Perceptions of Japanese and Dutch women with early breast cancer about monitoring their quality of life.

OBJECTIVE: Monitoring quality of life (QoL) in patients with cancer can provide insight into functional, psychological and social consequences associated with illness and its treatment. The primary objective of this study is to examine the influence of cultural factors on the communication between the patient and the health care provider and the perceived QoL in women with breast cancer in Japan and the Netherlands. METHODS: In Japanese and Dutch women with early breast cancer, the number, content and frequency of QoL-related issues discussed at the medical encounter were studied. Patients completed questionnaires regarding QoL and evaluation of communication with the CareNoteBook. RESULTS: The total number, frequency and content of QoL-related issues discussed differed between the two countries. Japanese women (n = 134) were significantly more reticent in discussing QoL-issues than the Dutch women (n = 70) (p < .001). Furthermore, Dutch patients perceived the CareNoteBook methodology significantly more positively than the Japanese patients (p < .001). Both groups supported the regular assessment via a CareNoteBook methodology. CONCLUSIONS: Japanese women are more reluctant in expressing their problems with the illness, its treatment and patient-physician communication than Dutch women.

Addition of zoledronic acid to neoadjuvant chemotherapy is not beneficial in patients with HER2-negative stage II/III breast cancer: 5-year survival analysis of the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: Adjuvant bisphosphonates are associated with improved breast cancer survival in postmenopausal patients. Addition of zoledronic acid (ZA) to neoadjuvant chemotherapy did not improve pathological complete response in the phase III NEOZOTAC trial. Here we report the results of the secondary endpoints, disease-free survival, (DFS) and overall survival (OS). PATIENTS AND METHODS: Patients with HER2-negative, stage II/III breast cancer were randomized to receive the standard 6 cycles of neoadjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy with or without 4 mg intravenous (IV) ZA administered within 24 h of chemotherapy. This was repeated every 21 days for 6 cycles. Cox regression models were used to evaluate the effect of ZA and covariates on DFS and OS. Regression models were used to examine the association between insulin, glucose, insulin growth factor-1 (IGF-1) levels, and IGF-1 receptor (IGF-1R) expression with survival outcomes. RESULTS: Two hundred forty-six women were eligible for inclusion. After a median follow-up of 6.4 years, OS for all patients was significantly worse for those who received ZA (HR 0.468, 95% CI 0.226-0.967, P = 0.040). DFS was not significantly different between the treatment arms (HR 0.656, 95% CI 0.371-1.160, P = 0.147). In a subgroup analysis of postmenopausal women, no significant difference in DFS or OS was found for those who received ZA compared with the control group (HR 0.464, 95% CI 0.176-1.222, P = 0.120; HR 0.539, 95% CI 0.228-1.273, P = 0.159, respectively). The subgroup analysis of premenopausal patients was not significantly different for DFS and OS ((HR 0.798, 95% CI 0.369-1.725, P = 0.565; HR 0.456, 95% CI 0.156-1.336, P = 0.152, respectively). Baseline IGF-1R expression was not significantly associated with DFS or OS. In a predefined additional study, lower serum levels of insulin were associated with improved DFS (HR 1.025, 95% CI 1.005-1.045, P = 0.014). CONCLUSIONS: Our results suggest that ZA in combination with neoadjuvant chemotherapy was associated with a worse OS in breast cancer (both pre- and postmenopausal patients). However, in a subgroup analysis of postmenopausal patients, ZA treatment was not associated with DFS or OS. Also, DFS was not significantly different between both groups. IGF-1R expression in tumor tissue before and after neoadjuvant treatment did not predict survival. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01099436 , April 2010.

Impact of Comorbidities and Age on Cause-Specific Mortality in Postmenopausal Patients with Breast Cancer.

