Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27.

BACKGROUND: Histological subtype, (invasive ductal breast cancer (IDBC)/invasive lobular breast cancer (ILBC)), might be a marker for differential response to endocrine therapy in breast cancer. METHODS: Clinical trial MA.27 compared 5 years of adjuvant anastrozole or exemestane in postmenopausal patients with hormone receptor positive early breast cancer. We evaluated IDBC versus ILBC (based on original pathology reports) as predictor for event-free survival (EFS) and overall survival (OS). RESULTS: A total of 5709 patients (5021 with IDBC and 688 with ILBC) were included (1876 were excluded because of missing or other histological subtype). Median follow-up was 4.1 years. Overall, histological subtype did not influence OS or EFS (HR (hazard ratio) 1.14, 95% confidence interval (CI) [0.79-1.63], P = 0.49 and HR 1.04, 95% CI [0.77-1.41], P = 0.81, respectively). There was no significant difference in OS between treatment with exemestane versus treatment with anastrozole in the IDBC group (HR = 0.92, 95% CI [0.73-1.16], P = 0.46). In the ILBC group, a marginally significant difference in favour of treatment with anastrozole was seen (HR = 1.79, 95% CI [0.98-3.27], P = 0.055). In multivariable analysis a prognostic effect of the interaction between treatment and histological subtype on OS (but not on EFS) was noted, suggesting a better outcome for patients with ILBC on anastrozole (HR 2.1, 95% CI [0.99-4.29], P = 0.05). After stepwise selection in the multivariable model, a marginally significant prognostic effect for the interaction variable (treatment with histological subtype) on OS (but not on EFS) was noted (Ratio of HR 2.1, 95% CI [1.00-4.31], P = 0.05). CONCLUSION: Our data suggest an interaction effect between treatment and histology (P = 0.05) on OS. Here, patients with ILBC cancers had a better OS when treated with anastrozole versus exemestane, whereas no difference was noted for patients with IDBC. CLINICAL TRIAL INFORMATION: NCT00066573.

Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials.

BACKGROUND: We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. METHODS: Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. RESULTS: In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. CONCLUSIONS: Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. CLINICAL TRIALS NUMBERS: CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.

Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study.

PURPOSE: This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms' tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients. METHODS: Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab-chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A-C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination. RESULTS: Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely. CONCLUSIONS: Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab-chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves.

Real world patterns of care in HER2-overexpressing breast cancer: Results of a survey of TEACH clinical trial investigators in 2011.

BACKGROUND: HER2-overexpressing breast cancer (BC) is common among young patients and poses a public health burden. Adjuvant anti-HER2/neu therapy with trastuzumab reduces the risk of recurrence and improves survival. METHODS: A web-based survey was sent to 386 physicians of the "TEACH" trial in 2011 to determine access to HER2/neu testing and treatment patterns for HER2-overexpressing BC. RESULTS: There were 151 responders (39%) from 28 countries. Ninety-seven percent reported HER2/neu expression is routinely measured in their institutions by immunohistochemistry (85%), FISH (80%) and other methods (16%). Twenty percent of responders from Asia reported that the test was not routinely available. Forty-eight percent of participants reported instances when adjuvant HER2-directed therapy was recommended to a patient who eventually did not receive it. Reasons for not receiving trastuzumab was cost (73%, p < 0.0001) in low- and middle-income countries and co-morbidities in high-income countries (43%, p = 0.003). CONCLUSIONS: This survey reflects the availability of HER2/neu testing and anti-HER2/neu therapy among physicians who participated in TEACH. A high proportion of women with HER2-overexpressing BC may not receive standard adjuvant therapy due to unavailability of the test and cost of therapy. Despite having some limitations, such as a possible selection bias of participating physicians, variable definitions of access to healthcare among respondents, and changes in trastuzumab availability since 2011, our results demonstrate that access to care and region of practice impact the implementation of cancer treatments.

New onset vasomotor symptoms but not musculoskeletal symptoms associate with clinical outcomes on extended adjuvant letrozole - Analyses from NCIC CTG MA.17.

