1771 | 414 | Ref | Ref | Ref | |
| Yes | 935 | 173 | 0.87 | 0.72 | 1.04 | 992 | 180 | 0.94 | 0.76 | 1.16 | |
| Breast Cancer Mortality | n=3659 (369 events) | n=2763 (246 events) | |||||||||
| n | events | HRa,d | 95% CI | n | events | HRa,d | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 1352 | 141 | Ref | Ref | Ref | 1183 | 122 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 132 | 1.04 | 0.81 | 1.35 | 878 | 74 | 1.08 | 0.78 | 1.50 | |
| Regular (≥6g/day) | 1096 | 96 | 0.95 | 0.71 | 1.27 | 702 | 50 | 1.12 | 0.77 | 1.62 | |
| p for trend | .77 | .53 | |||||||||
| Non-drinker (<0.36 g/day) | 1352 | 141 | Ref | Ref | Ref | 1183 | 122 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 132 | 1.04 | 0.81 | 1.35 | 878 | 74 | 1.08 | 0.78 | 1.50 | |
| Regular low (6-<12 g/day) | 356 | 31 | 0.89 | 0.59 | 1.35 | 259 | 22 | 1.40 | 0.86 | 2.29 | |
| Regular medium (12-<24 g/day) | 414 | 38 | 1.12 | 0.76 | 1.64 | 241 | 16 | 0.91 | 0.52 | 1.61 | |
| Regular high (≥24 g/day) | 326 | 27 | 0.83 | 0.53 | 1.30 | 202 | 12 | 1.03 | 0.55 | 1.92 | |
| p for trend | .66 | .81 | |||||||||
| Continuous 6 g/day | 3659 | 369 | 1.00 | 0.99 | 1.01 | 2763 | 246 | 1.00 | 0.99 | 1.02 | |
| Wine | |||||||||||
| No | 1273 | 140 | Ref | Ref | Ref | 1099 | 114 | Ref | Ref | Ref | |
| Yes | 2386 | 229 | 0.97 | 0.75 | 1.25 | 1664 | 132 | 0.98 | 0.71 | 1.35 | |
| Beer | |||||||||||
| No | 2356 | 240 | Ref | Ref | Ref | 1924 | 173 | Ref | Ref | Ref | |
| Yes | 1303 | 129 | 1.03 | 0.80 | 1.34 | 839 | 73 | 1.47 | 1.06 | 2.03 | |
| Liquor | |||||||||||
| No | 2724 | 297 | Ref | Ref | Ref | 1771 | 173 | Ref | Ref | Ref | |
| Yes | 935 | 72 | 0.82 | 0.62 | 1.09 | 992 | 73 | 0.86 | 0.62 | 1.20 | |
| CVD Mortality | n=3659 (314 events) | n=2763 (234 events) | |||||||||
| n | events | HRa,e | 95% CI | n | events | HRa,e | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 1352 | 139 | Ref | Ref | Ref | 1183 | 116 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 95 | 0.96 | 0.73 | 1.27 | 878 | 60 | 0.83 | 0.59 | 1.18 | |
| Regular (≥6g/day) | 1096 | 80 | 0.89 | 0.66 | 1.22 | 702 | 58 | 0.96 | 0.67 | 1.38 | |
| p for trend | .49 | .71 | |||||||||
| Non-drinker (<0.36 g/day) | 1352 | 139 | Ref | Ref | Ref | 1183 | 116 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 1211 | 95 | 0.96 | 0.73 | 1.27 | 878 | 60 | 0.83 | 0.59 | 1.18 | |
| Regular low (6-<12 g/day) | 356 | 23 | 0.85 | 0.52 | 1.36 | 259 | 18 | 0.87 | 0.49 | 1.54 | |
| Regular medium (12-<24 g/day) | 414 | 28 | 0.84 | 0.54 | 1.30 | 241 | 20 | 0.91 | 0.54 | 1.54 | |
| Regular high (≥24 g/day) | 326 | 29 | 1.00 | 0.65 | 1.56 | 202 | 20 | 1.11 | 0.67 | 1.86 | |
