Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy.

BACKGROUND: Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. PATIENTS AND METHODS: SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). RESULTS: Intention-to-treat population included 4851 women in SOLE (n = 2425 in the intermittent and n = 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n = 78 in the intermittent and n = 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. CONCLUSIONS: Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.

Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99.

Background: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated. Patients and methods: One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity. Results: Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P =0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related. Conclusion: The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients.

Symptoms of endocrine treatment and outcome in the BIG 1-98 study.

There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen. Data on patients randomized into the monotherapy arms of the BIG 1-98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n = 4,798) and at the 12-month landmark (n = 4,682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed for disease-free survival (DFS) and for breast cancer free interval (BCFI), using regression analysis to estimate hazard ratios (HR) and 95 % confidence intervals (CI). Median follow-up was 7.0 years. Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses [e.g., 12-month landmark, HR (95 % CI) for DFS = 0.65 (0.49-0.87), and for BCFI = 0.70 (0.49-0.99)]. By contrast, reporting of vasomotor symptoms was less clearly associated with DFS [12-month DFS HR (95 % CI) = 0.82 (0.70-0.96)] and BCFI (12-month DFS HR (95 % CI) = 0.97 (0.80-1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes. While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.

Long-term results of International Breast Cancer Study Group Trial VIII: adjuvant chemotherapy plus goserelin compared with either therapy alone for premenopausal patients with node-negative breast cancer.

BACKGROUND: The International Breast Cancer Study Group Trial VIII compared long-term efficacy of endocrine therapy (goserelin), chemotherapy [cyclophosphamide, methotrexate and fluorouracil (CMF)], and chemoendocrine therapy (CMF followed by goserelin) for pre/perimenopausal women with lymph-node-negative breast cancer. PATIENTS AND METHODS: From 1990 to 1999, 1063 patients were randomized to receive (i) goserelin for 24 months (n = 346), (ii) six courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or (iii) six courses of CMF plus 18 months goserelin (CMF→ goserelin; n = 357). Tumors were classified as estrogen receptor (ER) negative (19%), ER positive (80%), or ER unknown (1%); 19% of patients were younger than 40. Median follow-up was 12.1 years. RESULTS: For the ER-positive cohort, sequential therapy provided a statistically significant benefit in disease-free survival (DFS) (12-year DFS = 77%) compared with CMF alone (69%) and goserelin alone (68%) (P = 0.04 for each comparison), due largely to the effect in younger patients. Patients with ER-negative tumors whose treatment included CMF had similar DFS (12-year DFS CMF = 67%; 12-year DFS CMF→ goserelin = 69%) compared with goserelin alone (12-year DFS = 61%, P= NS). CONCLUSIONS: For pre/perimenopausal women with lymph-node-negative ER-positive breast cancer, CMF followed by goserelin improved DFS in comparison with either modality alone. The improvement was the most pronounced in those aged below 40, suggesting an endocrine effect of prolonged CMF-induced amenorrhea.

Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: long-term follow up on IBCSG Trial IX.

BACKGROUND: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. PATIENTS AND METHODS: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years. RESULTS: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. CONCLUSION: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. CONCLUSIONS: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Fertility concerns, preservation strategies and quality of life in young women with breast cancer: Baseline results from an ongoing prospective cohort study in selected European Centers.

OBJECTIVES: Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. MATERIALS AND METHODS: Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. RESULTS: Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039). CONCLUSIONS: Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.

[Edema after cancer treatment]. / Odeme nach Tumorbehandlung.

Progress in cancer treatment induced a greater use of specific therapies for an increasing number of patients. These treatments can cause long lasting sequelae, which may reduce the quality of life of the concerned people. Lymphedema of the arm after primary treatment for breast cancer is generally a chronic morbidity, which can have serious consequences for patients including restriction of social and business activities. The present article gives an overview of causes, possible prevention and treatment of this condition, which affects in variable magnitude 25% of the women after breast cancer treatment. Primary prevention (less invasive surgery and less extensive radiotherapy) is extremely important, as an established lymphedema is not curable. However secondary and tertiary prevention, early detection and treatment, play the decisive role in the every day life.

Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial.

