A 57-year-old man who developed arthritis during R-CHOP chemotherapy for non-Hodgkin lymphoma Rituximab is a chimeric human-mouse anti-CD20 monoclonal antibody , which is used in the treatment of both B-cell lymphomas and rheumatic diseases . We describe a case of a previously healthy 57-year-old man developing arthritis while being treated with rituximab-CHOP chemotherapy -LRB- R-CHOP -RRB- for a non-Hodgkin lymphoma . The remittant arthritis developed at successively shorter time-intervals after R-CHOP administration and only improved after rituximab was removed from the chemotherapy schedule , suggesting a rituximab-related phenomenon , as extensive diagnostic testing ruled out any other diagnosis . Introduction Rituximab is increasingly used in the treatment of both B-cell lymphomas as well as rheumatic diseases . Several side-effects of rituximab are known , but until now only two reports described the development of arthritis after rituximab therapy -LSB- 1 , 2 -RSB- . Here we describe yet another case . Case A 57-year-old man was referred to the out-patient clinic of rheumatology because of arthritis of the right knee and left wrist . The patient had been in perfect health until he noticed a swelling of 2.5 cm under his right jaw . He was referred to a specialized oncology center where he was diagnosed with an aggressive follicular B-cell non-Hodgkin lymphoma -LRB- NHL -RRB- stage IVA with involvement of submandibular and mesenteric lymph nodes and bone marrow . Treatment was instituted with R-CHOP chemotherapy , which consists of cyclophosphamide , doxorubicin , vincristine , prednisone , and rituximab , given at a 3-week interval . During this treatment , granisetron -LRB- Kytril ® -RRB- was given and occasionally magnesiumoxide and paracetamol . Because this patient suffered from a low tumor burden , no tumor lysis profylaxis , i.e. , allopurinol was prescribed . Two and a half weeks after the first course of R-CHOP , the patient developed arthritis of his right knee and left wrist without morning stiffness or involvement of the small hand joints . He had no history of arthralgia , joint swelling , preceding trauma , fever , or infection nor did he have a history of inflammation of the eyes , Raynaud phenomenon , photosensitivity , sicca-syndrome , or inflammatory back pain . The further medical history disclosed several tick bites the year before , with a skin reaction . He rarely used alcohol -LRB- maximum of two glasses a day -RRB- . Family history revealed no rheumatic diseases . Physical examination showed a profusely swollen and painful right knee and left wrist . The other joints were not afflicted . Laboratory testing before the start of chemotherapy showed no abnormalities besides a erythrocyte sedimentation rate -LRB- ESR -RRB- of 21 mm/h . At the time of presentation with arthritis , there was ESR of 41 mm/h , C-reactive protein 256 mg/l , leucocytes 11.1 × 109/l , a normal liver and kidney function , and an IgM-rheumatoid factor -LRB- RF -RRB- 7 IE/ml , anti-cyclic citrulline peptide -LRB- a-CCP -RRB- < 1 AU/ml , anti-nuclear factor -LRB- ANF -RRB- negative , and urate of 0.25 mmol/l . A diagnostic puncture of synovial fluid from the right knee was performed , which revealed an inflammatory arthropathy -LRB- cell count 5,300 / mm3 , 14 % lymphocytes , 8 % mononuclear cells , and 78 % granulocytes -RRB- with no signs of malignant cells or crystals . Microbiological testing -LRB- Gram-stain , Ziehl -- Neelsen , and culture -RRB- of the synovial fluid showed no microorganisms . X-rays of both knee and wrist did not show bone involvement or chondrocalcinosis . The patient was treated with naproxen -LRB- 500 mg , twice daily -RRB- , with which both pain and swelling of the joints were reduced but not completely resolved . Four days after the second course of R-CHOP , the pain and swelling returned in all its severity and spontaneously regressed after 1 week . Shortly after the third course of R-CHOP , the patient experienced the same painful joint swellings , now also involving the left knee . This was in spite of intra-articular kenacort injections and prednisone maintenance therapy -LRB- 10 mg daily -RRB- , which was started between the courses of chemotherapy . Repeated pathological and microbiological testing of synovial fluid showed no new results . After these three courses of R-CHOP , the effect on the NHL was evaluated and disclosed that the intra-abdominal NHL-mass was somewhat reduced , and the remnant of the submandibular lymph node had disappeared . Since the causal relationship between the -LRB- activity of -RRB- arthritis and the courses of R-CHOP and rituximab being the only component of R-CHOP of which the development of arthritis is described after the administration of this drug -LSB- 1 , 2 -RSB- , the decision was made to give the fourth and fifth course of chemotherapy without rituximab . This time there was no increase in pain or swelling of the joints . Well over a year after the first R-CHOP chemotherapy , the patient is fully recovered . Evaluation of his NHL shows a near complete remission , and no further treatment was indicated . The arthritis has fully resolved . Discussion Arthritis developing during the course of R-CHOP chemotherapy is very unusual . The arthritis developed after successively shorter time-intervals after the R-CHOP administration while no arthritis occurred when CHOP was given without rituximab . This suggests a probably rituximab related , immune-mediated phenomenon . We were not able to detect antibodies against rituximab or immune complexes that might strengthen this diagnosis . However , we did have strong arguments against the other differential diagnoses . The pattern of arthritis in this patient is unusual for a rheumatoid arthritis ; moreover , both IgM-RF and a-CCP were negative , while X-rays made of the afflicted joints disclosed no erosions . Spondylarthropathy very rarely develops after the age of 45 years . Moreover , inflammatory back pain was absent , and positive arguments for an infection causing reactive arthritis were lacking . Other autoimmune diseases like systemic lupus erythematosus -LRB- SLE -RRB- or Sjögren 's syndrome were also very unlikely looking at the clinical presentation , the absence of characteristic signs and symptoms , and the absence of the specific autoantibodies . A crystalarthropathy is a more likely candidate , as treatment of NHL can cause tumor lysis syndrome , which can give rise to gout . However , serum values of urine acid were repeatedly very low , and there where no other signs of tumor lysis syndrome . Moreover , repeated samples of synovial fluid failed to show any crystals , kidney function was normal ; the patient barely used alcohol and did not use diuretics . The X-rays of both the right knee and left wrist did not show signs of chondrocalcinosis . Latent infections provoked by the administration of R-CHOP were considered . However , repeated cultures , Gram-stain , and Ziehl -- Neelsen of synovial fluid did not disclose any bacteria or yeasts . Serologic testing for Borrelia Burgdorferi , Lues , Chlamydia trachomatis , Parvovirus B19 and PCR on Mycobacteria tuberculosis and Chlamydia trachomatis -LRB- both performed in the synovial fluid -RRB- proved to be negative . A wide spectrum of autoimmune manifestations , among others arthritis , is described in NHL -LSB- 3 -RSB- . However , arthritis is unlikely in this patient as autoimmune manifestation , as it developed during R-CHOP and the NHL responded well to this chemotherapy . Furthermore intra-articular localization of NHL was considered . However , both primary and secondary intra-articular localization of NHL is very rare -LSB- 4 -RSB- , and the fact that more than one joint is afflicted in this patient makes it even more unlikely . Moreover , magnetic resonance imaging -LRB- MRI -RRB- of both knees did not show tumor mass , and repeated punctures of synovial fluid of both knees did not show any malignant cells . On top of this , a computed tomography -LRB- CT -RRB- scan of the abdomen revealed regression of the mesenteric NHL-tumor mass after chemotherapy , which means that in the case of any presumed intra-articular localization of NHL , one would expect relapse of joint involvement in the course of chemotherapy instead of progression . An arthroscopy was considered but not performed because of the risks of infection in this immunocompromised patient , and the low expectancy of achieving the diagnosis by performing the arthroscopy as the presence of NHL intra-articular was considered to be very unlikely . Because our patient received high dosages of prednisone , the diagnosis of avascular bone necrosis was considered but ruled out by a MRI of both knees . None of the other medications our patient used are known to give arthritis . Ruling out the above-mentioned diagnoses and taking into account the relationship in time between the development of arthritis and the gifts of R-CHOP , one or more of the components of R-CHOP seem to be the most likely cause of the arthritis in our patient . Of all of the components of R-CHOP , only rituximab is known to be able to give arthritis -LSB- 1 , 2 -RSB- . Pijpe et al. described the development of arthritis in three patients who received rituximab for primary Sjögren 's syndrome . All of these patients had developed human antichimeric antibodies -LRB- HACAs -RRB- , which suggests an immune-mediated mechanism . Only one other patient tested positive for HACAs but was asymptomatic . The significance of HACAs being present is actually not quite sure as other studies show HACAs being present without specific clinical manifestations -LSB- 5 , 6 -RSB- or show HACAs being present but later becoming undetectable -LSB- 6 -RSB- . Repeated blood tests of our patient did not show any HACAs . The precise mechanism of action in the development of arthritis in our patient is still unknown . In conclusion , we describe a patient developing severe oligo-arthritis at successively shorter time-intervals after receiving CHOP-rituximab for a NHL . The arthritis is probably caused by an immune-mediated reaction to rituximab . As it is to be expected that rituximab will be used more frequently in future to treat both NHL as rheumatological diseases , we think it is important for physicians to be aware that rituximab may cause severe -LRB- oligo - -RRB- arthritis as a side effect .