| p for trend | .64 | .94 | |||||||||
| Continuous 6 g/day | 3659 | 314 | 1.00 | 0.99 | 1.01 | 2763 | 234 | 1.01 | 1.00 | 1.02 | |
| Wine | |||||||||||
| No | 1273 | 122 | Ref | Ref | Ref | 1099 | 99 | Ref | Ref | Ref | |
| Yes | 2386 | 192 | 1.04 | 0.79 | 1.37 | 1664 | 135 | 1.03 | 0.73 | 1.44 | |
| Beer | |||||||||||
| No | 2356 | 216 | Ref | Ref | Ref | 1924 | 176 | Ref | Ref | Ref | |
| Yes | 1303 | 98 | 1.13 | 0.85 | 1.50 | 839 | 58 | 1.18 | 0.82 | 1.69 | |
| Liquor | |||||||||||
| No | 2724 | 252 | Ref | Ref | Ref | 1771 | 168 | Ref | Ref | Ref | |
| Yes | 935 | 62 | 0.79 | 0.59 | 1.07 | 992 | 66 | 0.88 | 0.63 | 1.24 | |
Adjusted for age at diagnosis, AJCC stage, race/ethnicity, education, menopausal status at diagnosis, nulliparity at diagnosis, hormone receptor status, surgery, treatment (radiation therapy, chemotherapy, endocrine therapy), smoking status at diagnosis, physical activity at diagnosis, BMI at diagnosis, comorbidity at diagnosis, neighborhood SES, and history of alcohol dependence at diagnosis.
For recurrence models, censored at first of KPNC health plan disenrollment or Pathways Study drop-out, death, or end of study (December 31, 2021).
For all-cause mortality models, censored at end of study (December 31, 2021).
For breast cancer mortality models, censored at first of KPNC health plan disenrollment or Pathways Study drop-out, death from other causes, or end of study (December 31, 2021).
For CVD mortality models, censored at death from other causes or end of study (December 31, 2021).
NOTE: 0.36 g/day, 6 g/day, and 12 g/day of ethanol are approximately 0.25 drinks/week, 3.5 drinks/week, and 7 drinks/week, respectively
Stratified analyses for risk of recurrence and alcohol consumption at peri-diagnosis in Table 3 and post-diagnosis in Table 4 are shown by menopausal status at diagnosis, ER status, and obesity status at diagnosis. Effect modification by obesity was observed for peri-diagnosis (p for interaction=.09) and post-diagnosis drinking (p for interaction=.07). Specifically, in non-obese women, occasional (HR for 0.36-<0.6 g/day=1.29; 95% CI: 0.97–1.71) and regular drinking (HR for ≥6.0 g/day=1.19; 95% CI: 0.88–1.62) at peri-diagnosis were associated with non-statistically significant increased risk of recurrence, whereas in obese women, no associations were apparent for occasional (HR for 0.36-<0.6 g/day=0.96; 95% CI: 0.68–1.36) and regular drinking (HR for ≥6.0 g/day=0.90; 95% CI: 0.58–1.40). For six-months post-diagnosis drinking, the HRs were in the same direction and not statistically significant, yet they were stronger in magnitude for the non-obese women (p for trend=.06).
Table 3.