BACKGROUND: The aim was to study the impact of comorbidities and age on breast cancer mortality, taking into account competing causes of death. SUBJECTS, MATERIALS, AND METHODS: Cohort analysis of Dutch and Belgian patients with postmenopausal, early hormone receptor-positive breast cancer included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. This is a randomized controlled trial of patients who had completed local treatment with curative intent and were randomized to receive exemestane for 5 years, or sequential treatment of tamoxifen followed by exemestane for a duration of 5 years. Patients were categorized by number of comorbidities (no comorbidities, 1-2 comorbidities, and >2 comorbidities) and age (<70 years and ≥70 years). Main outcome was breast cancer mortality considering other-cause mortality as competing event; cumulative incidences were calculated using the Cumulative Incidence Competing Risk Methods, and the Fine and Gray model was used to calculate the effect of age and comorbidities for the cause-specific incidences of breast cancer death, taking into account the effect of competing causes of death. RESULTS: Overall, 3,159 patients were included, of which 2,203 (69.7%) were aged <70 years and 956 (30.3%) were aged ≥70 years at diagnosis. Cumulative incidence of breast cancer mortality was higher among patients ≥70 without comorbidities (22.2%, 95% CI, 17.5-26.9) compared with patients <70 without comorbidities (15.6%, 95% CI, 13.6-17.7, reference group), multivariable subdistribution hazard ratio (sHR) 1.49 (95% CI, 1.12-1.97, p = .005) after a median follow-up of 10 years. Use of chemotherapy was lower in older patients (1%, irrespective of the number of comorbidities) compared with younger patients (50%, 44%, and 38% for patients with no, 1-2, or >2 comorbidities, p < .001). CONCLUSION: Older patients without comorbidities have a higher risk of dying due to breast cancer than younger counterparts, even when taking into account higher competing mortality, while use of chemotherapy in this group was low. These findings underline the need to take into account comorbidities, age, and competing mortality in the prognosis of breast cancer for accurate decision making. IMPLICATIONS FOR PRACTICE: Older patients without comorbidity are at increased risk of dying from breast cancer, despite a higher other-cause mortality. This study shows that including age and comorbidity for the assessment of breast cancer mortality and other-cause mortality is indispensable for treatment decision making in older patients. Future prognostic tools for breast cancer prognosis should incorporate these items as well as risk of toxicity of adjuvant chemotherapy to adequately predict outcomes to optimize personalized treatment for older patients with early breast cancer.

Prolonging the duration of post-infusion scalp cooling in the prevention of anthracycline-induced alopecia: a randomised trial in patients with breast cancer treated with adjuvant chemotherapy.

PURPOSE: Scalp cooling as a method to reduce the incidence of chemotherapy-induced alopecia (CIA) is increasingly used in daily practice worldwide. However, in patients treated with 5-fluorouracil, epirubicin and cyclophosphamide (FEC), scalp cooling fails in 48-67% of patients. This study investigated the efficacy of extended duration of post-infusion scalp cooling in breast cancer patients treated with this regimen. METHODS: In this prospective multi-centre randomised study, 102 patients with early breast cancer treated with adjuvant FEC chemotherapy were randomly assigned in a 1:1 ratio to a post-infusion cooling time of 90 or 150 min. The primary endpoint was the need to wear a wig or other head covering to mask visible hair loss. RESULTS: Sixteen out of 48 patients (33%) treated with 90 min of post-infusion cooling did not need any head covering, compared with 21 out of 46 patients (45%) treated with 150 min of post-infusion cooling (p = 0.2). WHO grades 2-3 (moderate-complete) alopecia were reported more often in patients treated with 90-min post-infusion cooling time (n = 25/51 (49%) versus n = 17/51 (33%); p = 0,02). Scalp cooling was well-tolerated (mean Visual Analogue Score 7.4) and only three patients (3%) stopped due to intolerance during treatment. CONCLUSIONS: Extending the duration of 90-min post-infusion scalp cooling to 150 min in patients treated with adjuvant FEC chemotherapy was well-tolerated but did not significantly diminish the need for head covering. However, grades 2-3 alopecia was seen less often with prolonged post-infusion scalp cooling.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer.

PURPOSE: For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. METHODS: In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. RESULTS: In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. CONCLUSIONS: This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. METHODS: The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5-3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. FINDINGS: 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0-10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65-69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0·96, 0·88-1·05; p=0·39). INTERPRETATION: The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. FUNDING: Pfizer, Dutch Cancer Foundation.

Poor Prognosis After Second Locoregional Recurrences in the CALOR Trial.

