Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer : BIG 1-98 The BIG 1-98 trial is a large , randomized , independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer . We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients , which compares monotherapy with letrozole versus tamoxifen . This pre-planned core analysis allowed the use of patient data from the monotherapy arms of letrozole and tamoxifen and from the sequential arms prior to the drug switch point . Patients randomized to letrozole had a 19 % improved disease-free survival -LRB- hazard ratio -LSB- HR -RSB- = 0.81 ; P = 0.003 -RRB- , due especially to reduced distant metastases -LRB- HR = 0.73 ; P = 0.001 -RRB- . A 14 % risk reduction of fatal events in favor of letrozole was also observed -LRB- P = NS -RRB- . The results from the monotherapy arms alone confirmed the findings from the primary core analysis . Based on the results from this trial , the aromatase inhibitor letrozole -LRB- Femara ® -RRB- is currently recommended as a part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer and has recently been approved in the early adjuvant setting in both Europe and the United States . A subsequent analysis after additional follow-up will address the question of monotherapy versus sequential therapy . Introduction and rationale During the last century the management of primary breast cancer has evolved from gross surgical intervention to a sophisticated approach involving surgical , radiotherapeutic , hormonal , chemotherapeutic , and targeted biologic strategies . Currently , pharmacologic treatment is tailored according to disease and patient characteristics , including tumor size , histologic grade , lymph-node involvement , hormone receptor -LRB- HR -RRB- status , and human epidermal growth factor receptor-2 -LRB- HER2 -RRB- overexpression . The benefits from adjuvant chemotherapy , adjuvant hormonal therapy , and adjuvant therapy with trastuzumab have been well-established -LSB- 1 , 2 -RSB- . Patients with early breast cancer presenting with estrogen receptor -LRB- ER -RRB- - positive and/or progesterone receptor -LRB- PgR -RRB- - positive tumors typically receive adjuvant hormonal therapy . Adjuvant therapy with tamoxifen , a selective estrogen receptor modulator -LRB- SERM -RRB- , significantly reduces the risk of breast cancer recurrence -LSB- 1 -RSB- ; the Early Breast Cancer Trialists Collaborative Group reported that 5 years of tamoxifen reduces the annual breast cancer death rate by 31 % and is significantly more effective than just 1 -- 2 years of tamoxifen in ER-positive breast cancer -LSB- 1 -RSB- . However , intrinsic estrogenic activity -LSB- 3 -- 5 -RSB- and increased risk of endometrial cancer -LSB- 6 -RSB- and thromboembolism -LSB- 7 , 8 -RSB- have emerged as disadvantages when using tamoxifen . Based on current published data , extending the course of adjuvant tamoxifen beyond 5 years is not beneficial -LSB- 9 -RSB- despite the persistent risk of relapse in patients with HR + breast cancer -LSB- 10 -RSB- . In the first-line treatment of advanced breast cancer , the third-generation aromatase inhibitors -LRB- AIs -RRB- have shown superior or equivalent efficacy compared with tamoxifen -LSB- 11 -- 15 -RSB- . Letrozole demonstrated significant superiority in time to progression and overall response rate -LSB- 12 -RSB- and , in addition , an early survival benefit -LSB- 11 -RSB- . This indicates that a subset of the breast tumors is inherently less sensitive to tamoxifen -LSB- 16 -RSB- and that resistance to tamoxifen is acquired more quickly -LSB- 17 -RSB- . This superiority of letrozole over tamoxifen in the advanced setting led to the hypothesis that this AI may also be superior to tamoxifen when administered in the adjuvant setting . The Breast International Group -LRB- BIG -RRB- 1-98 was designed , coordinated , analyzed , and reported by an independent academic group and currently is the largest ongoing adjuvant trial in breast cancer investigating the role of an AI . This review summarizes the design and results from the primary core analysis of the BIG 1-98 trial , which compared monotherapy with letrozole to monotherapy with tamoxifen and identified letrozole as a better alternative to tamoxifen in this setting . It also summarizes some of the additional published research using the BIG 1-98 database . Trial design and patients BIG 1-98 was a randomized , phase III , double-blind trial with two randomization options : two-arms -LRB- A or B -RRB- and four-arms -LRB- A , B , C or D -RRB- -LRB- see Fig. 1 -RRB- for women with operable invasive HR + -LRB- ER + and/or PgR + -RRB- breast cancer . The treatment arms were : -LRB- A -RRB- initial therapy with tamoxifen for 5 years , -LRB- B -RRB- initial therapy with letrozole for 5 years , -LRB- C -RRB- initial therapy with tamoxifen for 2 years followed by letrozole for 3 years , or -LRB- D -RRB- initial therapy with letrozole for 2 years followed by tamoxifen for 3 years . The doses administered were 2.5 mg/day of letrozole and 20 mg/day of tamoxifen . Fig. 1BIG-98 trial design Between March 1998 and March 2000 , 1,835 women were randomly assigned to arms A or B , and between April 1999 and May 2003 a further 6,193 were assigned to arms A , B , C , or D . The primary core analysis compared treatment effects of patients randomized to receive letrozole initially -LRB- arms B and D -RRB- and those assigned to receive tamoxifen initially -LRB- arm A and C -RRB- . In the sequential treatment groups -LRB- arms C and D -RRB- , only events that occurred up to 30 days after switching treatments were included in the analysis . In total , 8,010 patients were included in the primary core analysis : 4,003 in the initial letrozole group -LRB- arms B and D -RRB- and 4,007 in the initial tamoxifen group -LRB- arms A and C -RRB- -LRB- see Fig. 2 -RRB- . Patient characteristics were similar in the two treatment groups . Overall , the trial included 41.3 % node-positive and 57.3 % node-negative women , while 1.4 % had unknown nodal status . Positive HR status was an eligibility criterion . The majority of patients -LRB- 63.1 % -RRB- had both ER + and PgR + tumors . A total of 25.3 % of women received adjuvant or neoadjuvant chemotherapy . Fig. 2CONSORT -LRB- Consolidated Standards of Reporting Trials -RRB- flowchart of the BIG 1-98 trial . The primary core analysis includes all 8,010 assessable patients , but events and follow-up in the sequential treatment groups -LRB- L → T and T → L -RRB- are truncated at 30 days after switching to the other treatment . L denotes letrozole and T tamoxifen . Reprinted from -LSB- 18 , Supplementary Appendix -RSB- End points The primary end point of the trial was disease-free survival -LRB- DFS -RRB- , defined as the time from randomization to first occurrence of : invasive recurrence in ipsilateral breast , chest wall , regional site -LRB- internal mammary/axilla -RRB- , or distant site -LRB- including ipsilateral supraclavicular -RRB- ; contralateral breast cancer -LRB- invasive -RRB- ; second malignancy -LRB- non-breast -RRB- ; or death without prior cancer event . Protocol-specified secondary end points in the BIG 1-98 trial were : overall survival -LRB- OS -RRB- , defined as time from randomization to death from any cause ; systemic DFS , defined as time from randomization to distant recurrence ; second non-breast malignancy or death from any cause -LRB- ignoring local and contralateral-breast events -RRB- ; and safety . Three additional end points were