- Email: [email protected]
Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women's Health Initiative Observational Study
prognostic associations of obesity in hormone receptor-negative breast cancer, unless Sparano and colleagues’ results are replicated in other studies using modern chemotherapy, weight loss intervention trials should include the full range of breast cancer subtypes. It is only through the conduct of such trials that definitive evidence regarding the prognostic effects of obesity and potential bene-
ficial effects of weight loss will be identified.
Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study
tional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided. Results.dAfter a mean of 11.3 (SD ¼ 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR ¼ 1.55, 95% CI ¼ 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR ¼ 1.03, 95% CI ¼ 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR ¼ 1.32, 95% CI ¼ 0.90 to 1.93, P ¼ .15), and more all-cause deaths after breast cancer (HR ¼ 1.65, 95% CI ¼ 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers. Conclusions.dConsistent with WHI randomized trial findings, estrogen plus progestin use is associated
Chlebowski RT, Manson JE, Anderson GL, et al (Los Angeles Biomedical Res Inst at Harbor-UCLA Med Ctr, Torrance, CA; Harvard Med School, Boston, MA; Fred Hutchinson Cancer Res Ctr, Seattle, WA; et al) J Natl Cancer Inst 105:526-535, 2013
Background.dIn the Women’s Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied. Methods.dWe identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n ¼ 25 328) or estrogen and progestin users (n ¼ 16 121). Multivariable-adjusted Cox propor-
324
P. J. Goodwin, MD, MSc, FRCPC
References 1. Abe R, Kumagai N, Kimura M, Hirosaki A, Nakamura T. Biological characteristics of breast cancer in obesity. Tohoku J Exp Med. 1976;120: 351-359.
Breast Diseases: A Year BookÒ Quarterly Vol 24 No 4 2014
2. Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat. 2010;123: 627-635. 3. Niraula S, Ocana A, Ennis M, Goodwin PJ. Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res Treat. 2012;134:769-781.
with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected. This analysis of the WHI observational study provides further evidence that combined estrogen plus progestin hormone therapy (HT) increases the incidence of breast cancer and, by extension, increases deaths due to breast cancer. The results of this observational study are consistent with the findings from 2 benchmark studies of combined HT: the WHI Randomized Trial1 and the Million Women Study (MWS).2 The increased risk of breast cancer observed in this current study (HR ¼ 1.55 [95% CI, 1.41-1.70]) falls midway between the results of the MWS, with a relative risk (RR) of 1.96 (95% CI, 1.90-2.02), and the WHI Randomized Study, with a HR of 1.25 (95% CI, 1.07-1.46). Differences in study design and population clearly contribute to differences in results, but the consistently increased risk for breast cancer with the use of HT in all 3 large-scale studies (with a combined
total of 18 673 breast cancer cases) is remarkable. In addition to confirming an increased risk for breast cancer with the used of combined HT, this study also noted a higher risk for breast cancer when combined HT is initiated at the time of menopause than is the case when HT is started following a prolonged interval after menopause. Combined HT started at menopause increases the risk for breast cancer to a HR of 1.68 (95% CI, 1.52-1.86), but when HT is started 5 or more years after menopause and used for less than 5 years, the risk is no longer statistically significant (HR ¼ 1.19 [95% CI, 0.92-1.55]). This finding is similar to data from the MWS that also noted a much lower risk for breast cancer among women who started HT more than 5 years after menopause and used it for less than 5 years (RR ¼ 1.34 [95% CI, 1.16-1.54]) than among women who began combination therapy prior to or at menopause (RR ¼ 2.27 [95% CI, 2.18-2.36]).1 This slight protection when HT is delayed has been hypothesized to account for the lower risk for breast cancer among participants in the WHI Randomized Trial, where a majority of women began HT more than 5 years after menopause.2 The data presented by Chlebowski and colleagues in this current study also provide additional evidence that women using combined HT are at increased risk for breast cancer-related death. The absolute numbers of deaths due to breast cancer in the study were remarkably low, with just under 140 deaths among 2236 cases. When the data were censored for adherence to therapy, the risk of death related to breast cancer was higher among women using combined HT group (HR ¼ 1.41); however, due to the small