O O O O O B O O O O O B 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 B 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 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 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 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 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 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 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 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 B 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 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 B 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 B 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 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 B 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 B O O O O O O O B 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 B O O O O O O O O B 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 B O O O O O


A decade of letrozole : FACE Third-generation nonsteroidal aromatase inhibitors -LRB- AIs -RRB- , letrozole and anastrozole , are superior to tamoxifen as initial therapy for early breast cancer but have not been directly compared in a head-to-head adjuvant trial . Cumulative evidence suggests that AIs are not equivalent in terms of potency of estrogen suppression and that there may be differences in clinical efficacy . Thus , with no data from head-to-head comparisons of the AIs as adjuvant therapy yet available , the question of whether there are efficacy differences between the AIs remains . To help answer this question , the Femara versus Anastrozole Clinical Evaluation -LRB- FACE -RRB- is a phase IIIb open-label , randomized , multicenter trial designed to test whether letrozole or anastrozole has superior efficacy as adjuvant treatment of postmenopausal women with hormone receptor -LRB- HR -RRB- - and lymph node-positive breast cancer . Eligible patients -LRB- target accrual , N = 4,000 -RRB- are randomized to receive either letrozole 2.5 mg or anastrozole 1 mg daily for up to 5 years . The primary objective is to compare disease-free survival at 5 years . Secondary end points include safety , overall survival , time to distant metastases , and time to contralateral breast cancer . The FACE trial will determine whether or not letrozole offers a greater clinical benefit to postmenopausal women with HR + early breast cancer at increased risk of early recurrence compared with anastrozole . Introduction The aromatase inhibitors -LRB- AIs -RRB- have proven to be a powerful drug class for use in hormone-sensitive breast cancer and have shown superiority over the selective estrogen-receptor modulator -LRB- SERM -RRB- tamoxifen in preclinical models of hormone-dependent breast cancer -LSB- 1 -RSB- and in randomized controlled trials in patients with advanced breast cancer -LSB- 2 -RSB- and early breast cancer -LSB- 3 , 4 -RSB- . Initial adjuvant therapy with either letrozole -LRB- Femara ® -RRB- or anastrozole -LRB- Arimidex ® -RRB- was shown to be significantly more effective than tamoxifen in both the Breast International Group -LRB- BIG -RRB- 1-98 and Anastrozole and Tamoxifen Alone or in Combination -LRB- ATAC -RRB- randomized controlled trials in postmenopausal women with localized breast cancer -LSB- 3 , 4 -RSB- . In the BIG 1-98 primary core analysis , patients with hormone receptor-positive -LRB- HR + -RRB- tumors randomized to receive letrozole initially were compared with those assigned to receive tamoxifen initially -LRB- N = 8,010 -RRB- . After a median follow-up of 25.8 months , 351 events had occurred in the letrozole group -LRB- n = 4,003 -RRB- and 428 events in the tamoxifen group -LRB- n = 4,007 -RRB- , with 5 -- year disease-free survival -LRB- DFS -RRB- estimates of 84.0 % and 81.4 % , respectively . Letrozole significantly reduced the risk of breast cancer recurrence -LRB- hazard ratio = 0.81 ; 95 % confidence interval -LSB- CI -RSB- 0.70 , 0.93 ; P = 0.003 -RRB- , especially the risk of distant recurrence -LRB- hazard ratio = 0.73 ; 95 % CI 0.60 , 0.88 ; P = 0.001 -RRB- -LSB- 3 -RSB- . An analysis limited to patients randomized to either letrozole-only or tamoxifen-only arms -LRB- N = 4,922 -RRB- was recently published and allows for more direct comparisons with results from other trials of continuous therapy with a single endocrine agent -LSB- 5 -RSB- . Results from the letrozole-only or tamoxifen-only arms were consistent with those published for the primary core analysis and showed that letrozole significantly reduced the risk of DFS events -LRB- hazard ratio = 0.82 ; 95 % CI 0.71 , 0.95 ; P = 0.007 -RRB- -LSB- 5 , 6 -RSB- and the risk of distant metastases . After a median follow-up of 51 months , 352 DFS events -LRB- 14.3 % -RRB- were observed in the letrozole-only group -LRB- n = 2,463 -RRB- , compared with 418 DFS events -LRB- 16.9 % -RRB- in the tamoxifen-only group -LRB- n = 2,459 -RRB- -LSB- 5 , 6 -RSB- . The ATAC trial , which compared anastrozole with tamoxifen for 5 years , did not have receptor positivity as a study requirement . After a median follow-up of 68 months -LRB- n = 6,186 -RRB- , anastrozole significantly prolonged DFS -LRB- 575 events with anastrozole vs. 651 events with tamoxifen ; hazard ratio = 0.87 , 95 % CI 0.78 , 0.97 ; P = 0.01 -RRB- and time-to-recurrence -LRB- 402 vs. 498 events ; hazard ratio = 0.79 , 95 % CI 0.70 , 0.90 ; P = 0.0005 -RRB- , and significantly reduced the risk of developing distant metastases -LRB- 324 vs. 375 events ; hazard ratio = 0.86 , CI 0.74 , 0.99 ; P = 0.04 -RRB- and contralateral breast cancers -LRB- 35 vs. 59 events ; 42 % reduction , 95 % CI 12 , 62 ; P = 0.01 -RRB- in the intent-to-treat -LRB- ITT -RRB- population -LSB- 4 -RSB- . However , neither the time to distant recurrence nor distant DFS -LRB- DDFS -RRB- were significantly improved with anastrozole in the HR + population -LSB- 7 -RSB- . While both letrozole and anastrozole have been evaluated extensively in early breast cancer , no head-to-head trial of these two AIs has been conducted in this setting . This report will focus on the design of the Femara versus Anastrozole Clinical Evaluation -LRB- FACE -RRB- trial , and describe how it will prospectively address potential efficacy and safety differences between the two AIs . Rationale for head-to-head trial An American Society of Clinical Oncology technology assessment concluded that AIs should be included in the adjuvant treatment of postmenopausal women with HR + breast cancer -LSB- 8 -RSB- but did not recommend one AI over another . The National Comprehensive Cancer Network has also recommended initial adjuvant therapy with an AI -LRB- specifically letrozole or anastrozole -RRB- as an alternative to tamoxifen -LSB- 9 -RSB- . Some evidence suggests that AIs may not be equivalent , even though they belong to the same pharmacologic class of agents ; differences have been reported in terms of potency , suppression of aromatization , antitumor effects , and pharmacogenomics . However , whether or not one AI is superior in treating early breast cancer is not known . Relative potency Bhatnagar and colleagues compared the aromatase-inhibiting potency of letrozole and anastrozole in a variety of aromatase-containing cellular endocrine and tumor models -LSB- 10 , 11 -RSB- . While letrozole and anastrozole were