BACKGROUND: Isolated locoregional recurrences (ILRRs) of breast cancer confer a significant risk for the development of distant metastasis. Management practices and second ILRR events in the Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial were investigated. METHODS: In this study, 162 patients with ILRR were randomly assigned to receive postoperative chemotherapy or no chemotherapy. Descriptive statistics characterize outcomes according to local therapy and the influence of hormone receptor status on subsequent recurrences. Competing risk regression models, Kaplan-Meier estimates, and Cox proportional hazards models were used to evaluate associations between treatment, site of second recurrence, and outcome. RESULTS: The median follow-up period was 4.9 years. Of the 98 patients who received breast-conserving primary surgery 89 had an ipsilateral-breast tumor recurrence. Salvage mastectomy was performed for 73 patients and repeat lumpectomy for 16 patients. Another eight patients had nodal ILRR, and one patient had chest wall ILRR. Among 64 patients whose primary surgery was mastectomy, 52 had chest wall/skin ILRR, and 12 had nodal ILRR. For 15 patients, a second ILRR developed a median of 1.6 years (range 0.08-4.8 years) after ILRR. All second ILRRs occurred for patients with progesterone receptor-negative ILRR. Death occurred for 7 (47 %) of 15 patients with a second ILRR and 19 (51 %) of 37 patients with a distant recurrence. As shown in the multivariable analysis, the significant predictors of survival after either a second ILRR or distant recurrence were chemotherapy for the primary cancer (hazard ratio [HR], 3.55; 95 % confidence interval [CI], 1.15-10.9; p = 0.03) and the interval (continuous) from the primary surgery (HR, 0.87; 95 % CI, 0.75-1.00; p = 0.05). CONCLUSIONS: Second ILRRs represented about one third of all recurrence events after ILRR, and all were PR-negative. These second ILRRs and distant metastases portend an unfavorable outcome.

Results of 20- versus 45-min post-infusion scalp cooling time in the prevention of docetaxel-induced alopecia.

PURPOSE: For patients, chemotherapy-induced alopecia (CIA) is one of the most distressing side effects of treatment. Scalp cooling can prevent or minimise CIA; the results may depend on the duration of cooling. Since a previous study on post-infusion cooling time in patients treated with docetaxel chemotherapy found no difference between 90 and 45 min, we investigated whether hair-preserving results could be maintained with a shorter post-infusion cooling time. METHODS: In this prospective, multi-centre randomised study, 134 patients who started treatment with docetaxel 75-100 mg/m(2) in a 3-weekly schedule were randomly assigned in a 1:1 ratio to a post-infusion cooling time of 45 or 20 min. The primary end point was the need for a wig or other head covering as assessed by the patient. A visual analogue scale (VAS) with a range from 0 (not tolerable) to 10 (very tolerable) was used to measure tolerance. RESULTS: Scalp cooling results were similar for 45- and 20-min post-infusion cooling times. Thirty-three out of 45 patients (73 %) treated with 20 min of post-infusion cooling did not need a form of head covering, compared with 41 out of 52 patients (79 %) treated with 45 min of post-infusion cooling (p = 0.5). The procedure was well tolerated (mean visual analogue score 8.3). Six patients stopped due to intolerance during the first treatment cycle. CONCLUSIONS: A 20-min post-infusion cooling time is effective and tolerable for patients treated with scalp cooling to prevent docetaxel-induced alopecia. TRIAL REGISTRATION: Trialregister.nl Identifier, NTR 1856.

The prognostic relevance of the mitotic activity index in axillary lymph node-negative breast cancer.

The aim of the present study is to look at the mitotic activity index (MAI) as a prognostic factor in a prospective population-based cohort of lymph node-negative invasive breast cancer patients. Analyses were based on 2,048 breast-conserving therapies in 1,971 patients, node-negative, and without any form of adjuvant systemic therapy with long-term follow-up. The 15-year distant metastases-free survival (DMFS) for women ≤55 years was 88.3 % for low MAI values (≤12) versus 73.4 % for high MAI values (>12); (HR 2.8; 95 % CI 1.8-4.4; p < 0.001). Multivariate analyses for DMFS showed significance for MAI. For MAI and Bloom-Richardson grading, by performing a likelihood ratio test, we showed the statistical significance for both. For women >55-years, the MAI was not an independent significant factor. We also confirmed the above findings for disease-specific survival. When multi-gene assays are not available, the MAI remains a robust prognostic marker in women younger than 55 years of age with early node-negative breast cancer.