PURPOSE: New onset symptoms on adjuvant aromatase inhibitors for hormone receptor positive early breast cancer may associate with clinical outcomes. We performed this exploratory analysis of the association of new onset musculoskeletal (MSK) and vasomotor (VM) symptoms with clinical outcomes in the NCIC CTG MA.17 trial 5 years of extended adjuvant endocrine therapy with letrozole after tamoxifen. METHODS: Symptoms were collected at baseline, 1, 6, and every 12 months on study. Multivariate Cox Models adjusting for age, nodal status, duration of tamoxifen and prior chemotherapy were used to compare disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) based on data collected before, and after, the unblinding between women with VM or MSK symptoms and those without. RESULTS: Data post-unblinding showed new VM symptoms on extended letrozole significantly improved DFS and DDFS when occurring 1 month (DFS HR 0.52, 95% CI, 0.28-0.96; p = 0.04; DDFS HR 0.49, 95% CI, 0.24-0.99; p = 0.046) and 6 months (DFS HR 0.43, 95% CI, 0.24-0.78; p = 0.006; DDFS HR 0.44, 95% CI, 0.22-0.85; p = 0.02) after treatment initiation. Those with new VM symptoms at 12 months also had a significantly better DFS (HR 0.47, 95% CI 0.26, 0.84; P = 0.01) and a trend in improved DDFS. Only a trend to improved OS was found for those with VM symptoms 6 month after treatment. No significant improvement was found for those with new MSK symptoms at any time point or for any endpoint. CONCLUSIONS: New onset VM symptoms with extended letrozole may be useful in predicting treatment benefit.

Drug withdrawal in women with progressive metastatic breast cancer while on aromatase inhibitor therapy.

BACKGROUND: Acquiring resistance to endocrine therapy is common in metastatic hormone-receptor-positive breast cancer (MBC). These patients most often transition either to next-line endocrine therapy or to systemic chemotherapy. However, withdrawal of endocrine therapy and observation as is selectively practiced in prostate cancer is another potential strategy for breast cancer patients. METHODS: A prospective, single-arm phase II trial of aromatase inhibitor (AI) withdrawal was performed in women with MBC, who had disease progression on AI therapy. The primary objective was to estimate the clinical benefit rate (defined as complete or partial response, or stable disease for at least 24 weeks, by RECIST criteria). Participants were monitored clinically and radiographically off all therapy at 8, 16 and 24 weeks after treatment and every 12 weeks thereafter until disease progression. RESULTS: Twenty-four patients (of 40 intended) were enrolled when the study was closed due to slow accrual. Clinical benefit rate overall was 46% (95% CI 26% to 67%). Median progression-free survival from time of AI withdrawal was 4 months. Two patients have remained progression free, off all treatment, for over 60 months. CONCLUSIONS: Despite suboptimal patient accrual, our results suggest that selected patients with metastatic breast cancer progressing on AI therapy can experience disease stabilisation and a period of observation after AI withdrawal. A randomised phase II trial is planned.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole.

BACKGROUND: MA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen. PATIENTS AND METHODS: Exploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis. RESULTS: At diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13-0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51-0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03-0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22-0.94; P = 0.03). CONCLUSIONS: Extended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.

A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women.

We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.

A randomized, placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women.