approximately equipotent in a cell-free aromatase system -LRB- human placental microsomes -RRB- , letrozole was found to be more potent than anastrozole in inhibiting intracellular aromatase in intact rodent cells -LRB- 50 % inhibitory concentration -LSB- IC50 -RSB- 20 vs. 600 nM , respectively -RRB- , normal human adipose fibroblasts -LRB- 0.8 vs. 14 nM -RRB- , and human cancer cell lines -LRB- MCF-7Ca 0.07 vs. 0.82 nM and JEG-3 0.07 vs. 0.99 nM -RRB- . Miller and colleagues reported that letrozole and anastrozole were more potent than aminoglutethimide in vitro against tumor samples obtained from postmenopausal women with breast cancer , with letrozole demonstrating the lowest IC50 -LRB- 2 nM , 8 nM , and 20 μM , respectively -RRB- -LSB- 12 -RSB- . Letrozole was compared with anastrozole in vivo in athymic mice inoculated with MCF7 cells -LSB- 13 -RSB- . Tumor volumes increased to 145.9 % in controls and decreased to 22.4 % with letrozole 10 μg , and to 95.6 % or 78.2 % with anastrozole 10 or 60 μg , respectively . These results are consistent with a higher in vitro potency of letrozole in cell-based assays -LSB- 13 -RSB- . Suppression of aromatization The effects of letrozole and anastrozole on suppression of total-body aromatization and plasma estrogen concentrations have been compared in patients with metastatic breast cancer -LSB- 14 , 15 -RSB- . Levels of aromatase were detectable in 11 of 12 patients during treatment with anastrozole -LRB- mean percentage inhibition in the whole group , 97.3 % -RRB- but in none of the 12 patients during treatment with letrozole -LRB- > 99.1 % suppression in all patients ; Wilcoxon , P = 0.0022 , comparing the two drug regimens -RRB- . Suppression of estrone and estrone sulfate was found to be significantly greater during treatment with letrozole compared with anastrozole -LRB- P = 0.019 and P = 0.0037 , respectively -RRB- . Another study conducted in 54 postmenopausal women with invasive breast cancer showed that more complete inhibition of aromatase was achieved by 2.5 mg of letrozole than 1 mg of anastrozole , resulting in significantly greater suppression of estradiol -LRB- P < 0.0001 -RRB- -LSB- 15 -RSB- . Thus , letrozole reduces estradiol levels to a greater degree than anastrozole , but it is not known whether this difference is clinically relevant . Breast cancer proliferation Biological changes in breast tumors occurring within 14 days of starting treatment may predict the efficacy of different endocrine agents in the adjuvant setting and could prove to be useful surrogate markers to compare drug efficacy -LSB- 16 -RSB- . A study of neoadjuvant endocrine therapy compared the effects of letrozole and anastrozole on the expression of HRs and markers of tumor proliferation in postmenopausal women with estrogen receptor -LRB- ER -RRB- - positive breast cancer -LSB- 16 -RSB- . Neoadjuvant letrozole and anastrozole decreased overall ER expression -LRB- Allred score -RRB- after 14 days , but more cases showed a reduction in progesterone receptor -LRB- PgR -RRB- expression following letrozole treatment -LRB- 75/106 -RRB- than with anastrozole treatment -LRB- 65/102 -RRB- . Furthermore , only letrozole significantly reduced proliferation at lower Allred ER expression levels -LRB- scores 2 -- 5 -RRB- . This is a potentially important finding , because it has been suggested that a greater suppression in proliferation may lead to improved DFS -LSB- 17 -RSB- . Clinical activity Letrozole and anastrozole have not been directly compared in the adjuvant setting , but data from a randomized , head-to-head trial in patients with advanced breast cancer are available -LSB- 18 -RSB- . Postmenopausal women with advanced breast cancer -LRB- N = 713 -RRB- that had progressed either during antiestrogen therapy or within 12 months of completing that therapy were randomized to receive letrozole -LRB- 2.5 mg per day -RRB- or anastrozole -LRB- 1 mg per day -RRB- . Letrozole was significantly superior to anastrozole in terms of overall response rate -LRB- 19.1 % vs. 12.3 % , P = 0.013 -RRB- , but there were no significant differences in median time to progression , the primary end point of the trial . Both agents were well-tolerated , and there were no significant differences in safety . Anastrozole and letrozole in the adjuvant setting have demonstrated superiority to tamoxifen in significantly reducing the risk of recurrence . In the ATAC trial , at 68 months ' median follow-up , anastrozole significantly reduced the risk of distant metastases in the ITT population by 14 % -LRB- P = 0.04 -RRB- but not significantly in the HR + patient subgroup -LRB- hazard ratio = 0.84 ; P = 0.06 -RRB- -LSB- 4 -RSB- . A recent study of the recurrence rates after 2.5 and 5 years from the ATAC study showed that there were fewer recurrence events with anastrozole at these time points due to reductions in contralateral , primary , loco-regional , and distant recurrences -LSB- 19 -RSB- . In addition , at 25.8 months ' median follow-up in the BIG 1-98 trial , letrozole significantly reduced the risk of distant metastases by 27 % -LRB- P = 0.001 -RRB- in the HR + population , and another analysis of the early risk of relapse in 5,980 patients , with a median follow-up of 25 months , showed that letrozole reduced distant recurrences early on -LSB- 3 , 20 -RSB- . The recently reported analysis of letrozole-only and tamoxifen-only arms in the BIG 1-98 trial showed that the time to distant metastases advantage for letrozole was consistent with these findings from the primary core analysis -LSB- 5 -RSB- . These data are potentially important , because the development of distant metastases directly translates into decreased survival . The ATAC trial showed a 3 % relative improvement in overall survival -LRB- OS -RRB- -LRB- P = 0.7 -RRB- with anastrozole at 68 months of follow-up , while a 9 % relative improvement in OS -LRB- P = 0.35 -RRB- was seen with letrozole at 51 months of follow-up -LSB- 3 , 5 -RSB- . Subset analyses of randomized trials comparing letrozole or anastrozole with either tamoxifen or placebo demonstrated differences between these AIs and suggested that specific patient populations may derive differing degrees of benefit from a particular AI . In the trial , retrospective subgroup analyses with a median follow-up of 33 months revealed no significant benefit of anastrozole over tamoxifen in patients with node-positive tumors and with prior chemotherapy -LSB- 21 -RSB- , and these findings were confirmed in the 4-year update of the ATAC trial . Thus , the hazard ratio for risk of recurrence in patients with four or more positive nodes was 0.96 -LRB- 95 % CI 0.72 , 1.25 -RRB- , and in patients with prior chemotherapy , it was 0.98 -LRB- 95 % CI 0.76 , 1.28 -RRB- , indicating no differences between treatments -LSB- 22 , 23 -RSB- . No analyses in similar subgroups were presented in the 68-month update -LSB- 4 -RSB- . Prospectively planned subgroup analysis revealed a benefit of letrozole over tamoxifen in patients who had received chemotherapy and in those with node-positive tumors -LSB- 3 , 5 -RSB- . In the former subset , letrozole reduced the risk of recurrence after 5 years -LRB- hazard ratio 0.70 ; 95 % CI 0.54 , 0.92 ; P = 0.01 -RRB- . In the node-positive subset , letrozole reduced the risk of an event ending a period of DFS by 29 % -LRB- hazard ratio 0.71 , 95 % CI 0.59 , 0.85 ; P < 0.001 -RRB- . The advantage for letrozole in these patient subsets was confirmed in the recent analysis of the letrozole-only and tamoxifen-only arms of BIG 1-98 -LSB- 5 -RSB- . Interestingly , with longer follow-up of 51 months in this monotherapy analysis , there was an emerging benefit in the node-negative group , as letrozole reduced the relative risk of recurrence by 12 % in this patient population . The MA .17 trial , evaluating the efficacy of extended adjuvant letrozole therapy , although not positive for OS in the overall population , demonstrated that OS was statistically significantly improved with letrozole among lymph node-positive breast cancer patients compared with placebo -LRB- hazard ratio 0.61 ; 95 % CI 0.38 , 0.98 ; P = 0.04 -RRB- -LSB- 24 -RSB- . The question of whether one third-generation AI is superior for the adjuvant treatment of postmenopausal women with HR + breast cancer remains , as does the question of whether there are any specific patient populations who derive particular benefit from a specific AI . Patients with early breast cancer can be assigned to risk groups on the basis of clinical and pathological characteristics . In the St. Gallen Guidelines -LSB- 25 -RSB- , node-positive patients are considered to be in the intermediate - or high-risk group depending on the number of positive nodes and human epidermal growth factor receptor-2 -LRB- HER2 -RRB- expression -LRB- see Table 1 -RRB- . The guidelines state that endocrine therapy with an AI is a recommended option for patients with node-positive tumors who are in the intermediate - or high-risk groups . As high-risk patients are at greater risk of relapse , a drug specifically effective in this patient population would provide the oncology community with valuable information that may alter the outcomes of these patients . Table 1Risk categories for early breast cancer according to the St. Gallen Guidelines . Reprinted from -LSB- 25 -RSB- , with permission from the European Society for Medical OncologyLow risk Steroid hormone receptors expression , node-negative , and all of the following features : pT ≤ 2 cmGrade 1No peritumoral vascular invasionHER2/neu gene neither overexpressed nor amplifiedAge ≥ 35 yearsIntermediate riskNode-negative and at least one of the following features : pT > 2 cmGrade 2 -- 3Peritumoral vascular invasionHER2/neu gene either overexpressed or amplifiedAge < 35 yearsNode positive -LRB- 1 -- 3 involved nodes -RRB- and HER2/neu gene neither overexpressed nor amplifiedHigh riskNode positive -LRB- 1 -- 3 involved nodes -RRB- and HER2/neu gene either overexpressed or amplifiedNode-positive -LRB- 4 or more involved nodes -RRB- HER2 human epithelial growth factor receptor 2 pT pathological tumor size -LRB- i.e. size of the invasive component -RRB- Is one AI superior in early breast cancer ? Microarray analysis was used to study the effects of various hormone therapies on ER + MCF-7 cells , stably transfected with the aromatase gene -LRB- MCF-7aro cells -RRB- -LSB- 26 -RSB- . The study found that hormonal stimulation of gene expression can be counteracted by treatment with AIs -LRB- letrozole and anastrozole -RRB- and an anti-estrogen -LRB- tamoxifen -RRB- , but that each agent had its own unique effects on gene expression -LRB- see Fig. 1 -RRB- , suggesting possible differences between letrozole and anastrozole -LSB- 26 -RSB- . Although differences between letrozole and anastrozole have been demonstrated in preclinical models , it is widely recognized that preclinical findings do not always translate into clinical results , and that comparisons in one treatment setting or subpopulation can not be extrapolated to another . A prospective trial is therefore needed to address the question of whether one AI is superior to another . Fig. 1Changes in inhibitor-responsive genes after treatment with letrozole , anastrozole , or tamoxifen . The Venn diagrams show the numbers of genes responsive to individual inhibitors in hormone-regulated genes . Reprinted from -LSB- 26 -RSB- , with permission from the American Association for Cancer Research FACE was designed to test whether there is a preferable AI for the adjuvant treatment of postmenopausal women with HR + and lymph node-positive cancer -LSB- 27 -RSB- . Node-positive patients were selected , because this population has a higher risk of relapse , and recurrence events occur earlier than in node-negative patients -LSB- 20 , 28 , 29 -RSB- . Thus , conducting the FACE trial in patients with lymph node-positive early breast cancer will provide an answer more quickly than conducting a trial in a broader population that includes patients with node-negative tumors . FACE trial design FACE is a phase IIIb open-label , randomized , multicenter trial -LSB- 30 -RSB- . The primary objective of the trial is to compare DFS at 5 years for letrozole and anastrozole . Secondary objectives are to assess safety , OS , time to distant metastases , and time to contralateral breast cancer -LSB- 27 -RSB- . Patients The trial is recruiting 4,000 patients from up to 250 international sites . Eligible patients are postmenopausal women with HR + and lymph node-positive tumors who have recently undergone surgery for primary breast cancer -LRB- pathologic or clinical stage IIA , IIB , or IIIA -RRB- . All patients must provide written informed consent . HR + tumors are defined as tumors with any detectable ER or PgR expression by institutional standards . Patients who are PgR + and ER − are eligible for the trial . Pathologic assessment of axillary lymph nodes is determined by sentinel node biopsy and/or axillary lymph node dissection . Patients are stratified according to the number of involved lymph nodes and HER2 tumor status . Adjuvant trastuzumab is permitted in patients with HER2 + tumors . Other inclusion criteria include World Health Organization performance status of 0 or 1 , lipid panel -LRB- fasting total cholesterol and triglycerides -RRB- ≤ grade 1 -LRB- National Cancer Institute Common Terminology Criteria for Adverse Events v3 .0 -RRB- , and adequate hematologic , hepatic , and renal function . Patients with T4 tumors , metastatic disease , contralateral breast cancer including ductal carcinoma in situ , or evidence of disease progression are excluded . Other exclusion criteria include prior neoadjuvant endocrine therapy ; hormone replacement therapy -LRB- except intravaginal estradiol preparations -RRB- not stopped at least 4 weeks before randomization ; adjuvant anti-estrogen therapy for > 1 month immediately following surgery , radiotherapy , and/or chemotherapy ; breast cancer chemoprevention with anti-estrogens if < 18 months between stopping and diagnosis of breast cancer ; and therapy with any hormonal agent , such as raloxifene , for management of osteoporosis . Randomized trial design and treatments Eligible patients are randomized to receive either letrozole 2.5 mg or anastrozole 1 mg daily for up to 5 years -LRB- see Fig. 2 -RRB- . The date of randomization must be no more than 12 weeks from completion of surgery or 4 weeks after completion of adjuvant chemotherapy . Treatment assignments are balanced based on the number of lymph nodes -LRB- 1 -- 3 , 4 -- 9 , 10 + -RRB- and HER2 status -LRB- positive , negative , or unknown -RRB- . Treatment will commence within 30 days of randomization and following the completion