defined in the statistical analysis plan : -LRB- 1 -RRB- DFS excluding second , non-breast malignancies ; -LRB- 2 -RRB- time to recurrence , defined as time from randomization to first breast cancer recurrence -LRB- excluding second , non-breast cancers and censoring data on patients who died without a prior cancer event -RRB- ; and -LRB- 3 -RRB- time to distant recurrence , defined as the time from randomization to the first breast cancer recurrence at a distant site . Efficacy analyses Primary , secondary , and additional end points At 25.8 months of follow-up , letrozole improved DFS by 19 % -LRB- P = 0.003 -RRB- . The cumulative incidence of breast cancer relapse was significantly reduced with letrozole compared with tamoxifen -LRB- see Fig. 3 -RRB- . The difference was evident from 1 year after randomization and at 5 years was 10.3 % in the letrozole group compared with 13.6 % in the tamoxifen group -LRB- P < 0.001 -RRB- . In addition , letrozole significantly improved systemic DFS compared with tamoxifen -LRB- hazard ratio 0.83 ; 95 % CI 0.72 -- 0.97 -RRB- . There was significant improvement with letrozole compared with tamoxifen for the additional end point of DFS excluding second non-breast cancers -LRB- hazard ratio 0.79 ; 95 % CI 0.68 -- 0.92 -RRB- . Letrozole was particularly effective in decreasing the risk of distant recurrence by 27 % compared with tamoxifen -LRB- hazard ratio 0.73 ; 95 % CI 0.60 -- 0.88 ; P = 0.001 -RRB- -LRB- see Fig. 4 -RRB- . A non-significant 14 % improvement in OS was observed in patients receiving letrozole . Thus , 166 deaths -LRB- 4.1 % -RRB- were observed in the letrozole group compared with 192 deaths -LRB- 4.8 % -RRB- in the tamoxifen group . Fig. 3Cumulative incidence of a breast cancer relapse in the BIG 1-98 trial . Reprinted from -LSB- 18 -RSB- with permission from the Massachusetts Medical SocietyFig . 4Cox proportional-hazards model of data from the BIG 1-98 trial . The size of the boxes is inversely proportional to the standard error of the hazard ratio . The dashed vertical shows the hazard-ratio estimate for the overall analysis of the primary study end point -LRB- disease-free survival -RRB- . Reprinted from -LSB- 18 -RSB- with permission from the Massachusetts Medical Society Subgroup analyses Prospectively planned subgroup analyses , using the Cox proportional-hazards model , for primary , secondary , and additional end points are summarized in Fig. 4 . Subgroup analysis showed that the beneficial effect of letrozole on DFS was seen in ER + tumors irrespective of PgR receptor status or patient age -LSB- 18 -RSB- . The role of ER and PgR in trials comparing AIs with tamoxifen remains an area of continued research -LSB- 19 , 20 -RSB- . To explore this further , a central assessment of ER , PgR , and HER2 was recently completed for 6,500 patients in BIG 1-98 . Results from the first 3,533 patients on the two monotherapy arms with ER + tumors -LRB- by central assessment -RRB- and centrally assessed PgR and HER2 confirmed the results reported above from the local assessment of receptor status -LSB- 18 , 21 -RSB- , indicating that PgR status in ER + tumors does not predict responsiveness to letrozole when compared with tamoxifen . The small group of patients with HER2 overexpression/amplification in the tumor had a higher rate of recurrence with both treatments , but the superiority of letrozole over tamoxifen was similar irrespective of HER2 status -LSB- 21 -RSB- . For the primary end point of DFS , the relative risk reductions for letrozole compared with tamoxifen were 29 % in patients with node-positive tumors -LRB- hazard ratio 0.71 , 95 % CI 0.59 -- 0.85 -RRB- , 24 % in patients with tumors > 2 cm -LRB- hazard ratio 0.76 , 95 % CI 0.63 -- 0.92 -RRB- , and 30 % in patients with prior chemotherapy -LRB- hazard ratio 0.70 , 95 % CI 0.54 -- 0.92 -RRB- . An additional logistic regression analysis of BIG 1-98 was performed to retrospectively identify clinical and pathological factors predictive of early breast cancer recurrence -LSB- 22 -RSB- . The final model , based on 5,980 patients from the four-arm option and 212 events , identified the following significant factors : tumor size -LRB- P < 0.001 -RRB- , ER/PgR status -LRB- P < 0.001 -RRB- , node positivity -LRB- P < 0.001 -RRB- , and tumor grade -LRB- P < 0.001 -RRB- . There was a significant interaction between node positivity and treatment -LRB- P = 0.003 -RRB- . Patients with the greatest risk of recurrence had ≥ 4 positive nodes , tumors ≥ 5 cm , ER + / PgR − tumors , and grade 3 tumors . The increase in risk associated with increased node positivity was greater for patients randomized to tamoxifen than to letrozole -LSB- 22 -RSB- . Letrozole-only versus tamoxifen-only arms The superiority of letrozole was confirmed in a protocol-defined supplementary analysis , which was restricted to the 4,922 patients randomized to the monotherapy tamoxifen or letrozole arms . At a median follow-up of 51 months , letrozole provided a significant benefit for the end points DFS -LRB- P = 0.007 -RRB- , DFS excluding secondary malignancy -LRB- P = 0.01 -RRB- , time to recurrence -LRB- P = 0.004 -RRB- , and time to distant recurrence -LRB- P = 0.03 -RRB- -LRB- see Table 1 -RRB- -LSB- 23 -RSB- . Table 1Efficacy end points in patients randomized to treatment with letrozole -LRB- n = 2,463 -RRB- or tamoxifen -LRB- n = 2,459 -RRB- for 5 years in the BIG 1-98 trial -LSB- 23 -RSB- End pointEvents Hazard ratio95 % CIP-valueLetTamDFS -LRB- primary protocol definition -RRB- 3524180.820.71 -- 0.950.007 Overall survival1942110 .910.75 -- 1.110.35 Systemic DFS3313740 .870.75 -- 1.010.07 DFS -LRB- ignoring second non-breast cancer -RRB- 3073640.830.71 -- 0.960.01 Time to recurrence2312910 .780.65 -- 0.920.004 Time to distant recurrence1932340 .810.67 -- 0.980.03 DFS disease-free survival , Let letrozole , Tam tamoxifen , CI confidence interval Safety All adverse events were graded according to the Common Toxicity Criteria of the National Cancer Institute -LRB- version 2 -RRB- . Predefined adverse events were specifically asked and documented at each study visit . Furthermore , the IBCSG Coordinating Center conducted a medical review -LRB- reviewers were blinded to randomization -RRB- of all grade 3 -- 5 cardiovascular events and other grade 3 -- 5 adverse events that were considered clinically relevant but whose cause was unclear , and all deaths of women in whom there was no prior cancer-related event . The results of BIG 1-98 showed that letrozole was well-tolerated and had a safety profile different from tamoxifen -LRB- see Table 2 -RRB- -LSB- 18 -RSB- . A more detailed analysis of cardiovascular side effects , including baseline risk factors and cholesterol values over time , has recently been presented -LSB- 24 -RSB- . Table 2Cardiovascular adverse events and significant other adverse events among patients included in the BIG 1-98 safety analysis -LSB- 18 -RSB- Adverse event Incidence of any grade -LRB- % -RRB- P-valueLetrozole -LRB- n = 3,975 -RRB- Tamoxifen -LRB- n = 3,988 -RRB- Cerebrovascular accident or transient ischemic attack1 .01.00.91 Thromboembolic event1 .53.5 < 0.001 Cardiac event4 .13.80.61 Other cardiovascular event0 .50.20.04 Vaginal bleeding3 .36.6 < 0.001 Hot flashes33 .538.0 < 0.001 Night sweats13 .916.20.004 Fracture5 .74.0 < 0.001 Arthralgia20 .312.3 < 0.001 Tamoxifen compared with letrozole was associated with an increased risk of thromboembolism , vaginal bleeding , and more endometrial biopsies -LRB- 9.1 % vs. 2.3 % , respectively ; P < 0.001 -RRB- , with a higher incidence of invasive endometrial cancers -LRB- 0.3 % vs. 0.1 % , respectively ; P = 0.18 -RRB- . In addition , tamoxifen was associated with a higher incidence of hot flushes -LRB- 38.0 % vs. 33.5 % , respectively ; P < 0.001 -RRB- and night sweats -LRB- 16.2 % vs. 13.9 % ; respectively ; P = 0.004 -RRB- . There was a higher incidence of arthralgia and skeletal events with letrozole compared with tamoxifen , including a higher rate of fractures -LRB- 5.7 % vs. 4.0 % , respectively ; P < 0.001 -RRB- and a shorter time to first fracture . Hypercholesterolemia was among the adverse events listed on the case-report forms and was graded at each study visit during treatment -LSB- 18 -RSB- . A total of 43.6 % of letrozole-treated and 19.2 % of patients in the tamoxifen group had hypercholesterolemia , reported at least once during treatment -LSB- 18 -RSB- . Nevertheless , more than 80 % of reported hypercholesterolemia was grade 1 , and thus of uncertain clinical significance . In addition , serum total cholesterol values remained stable throughout the trial in the letrozole arm but decreased in the tamoxifen arm by approximately 13 % , which is consistent with the known lipid-lowering effect of tamoxifen -LSB- 25 -RSB- . Thus , median changes in cholesterol values from baseline were 0 , 0 , and − 1.8 % at 6 , 12 , and 24 months in the letrozole group and − 12.0 , − 13.5 , and − 14.1 % in the tamoxifen group . The overall incidence of cardiovascular events was similar for the letrozole and tamoxifen groups . Although there were higher incidences of grade 3 -- 5 cardiac events and cardiac failure in the letrozole arm , the incidences were low in both groups -LRB- 2.1 % vs. 1.1 % ; P < 0.001 and 0.8 % vs. 0.4 % , P = 0.01 , respectively -RRB- in this older patient population at competing risk for cardiovascular events -LSB- 18 -RSB- . Discussion Clinical implications of BIG 1-98 The results of the primary core analysis -LSB- 18 -RSB- , which included all available data from patients randomly assigned to the monotherapy arms and data from the sequential therapy arms censored at the time of the therapy switch , as well as the results from a recently published analysis limited to patients randomly assigned to the continuous therapy arms -LSB- 23 -RSB- , demonstrate a significant benefit of letrozole over tamoxifen . Letrozole is at least as well-tolerated as tamoxifen , offering patients and physicians a true alternative . However , bone metabolism is differently affected by letrozole and tamoxifen . Patients receiving AIs are at increased risk for bone loss and osteoporosis and should therefore receive appropriate monitoring and medical intervention as part of daily practice . As a result of the findings from BIG 1-98 , letrozole was approved both in Europe and the United States as an early adjuvant treatment for postmenopausal women with HR + breast cancer . The 2007 St. Gallen international consensus guidelines -LSB- 26 -RSB- and updated National Comprehensive Cancer Network -LRB- NCCN -RRB- guidelines -LSB- 27 -RSB- recommend letrozole as an option for adjuvant treatment of early breast cancer . In the 2007 St. Gallen Guidelines , use of an AI is considered as an alternative to tamoxifen for postmenopausal women with low - , intermediate - , or high-risk tumors that are classified as endocrine-responsive or endocrine response uncertain -LSB- 26 -RSB- . Similarly , in the NCCN guidelines , letrozole is a recommended adjuvant hormonal therapy for all postmenopausal women with hormone-responsive tumors , regardless of HER2 status -LSB- 27 -RSB- . The current guidelines do not recommend one AI over another but emphasize that treatment should be selected on the basis of clinical trial evidence in specific settings -LSB- 27 -RSB- , nor do the guidelines provide recommendations as concerns the optimal use of the AIs as upfront monotherapy or sequenced with tamoxifen . Results from the Arimidex , Tamoxifen , Alone or in Combination -LRB- ATAC -RRB- trial provided evidence for superior DFS with anastrozole versus tamoxifen used as initial adjuvant hormonal therapy in postmenopausal women with HR + breast cancer -LSB- 28 , 29 -RSB- . At a median follow-up of 68 months , no survival advantage has been observed in the ATAC trial , and it remains an open question whether the DFS advantage observed in AI trials will translate into an OS advantage . Both letrozole and anastrozole have demonstrated superiority over tamoxifen as initial adjuvant therapy -LSB- 18 , 28 -RSB- , but a direct comparison of letrozole with anastrozole awaits the results of a randomized head-to-head trial -LRB- Femara Anastrozole Clinical Evaluation -LSB- FACE -RSB- -RRB- -LSB- 30 , 31 -RSB- . The adjuvant FACE trial compares upfront therapy with letrozole 2.5 mg with anastrozole 1 mg daily for up to 5 years in postmenopausal , HR + , node-positive breast cancer patients . In addition , recruitment of a direct comparison of anastrozole and exemestane -LRB- MA .27 -RRB- has been completed recently . Other trials demonstrated better disease control when an AI was given after 2 -- 3 years of adjuvant tamoxifen -LSB- 32 -RSB- , but so far , no trial has reported on a regimen of an AI given 2 -- 3 years before tamoxifen . Initial treatment with the `` gold standard '' tamoxifen followed by an AI may be a logical long-term strategy because of the lack of complete cross-resistance between these hormonal strategies . On the other hand , the greater anti-estrogenic potency and higher anti-tumor activity of AIs over tamoxifen , as demonstrated in preclinical models and randomized clinical trials -LSB- 12 , 17 , 33 , 34 -RSB- , may suggest that it is preferable to use an AI upfront to avoid early relapses that may occur while on tamoxifen therapy . Thus , the key question , `` should AIs be given as initial therapy or used sequentially after tamoxifen ? '' is as yet unanswered . Physicians often extrapolate data from switch trials , e.g. , the Intergroup Exemestane Study -LSB- 35 , 36 -RSB- or the MA .17 trial -LSB- 33 , 37 -RSB- to sequential trials -LRB- e.g. , BIG 1-98 , Austrian Breast and Colorectal Cancer Study Group -LSB- ABCSG -RSB- 8 -LSB- 38 -RSB- -RRB- . In these sequential trials , events are included in the analysis from treatment start and not from point of switch after 2 -- 3 years of tamoxifen . Sequential and switch trials investigate obviously the same intervention but are conducted in different patient groups , thus , results are expected to be different and are different indeed . Best use of AIs remains an open question , at least until results of BIG 1-98 from the sequential use of letrozole and tamoxifen , in comparison with continuous monotherapy , as well as from the Tamoxifen and Exemestane Adjuvant Multicenter trial investigating exemestane monotherapy versus tamoxifen followed by exemestane -LSB- 39 -RSB- and from an updated analysis of ABCSG-8 , become available . Conclusions BIG 1-98 has shown that the AI letrozole results in better disease control than tamoxifen when given as initial endocrine therapy for postmenopausal women with hormone-responsive early breast cancer . Letrozole significantly reduced the risk of recurrence and of distant recurrence and has a reasonable safety profile -LSB- 18 -RSB- . The comparison between the monotherapy and the sequential treatment arms within the BIG 1-98 trial are eagerly awaited and are expected to have an important impact on the management of breast cancer .