BACKGROUND: Aromatase inhibitors are considered standard adjuvant endocrine treatment of postmenopausal women with hormone receptor-positive breast cancer, but it remains uncertain whether aromatase inhibitors should be given upfront or sequentially with tamoxifen. Awaiting results from ongoing randomized trials, we examined prognostic factors of an early relapse among patients in the BIG 1-98 trial to aid in treatment choices. PATIENTS AND METHODS: Analyses included all 7707 eligible patients treated on BIG 1-98. The median follow-up was 2 years, and the primary end point was breast cancer relapse. Cox proportional hazards regression was used to identify prognostic factors. RESULTS: Two hundred and eighty-five patients (3.7%) had an early relapse (3.1% on letrozole, 4.4% on tamoxifen). Predictive factors for early relapse were node positivity (P < 0.001), absence of both receptors being positive (P < 0.001), high tumor grade (P < 0.001), HER-2 overexpression/amplification (P < 0.001), large tumor size (P = 0.001), treatment with tamoxifen (P = 0.002), and vascular invasion (P = 0.02). There were no significant interactions between treatment and the covariates, though letrozole appeared to provide a greater than average reduction in the risk of early relapse in patients with many involved lymph nodes, large tumors, and vascular invasion present. CONCLUSION: Upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors.

[Late idiopathic pneumopathy following bone marrow transplantation]. / Späte idiopathische Pneumopathie nach Knochenmarktransplantation.

4 of the 198 patients treated by bone marrow transplantation in Basel, Switzerland, with a follow-up of more than one year after therapy, developed a severe restrictive pneumopathy. In none of the 4 patients could an infectious pathogen be isolated, but all of them had signs of a chronic graft-versus-host disease. The 4 cases are described in detail.

[Flow cytometry identification of CD34-positive cells]. / Flowzytometrische Identifizierung von CD34-positiven Zellen.

In the present study three clinical applications of flow-cytometric quantification of CD34-positive cells in the field of blood and marrow transplantation are evaluated. By daily determination of CD34-positive cells in the peripheral blood after mobilization of stem cells with chemotherapy or growth-factors it is possible to set the optimal time for collection of the transplant material. Thereafter the yield of CD34-positive cells within the harvested material is determined. Finally, the efficacy of positive CD34 selection using a biotin-avidin column is evaluated. Initial experience is presented here.

[Hydroxyurea, erythrocyte volumes and hemoglobin F]. / Hydroxyurea, Erythrozytenvolumen und Hämoglobin F.

Hydroxyurea is used in the treatment of sickle cell anemia and beta-thalassemia major to increase the content of hemoglobin F (HbF) and presumably ameliorate clinical symptoms. Under therapy with hydroxyurea an increase of the mean corpuscular volume (MCV) of the erythrocytes can be observed. To evaluate a possible estimation of the content of HbF using the increase of MCV under treatment with hydroxyurea, we measured MCV and HbF during therapy with hydroxyurea. The median MCV before therapy was 87.8 fl (range 74.3-95.7) and under hydroxyurea 104.1 fl (81.0-139.5), and the median HbF 1.8% (0.1-5.4). Although both MCV and HbF increased under treatment with hydroxyurea, a linear correlation between these two parameters was not detectable. Therefore, MCV cannot replace the measurement of HbF.

Autoantibodies against the platelet glycoproteins (GP) IIb/IIIa, Ia/IIa, and IV and partial deficiency in GPIV in a patient with a bleeding disorder and a defective platelet collagen interaction.

To evaluate the physiologic importance of the different collagen receptors on platelets, we screened 806 patients admitted to the hospital because of hemorrhagic diathesis for eventual laboratory evidence of a pathologic platelet collagen interaction, and found 5 patients with an isolated deficiency in collagen-induced platelet aggregation. Four of these five patients had a partial defect, one had a complete defect. The structural and functional analysis of the platelets from the patient with a complete defect showed a deficiency in glycoprotein (GP) IV and autoantibodies against GPIIb/IIIa, GPIa/IIa, and GPIV. Patient plasma had only a minimal effect on normal control platelets and Naka-negative platelets. The analyses of the defect in the patient and of the data in the literature suggest that a single defect may not result in clinical bleeding (GPIV-deficient patients do not bleed), but may become symptomatic in combination with another defect such as the autoantibodies against GPIa/IIa, GPIV, and/or GPIIb/IIIa, all of which are involved in platelet collagen interactions (three of four of our immune thrombocytopenic purpura patients with anti-GPIV and anti-GPIIb/IIIa autoantibodies had a bleeding disorder). We hypothesize that it is the synergism of two abnormalities that results in the defective function, a mechanism that is in agreement with earlier studies on platelet collagen interaction that suggests that a double defect in platelet collagen interactions is required to become clinically apparent.