of standard chemotherapy -LRB- if given -RRB- and concurrently with radiotherapy -LRB- if given -RRB- . Patients receive treatment with the allocated AI for up to 5 years or until disease recurrence/relapse . Recurrence and survival will be assessed every 12 months . Fig. 2FACE randomized trial design Efficacy end points The primary end point is DFS , defined as the time from the date of randomization to the date of the first documentation of re-occurrence of invasive breast cancer in local , regional , or distant sites ; new invasive breast cancer in the contralateral breast ; or death from any cause . Secondary efficacy end points include OS , defined as the time from the date of randomization to date of death from any cause ; breast cancer-free survival , defined as the time from date of randomization to the date of death due to breast cancer ; time to development of distant metastases , defined as the time from date of randomization to the date of the first development of any recurrent or metastatic disease in sites other than the local mastectomy scar , the ipsilateral breast in case of breast conservation , or the contralateral breast ; and time to development of contralateral breast cancer , defined as the time from date of randomization to the date of the first development of any disease in the contralateral breast . Although the FACE trial , co-chaired by Drs. Ian Smith and Joyce O'Shaughnessy , is an open-label trial , analysis of the data in a blinded fashion will make the data from this trial comparable with that obtained in a single-blinded trial . Both patients and their physicians will know which drug is being taken , but the analysis of the data will be conducted blinded to study treatment . The sponsor of the trial will not have access to the database , and all efficacy analyses will be conducted by an independent academic organization -LRB- the Instituto Nazionale Tumori , Milan , Italy -RRB- , which will receive the data in a blinded manner . The data will be reviewed by an Independent Data Monitoring Committee , chaired by Professor Martine Piccart . The Independent Data Monitoring Committee will then make recommendations to a Trial Steering Committee chaired by Dr. Kathy Pritchard . The Independent Data Monitoring Committee will decide when the data will be released . The final analysis will be performed after the expected total number of DFS events have occurred . This is anticipated to be 7 years after the start of the study , following an accrual period of about 2 years and a minimum of 5 years of further follow-up . There are two planned interim analyses , scheduled to occur after one third and subsequently after two thirds of the maximum number of events have been observed . The interim analyses will be conducted after 320 and 639 events , respectively , have been recorded . In addition , analyses of secondary end points will be conducted at the interim time points . FACE is powered to detect a 3.5 % absolute difference between the two treatment arms in DFS at 5 years . The 3.5 % difference corresponds to a hazard ratio of 0.83 in favor of letrozole , corresponding to 5-year DFS values of 80.0 % and 76.5 % for letrozole and anastrozole , respectively . Safety end points General patient safety and drug tolerability will be evaluated . Adverse events are recorded at every visit and graded for severity using the National Cancer Institute Common Terminology Criteria for Adverse Events v3 .0 . A checklist of adverse events is used to solicit adverse event information from patients . Safety analyses specifically include cardiovascular events and bone fracture events . All patients are evaluated clinically for osteoporosis and fracture risks . Bone mineral density testing is recommended at least every 2 years for all patients during study therapy by dual X-ray absorptiometry , peripheral dual X-ray absorptiometry , or ultrasound densitometry . Osteoporosis may be managed as clinically indicated using calcium supplements , vitamin D , or bisphosphonates . Measurements of fasting serum lipids are obtained at 6 and 12 months and then annually thereafter for the duration of the study treatment . Other laboratory assessments include hematology and blood chemistry . Other head-to-head studies Other trials that are directly comparing AIs are also under way . A randomized phase III trial -LSB- 31 -RSB- is comparing neoadjuvant therapy with exemestane , letrozole , or anastrozole in postmenopausal women undergoing surgery for stage II or stage III breast cancer . Another ongoing randomized trial , MA .27 -LSB- 32 -RSB- , has been designed to compare the event-free survival of postmenopausal women with HR + primary breast cancer when treated with exemestane or anastrozole . Results from these trials and ongoing pharmacogenomic studies -LSB- 26 -RSB- will also help individualize AI therapy for early breast cancer . The study of inherited genetic polymorphisms that affect drug response and toxicity promises to help physicians individualize hormone treatment . For example , `` slow metabolizers '' of tamoxifen may have a worse outcome in the adjuvant setting with tamoxifen treatment than `` fast metabolizers , '' suggesting that these patients might be better treated with an AI -LSB- 33 -- 35 -RSB- . Polymorphisms in tamoxifen metabolizing cytochrome P -LRB- CYP -RRB- 2D6 gene affect the plasma concentration of tamoxifen active metabolites : women with the CYP2D6 * 4 / * 4 or wt / * 4 genotype could have lower benefit of tamoxifen treatment and tend to have a higher risk of disease relapse -LSB- 35 , 36 -RSB- . Genetic polymorphisms in the aromatase gene , CYP19 , have recently been characterized -LSB- 37 -RSB- . Eighty-eight polymorphisms were identified , resulting in 44 haplotypes . Functional genomic studies revealed that polymorphisms may lead to changes in aromatase activity and altered affinity for AIs . These findings indicate that genetic variation in CYP19 might contribute to variation in the pathophysiology of estrogen-dependent disease . Clinical trials have been initiated to study the impact of genetic differences on response to AI therapy and may eventually lead to patient-specific selection of therapy based on optimizing efficacy and toxicity . Conclusions Letrozole and anastrozole have both demonstrated superior efficacy compared with tamoxifen as initial therapy for early breast cancer -LSB- 3 , 4 -RSB- . Preclinical and clinical evidence suggests that AIs do not have identical pharmacodynamic profiles , but it is not known whether one agent may be more effective as adjuvant therapy for early breast cancer . Differences in potency in preclinical studies , and the reduction in distant metastases in the BIG 1-98 study , suggest the potential for clinical efficacy differences between AIs . Based on the results of these trials , international guidelines now recommend adjuvant hormone therapy with an AI -LSB- 9 , 25 -RSB- in patients with an increased risk of early recurrence . The FACE trial is addressing an important medical question in the oncology community : whether or not letrozole offers greater clinical benefit to postmenopausal women with HR + early breast cancer at increased risk of early recurrence compared with anastrozole . Results from the FACE trial may refine the treatment strategies for treating breast cancer in postmenopausal women .