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O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O B O O O O O O B O O O O O O O O O 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O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O B O O O O O O B O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O

adjuvant therapy
aromatase inhibitor
breast cancer
letrozole
tamoxifen


Alcohol consumption , cigarette smoking , and endometrial cancer risk : results from the Netherlands Cohort Study Objective To examine the association between alcohol consumption , cigarette smoking , and endometrial cancer . Introduction Endometrial cancer is the most frequently diagnosed gynecologic cancer in Europe -LSB- 1 -RSB- . The development of endometrial cancer has been related to exposure to estrogens unopposed by progestagens -LSB- 2 -RSB- . Many studies have shown a positive association between alcohol ingestion and estrogen levels in postmenopausal women . For instance , cross-sectional data from the European Prospective Investigation into Cancer and Nutrition -LRB- EPIC -RRB- suggested that elevated blood levels of estrone are observed with increasing alcohol consumption in postmenopausal women -LSB- 3 -RSB- . Thus , alcohol could be expected to increase endometrial cancer risk by elevating estrogen levels . An important determinant of estrogen levels in women is use of unopposed hormone replacement therapy -LRB- HRT -RRB- . Accordingly , use of unopposed HRT is consistently associated with an increased risk of endometrial cancer -LSB- 4 -- 6 -RSB- . Furthermore , it has been suggested that alcohol consumption increases estradiol levels in particular in postmenopausal women who are on HRT -LSB- 7 , 8 -RSB- . However , previous studies have indicated that alcohol consumption is either weakly or not associated with a reduced risk of endometrial cancer and no significant interaction with use of HRT has been found -LSB- 9 -RSB- . Although several studies have analyzed the association between alcohol consumption and endometrial cancer risk -LSB- 10 -- 22 -RSB- , only few studies have examined the risk associated with various measures of alcohol consumption -LRB- e.g. , amount and type of alcohol -RRB- including only one comprehensive prospective cohort study -LSB- 18 -RSB- . In contrast to alcohol , smoking has been hypothesized to exert anti-estrogenic effects -LSB- 23 -RSB- and to lower the risk of endometrial cancer in this way . Also , an effect modification by use of HRT seems reasonable -LSB- 24 -RSB- . Furthermore , it has been suggested that body mass index -LRB- BMI -RRB- and age at menopause might mediate part of the inverse association between smoking and endometrial cancer -LSB- 24 -RSB- . Earlier prospective studies -LSB- 22 , 25 -- 29 -RSB- have generally suggested that smoking is associated with a slight to moderate protection against endometrial cancer . However , to date , only the largest and most recent prospective cohort study has reported a significantly reduced risk in both current and past smokers -LSB- 29 -RSB- . Moreover , this large study explored the relationship between HRT and smoking and found no effect-modification , and also found that the association between smoking and endometrial cancer was not confounded by alcohol use -LSB- 29 -RSB- . The evidence from other epidemiological studies with regard to an effect-modification by use of HRT is ambiguous -LSB- 24 -RSB- . As many case -- control -LSB- 24 -RSB- , but only a few cohort studies have reported on the association between smoking and endometrial cancer -LSB- 22 , 25 -- 29 -RSB- , the International Agency for Research on Cancer concludes that prospective cohort studies , in which selection and recall bias are minimized , are scarce -LSB- 30 -RSB- . Only two cohort studies have explored the association between smoking and endometrial cancer comprehensively by examining the risk associated with all common quantitative smoking measures -LRB- e.g. , smoking duration , time since cessation -RRB- -LSB- 28 , 29 -RSB- . Since only few prospective cohort studies have investigated the association between alcohol consumption , cigarette smoking , and endometrial cancer comprehensively , important features of this relationship are under-explored . Hence , we aim to provide additional evidence based on prospective data . Moreover , we intend to elucidate the hormonal mechanisms underlying endometrial carcinogenesis by investigating , first , whether BMI and age at menopause might act as intermediary variables in the association between smoking and endometrial cancer and by examining , second , whether there is evidence regarding a potential effect modification by HRT use . Materials and methods The Netherlands Cohort Study -LRB- NLCS -RRB- started in September 1986 when 62,573 women aged 55 -- 69 years were enrolled in the cohort . Ethical approval was obtained from the ethics committee of the University Hospital Maastricht . All women were presumed to be postmenopausal . At baseline , data on dietary habits and other risk factors -LRB- such as alcohol consumption , smoking history , reproductive history , and anthropometry -RRB- were collected by means of a self-administered questionnaire . Data analysis was conducted according to the case -- cohort approach . In this approach , cases are derived from the cohort -LRB- providing numerator information for the incidence rates -RRB- , while the accumulated person-years at risk of the cohort are estimated from a random sample from the cohort , i.e. , the subcohort -LRB- providing denominator information for the incidence rates -RRB- . Following this approach , a subcohort of 2,589 women was sampled after the baseline exposure measurement . The subcohort has been followed up biennially by mail for vital status information . The vital status of subcohort members , who did not respond was completed by contacting the municipal population registers . Incident cases occurring in the entire cohort were detected by annual record linkages to the Netherlands Cancer Registry and the nationwide network and registry of histopathology and cytopathology in the Netherlands -LRB- PALGA -RRB- . Further details on the design of the study and methods of follow-up have been presented elsewhere -LSB- 31 , 32 -RSB- . The present analysis is restricted to cancer incidence in the 11.3-year follow-up period from September 1986 to December 1997 . The completeness of cancer follow up was estimated to be at least 96 % -LSB- 33 -RSB- , and no subcohort members were lost to follow up . Three hundred and twenty-seven incident , microscopically confirmed , invasive , primary endometrial carcinomas were detected after a follow-up period of 11.3 years . Cases were excluded from analysis if they had been diagnosed with non-epithelial tumors -LRB- n = 12 -RRB- , and if information on either alcohol consumption or cigarette smoking was incomplete -LRB- n = 35 -RRB- . Women were eligible for the subcohort if they did not report at baseline that they had undergone hysterectomy . Application of this inclusion criterion yielded a subcohort of 2,229 members . Individuals were excluded from the analysis if they had been diagnosed with cancer other than skin cancer at baseline -LRB- n = 151 -RRB- and if information on either alcohol consumption