Mammographically detected breast density has been correlated with breast cancer risk. Breast density appears to be influenced by hormonal factors including increasing age, postmenopausal status, number of pregnancies, lower body weight, hormone replacement therapy, and tamoxifen therapy. The aromatase inhibitor letrozole profoundly reduces breast and circulating estrogen levels in postmenopausal women. We hypothesize that letrozole may reduce breast density and report here on its effects on mammographic breast density, bone mineral density (BMD), bone biomarkers, plasma hormone, and serum lipid levels. MAP1 was a multicenter, randomized, double-blind, placebo-controlled, feasibility trial in which postmenopausal women with or without prior invasive breast cancer were randomized in a 2:1 ratio of letrozole (2.5 mg daily) or placebo for 12 months and followed for a total of 24 months. Eligible women had an estimated >25% breast density on baseline mammogram. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms as estimated by a computer-assisted thresholding program. Baseline and 12-month mammographic density was also assessed in a blinded manner by visual inspection. Secondary endpoints included changes in serum hormones, plasma lipid levels, bone biomarkers, and BMD. Data are available for 67 women (44 on letrozole and 23 on placebo). No significant changes in PD were noted between the treatment arms at either 12 or 24 months. No distinguishable difference in density measurements by visual inspection were noted between baseline and 12-month mammograms. A significant decrease in percentage change in T-score of the femoral neck at 12 months was noted in the letrozole arm without other significant changes in BMD parameters. Lipid values did not differ between treatment groups except for a borderline significant decrease in total cholesterol at 3 months among women treated with letrozole. Letrozole therapy was associated with a significant reduction in mean serum estradiol, estrone, and estrone sulfate levels at 12 months, but not at 24 months. A significant increase in serum IGF-1 levels was also noted in the letrozole group compared to the placebo group at both 12 and 24 months. To conclude, compared with placebo, 12 months of letrozole therapy does not appear to have a significant effect on mammographic PD. Twelve months of letrozole was associated with a decrease of uncertain clinical significance in the T-score of the femoral neck at 12 months which was reversible at 24 months with recovery of estrogen levels. Letrozole therapy was found to increase IGF-1 levels at 12 and 24 months.

Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17.

BACKGROUND: MA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole. PATIENTS AND METHODS: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. RESULTS: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16-95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55-0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62-1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39-0.97, P = 0.033). CONCLUSIONS: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.

Screening mammography for young women treated with supradiaphragmatic radiation for Hodgkin's lymphoma.

BACKGROUND: Female survivors of Hodgkin's lymphoma (HL) treated with supradiaphragmatic radiation therapy (SRT) are at increased risk of breast cancer (BC), but there is little data on the optimal screening strategy. PATIENT AND METHODS: We report a prospective surveillance study of women treated for HL with SRT before age 30 participating in a high-risk screening clinic. Starting 8 years after treatment, women received annual mammography and clinical follow-up from 1997 to 2006. Method of detection and characteristics of BCs were identified. RESULTS: In all, 115 female HL survivors attended at least one clinic; 100 participated in annual surveillance. The majority had mammography alone; adjunctive magnetic resonance imaging (MRI) was used more frequently in women with high breast density (P = 0.025). Median age at first mammogram was 36 years and decreased with more recent year of diagnosis. Twelve of the 100 participating women (12%) were diagnosed with BC after a median of 5 years of surveillance (range, 1-9). Seven BCs presented as palpable masses [six invasive, one ductal carcinoma in situ (DCIS)], five were detected by mammography (one invasive, four DCIS). CONCLUSIONS: Despite earlier initiation of mammographic screening, most BCs were detected clinically and had unfavorable pathologic characteristics. Evaluation of more intensive screening and the contribution of MRI for earlier detection is warranted.

The National Cancer Institute of Canada Clinical Trials Group MAP.3 trial: an international breast cancer prevention trial.

Several large phase III trials have demonstrated that tamoxifen-and more recently, raloxifene-can effectively reduce the incidence of invasive breast cancer by 50%. However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (AIS) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has developed a randomized phase III study to determine the efficacy of an ai (exemestane) to reduce the incidence of invasive breast cancer in postmenopausal women at an increased risk for developing breast cancer. The NCIC CTG map.3 (ExCel) trial is a double-blind placebo-controlled multicentre, multinational trial. Based on the known preclinical and clinical profile of the ais, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifene.

Pilot study of the impact of letrozole vs. placebo on breast density in women completing 5 years of tamoxifen.

Breast density, a strong risk factor for breast cancer, is reduced by the anti-estrogen, tamoxifen (TAM). We examined whether aromatase inhibitor (AI) therapy results in further reductions in breast density among women completing 5 years of TAM. Among a sample of women with early-onset breast cancer who were randomized to letrozole (LET)(n=56) or placebo (PLAC)(n=48) after 5 years of TAM, we examine the change in percent density at 9-15 months as well as a per-year change in PD by treatment group. There was no difference in the adjusted mean change (-1.0%, LET; -0.3%, PLAC (P=0.58)) or the percentage change (-2.7%, LET; -3.0%, PLAC (P=0.96)) in PD between treatment groups at 9-15 months. Results were similar for longitudinal change (-0.68% per year, LET; -0.12% per year, PLAC (P=0.23)). Breast density does not appear to be a clinically relevant biomarker in women who already have low PD following 5 years of TAM.