Associations of alcohol consumption around breast cancer diagnosis and recurrence in the Pathways Study, stratified by estrogen-related factors
| Premenopausal | Postmenopausal | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| n=1059 (162 events) | n=2600 (362 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 388 | 55 | Ref | Ref | Ref | 964 | 131 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 355 | 63 | 1.18 | 0.79 | 1.75 | 856 | 128 | 1.13 | 0.87 | 1.46 | |
| Regular (≥6 g/day) | 316 | 44 | 1.13 | 0.71 | 1.77 | 780 | 103 | 1.05 | 0.78 | 1.40 | |
| p for trend | .58 | .71 | |||||||||
| p for interaction=.97 | |||||||||||
| Continuous 6 g/day | 1059 | 162 | 1.00 | 0.98 | 1.02 | 2600 | 362 | 1.00 | 0.99 | 1.01 | |
| ER-negative | ER-positive | ||||||||||
| n=586 (105 events) | n=3071 (419 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 227 | 39 | Ref | Ref | Ref | 1123 | 147 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 207 | 40 | 0.92 | 0.57 | 1.50 | 1004 | 151 | 1.18 | 0.93 | 1.51 | |
| Regular (≥6 g/day) | 152 | 26 | 0.90 | 0.51 | 1.59 | 944 | 121 | 1.11 | 0.85 | 1.46 | |
| p for trend | .71 | .38 | |||||||||
| p for interaction=.88 | |||||||||||
| Continuous 6 g/day | 586 | 105 | 1.00 | 0.98 | 1.02 | 3071 | 419 | 1.00 | 0.99 | 1.01 | |
| Obese (BMI≥30 kg/m2) | Non-obese (BMI<30 kg/m2) | ||||||||||
| n=1222 (192 events) | n=2437 (332 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 529 | 88 | Ref | Ref | Ref | 823 | 98 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 430 | 69 | 0.96 | 0.68 | 1.36 | 781 | 122 | 1.29 | 0.97 | 1.71 | |
| Regular (≥6 g/day) | 263 | 35 | 0.90 | 0.58 | 1.40 | 833 | 112 | 1.19 | 0.88 | 1.62 | |
| p for trend | .65 | .27 | |||||||||
| p for interaction=.09 | |||||||||||
| Continuous 6 g/day | 1222 | 192 | 1.00 | 0.99 | 1.02 | 2437 | 332 | 1.00 | 0.99 | 1.01 | |
Adjusted for age at diagnosis, AJCC stage, race/ethnicity, education, menopausal status at diagnosis, nulliparity at diagnosis, hormone receptor status, surgery, treatment (radiation therapy, chemotherapy, hormonal therapy), smoking status at diagnosis, physical activity at diagnosis, BMI at diagnosis, comorbidity at diagnosis history of alcohol dependence at diagnosis, and neighborhood SES, while excluding menopausal status, hormone receptor status, and BMI as appropriate depending on stratified model.
For recurrence models, censored at first of KPNC health plan disenrollment or Pathways Study drop-out, death, or end of study (December 31, 2021).
NOTE: 0.36 g/day and 6 g/day of ethanol are approximately 0.25 drinks/week and 3.5 drinks/week, respectively
Table 4.
Associations of alcohol consumption at 6 months post-breast cancer diagnosis and recurrence in the Pathways Study, stratified by estrogen-related factors
| Premenopausal | Postmenopausal | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| n=725 (107 events) | n=2038 (265 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 320 | 47 | Ref | Ref | Ref | 863 | 121 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 244 | 35 | 1.03 | 0.62 | 1.71 | 634 | 77 | 1.12 | 0.82 | 1.53 | |
| Regular (≥6 g/day) | 161 | 25 | 1.66 | 0.92 | 2.99 | 541 | 67 | 1.16 | 0.82 | 1.63 | |
| p for trend | .12 | .38 | |||||||||
| p for interaction=.32 | |||||||||||
| Continuous 6 g/day | 725 | 107 | 1.03 | 1.01 | 1.06 | 2038 | 265 | 1.00 | 0.99 | 1.01 | |