or cigarette smoking was missing -LRB- n = 177 -RRB- . After these exclusions , 280 cases and 1,901 subcohort members remained available for analysis . Questionnaire data Consumption of alcoholic beverages during the year preceding the baseline interview was assessed by consumption frequency questions on beer , red wine , white wine , sherry , other fortified wine , liqueur , and liquor . Categories ranked from ` never ' to ` 6 -- 7 times per week ' and information on the number of glasses per consumption day was also requested . Questionnaire data of all cases and subcohort members were key entered twice and processed in a manner blinded with regard to case/subcohort status in order to minimize observer bias in the coding and interpretation of data . The questionnaire has been validated against a nine-day diet record -LSB- 34 , 35 -RSB- . The Pearson correlation coefficient between the mean daily ethanol intake assessed by the questionnaire and that estimated by the nine-day record was 0.86 for all subjects and 0.78 for users of alcoholic beverages -LSB- 34 -RSB- . Respondents that reported to drink alcohol less than once per month were considered non-drinkers . Four items from the questionnaire -LRB- red wine , white wine , sherry , and liqueur -RRB- were combined into one single wine variable since these items were highly correlated and separate analysis would have resulted in small numbers of subjects within each stratum . Mean daily alcohol consumption was calculated using the Dutch food composition table -LSB- 36 -RSB- . Based on data from a pilot study , standard glasses were defined as follows : 200 ml for beer , 105 ml for wine , 80 ml for sherry , and 45 ml for both liqueur and liquor , corresponding to 8 g , 10 g , 11 g , 7 g , and 13 g of alcohol , respectively . Smoking was addressed at baseline by questions on age at first exposure to smoking , age at last exposure to smoking , smoking frequency , and smoking duration of cigarette , cigar , and pipe smokers . As the vast majority of smoking subcohort members was cigarette smokers , analyses were restricted to that particular group . Based on the questionnaire data , the following cigarette smoking variables were constructed : cigarette smoking status -LRB- never versus ever and never versus former or current -RRB- , frequency -LRB- number of cigarettes per day -RRB- , duration -LRB- years -RRB- , age at first exposure -LRB- years -RRB- , and time since cessation -LRB- years -RRB- . Time since cessation was calculated as ` age at baseline ' minus ` age at smoking cessation ' . Concerning the use of HRT , women were asked whether they had ever used HRT because of complaints related to the menopause . We can assume that all members of our cohort were postmenopausal in 1986 , when the baseline questionnaires were completed , and that possible treatment with HRT took place prior to 1986 in most women . Based on information regarding HRT prescription in the Netherlands in the past -LSB- 37 -- 39 -RSB- , we assume that all HRT users enrolled in the NLCS were treated with unopposed oral estrogens . Data analysis A variable was considered a confounder if -LRB- I -RRB- it was associated with endometrial cancer risk , if -LRB- II -RRB- it was associated with alcohol consumption or cigarette smoking , and if -LRB- III -RRB- age-adjusted hazard ratios changed by more than 10 % after adjustment for the potentially confounding factor . Based on the literature -LSB- 40 -RSB- and previous analyses , we considered the following variables as potential confounders : age -LRB- continuous -RRB- , age at menarche -LRB- continuous -RRB- , use of oral contraceptives -LRB- ever versus never -RRB- , duration of oral contraceptive use -LRB- continuous -RRB- , age at first child birth -LRB- continuous -RRB- , parity -LRB- continuous -RRB- , age at menopause -LRB- continuous -RRB- , use of postmenopausal hormones -LRB- ever versus never -RRB- , duration of postmenopausal hormone use -LRB- continuous -RRB- , non-occupational physical activity -LRB- categorized -RRB- , BMI -LRB- continuous -RRB- , height -LRB- continuous -RRB- , energy intake -LRB- continuous -RRB- , total fat intake -LRB- continuous -RRB- , intake of saturated fat -LRB- continuous -RRB- , intake of carbohydrates -LRB- continuous -RRB- , intake of dietary fiber -LRB- continuous -RRB- , intake of vegetables -LRB- continuous -RRB- , intake of fruits -LRB- continuous -RRB- , coffee consumption -LRB- yes versus no -RRB- , education -LRB- categorized -RRB- , diagnosis of hypertension -LRB- yes versus no -RRB- , diagnosis of diabetes mellitus -LRB- yes versus no -RRB- , family history of endometrial cancer -LRB- yes versus no -RRB- , and if applicable : total alcohol consumption per day -LRB- continuous -RRB- , type of alcoholic beverage -LRB- categorized -RRB- , current smoking -LRB- yes versus no -RRB- , number of cigarettes smoked per day -LRB- continuous -RRB- , and duration of smoking -LRB- continuous -RRB- . Incidence rate ratios -LRB- RR -RRB- and corresponding 95 percent confidence intervals -LRB- 95 % CI -RRB- for endometrial cancer were estimated in the age-adjusted and multivariate case -- cohort analyses with categorized and continuous alcohol and cigarette smoking variables , using the Cox proportional hazards model -LSB- 41 -RSB- processed with the Stata statistical software package -LSB- 42 -RSB- . Standard errors were estimated using the robust Hubert -- White sandwich estimator to account for additional variance introduced by sampling from the cohort . This method is equivalent to the variance -- covariance estimator by Barlow -LSB- 43 -RSB- . The proportional hazards assumption was tested using the scaled Schoenfeld residuals -LSB- 44 -RSB- . Tests for dose-response trends in risk of endometrial cancer were assessed by fitting ordinal exposure variables as continuous terms . Tests for interaction were performed by using the Wald test . Two-sided p values are reported throughout the paper . Results The percentage of women reporting alcohol consumption was similar among cases and subcohort members -LRB- 67.5 % and 66.9 % , respectively -RRB- , as was the mean alcohol consumption per day among users in both groups -LRB- 7.7 g with standard deviation -LRB- sd -RRB- = 10.8 , and 8.5 g -LRB- sd = 10.4 -RRB- , respectively -RRB- . Current smoking was less prevalent among cases than among subcohort members -LRB- 15.4 % vs. 21.8 % -RRB- , but the number of cigarettes smoked per day did not differ considerably between smokers in both groups -LRB- 13.6 -LRB- sd = 8.4 -RRB- and 13.2 -LRB- sd = 8.1 -RRB- , respectively -RRB- . Drinkers reported a slightly higher age at menopause and a higher prevalence of both oral contraceptive use and current cigarette smoking than non-drinkers -LRB- see Table 1 -RRB- . With regard to smoking status , former and current smokers were slightly leaner and had fewer children than never-smokers . On average , current smokers reported having reached menopause 1 year earlier than former-smokers and never-smokers . The prevalence of both oral contraceptive use and alcohol use was higher among smokers than among never-smokers . Also , average alcohol consumption was approximately twice as high among smokers as among never-smokers -LRB- see Table 1 -RRB- . Table 1Means -LRB- standard deviation -RRB- and distribution -LRB- n -RRB- of potential confounders according to alcohol consumption and cigarette smoking status among subcohort members , the Netherlands Cohort Study -LRB- 1986 -- 1995 -RRB- CharacteristicUnitAlcohol consumption statusCigarette smoking statusNo -LRB- n = 630 -RRB- Yes -LRB- n = 1,271 -RRB- Never -LRB- n = 1,100 -RRB- Former -LRB- n = 387 -RRB- Current -LRB- n = 414 -RRB- Mean -LRB- sd -RRB- Mean -LRB- sd -RRB- Mean -LRB- sd -RRB- Mean -LRB- sd -RRB- Mean -LRB- sd -RRB- AgeYears61 .8 -LRB- 4.3 -RRB- 61.4 -LRB- 4.3 -RRB- 62.0 -LRB- 4.3 -RRB- 61.1 -LRB- 4.4 -RRB- 60.7 -LRB- 4.1 -RRB- Body Mass Indexkg/m225 .4 -LRB- 3.9 -RRB- 24.9 -LRB- 3.4 -RRB- 25.3 -LRB- 3.5 -RRB- 24.7 -LRB- 3.3 -RRB- 24.6 -LRB- 3.8 -RRB- ParityNumber of children2 .8 -LRB- 2.4 -RRB- 2.7 -LRB- 2.2 -RRB- 3.0 -LRB- 2.4 -RRB- 2.5 -LRB- 1.8 -RRB- 2.5 -LRB- 2.1 -RRB- Age at 1st child birthYears22 .0 -LRB- 11.2 -RRB- 21.9 -LRB- 11.3 -RRB- 22.2 -LRB- 11.2 -RRB- 22.3 -LRB- 11.3 -RRB- 20.8 -LRB- 11.3 -RRB- Age at menopauseYears48 .3 -LRB- 4.8 -RRB- 49.2 -LRB- 4.3 -RRB- 49.1 -LRB- 4.4 -RRB- 49.2 -LRB- 4.1 -RRB- 48.1 -LRB- 4.8 -RRB- Total energy intake -LRB- including alcohol -RRB- kcal1 ,628 -LRB- 415 -RRB- 1,724 -LRB- 386 -RRB- 1,694 -LRB- 393 -RRB- 1,676 -LRB- 406 -RRB- 1,705 -LRB- 406 -RRB- Alcohol consumption G/day0 -LRB- 0 -RRB- 8.5 -LRB- 10.4 -RRB- 5.7 -LRB- 7.8 -RRB- 10.4 -LRB- 11.2 -RRB- 12.5 -LRB- 12.8 -RRB- CigarettesNo . / day13 .0 -LRB- 8.8 -RRB- 11.1 -LRB- 8.1 -RRB- 0 -LRB- 0 -RRB- 9.8 -LRB- 8.0 -RRB- 13.2 -LRB- 8.1 -RRB- n -LRB- % -RRB- an -LRB- % -RRB- an -LRB- % -RRB- an -LRB- % -RRB- an -LRB- % -RRB- aOral contraceptive useEver124 -LRB- 20.0 -RRB- 336 -LRB- 26.7 -RRB- 223 -LRB- 20.6 -RRB- 127 -LRB- 32.9 -RRB- 110 -LRB- 26.8 -RRB- Physical activity > 30 min/day425 -LRB- 69.1 -RRB- 975 -LRB- 77.8 -RRB- 796 -LRB- 74.1 -RRB- 306 -LRB- 79.5 -RRB- 298 -LRB- 72.9 -RRB- Diagnosis of hypertensionYes198 -LRB- 31.4 -RRB- 351 -LRB- 27.6 -RRB- 339 -LRB- 30.8 -RRB- 107 -LRB- 27.7 -RRB- 103 -LRB- 24.9 -RRB- Diagnosis of diabetesYes33 -LRB- 5.2 -RRB- 40 -LRB- 3.2 -RRB- 48 -LRB- 4.4 -RRB- 13 -LRB- 3.4 -RRB- 12 -LRB- 2.9 -RRB- Hormone replacement therapyEver62 -LRB- 10.0 -RRB- 152 -LRB- 12.1 -RRB- 107 -LRB- 9.9 -RRB- 58 -LRB- 15.1 -RRB- 49 -LRB- 12.0 -RRB- Family history of endometrial cancerYes20 -LRB- 3.2 -RRB- 32 -LRB- 2.5 -RRB- 23 -LRB- 2.1 -RRB- 16 -LRB- 4.1 -RRB- 13 -LRB- 3.1 -RRB- Alcohol usersYes -- -- 663 -LRB- 60.3 -RRB- 312 -LRB- 80.6 -RRB- 296 -LRB- 71.5 -RRB- Currently smoking cigarettesYes118 -LRB- 18.7 -RRB- 296 -LRB- 23.3 -RRB- -- -- -- a The percentage reported for some variables does sometimes not correspond with the numbers per smoker stratum since part of the information for these variables was missing Based on the literature and based on the methodological criteria specified above , we found the following confounders : age , BMI , parity , oral contraceptive use , non-occupational physical activity , hypertension , age at first child birth , and age at menopause . Alcohol consumption and cigarette smoking status were found to confound each other 's association with endometrial cancer . We controlled for all these confounders in multivariate analyses . In additional analyses , we mutually controlled the age-adjusted risk estimates regarding qualitative smoking measures for the other smoking measures . The multivariate risk estimates did not change substantially when oral contraceptive use -LRB- ever/never -RRB- was replaced by duration of oral contraceptive use -LRB- data not shown -RRB- . Accordingly , we considered it sufficient to control only for oral contraceptive use -LRB- ever/never -RRB- . Table 2 shows the results for the association between alcohol consumption and endometrial cancer . The multivariate adjusted RR associated with alcohol consumption was 1.06 -LRB- 95 % CI = 0.78 -- 1.43 -RRB- . The multivariate RRs of endometrial cancer for women who consumed up to 4 , 5 -- 14 , 15 -- 29 , and 30 or more gram of alcohol per day versus non-drinkers were 1.09 -LRB- 95 % CI = 0.78 -- 1.52 -RRB- , 0.95 -LRB- 95 % CI = 0.62 -- 1.45 -RRB- , 0.94 -LRB- 95 % CI = 0.52 -- 1.69 -RRB- , and 1.78 -LRB- 95 % CI = 0.88 -- 3.60 -RRB- , respectively . No significant trend was observed -LRB- ptrend = 0.62 -RRB- . Table 2Rate ratios of endometrial cancer according to baseline alcohol consumption in the Netherlands Cohort Study , 1986 -- 1997Alcohol consumption -LRB- g / day -RRB- Age adjustedMultivariate adjustedCategorical medianCasesPerson-years in subcohortRR -LRB- 95 % CI -RRB- aCasesPerson-years in subcohortRR -LRB- 95 % CI -RRB- bTotal alcohol No0916 ,6411 -LRB- ref . -RRB- 825,8371 -LRB- ref . -RRB- Yes4 .018913,7461.01 -LRB- 0.77 -- 1.32 -RRB- 17212,1371.06 -LRB- 0.78 -- 1.43 -RRB- 0.1 -- 41.61147,5991.10 -LRB- 0.82 -- 1.48 -RRB- 1056,6431.09 -LRB- 0.78 -- 1.52 -RRB- 5 -- 149.1473,6400.94 -LRB- 0.65 -- 1.37 -RRB- 393,2790.95 -LRB- 0.62 -- 1.45 -RRB- 15 -- 2920.9171,8220.69 -LRB- 0.40 -- 1.18 -RRB- 171,5750.94 -LRB- 0.52 -- 1.69 -RRB- ≥ 3037.3116841.20 -LRB- 0.62 -- 2.34 -RRB- 116391.78 -LRB- 0.88 -- 3.60 -RRB- p trend0 .490.62 Alcohol from wine Yes3 .218213,0091.06 -LRB- 0.81 -- 1.37 -RRB- 16611,5071.13 -LRB- 0.84 -- 1.52 -RRB- 0.1 -- 41.51258,0721.17 -LRB- 0.88 -- 1.55 -RRB- 1127,1131.16 -LRB- 0.84 -- 1.59 -RRB- 5 -- 148.9383,1460.91 -LRB- 0.61 -- 1.36 -RRB- 352,7841.07 -LRB- 0.68 -- 1.67 -RRB- ≥ 1521.8191,7910.80 -LRB- 0.48 -- 1.35 -RRB- 191,6111.11 -LRB- 0.64 -- 1.93 -RRB- p trend0 .430.64 Alcohol from beer Yes1 .14291,8731.15 -LRB- 0.76 -- 1.74 -RRB- 261,6291.30 -LRB- 0.82 -- 2.07 -RRB- Alcohol from liquor Yes3 .7342,6480.93 -LRB- 0.64 -- 1.37 -RRB- 312,3491.11 -LRB- 0.73 -- 1.68 -RRB- aRR = rate ratios ; CI = confidence interval ; n.a. = not applicablebRate ratios adjusted for age -LRB- years -RRB- , body mass index -LRB- kg/m2 -RRB- , parity -LRB- number of children -RRB- , use of oral contraceptives -LRB- ever versus never -RRB- , non-occupational physical activity -LRB- low , moderate , active , very active -RRB- , hypertension -LRB- yes versus no -RRB- , age at first child birth -LRB- years -RRB- , age at menopause -LRB- years -RRB- , and current cigarette smoking -LRB- yes versus no -RRB- The multivariate RR of endometrial cancer for wine-consumers versus non-consumers was slightly , but non-significantly , elevated -LRB- RR = 1.13 , 95 % CI = 0.84 -- 1.52 -RRB- . The RRs were also slightly , but non-significantly elevated when calculated according to different levels of wine consumption and no significant trend was observed -LRB- ptrend = 0.64 -RRB- . The multivariate RR of endometrial cancer associated with drinking beer equaled 1.30 -LRB- 95 % CI = 0.82 -- 2.07 -RRB- and the RR for drinking liquor was 1.11 -LRB- 95 % CI = 0.73 -- 1.68 -RRB- . Regarding smoking , age-adjusted analysis revealed an inverse association between ever-smoking and endometrial cancer risk -LRB- RR = 0.70 , 95 % CI = 0.54 -- 0.92 , see Table 3 -RRB- . We observed significant inverse trends of endometrial cancer risk with all quantitative smoking measures . However , these trends became non-significant when never-smokers were excluded . Some of these age-adjusted risk estimates changed substantially after additional adjustment for current smoking status , smoking frequency and smoking duration -LRB- see Table 3 -RRB- . Table 3Rate