number of deaths, this was not statistically significant (95% CI, 0.89-2.23). The absolute risk of 2 deaths due to breast cancer per 10 000 women years may appear to be insignificant, but given that 1 in 5 postmenopausal women in the United States use HT, this modifiable risk factor represents a significant public health issue. In addition to a higher risk for deaths related to breast cancer, this study noted that there were more all-cause deaths after breast cancer among combined HT users than among nonusers (HR ¼ 1.65 [95% CI, 1.29-2.12]). This research has the potential for multiple biases, which are inherent in an observational study. But the researchers took precautions to limit screening bias by requiring a screening mammogram for all participants at entry to the study. Characteristics of the breast cancers diagnosed during the study period were slightly different, with more estrogen-/progestin-positive breast cancers in the combined HT group and more triple-negative breast cancers in the non-HT users. However, both groups had breast cancers of similar size with similar lymph node involvement, suggesting that there was no difference in stage when the cancers were diagnosed. Although this was not a multinational study, participants were recruited from 40 centers throughout the United States. Over 41 000 women were enrolled and followed over 11.3 years, resulting in 2236 breast cancers occurring during the study period. Since there was no randomization in this study, it may accurately reflect the risk among postmenopausal women in the United States who made a decision to use or not use HT based on their knowledge of the risks and benefits of therapy. The risk of thromboembolic
events associated with HT was not within the scope of this study, and it did not address the lower risk for breast cancer among postmenopausal women using estrogen therapy alone that was reported in the WHI Randomized Trial1 or the MWS.2 Although the risk of breast cancer seems to be modified somewhat by starting HT later in menopause and using it for a shorter period of time, it is difficult to imagine scenarios where women would initiate therapy 5 years after their menopause, when symptoms have generally abated. Health care providers should already be counseling all female patients requesting HT about the increased risk of breast cancer and possible increased risk of death with combined HT. Women with bothersome symptoms should be offered alternative treatment for the management of menopausal symptoms. For women with severe symptoms not controlled with other methods, HT should be considered at the lowest dose possible and for the shortest period possible to mitigate symptoms, but only after the risk of therapy is discussed and understood. The large scale of this study and the long-term follow-up makes this sentinel research study on par with the WHI Randomized Trial1 and the MWS.2 The consistency of the results of these 3 studies taken together should resolve any remaining doubt about the risk of breast cancer among women using combined HT. S. Day, APRN, BC, FNP T. B. Bevers, MD
References 1. Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast
Breast Diseases: A Year BookÒ Quarterly Vol 24 No 4 2014
325
cancer incidence and mortality in postmenopausal women. JAMA. 2010;304:1684-1692.
2. Beral V, Reeves G, Bull D, Green J; Million Women Study Collaborators. Breast cancer risk in relation to the
interval between menopause and starting hormone therapy. J Natl Cancer Inst. 2011;103:296-305.
High- and Low-Fat Dairy Intake, Recurrence, and Mortality After Breast Cancer Diagnosis
outcomes. Compared with the reference (0 to <0.5 servings/day), those consuming larger amounts of high-fat dairy had higher breast cancer mortality (0.5 to <1.0 servings/day: hazard ratio [HR] ¼ 1.20, 95% confidence interval [CI] ¼ 0.82 to 1.77; and $1.0 servings/ day: HR ¼ 1.49, 95% CI ¼ 1.00 to 2.24, Ptrend ¼ .05), higher all-cause mortality (Ptrend < .001), and higher non-breast cancer mortality (Ptrend ¼ .007); the relationship with breast cancer recurrence was positive but not statistically significant. The higher risk appeared consistent across different types of high-fat dairy products. Conclusions.dIntake of high-fat dairy, but not low-fat dairy, was related to a higher risk of mortality after breast cancer diagnosis.