| ER-negative | ER-positive | ||||||||||
| n=431 (76 events) | n=2330 (296 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 209 | 36 | Ref | Ref | Ref | 973 | 132 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 133 | 25 | 1.10 | 0.61 | 2.00 | 744 | 87 | 1.05 | 0.78 | 1.42 | |
| Regular (≥6 g/day) | 89 | 15 | 0.96 | 0.47 | 1.94 | 613 | 77 | 1.32 | 0.96 | 1.83 | |
| p for trend | .96 | .11 | |||||||||
| p for interaction=.90 | |||||||||||
| Continuous 6 g/day | 431 | 76 | 0.99 | 0.96 | 1.02 | 2330 | 296 | 1.01 | 1.00 | 1.02 | |
| Obese (BMI≥30 kg/m2) | Non-obese (BMI<30 kg/m2) | ||||||||||
| n=882 (125 events) | n=1881 (247 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 437 | 75 | Ref | Ref | Ref | 746 | 93 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 290 | 30 | 0.66 | 0.40 | 1.07 | 588 | 82 | 1.35 | 0.96 | 1.88 | |
| Regular (≥6 g/day) | 155 | 20 | 1.26 | 0.72 | 2.21 | 547 | 72 | 1.41 | 0.98 | 2.02 | |
| p for trend | .97 | .06 | |||||||||
| p for interaction=.07 | |||||||||||
| Continuous 6 g/day | 882 | 125 | 1.01 | 0.99 | 1.03 | 1881 | 247 | 1.01 | 1.00 | 1.02 | |
Adjusted for age at diagnosis, AJCC stage, race/ethnicity, education, surgery, menopausal status at diagnosis, nulliparity at diagnosis, hormone receptor status, surgery, treatment (radiation therapy, chemotherapy, hormonal therapy), smoking status at diagnosis, physical activity at diagnosis, BMI at diagnosis, comorbidity at diagnosis, history of alcohol dependence at diagnosis, and neighborhood SES, while excluding menopausal status, hormone receptor status, and BMI as appropriate depending on stratified model.
For recurrence models, censored at first of KPNC health plan disenrollment or Pathways Study drop-out, death, or end of study (December 31, 2021).
NOTE: 0.36 g/day and 6 g/day of ethanol are approximately 0.25 drinks/week and 3.5 drinks/week, respectively
Similarly, stratified analyses for risk of all-cause mortality and alcohol consumption at peri-diagnosis and post-diagnosis are shown in Table 5 and Table 6, respectively. Effect modification by obesity was present for all-cause mortality risk for peri-diagnosis (p for interaction=.05) and post-diagnosis drinking (p for interaction=.02). For obese women, increasing peri-diagnosis consumption of alcohol was associated with decreased risk of all-cause mortality (p for trend=.04) with a statistically significant decreased risk for occasional drinking (HR for 0.36-<0.6 g/day=0.71; 95% CI: 0.54–0.94) but not significant for regular drinking (HR for ≥6.0 g/day=0.77; 95% CI: 0.56–1.08). In contrast, for non-obese women, occasional (HR for 0.36-<0.6 g/day=1.22; 95% CI: 0.97–1.53) and regular drinking (HR for ≥6.0 g/day=1.03; 95% CI: 0.81–1.31) were not associated with risk of all-cause mortality with no dose-response effect (p for trend=.80). For consumption at post-diagnosis, results were similar yet attenuated compared with peri-diagnosis consumption. In obese and non-obese stratified models of risk of breast cancer mortality (Supplemental Table 2) and CVD mortality (Supplemental Table 3), a similar pattern of lower risks in the obese women but not non-obese women was observed for peri-diagnosis and post-diagnosis drinking for CVD mortality (p for trend=.04 and .20) but not breast cancer mortality (p for trend=.73 and 0.29).
Table 5.