ratios of endometrial cancer according to baseline cigarette smoking features in the Netherlands Cohort Study , 1986 -- 1997Cigarette smoking featuresCategorical medianAdjusted for ageAdjusted for age , current smoking status , frequency and duration of smokingAdjusted for all confoundersCasesPerson-years in subcohortRR -LRB- 95 % CI -RRB- aCasesPerson-years in subcohortRR -LRB- 95 % CI -RRB- bCasesPerson-years in subcohortRR -LRB- 95 % CI -RRB- cSmoking status Neverdn.a .18711,8721 -LRB- ref . -RRB- -- -- -- 16910,3301 -LRB- ref . -RRB- Ever smokers938 ,5160.70 -LRB- 0.54 -- 0.92 -RRB- -- -- -- 857,6440.71 -LRB- 0.53 -- 0.95 -RRB- Neverd18711 ,8721 -LRB- ref . -RRB- -- -- -- 16910,3301 -LRB- ref . -RRB- Former smokersn.a504 ,1810.77 -LRB- 0.55 -- 1.07 -RRB- -- -- -- 473,7570.83 -LRB- 0.58 -- 1.20 -RRB- Current smokersn.a434 ,3340.64 -LRB- 0.45 -- 0.91 -RRB- -- -- -- 383,8880.59 -LRB- 0.40 -- 0.88 -RRB- p trend0 .010.01 Frequency -LRB- cigarettes/day -RRB- Neverd018711 ,8721 -LRB- ref . -RRB- 18711,8721 -LRB- ref . -RRB- 16910,3301 -LRB- ref . -RRB- 0.1 -- 9 4383,7190.65 -LRB- 0.45 -- 0.95 -RRB- 373,5690.86 -LRB- 0.49 -- 1.50 -RRB- 333,2231.07 -LRB- 0.58 -- 1.98 -RRB- 10 -- 19 12282,4380.74 -LRB- 0.48 -- 1.14 -RRB- 272,4151.02 -LRB- 0.54 -- 1.92 -RRB- 252,2141.28 -LRB- 0.66 -- 2.46 -RRB- 20 +20222,0140.70 -LRB- 0.44 -- 1.12 -RRB- 222,0141.03 -LRB- 0.46 -- 2.29 -RRB- 211,7981.31 -LRB- 0.56 -- 3.03 -RRB- p trend0 .040.750.43 Duration -LRB- years -RRB- Neverd018711 ,8721 -LRB- ref . -RRB- 18711,8721 -LRB- ref . -RRB- 16910,3301.0 -LRB- ref . -RRB- 0.1 -- 19 10.5232,0090.74 -LRB- 0.47 -- 1.17 -RRB- 221,9910.71 -LRB- 0.42 -- 1.18 -RRB- 211,8480.77 -LRB- 0.43 -- 1.39 -RRB- 20 -- 3930524,2740.79 -LRB- 0.57 -- 1.10 -RRB- 514,1200.80 -LRB- 0.47 -- 1.34 -RRB- 473,6900.89 -LRB- 0.51 -- 1.56 -RRB- 40 +411319700.42 -LRB- 0.23 -- 0.75131,8870.44 -LRB- 0.19 -- 1.02 -RRB- 111,6970.37 -LRB- 0.15 -- 0.90 -RRB- p trend0 .000.100.13 Age at first exposure -LRB- years -RRB- Neverdn.a18711 ,8721 -LRB- ref . -RRB- 18711,8721 -LRB- ref . -RRB- 16910,3301 -LRB- ref . -RRB- < 1917343,0980.71 -LRB- 0.48 -- 1.05 -RRB- 322,9470.78 -LRB- 0.34 -- 1.80 -RRB- 282,7240.91 -LRB- 0.37 -- 2.23 -RRB- 19 -- 2420212,5240.53 -LRB- 0.33 -- 0.86 -RRB- 202,3710.60 -LRB- 0.29 -- 1.27 -RRB- 202,1020.88 -LRB- 0.38 -- 2.02 -RRB- 25 +30312,6910.73 -LRB- 0.49 -- 1.09 -RRB- 312,5960.82 -LRB- 0.47 -- 1.46 -RRB- 282,3251.00 -LRB- 0.53 -- 1.87 -RRB- p trend0 .010.470.94 Time since cessation -LRB- years -RRB- Neverdn.a18711 ,8721 -LRB- ref . -RRB- 18711,8721 -LRB- ref . -RRB- 16910,3301 -LRB- ref . -RRB- 20 + e26 .5201,1421.11 -LRB- 0.68 -- 1.84 -RRB- 171,0410.80 -LRB- 0.41 -- 1.57 -RRB- 179431.12 -LRB- 0.52 -- 2.41 -RRB- 10 -- 19e14141 ,4590.62 -LRB- 0.35 -- 1.09 -RRB- 141,4160.38 -LRB- 0.14 -- 1.03 -RRB- 131,2700.50 -LRB- 0.17 -- 1.45 -RRB- 0.1 -- 9e5131 ,3920.60 -LRB- 0.33 -- 1.08 -RRB- 131,3470.32 -LRB- 0.10 -- 1.06 -RRB- 121,2570.50 -LRB- 0.12 -- 2.00 -RRB- p trend0 .030.060.26 aRR = rate ratios ; CI = confidence interval ; n.a. = not applicablebRRs were adjusted for age -LRB- years -RRB- . In addition , frequency was adjusted for current smoking status -LRB- yes/no -RRB- and duration -LRB- years -RRB- ; duration was adjusted for current smoking status and frequency -LRB- cigarettes/day -RRB- ; age at first exposure was adjusted for current smoking status , frequency , and duration ; time since cessation was adjusted for frequency and durationcRRs were adjusted as mentioned under footnote b and additionally for body mass index -LRB- kg/m2 -RRB- , parity -LRB- number of children -RRB- , use of oral contraceptives -LRB- ever versus never -RRB- , non-occupational physical activity -LRB- low , moderate , active , very active -RRB- , hypertension -LRB- yes versus no -RRB- , age at first child birth -LRB- years -RRB- , age at menopause -LRB- years -RRB- , and alcohol consumption -LRB- gram / day -RRB- dNever smoked cigars , pipe , or cigaretteseEx-smokers only When we adjusted for all confounders , multivariate analysis showed a statistically significant 29 % reduced risk of endometrial cancer for ever-smokers when contrasted with never-smokers . When considered separately , the risk reduction appeared to be stronger among current smokers -LRB- RR = 0.59 , 95 % CI = 0.40 -- 0.88 -RRB- than among former smokers -LRB- RR = 0.83 , 95 % CI = 0.58 -- 1.20 -RRB- . Tests for trends were not significant for any of the quantitative smoking variables when these were adjusted for age and additional confounders . The strongest reduction in risk , which could be observed in both univariate and multivariate models , was associated with a smoking history of 40 or more years compared with having never smoked -LRB- RR = 0.37 , 95 % CI = 0.15 -- 0.90 -RRB- . Moreover , we observed a non-significant 50 % reduction in risk in women that quit smoking either nine or less years ago or that quit 10 -- 19 years ago . The data indicated no association between age at first smoking exposure and endometrial cancer . Omitting age at menopause and BMI from the multivariate models either separately or simultaneously did not cause meaningful changes in the corresponding estimates . No interactions in determining endometrial cancer risk could be observed between alcohol consumption and HRT use -LRB- p = 0.43 -RRB- , BMI -LRB- p = 0.38 -RRB- , age at menopause -LRB- p = 0.39 -RRB- , or current cigarette smoking -LRB- p = 0.83 -RRB- . When we stratified multivariate alcohol analyses according to smoking status , we observed a non-significantly lower risk of endometrial cancer among alcohol consumers that have ever smoked -LRB- RR = 0.91 , 95 % CI = 0.52 -- 1.58 -RRB- than among alcohol consumers that have never smoked -LRB- RR = 1.16 , 95 % CI = 0.81 -- 1.67 -RRB- . Concerning smoking and HRT use , the interaction term was not statistically significant -LRB- p = 0.11 -RRB- . In this subset analysis , current smoking was associated with a reduced risk of endometrial cancer in women not using HRT -LRB- RR = 0.54 , 95 % CI = 0.35 -- 0.84 -RRB- . In current smokers that did use HRT , the RR was 1.32 -LRB- 95 % CI = 0.57 -- 3.04 -RRB- . Numbers were very small however : only 28 women were current smokers and used HRT and only eight women were current smokers and did not use HRT . Discussion Our results do not suggest a meaningful association between alcohol consumption and endometrial cancer risk . Current smoking is associated with a reduced risk of endometrial cancer . This inverse relationship is neither mediated by BMI nor by age at menopause . Regarding the biological mechanism underlying endometrial carcinogenesis , the so-called `` unopposed estrogen hypothesis '' is widely accepted -LSB- 2 -RSB- . According to this hypothesis endometrial cancer develops when the endometrium is exposed to high levels of unopposed endogenous or exogenous estrogens for a long period of time . This exposure results in elevated mitotic proliferation of endometrial cells which , in turn , increases the risk of DNA replication errors and DNA mutations which can lead to endometrial cancer -LSB- 2 -RSB- . Although female alcohol consumers could be expected to be at increased risk of endometrial cancer due to their hormonal profile , we have not detected significant associations between alcohol consumption and endometrial cancer