mortality; low-fat dairy consumption was associated with decreased overall mortality but was found to be of only borderline significance with regard to breast cancer-specific mortality. Overall dairy intake was not significantly associated with breast cancer outcomes, suggesting that there may be additional contributing factors. Other clues that the story is more complex than a straightforward “high-fat dairy is bad, low-fat dairy is good” interpretation is suggested by the somewhat incongruent demographics of the highfat dairy group. For example, the fact that the women in the high-fat dairyintake group had both higher levels of physical activity and higher body mass index suggests that the group’s composition may have been mixed in terms of overall health and that other lifestyle factors may be involved in the improved mortality rate of the low-fatdairy-consuming group. Other important caveats about the study include the fact that the majority of participants (75%) were postmenopausal, and the study excluded women with stage IIIB-IV tumors, which represents a potentially significant bias against inclusion of fast-moving, aggressive cancers, as these tend to be more common in younger women. As such, the applicability of these dairy fat results may be better confined to postmenopausal women with early-stage, non-aggressive disease. In spite of its large size, the study offers limited statistical power for subset analyses to compare patients by menopausal status and
Kroenke CH, Kwan ML, Sweeney C, et al (Kaiser Permanente, Oakland, CA; Univ of Utah, Salt Lake City) J Natl Cancer Inst 105:616-623, 2013
Background.dDietary fat in dairy is a source of estrogenic hormones and may be related to worse breast cancer survival. We evaluated associations between high- and low-fat dairy intake, recurrence, and mortality after breast cancer diagnosis. Methods.dWe included 1893 women from the Life After Cancer Epidemiology study diagnosed with early-stage invasive breast cancer from 1997 to 2000, who completed the Fred Hutchinson Cancer Research Center Food Frequency Questionnaire after diagnosis. A total of 349 women had a recurrence and 372 died during a median follow-up of 11.8 years, with 189 deaths from breast cancer. We used delayed entry Cox proportional hazards regression to evaluate associations between categories of the cumulative average of dairy fat at baseline and at follow-up 5 to 6 years later and subsequent outcomes. Tests of statistical significance were two-sided. Results.dIn multivariableadjusted analyses, overall dairy intake was unrelated to breast cancer-specific outcomes, although it was positively related to overall mortality. Low-fat dairy intake was unrelated to recurrence or survival. However, high-fat dairy intake was positively associated with
326
In the last several years, the role of diet in cancer prevention and survival has garnered much attention. Given this fact, together with recent concerns about food preparation methods and unwanted antibiotics and hormones in food sources, this study by Kroenke and colleagues provides intriguing and timely insights into the potential association between high-fat dairy intake and poor breast cancer outcomes. Prior to this work, no study of breast cancer outcomes had specifically compared the influence of low-fat and high-fat intake from dairy sources. Interestingly, high-fat dairy intake was associated with increased breast cancer mortality and higher overall
Breast Diseases: A Year BookÒ Quarterly Vol 24 No 4 2014
ficial effects of weight loss will be identified.
Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study
tional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided. Results.dAfter a mean of 11.3 (SD ¼ 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR ¼ 1.55, 95% CI ¼ 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR ¼ 1.03, 95% CI ¼ 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR ¼ 1.32, 95% CI ¼ 0.90 to 1.93, P ¼ .15), and more all-cause deaths after breast cancer (HR ¼ 1.65, 95% CI ¼ 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers. Conclusions.dConsistent with WHI randomized trial findings, estrogen plus progestin use is associated
Chlebowski RT, Manson JE, Anderson GL, et al (Los Angeles Biomedical Res Inst at Harbor-UCLA Med Ctr, Torrance, CA; Harvard Med School, Boston, MA; Fred Hutchinson Cancer Res Ctr, Seattle, WA; et al) J Natl Cancer Inst 105:526-535, 2013
Background.dIn the Women’s Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied. Methods.dWe identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n ¼ 25 328) or estrogen and progestin users (n ¼ 16 121). Multivariable-adjusted Cox propor-
324
P. J. Goodwin, MD, MSc, FRCPC
References 1. Abe R, Kumagai N, Kimura M, Hirosaki A, Nakamura T. Biological characteristics of breast cancer in obesity. Tohoku J Exp Med. 1976;120: 351-359.
Breast Diseases: A Year BookÒ Quarterly Vol 24 No 4 2014
2. Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat. 2010;123: 627-635. 3. Niraula S, Ocana A, Ennis M, Goodwin PJ. Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res Treat. 2012;134:769-781.