Associations of alcohol consumption around breast cancer diagnosis and all-cause mortality in the Pathways Study, stratified by estrogen-related factors
| Premenopausal | Postmenopausal1 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| n=1059 (150 events) | n=2600 (684 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 388 | 58 | Ref | Ref | Ref | 964 | 284 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 355 | 57 | 1.17 | 0.78 | 1.75 | 856 | 211 | 0.94 | 0.78 | 1.13 | |
| Regular (≥6 g/day) | 316 | 35 | 0.93 | 0.58 | 1.50 | 780 | 189 | 0.89 | 0.72 | 1.09 | |
| p for trend | .87 | .25 | |||||||||
| p for interaction=.42 | |||||||||||
| Continuous 6 g/day | 1059 | 150 | 0.99 | 0.97 | 1.01 | 2600 | 684 | 1.00 | 0.99 | 1.00 | |
| ER-negative | ER-positive | ||||||||||
| n=586 (155 events) | n=3071 (679 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 227 | 64 | Ref | Ref | Ref | 1123 | 278 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 207 | 59 | 0.97 | 0.65 | 1.43 | 1004 | 209 | 0.97 | 0.80 | 1.17 | |
| Regular (≥6 g/day) | 152 | 32 | 0.72 | 0.43 | 1.18 | 944 | 192 | 0.94 | 0.77 | 1.16 | |
| p for trend | .23 | .56 | |||||||||
| p for interaction=.39 | |||||||||||
| Continuous 6 g/day | 586 | 155 | 0.98 | 0.96 | 1.00 | 3071 | 679 | 1.00 | 0.99 | 1.00 | |
| Obese (BMI≥30 kg/m2) | Non-obese (BMI<30 kg/m2) | ||||||||||
| n=1222 (321 events) | n=2437 (513 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 529 | 164 | Ref | Ref | Ref | 823 | 178 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 430 | 100 | 0.71 | 0.54 | 0.94 | 781 | 168 | 1.22 | 0.97 | 1.53 | |
| Regular (≥6 g/day) | 263 | 57 | 0.77 | 0.56 | 1.08 | 833 | 167 | 1.03 | 0.81 | 1.31 | |
| p for trend | .04 | .80 | |||||||||
| p for interaction=.05 | |||||||||||
| Continuous 6 g/day | 1222 | 321 | 0.99 | 0.98 | 1.00 | 2437 | 513 | 1.00 | 0.99 | 1.00 | |
Adjusted for age at diagnosis, AJCC stage, race/ethnicity, education, menopausal status at diagnosis, nulliparity at diagnosis, hormone receptor status, surgery, treatment (radiation therapy, chemotherapy, endocrine therapy), smoking status at diagnosis, physical activity at diagnosis, BMI at diagnosis, comorbidity at diagnosis, neighborhood SES, and history of alcohol dependence at diagnosis, while excluding menopausal status, hormone receptor status, and BMI as appropriate depending on stratified model.
For all-cause mortality models, censored at end of study (December 31, 2021).
NOTE: 0.36 g/day and 6 g/day of ethanol are approximately 0.25 drinks/week and 3.5 drinks/week, respectively
Table 6.
Associations of alcohol consumption 6 months post-breast cancer diagnosis and all-cause mortality in the Pathways Study, stratified by estrogen-related factors
| Premenopausal | Postmenopausal | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| n=725 (96 events) | n=2038 (498 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 320 | 55 | Ref | Ref | Ref | 863 | 232 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 244 | 26 | 0.58 | 0.34 | 1.00 | 634 | 137 | 0.98 | 0.78 | 1.24 | |
| Regular (≥6 g/day) | 161 | 15 | 0.96 | 0.50 | 1.86 | 541 | 129 | 0.97 | 0.76 | 1.24 | |
| p for trend | .47 | .82 | |||||||||
| p for interaction=.10 | |||||||||||
| Continuous 6 g/day | 725 | 96 | 1.00 | 0.97 | 1.04 | 2038 | 498 | 1.00 | 1.00 | 1.01 | |
| ER-negative | ER-positive | ||||||||||
| n=431 (106 events) | n=2330 (488 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 209 | 53 | Ref | Ref | Ref | 973 | 234 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 133 | 35 | 0.98 | 0.60 | 1.60 | 744 | 128 | 0.85 | 0.67 | 1.08 | |
| Regular (≥6 g/day) | 89 | 18 | 0.76 | 0.40 | 1.45 | 613 | 126 | 0.95 | 0.75 | 1.22 | |
| p for trend | .46 | .57 | |||||||||
| p for interaction=.96 | |||||||||||
| Continuous 6 g/day | 431 | 106 | 0.99 | 0.96 | 1.01 | 2330 | 488 | 1.01 | 1.00 | 1.01 | |
| Obese (BMI≥30 kg/m2) | Non-obese (BMI<30 kg/m2) | ||||||||||