Clinical outcomes of ethnic minority women in MA.17: a trial of letrozole after 5 years of tamoxifen in postmenopausal women with early stage breast cancer.

BACKGROUND: Aromatase inhibitors are widely employed in the adjuvant treatment of early stage breast cancer. The impact of aromatase inhibitors has not been established in ethnic minority women. PATIENTS AND METHODS: The purpose of this study was to evaluate the impact of letrozole on minority women in MA.17, a placebo-controlled trial of letrozole following 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Retrospective comparison of disease-free survival (DFS), side effects, and mean changes in quality of life (QOL) scores from baseline between Caucasian and minority women was performed. RESULTS: Minority (n = 352) and Caucasian (n = 4708) women were analyzed. There was no difference between these groups in DFS (91.6% versus 92.4% respectively for 4 year DFS). Letrozole, compared with placebo, significantly improved DFS for Caucasians (HR = 0.55; P < 0.0001) but not for minorities (HR = 1.39; P = 0.53). Among women who received letrozole, minorities had a significantly lower incidence of hot flashes (49% versus 58%; P = 0.02), fatigue (29% versus 39%; P = 0.005), and arthritis (2% versus 7%; P = 0.006) compared with Caucasians. Mean change in QOL scores for minority women who received letrozole demonstrated improved mental health at the 6-month assessment (P = 0.02) and less bodily pain at the 12-month assessment (P = 0.046). CONCLUSION: Letrozole improved DFS in Caucasians but a definite benefit in minority women has not yet been demonstrated. Minority women tolerated letrozole better than Caucasians in terms of toxicity. These results need confirmation in other trials of aromatase inhibitors.

Body cooling between two bouts of exercise in the heat enhances subsequent performance.

The purpose was to assess whether body cooling between 2 bouts of exercise in the heat enhances performance during the second exercise session. Using a random, crossover design, 15 subjects (3 women, 12 men; 28 +/- 2 years, 180 +/- 2 cm, 69 +/- 2.3 kg) participated in all 3 trials. Subjects ran 90 minutes on hilly trails in a hot environment (approximately 27 degrees C) before 12 minutes of either cold water immersion (CWI; 13.98 degrees C), ice water immersion (IWI; 5.23 degrees C), or a mock treatment (MT) of sitting in a tub with no water (29.50 degrees C). After immersion, subjects ran a 2-mile race. CWI had faster (p < 0.05) performance time (725 seconds) than MT (769 seconds). CWI and IWI had significantly (p < 0.05) lower rectal temperatures postimmersion than MT as well as postrace (p < 0.05). Heart rate also remained significantly lower (p < 0.05) during the CWI and IWI trials for the first half of the race. In conclusion, CWI enhances performance (6% improvement in race time) in the second bout of exercise, supporting its potential role as an ergogenic aid in athletic performance.

The extended adjuvant NCIC CTG MA.17 trials: initial and rerandomization studies.

Based upon the results of the NCIC CTG MA.17 trial, letrozole has become the only approved aromatase inhibitor (AI) in the extended adjuvant treatment setting following 5 years of tamoxifen therapy. In this trial, the AI letrozole decreased the overall risk of breast cancer recurrence by 42% compared with placebo in postmenopausal women completing 5 years of tamoxifen. The benefit of letrozole exceeded the expected difference after median follow-up of more than 2 years and led to the unblinding of the trial. The 30-month updated analyses found a 4.8%, 4-year disease-free survival improvement overall, an improvement in distant disease-free recurrence in both node-negative and node-positive patients, and a survival benefit for node-positive patients. Generally well tolerated, letrozole caused some adverse events including arthralgias and osteoporosis. However, results from the Zometa-Femara adjuvant synergy trial (Z-FAST) suggest that zoledronic acid, when used concomitantly with letrozole, is able to manage bone loss in postmenopausal women with early breast cancer.

The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L).

BACKGROUND: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L). PATIENTS AND METHODS: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing approximately 5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial. RESULTS: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups. CONCLUSIONS: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.