with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected. This analysis of the WHI observational study provides further evidence that combined estrogen plus progestin hormone therapy (HT) increases the incidence of breast cancer and, by extension, increases deaths due to breast cancer. The results of this observational study are consistent with the findings from 2 benchmark studies of combined HT: the WHI Randomized Trial1 and the Million Women Study (MWS).2 The increased risk of breast cancer observed in this current study (HR ¼ 1.55 [95% CI, 1.41-1.70]) falls midway between the results of the MWS, with a relative risk (RR) of 1.96 (95% CI, 1.90-2.02), and the WHI Randomized Study, with a HR of 1.25 (95% CI, 1.07-1.46). Differences in study design and population clearly contribute to differences in results, but the consistently increased risk for breast cancer with the use of HT in all 3 large-scale studies (with a combined
total of 18 673 breast cancer cases) is remarkable. In addition to confirming an increased risk for breast cancer with the used of combined HT, this study also noted a higher risk for breast cancer when combined HT is initiated at the time of menopause than is the case when HT is started following a prolonged interval after menopause. Combined HT started at menopause increases the risk for breast cancer to a HR of 1.68 (95% CI, 1.52-1.86), but when HT is started 5 or more years after menopause and used for less than 5 years, the risk is no longer statistically significant (HR ¼ 1.19 [95% CI, 0.92-1.55]). This finding is similar to data from the MWS that also noted a much lower risk for breast cancer among women who started HT more than 5 years after menopause and used it for less than 5 years (RR ¼ 1.34 [95% CI, 1.16-1.54]) than among women who began combination therapy prior to or at menopause (RR ¼ 2.27 [95% CI, 2.18-2.36]).1 This slight protection when HT is delayed has been hypothesized to account for the lower risk for breast cancer among participants in the WHI Randomized Trial, where a majority of women began HT more than 5 years after menopause.2 The data presented by Chlebowski and colleagues in this current study also provide additional evidence that women using combined HT are at increased risk for breast cancer-related death. The absolute numbers of deaths due to breast cancer in the study were remarkably low, with just under 140 deaths among 2236 cases. When the data were censored for adherence to therapy, the risk of death related to breast cancer was higher among women using combined HT group (HR ¼ 1.41); however, due to the small
number of deaths, this was not statistically significant (95% CI, 0.89-2.23). The absolute risk of 2 deaths due to breast cancer per 10 000 women years may appear to be insignificant, but given that 1 in 5 postmenopausal women in the United States use HT, this modifiable risk factor represents a significant public health issue. In addition to a higher risk for deaths related to breast cancer, this study noted that there were more all-cause deaths after breast cancer among combined HT users than among nonusers (HR ¼ 1.65 [95% CI, 1.29-2.12]). This research has the potential for multiple biases, which are inherent in an observational study. But the researchers took precautions to limit screening bias by requiring a screening mammogram for all participants at entry to the study. Characteristics of the breast cancers diagnosed during the study period were slightly different, with more estrogen-/progestin-positive breast cancers in the combined HT group and more triple-negative breast cancers in the non-HT users. However, both groups had breast cancers of similar size with similar lymph node involvement, suggesting that there was no difference in stage when the cancers were diagnosed. Although this was not a multinational study, participants were recruited from 40 centers throughout the United States. Over 41 000 women were enrolled and followed over 11.3 years, resulting in 2236 breast cancers occurring during the study period. Since there was no randomization in this study, it may accurately reflect the risk among postmenopausal women in the United States who made a decision to use or not use HT based on their knowledge of the risks and benefits of therapy. The risk of thromboembolic
events associated with HT was not within the scope of this study, and it did not address the lower risk for breast cancer among postmenopausal women using estrogen therapy alone that was reported in the WHI Randomized Trial1 or the MWS.2 Although the risk of breast cancer seems to be modified somewhat by starting HT later in menopause and using it for a shorter period of time, it is difficult to imagine scenarios where women would initiate therapy 5 years after their menopause, when symptoms have generally abated. Health care providers should already be counseling all female patients requesting HT about the increased risk of breast cancer and possible increased risk of death with combined HT. Women with bothersome symptoms should be offered alternative treatment for the management of menopausal symptoms. For women with severe symptoms not controlled with other methods, HT should be considered at the lowest dose possible and for the shortest period possible to mitigate symptoms, but only after the risk of therapy is discussed and understood. The large scale of this study and the long-term follow-up makes this sentinel research study on par with the WHI Randomized Trial1 and the MWS.2 The consistency of the results of these 3 studies taken together should resolve any remaining doubt about the risk of breast cancer among women using combined HT. S. Day, APRN, BC, FNP T. B. Bevers, MD
References 1. Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast
Breast Diseases: A Year BookÒ Quarterly Vol 24 No 4 2014
325
cancer incidence and mortality in postmenopausal women. JAMA. 2010;304:1684-1692.