risk . This finding is consistent with the vast majority of previous studies -LSB- 13 , 15 -- 18 -RSB- . However , in the EPIC study , significantly elevated blood estrone levels were found only in postmenopausal women who consumed more than 25 g of alcohol per day compared to non-drinkers -LSB- 3 -RSB- . Thus , possibly , a marked increase in estrone concentrations , and ultimately in endometrial cancer risk , can only be observed in women who consume more than moderate amounts . This notion might be supported by our data as we have observed an -LRB- non-significantly -RRB- elevated risk of endometrial cancer in women who reported to drink more than 30 g of alcohol per day . Based on literature reviews -LSB- 7 , 8 -RSB- , we hypothesized that we might find a positive association between alcohol consumption and endometrial cancer risk in particular among HRT users . However , our findings do not support the hypothesis of an effect-modification by HRT use ; neither did most of the previous epidemiological studies -LSB- 13 , 17 , 18 -RSB- . Concerning smoking , an anti-estrogenic effect has been suggested -LSB- 23 -RSB- , which should lower the risk of endometrial cancer according to the unopposed estrogen hypothesis . Accordingly , our data indicated a significant risk reduction in current smokers , just like the Nurses ' Health Study did , which has reported a RR of 0.72 -LRB- 95 % CI = 0.57 -- 0.90 -RRB- for current smokers -LSB- 29 -RSB- . In contrast , other cohort studies have observed non-significant associations -LSB- 25 , 26 , 28 -RSB- . We found that the inverse association between smoking and endometrial cancer was more pronounced among current smokers than among former smokers . These findings are in line with the evidence from several case -- control -LSB- 17 , 45 -- 47 -RSB- and two cohort studies -LSB- 26 , 28 -RSB- and they suggest that the degree of protection might partly depend on the time since smoking cessation . Although not statistically significant , our prospective data support this notion , because we observed that endometrial cancer risk is possibly higher in women that quit smoking 20 or more years ago compared to the risk in women that quit 19 years ago or less . In the epidemiological literature , a few studies presented data on time since cessation -LSB- 17 , 28 , 29 , 48 -- 50 -RSB- , but only one of them found a significantly lowered risk among women that quit smoking less than 10 years ago -LSB- 48 -RSB- . Considering the risk associated with duration of smoking , we have observed a reduction in risk with a long smoking history , just like previous studies -LSB- 17 , 29 , 47 , 48 -RSB- . With regard to smoking intensity , we have found that smoking 20 or more cigarettes per day is associated with a non-significantly elevated risk of endometrial cancer . Though one needs to bear in mind that the corresponding confidence intervals were large , these point estimates are possibly not in line with the majority of previous studies , which generally indicated that a high smoking intensity -LRB- e.g. , smoking 20 or more cigarettes per day -RRB- is associated with a decreased risk of endometrial cancer -LSB- 17 , 22 , 28 , 29 , 45 , 47 , 48 , 51 -RSB- . This inconsistency could be explained by the lack of adjustment for other smoking variables in earlier studies : only one -LSB- 29 -RSB- out of six -LSB- 22 , 25 -- 29 -RSB- prospective cohort studies has adjusted its smoking frequency estimates for the potentially confounding effects of smoking duration . When we omitted smoking duration from our multivariate models , the RRs for smoking frequency also suggested an inverse association with endometrial cancer -LRB- data not shown -RRB- . Our results do not indicate any important association between the age at starting smoking and endometrial cancer risk . Four previous studies -LSB- 26 , 28 , 47 , 49 -RSB- found a -LRB- non-significant -RRB- risk reduction with young age at first exposure , that is , starting to smoke between age 15 -LSB- 28 -RSB- or age 20 or earlier -LSB- 49 -RSB- , but none of these studies has reported a significant trend . It has been hypothesized that smoking might lower the levels of estrogens partly by reducing the amount of fat tissue or by decreasing the age at menopause -LSB- 24 -RSB- . In our cohort , smokers were slightly leaner than non-smokers -LRB- 24.6 kg/m2 vs. 25.3 kg/m2 -RRB- . Moreover , on average , current smokers appeared to have reached menopause 1 year earlier than never-smokers and former smokers -LRB- 48.1 years vs. 49.1 years -RRB- . However , in conclusion , our analyses indicated that BMI and age at menopause are no mediating factors . In contrast to smoking , use of unopposed HRT increases endometrial cancer risk in postmenopausal women . Although an interaction between smoking and HRT use seems biologically plausible , the small numbers in our analysis did not allow to draw firm conclusions regarding a possible effect modification by HRT use . Moreover , we had no precise information on what type of HRT women in the NLCS have used . If we could have included such information in our analysis , results might differ according to type of HRT used . Another potential drawback of our study might be misclassification of self-reported alcohol consumption and/or self-reported cigarette smoking . However , these misclassifications might be non-differential owing to the prospective study design . Consequently , the risk estimates would probably be biased towards no effect . Moreover , the correlation between the alcohol consumption measured by the NLCS questionnaire and the measurement in a nine-day record was high due to the large variation in alcohol consumption -LSB- 34 -RSB- . An important strength of our study is that the exposures were assessed prior to the diagnosis of endometrial cancer . Therefore , our findings can not be influenced by recall bias . Moreover , selection bias is unlikely as the follow-up of subcohort members and cases was almost complete -LSB- 33 , 52 -RSB- . Another strength is the way alcohol consumption and cigarette smoking was assessed in the NLCS . The detailed assessment enabled us to evaluate associations between endometrial cancer and various measures of both exposures . Furthermore , we were able to control for confounding by the most important risk factors of endometrial cancer -LSB- 40 -RSB- . To sum up our major findings , we found that alcohol consumption is not associated with endometrial cancer . Current smoking was associated with a reduced risk of endometrial cancer in postmenopausal women . This association was probably not mediated by a decreased BMI or by an earlier age at menopause . Larger prospective studies with information on the type of HRT are needed in order to investigate possible effect modification by different types of HRT . Possibly , the incidence of endometrial cancer could be reduced if smoking was more common in female populations ; however , such a reduction would be overshadowed by a dramatically increasing incidence of many other chronic diseases . Thus , individuals should still be encouraged to quit or not to start smoking .

O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O B O B O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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