| n=882 (231 events) | n=1881 (363 events) | ||||||||||
| n | events | HRa,b | 95% CI | n | events | HRa,b | 95% CI | ||||
| Non-drinker (<0.36 g/day) | 437 | 134 | Ref | Ref | Ref | 746 | 153 | Ref | Ref | Ref | |
| Occasional (0.36-<6 g/day) | 290 | 61 | 0.67 | 0.47 | 0.94 | 588 | 102 | 1.04 | 0.79 | 1.38 | |
| Regular (≥6 g/day) | 155 | 36 | 0.75 | 0.49 | 1.16 | 547 | 108 | 1.12 | 0.84 | 1.48 | |
| p for trend | .05 | .46 | |||||||||
| p for interaction=.02 | |||||||||||
| Continuous 6 g/day | 882 | 231 | 1.00 | 0.98 | 1.01 | 1881 | 363 | 1.00 | 1.00 | 1.01 | |
Adjusted for age at diagnosis, AJCC stage, race/ethnicity, education, surgery, menopausal status at diagnosis, nulliparity at diagnosis, hormone receptor status, surgery, treatment (radiation therapy, chemotherapy, endocrine therapy), smoking status at diagnosis, physical activity at diagnosis, BMI at diagnosis, comorbidity at diagnosis, neighborhood SES, and history of alcohol dependence at diagnosis, while excluding menopausal status, hormone receptor status, and BMI as appropriate depending on stratified model.
For all-cause mortality models, censored at end of study (December 31, 2021).
NOTE: 0.36 g/day and 6 g/day of ethanol are approximately 0.25 drinks/week and 3.5 drinks/week, respectively
Finally, associations were similar and non-significant across the subgroups of menopausal status and ER status with no effect modification (Tables 5 and 6).
Discussion
In this analysis of 3,659 breast cancer survivors in the Pathways Study, alcohol consumption around and up to six months after breast cancer diagnosis was, in general, not associated with risk of recurrence or death. However, the risk associations varied by BMI. Specifically, in obese women, compared with no drinking, occasional consumption of two or more drinks per week (approximately one-quarter to one-half drink or more per day) was associated with a decreased risk of overall death, contributed in part by decreased risk of CVD death. Also, occasional consumption was possibly associated with an increased risk of recurrence in non-obese women. These results, in the largest prospective cohort to date of female breast cancer survivors, suggest that occasional, short-term alcohol consumption is generally not associated with poor outcomes after breast cancer diagnosis. Instead, moderate intake might be associated with improved survival in obese women.
Light to moderate alcohol consumption might reduce overall mortality in healthy cohorts due to possible beneficial effects on risk of CVD,25–29 yet we did not observe overall inverse associations in our breast cancer cohort. Instead, we appear to be the first to report that obese women experienced improved survival with moderate alcohol consumption, which was not observed in non-obese women. While we are unsure how to explain this finding, 693 obese women consumed alcohol compared with 529 obese women who did not, and they appeared more educated and physically active. This profile appears counterintuitive yet might reflect a healthier lifestyle contributing to better overall survival. Further, higher levels of alcohol consumption could lead to improvement in insulin sensitivity and reduction in insulin-like growth factor-I (IGF-I), as observed in an alcohol feeding trial of 63 healthy postmenopausal women.30,31 Reduced fasting insulin concentrations and lower IGF-I levels are associated with decreased risk of type 2 diabetes, CVD, and cancer. Finally, the pharmacokinetics of alcohol could be important to consider given that the volume of distribution of alcohol depends on age, sex, and degree of adiposity.32 Specifically, it can decrease with increasing BMI,33 which might limit the adverse health effects of alcohol due to lower levels of distribution from the plasma to other tissues. This phenomenon might also explain the possible increased, rather than decreased, risk of recurrence that we observed in the non-obese women.