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

anastrozole
aromatase inhibitors
breast cancer
femara
letrozole
tamoxifen


Estrogen

receptor

α

polymorphisms

and

postmenopausal

breast

cancer

risk

Background

The

estrogen

receptor

alpha

-LRB-

-RRB-

is

a

mediator

of

estrogen

response

in

the

breast

The

most

studied

variants

in

this

gene

are

the

PvuII

and

XbaI

polymorphisms

which

have

been

associated

to

lower

sensitivity

to

estrogen

We

evaluated

whether

these

polymorphisms

were

associated

with

breast

cancer

risk

by

means

of

an

association

study

in

a

population

of

Caucasian

postmenopausal

women

from

the

Rotterdam

study

and

a

meta-analysis

of

published

data

Introduction

Family

history

is

one

of

the

strongest

risk

factors

for

breast

cancer

-LSB-

-RSB-

It

has

been

shown

that

the

heritability

of

this

disease

is

-LSB-

-RSB-

The

most

important

determinants

of

risk

for

breast

cancer

are

related

to

endogenous

hormone

levels

and

major

reproductive

events

-LSB-

-RSB-

thus

suggesting

that

genes

in

the

estrogen

pathway

may

influence

breast

cancer

risk

The

estrogen

receptor

alpha

-LRB-

-RRB-

is

one

of

the

most

important

mediators

of

hormonal

response

in

estrogen-sensitive

tissues

such

as

the

breast

-LSB-

-RSB-

and

plays

a

crucial

role

in

breast

growth

and

differentiation

as

well

as

in

the

development

of

cancer

-LSB-

-RSB-

The

human

gene

is

localized

on

chromosome

-LSB-

-RSB-

it

extends

more

than

kb

and

includes

eight

exons

-LSB-

-RSB-

The

most

studied

variants

in

this

gene

are

the

PvuII

-LRB-

C/T

-RRB-

and

XbaI

-LRB-

G/A

-RRB-

polymorphisms

in

intron

and

bp

upstream

of

exon

respectively

-LSB-

-RSB-

These

variants

have

been

implicated

in

gene

expression

by

influencing

transcription

-LSB-

-RSB-

While

some

studies

have

found

an

increased

risk

for

the

A

and

T

alleles

of

the

XbaI

and

PvuII

polymorphisms

-LSB-

-RSB-

others

have

found

an

increased

risk

only

for

the

X

-LRB-

G

-RRB-

allele

of

XbaI

-LSB-

-RSB-

In

addition

other

studies

found

no

effect

at

all

for

either

of

these

polymorphisms

-LSB-

-RSB-

These

alleles

were

correlated

with

high

bone

mineral

density

and

height

in

other

studies

including

one

performed

in

our

study

population

-LSB-

-RSB-

suggesting

a

stronger

estrogenic

effect

in

P

-LRB-

C

-RRB-

and

X

-LRB-

G

-RRB-

allele

carriers

-LSB-

-RSB-

The

aim

of

our

study

was

to

evaluate

the

effect

of

these

polymorphisms

on

breast

cancer

risk

by

performing

an

association

analysis

in

a

population

based

study

of

Caucasian

postmenopausal

women

Further

we

performed

meta-analyses

of

all

available

published

data

on

these

polymorphisms

and

the

risk

of

breast

cancer

Materials

and

methods

Study

population

and

measurements

Our

study

population

is

part

of

the

Rotterdam

study

-LSB-

-RSB-

Inhabitants

of

the

suburb

of

Ommoord

aged

or

older

were

invited

to

participate

and

agreed

to

do

so

-LRB-

response

rate

-RRB-

Study

participants

signed

an

informed

consent

and

the

Medical

Ethics

Committee

of

the

Erasmus

Medical

Center

approved

the

study

Our

study

group

was

composed

of

postmenopausal

women

Information

on

risk

factors

such

as

age

at

entry

age

at

menarche

age

at

menopause

parity

body

mass

index

-LRB-

BMI

-RRB-

waist

hip

ratio

-LRB-

WHR

-RRB-

and

hormone

replacement

therapy

use

-LRB-

HRT

-RRB-

was

retrieved

at

baseline

through

a

questionnaire

BMI

was

calculated

by

dividing

the

weight

in

kilograms

by

the

height

-LRB-

in

meters

-RRB-

squared

-LSB-

-RSB-

Case

identification

and

validation

Three

different

databases

were

used

for

patient

identification

First

cases

diagnosed

by

general

practitioners

in

the

research

area

-LRB-

Ommoord

-RRB-

were

collected

-LRB-

International

Classification

of

Primary

Care

-LRB-

code

-RRB-

-RRB-

Second

the

Dutch

National

Registry

of

all

hospital

admissions

-LRB-

LMR

-RRB-

was

consulted

to

detect

all

malignancy

related

hospital

admissions

for

study

participants

Finally

regional

pathology

databases

were

linked

to

the

Rotterdam

Study

to

identify

patients

Subsequently

breast

cancer

cases

were

validated

by

a

physician

on

the

basis

of

medical

records

of

the

general

practitioner

discharge

letters

and

pathology

reports

Only

pathologically

confirmed

cases

were

considered

in

the

analysis

The

index

date

was

defined

as

the

earliest

date

found

in

the

pathology

report

Genotyping

data

analysis

Out

of

the

women

participating

in

our

study

-LRB-

-RRB-

were

successfully

genotyped

for

the

PvuII

and

XbaI

polymorphisms

The

genotyping

procedures

have

been

described

previously

-LSB-

-RSB-

Loss

to

follow

up

was

assessed

to

verify

it

was

independent

of

genotype

Categorical

variables

such

as

parity

and

HRT

were

compared

between

genotype

groups

using

the

chi-squared

test

Continuous

variables

-LRB-

age

at

entry

age

at

menopause

BMI

and

WHR

-RRB-

were

compared

using

the

independent

sample

Mann

Whitney

test

We

used

logistic

regression

to

study

the

risk

of

breast

cancer

by

genotype

This

analysis

was

performed

using

SPSS

version

since

there

is

no

clear

risk

allele

from

the

literature

we

took

the

TT

-LRB-

PvuII

-RRB-

and

AA

-LRB-

XbaI

-RRB-