2. Beral V, Reeves G, Bull D, Green J; Million Women Study Collaborators. Breast cancer risk in relation to the
interval between menopause and starting hormone therapy. J Natl Cancer Inst. 2011;103:296-305.
High- and Low-Fat Dairy Intake, Recurrence, and Mortality After Breast Cancer Diagnosis
outcomes. Compared with the reference (0 to <0.5 servings/day), those consuming larger amounts of high-fat dairy had higher breast cancer mortality (0.5 to <1.0 servings/day: hazard ratio [HR] ¼ 1.20, 95% confidence interval [CI] ¼ 0.82 to 1.77; and $1.0 servings/ day: HR ¼ 1.49, 95% CI ¼ 1.00 to 2.24, Ptrend ¼ .05), higher all-cause mortality (Ptrend < .001), and higher non-breast cancer mortality (Ptrend ¼ .007); the relationship with breast cancer recurrence was positive but not statistically significant. The higher risk appeared consistent across different types of high-fat dairy products. Conclusions.dIntake of high-fat dairy, but not low-fat dairy, was related to a higher risk of mortality after breast cancer diagnosis.
mortality; low-fat dairy consumption was associated with decreased overall mortality but was found to be of only borderline significance with regard to breast cancer-specific mortality. Overall dairy intake was not significantly associated with breast cancer outcomes, suggesting that there may be additional contributing factors. Other clues that the story is more complex than a straightforward “high-fat dairy is bad, low-fat dairy is good” interpretation is suggested by the somewhat incongruent demographics of the highfat dairy group. For example, the fact that the women in the high-fat dairyintake group had both higher levels of physical activity and higher body mass index suggests that the group’s composition may have been mixed in terms of overall health and that other lifestyle factors may be involved in the improved mortality rate of the low-fatdairy-consuming group. Other important caveats about the study include the fact that the majority of participants (75%) were postmenopausal, and the study excluded women with stage IIIB-IV tumors, which represents a potentially significant bias against inclusion of fast-moving, aggressive cancers, as these tend to be more common in younger women. As such, the applicability of these dairy fat results may be better confined to postmenopausal women with early-stage, non-aggressive disease. In spite of its large size, the study offers limited statistical power for subset analyses to compare patients by menopausal status and
Kroenke CH, Kwan ML, Sweeney C, et al (Kaiser Permanente, Oakland, CA; Univ of Utah, Salt Lake City) J Natl Cancer Inst 105:616-623, 2013
Background.dDietary fat in dairy is a source of estrogenic hormones and may be related to worse breast cancer survival. We evaluated associations between high- and low-fat dairy intake, recurrence, and mortality after breast cancer diagnosis. Methods.dWe included 1893 women from the Life After Cancer Epidemiology study diagnosed with early-stage invasive breast cancer from 1997 to 2000, who completed the Fred Hutchinson Cancer Research Center Food Frequency Questionnaire after diagnosis. A total of 349 women had a recurrence and 372 died during a median follow-up of 11.8 years, with 189 deaths from breast cancer. We used delayed entry Cox proportional hazards regression to evaluate associations between categories of the cumulative average of dairy fat at baseline and at follow-up 5 to 6 years later and subsequent outcomes. Tests of statistical significance were two-sided. Results.dIn multivariableadjusted analyses, overall dairy intake was unrelated to breast cancer-specific outcomes, although it was positively related to overall mortality. Low-fat dairy intake was unrelated to recurrence or survival. However, high-fat dairy intake was positively associated with
326
In the last several years, the role of diet in cancer prevention and survival has garnered much attention. Given this fact, together with recent concerns about food preparation methods and unwanted antibiotics and hormones in food sources, this study by Kroenke and colleagues provides intriguing and timely insights into the potential association between high-fat dairy intake and poor breast cancer outcomes. Prior to this work, no study of breast cancer outcomes had specifically compared the influence of low-fat and high-fat intake from dairy sources. Interestingly, high-fat dairy intake was associated with increased breast cancer mortality and higher overall
Breast Diseases: A Year BookÒ Quarterly Vol 24 No 4 2014