Alcohol has been found to increase the expression and proliferation of estrogen receptors in cultured human breast cancer cells8,34 and has been associated with the development of incident ER-positive breast cancer in postmenopausal women.35,36 However, we did not observe any interactions of alcohol intake by ER status and menopausal status on risk of recurrence. The trends were consistent across both groups. Interestingly, while not statistically significant, additional analyses in postmenopausal women with ER+ breast cancer suggest possible higher risk of recurrence for those who continue to drink up to six months after diagnosis (Supplemental Table 4).
Study strengths include being the largest cohort of breast cancer survivors with data on post-diagnosis alcohol consumption and sufficient follow-up time, and having the ability to adjust for important prognostic and treatment-related factors. Our study population had a reasonably wide range of alcohol intake, allowing exploration of higher levels of drinking and outcomes, and variability in types of alcohol consumed compared with previous cohort studies. The mean consumption in drinkers at baseline was 11.2 g/day (median 5.5), which is consistent with mean levels reported in studies of healthy female drinkers (3.2–12.6 g/day).3
Of note, our analysis did not examine patterns of change in post-diagnosis alcohol consumption, as we examined separate effects of peri-diagnosis and early post-diagnosis (up to six months) exposure on outcomes. Change in alcohol consumption from pre-diagnosis to early post-diagnosis may be a contributing factor in associations of alcohol and mortality. However, most women (84.4%) remained in the same or adjacent category of intake at follow-up. Our data also did not allow us to determine the timing of alcohol consumption during the day or week, the quantity consumed per drinking occasion, or whether alcohol was consumed alone or with a meal.32,37,38 We also relied on self-reported alcohol use, which can be prone to recall bias; however, alcohol levels have been shown to be highly reproducible using food records and 24-hour recalls.39,40 Finally, while we adjusted for multiple confounders related to alcohol exposure and the study outcomes, including abstainer bias, residual confounding cannot be completely ruled out.
In summary, we found that short-term alcohol consumption immediately before and up to six months after breast cancer diagnosis was generally not associated with risk of recurrence or mortality. However, in obese women, drinking more than two drinks per week (one-quarter to one-half a drink or more per day) was associated with lower risk of all-cause mortality, especially CVD mortality. Risk of recurrence was possibly greater in non-obese women who drink. Given that consuming alcohol is a potentially modifiable lifestyle factor after breast cancer diagnosis, further confirmation is warranted in other large prospective studies of breast cancer survivors with detailed exposure assessment and focus on body size.
Supplementary Material
Acknowledgements
We are grateful to all Pathways Study participants for their contributions.
Grant Support
This study was supported by the National Cancer Institute (U01 CA195565, R01 CA105274).
Abbreviations
- KPNC
Kaiser Permanente Northern California
- EHR
electronic health record
- FFQ
Food Frequency Questionnaire
- BMI
body mass index
- nSES
neighborhood socioeconomic status
- MET
metabolic equivalents
- AJCC
American Joint Committee on Cancer
- ER
estrogen receptor
- PR
progesterone receptor
- HER2
human epidermal growth factor receptor 2
- SD
standard deviation
- HR
hazard ratio
- CI
confidence interval
- CVD
cardiovascular disease
- IQ
interquartile
- IGF-I
insulin-like growth factor-I
Footnotes
Conflict of Interest
The authors have no conflicts to disclose.
Ethics Approval and Patient Consent Statement
The study was approved by the KPNC institutional review board. Written informed consent was obtained from study participants.
Contributor Information
Marilyn L. Kwan, Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Emily Valice, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA; Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Isaac J. Ergas, Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Janise M. Roh, Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Bette J. Caan, Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Elizabeth M. Cespedes Feliciano, Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Tatjana Kolevska, Department of Oncology, Kaiser Permanente Vallejo Medical Center, Vallejo, CA.
Terryl J. Hartman, Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.
Charles P. Quesenberry, Jr, Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Christine B. Ambrosone, Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
Lawrence H. Kushi, Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon request.