genotypes

as

reference

because

they

have

been

associated

to

lower

sensitivity

to

estrogen

in

our

population

-LSB-

-RSB-

We

also

performed

a

trend

test

to

evaluate

if

the

number

of

risk

alleles

carried

had

an

effect

on

disease

risk

Hardy-Weinberg

equilibrium

-LRB-

HWE

-RRB-

was

assessed

for

both

polymorphisms

using

Markov-Chain

Monte-Carlo

approximation

of

the

exact

test

implemented

in

the

GENEPOP

package

V

-LSB-

-RSB-

Meta-analysis

We

searched

PubMed

until

October

for

all

case-control

studies

on

the

association

of

the

PvuII

and

XbaI

polymorphisms

in

the

gene

and

breast

cancer

Our

search

strategy

was

based

on

the

keyword

breast

cancer

combined

with

estrogen

receptor

and

polymorphism

To

verify

that

all

studies

were

retrieved

the

reference

lists

of

all

publications

were

searched

for

additional

studies

We

excluded

studies

from

our

analyses

if

the

genotype

frequencies

in

the

control

population

were

out

of

Hardy-Weinberg

or

if

their

data

had

been

previously

used

in

another

study

To

quantify

the

strength

of

association

pooled

odds

ratios

-LRB-

ORs

-RRB-

and

confidence

intervals

-LRB-

CI

-RRB-

were

calculated

using

the

random-effects

model

of

the

DerSimonian

and

Laird

method

-LSB-

-RSB-

The

degree

of

heterogeneity

between

the

study

results

was

tested

by

the

inconsistency

statistic

-LRB-

-RRB-

Funnel

plots

were

used

to

evaluate

publication

bias

-LSB-

-RSB-

Data

were

analysed

using

Review

Manager

version

-LRB-

Cochrane

Collaboration

Oxford

UK

-RRB-

Results

The

total

loss

of

follow-up

for

the

genotyped

participants

was

and

it

was

not

dependent

on

genotype

-LRB-

P

-RRB-

The

genotype

frequencies

of

both

polymorphisms

were

in

HWE

proportions

-LRB-

P

for

PvuII

and

for

XbaI

-RRB-

In

Table

we

show

the

baseline

characteristics

of

our

study

population

We

found

that

all

cases

-LRB-

incident

and

prevalent

-RRB-

were

significantly

younger

at

entry

than

controls

-LRB-

P

-RRB-

and

also

died

earlier

during

follow-up

-LRB-

P

-RRB-

when

using

incident

cases

only

we

found

the

same

significant

differences

-LRB-

P

for

age

at

entry

P

for

age

at

death

-RRB-

We

also

found

that

cases

had

significantly

fewer

children

than

controls

-LRB-

P

-RRB-

We

did

not

find

any

significant

differences

in

these

baseline

characteristics

between

genotype

groups

-LRB-

data

not

shown

-RRB-

Table

characteristics

of

the

study

populationCasesControlsTotalTotal

studied

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

age

of

entry

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Mean

age

at

death

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Mean

age

at

menarche

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Mean

age

at

menopause

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Mean

number

of

children

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Parity

-LRB-

SD

-RRB-

-LRB-

child

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Hormone

replacement

therapy

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Mean

BMI

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Mean

WHR

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

P-value

There

were

women

with

previously

diagnosed

postmenopausal

breast

cancer

who

entered

the

study

During

follow-up

were

additionally

diagnosed

There

were

no

significant

differences

in

the

number

of

cases

between

the

PvuII

-LRB-

P

for

overall

cases

-RRB-

and

XbaI

genotypes

-LRB-

P

for

overall

cases

-RRB-

We

carried

out

a

logistic

regression

analysis

adjusting

for

age

at

entry

age

at

menopause

BMI

WHR

and

HRT

for

both

polymorphisms

separately

-LRB-

Table

-RRB-

Since

the

T

and

A

alleles

of

these

polymorphisms

have

been

correlated

to

lower

estrogenic

effects

we

used

the

TT

and

AA

genotypes

as

our

reference

categories

in

the

analyses

There

were

no

significant

differences

in

risk

for

breast

cancer

among

carriers

of

the

different

genotypes

of

the

PvuII

or

XbaI

polymorphisms

in

the

gene

There

was

a

non-significant

tendency

of

the

C

allele

of

PvuII

-LRB-

P-for

trend

-RRB-

and

G

allele

of

the

XbaI

-LRB-

P-for

trend

-RRB-

to

be

over

represented

in

patients

Table

ratios

for

breast

cancer

risk

for

PvuII

and

XbaI

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

To

evaluate

our

data

together

with

those

in

the

literature

we

performed

meta-analyses

We

identified

nine

articles

studying

the

relation

between

XbaI

and

PvuII

polymorphisms

and

the

risk

of

breast

cancer

-LSB-

-RSB-

We

excluded

from

our

analyses

one

study

-LSB-

-RSB-

since

the

data

was

used

in

another

study

-LSB-

-RSB-

Furthermore

two

studies

were

excluded

since

genotype

frequencies

of

controls

were

out

of

HWE

proportions

-LSB-

-RSB-

Using

the

random

effects

model

we

did

not

find

any

difference

in

risk

among

XbaI

and

PvuII

genotypes

-LRB-

Figs.

and

-RRB-

High

inter-study

heterogeneity

can

render

the

interpretation

of

the

results

of

a

meta-analysis

difficult

and

although

we

found

high

heterogeneity

in

the

G/A

versus

GG

comparison

there

was

no

significant

heterogeneity

in

the

other

three

comparisons

Additionally

the

evaluation

of

the

funnel

plots

did

not

suggest

evidence

for

publication

bias

Fig.

XbaI

polymorphism

and

breast

cancer

riskFig

Analysis

PvuII

polymorphism

and

breast

cancer

risk

Discussion

We

performed

an

association

study

to

evaluate

the

relationship

of

two

well-studied

polymorphisms

in

the

gene

and

the

risk

of

breast

cancer

in

Caucasian

postmenopausal

women

from

the

Rotterdam

Study

Using

logistic

regression

analysis

we

found

no

evidence

of

effect

with

only

a

non-significant

increase

in

breast

cancer

risk

for

AA

carriers

of

the

XbaI

polymorphism

-LRB-

overall

OR

CI

-RRB-

and

for

TT

carriers

of

the

PvuII

variant

-LRB-

overall

OR

CI

-RRB-

Additionally

we

performed

meta-analyses

of

published

data

to

examine

the

effect

of

both

polymorphisms

These

meta-analyses

also

suggest

there

are

no

differences

in

risk

among

genotype

groups

of

these

two

variants

The

XbaI

and

PvuII

polymorphisms

are

situated

in

intron

and

their

functionality

has

not

yet

been

demonstrated

Moreover

it

has

been

suggested

their

effects

could

be

the

result

of

high

linkage

disequilibrium

with

functional

variants

that

affect

sensitivity

to

estrogen

-LSB-

-RSB-

One

of

the

limitations

of

our

study

is

the

limited

number

of

breast

cancer

cases

present

in

our

population

Nevertheless

we

have

sufficient

power

-LRB-

β

-RRB-

to

detect

effects

of

or

higher

We

further

conducted

meta-analyses

off

all

studies

conducted

to

date

Our

data

suggests

that

these

two

polymorphisms

do

not

play

a

role

in

the

susceptibility

of

breast

cancer

in

elderly

Caucasian

women

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estrogen receptor
polymorphism
breast cancer


Tight blood glucose control : a recommendation applicable to any critically ill patient ? The issue of tight glucose control with intensive insulin therapy in critically ill patients remains controversial . Although compelling evidence supports this strategy in postoperative patients who have undergone cardiac surgery , the use of tight glucose control has been challenged in other situations , including in medical critically ill patients and in those who have undergone non-cardiac surgery . Similarly , the mechanisms that underlie the effects of high-dose insulin are not fully elucidated . These arguments emphasize the need to study the effects of tight glucose control in a large heterogeneous cohort of intensive care unit patients . Until the end of the past millenium , relatively little attention was given to control of blood sugar levels . In critically ill patients , hyperglycaemia was considered to be physiological because it results from the metabolic and hormonal changes that accompany the stress response to injury . In most intensive care units -LRB- ICUs -RRB- , blood sugar was checked every 4 -- 6 hours and hyperglycaemia -LRB- defined as blood sugar levels > 10 -- 12 mmol/l -LSB- 180 -- 216 mg/dl -RSB- -RRB- was corrected by subcutaneous or intravenous insulin . The presence of pre-existing diabetes mellitus or post-neurosurgical status often prompted more intense control of hyperglycaemia . Furthermore , the issue of glucose control was discussed in few sessions or satellite symposia during intensive care meetings . The deleterious effects of hyperglycaemia during critical illness have been characterized over the past few years , and include an increased susceptibility to infections and thromboses , macrovascular and microvascular changes , and delayed wound healing , among other effects -LRB- for review -LSB- 1 -RSB- -RRB- . Renewed interest in control of hyperglycaemia in critically ill patients -LRB- Fig. 1 -RRB- followed the publication of a study conducted by Van den Berghe and coworkers in 2001 -LSB- 2 -RSB- . Those investigators reported a 43 % decrease in relative intensive care mortality as well as consistent decreases in several surrogate markers of disease severity in patients randomly assigned to tight glucose control by intensive intravenous insulin therapy . A post hoc multivariate logistic regression analysis of these data suggested that control of hyperglycaemia played a more important role than did the amount of insulin administered -LSB- 3 -RSB- . Interestingly enough , at least two recent retrospective , large-scale studies -LSB- 4,5 -RSB- confirmed that outcome was improved in patients whose average blood glucose was maintained below 8 mmol/l -LRB- 144 mg/dl ; Table 1 -RRB- . Although the findings reported by Van den Berghe and coworkers are impressive , some concern arose regarding the applicability of these results to other types of patients . Of the patients studied , 63 % were admitted for follow up after cardiac surgery ; this high proportion was felt to be consistent with a particular benefit from tight glucose control with intensive insulin in these patients , but there is uncertainty regarding whether tight glucose control is beneficial in patients who have not undergone cardiac surgery . Fear of life-threatening hypoglycaemia and increased workload and costs probably underlie the reluctance of many intensivists to launch systematic protocols of tight glucose control . Indeed , many intensivists still use a high glucose threshold -LRB- 10 mmol/l -LSB- 180 mg/dl -RSB- -RRB- -LSB- 6 -RSB- . In a European survey -LRB- unpublished data -RRB- we found considerable variation in the glycaemic thresholds employed in ICUs , which ranged from 6 to 11.1 mmol/l -LRB- 108 -- 200 mg/dl -RRB- . Some arguments against generalized use of tight glucose control are reported in the present issue of Critical Care by Vriesendorp and coworkers -LSB- 7 -RSB- . In a retrospective study performed at one centre in Amsterdam , those authors found that , after oesophageal surgery in patients without significant cardiovascular compromise -LRB- ASA class I -- II -RRB- , postoperative hyperglycaemia was not a risk factor for infectious complications . Only by univariate analysis were they able to find an improvement in patients with blood glucose levels below 9.3 mmol/l -LRB- 167 mg/dl -RRB- in terms of length of ICU stay . These findings differ strikingly from those of other studies -LSB- 2,4,5 -RSB- . Although the report by Vriesendorp and coworkers challenges the concept of tight glucose control , it can hardly be considered a major piece of evidence against it . Indeed , blood glucose concentrations were presented as means of values recorded only over 48 hours , whereas the ICU stay extended up to 71 days , with a median of 3 days . Insulin was administered to only 9 % of the patients during the 48-hour period of observation . In addition , patients received a mean of only 22.5 g glucose/day , and were fed early after surgery with an enteral solution of ` immunonutrients ' -- a potential confounding factor with respect to infectious morbidity . However , despite these limitations , as well as others that are acknowledged by the authors , the findings of the study support the hypothesis that tight glucose control could be of greater benefit to patients with cardiovascular disease than to those without . In conclusion , as recently suggested by Van den Berghe -LSB- 8 -RSB- , further studies are needed to confirm the benefits of tight blood glucose control with intensive insulin therapy in a heterogeneous population of ICU patients . Hence , a large randomized prospective multicentre trial is warranted . Such study will also help in determining the physiological importance of the effects of insulin and , more importantly , will provide intensive care workers with key information for guiding the management of blood glucose in critically ill patients . Abbreviation ICU = intensive care unit . Competing interests The author -LRB- s -RRB- declare that they have no competing interests .

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