The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study.

BACKGROUND: Preclinical evidence shows that short-term fasting (STF) protects healthy cells against side effects of chemotherapy and makes cancer cells more vulnerable to it. This pilot study examines the feasibility of STF and its effects on tolerance of chemotherapy in a homogeneous patient group with early breast cancer (BC). METHODS: Eligible patients had HER2-negative, stage II/III BC. Women receiving (neo)-adjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) were randomized to fast 24 h before and after commencing chemotherapy, or to eat according to the guidelines for healthy nutrition. Toxicity in the two groups was compared. Chemotherapy-induced DNA damage in peripheral blood mononuclear cells (PBMCs) was quantified by the level of γ-H2AX analyzed by flow cytometry. RESULTS: Thirteen patients were included of whom seven were randomized to the STF arm. STF was well tolerated. Mean erythrocyte- and thrombocyte counts 7 days post-chemotherapy were significantly higher (P = 0.007, 95 % CI 0.106-0.638 and P = 0.00007, 95 % CI 38.7-104, respectively) in the STF group compared to the non-STF group. Non-hematological toxicity did not differ between the groups. Levels of γ-H2AX were significantly increased 30 min post-chemotherapy in CD45 + CD3- cells in non-STF, but not in STF patients. CONCLUSIONS: STF during chemotherapy was well tolerated and reduced hematological toxicity of TAC in HER2-negative BC patients. Moreover, STF may reduce a transient increase in, and/or induce a faster recovery of DNA damage in PBMCs after chemotherapy. Larger studies, investigating a longer fasting period, are required to generate more insight into the possible benefits of STF during chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01304251 , March 2011.

Minimal impact of adjuvant exemestane or tamoxifen treatment on mammographic breast density in postmenopausal breast cancer patients: a Dutch TEAM trial analysis.

BACKGROUND: Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. MATERIAL AND METHODS: Analogue mammograms of selected TEAM participants before start, and after one and two (and if available after three) years of adjuvant endocrine therapy were collected centrally and reviewed. Study endpoints were change in breast density over time, and correlations between breast density and locoregional recurrence (LRR), distance recurrence (DR), and contralateral breast cancer (CBC). RESULTS: Mammograms of 378 patients (181 tamoxifen, 197 exemestane) were included in the current per protocol analyses. Baseline breast density was low (breast density score<50% in 75% of patients) and not different between patients randomised to exemestane or tamoxifen (coefficient 0.16, standard error 0.17). Breast density did not change during treatment in exemestane (p=0.25) or tamoxifen users (p=0.59). No relation was observed between breast density and the occurrence of a LRR [hazards ratio (HR) 0.87, 95% CI 0.45-1.68, p=0.67], a DR (HR 1.02, 95% CI 0.77-1.35, p=0.90), or CBC (HR 1.31, 95% CI 0.63-2.72, p=0.48). CONCLUSION: The in general low breast density score in early postmenopausal breast cancer patients did not substantially change over time, and this pattern was not different between tamoxifen and exemestane users. Breast density was not a predictive marker for efficacy of adjuvant endocrine therapy.

Stick Together: A Nordic Walking Group Intervention for Breast Cancer Survivors.

Axillary lymph node dissection and axillary radiation as part of breast cancer treatment often result in arm and shoulder morbidity and limitations in daily functioning. Over and above the general benefits for cardiorespiratory fitness, Nordic Walking particularly targets at the muscles of the upper extremities and shoulder. This may increase shoulder range of motion and lead to a reduction in functional limitations. The aim of this study was to offer a Nordic Walking intervention to women after treatment for breast cancer and to investigate changes in subjective well-being and shoulder function. Three supervised Nordic Walking courses were organized (2009-2011). The intervention consisted of ten weekly 1-hour sessions focusing on upper body strength and condition. In total, 28 women participated in one of the cohorts. Results showed that after 10 weeks, patients' vitality had improved, whereas perceived shoulder symptom severity and limitations in daily activities had decreased. Goniometric data indicated that range of motion (forward flexion, abduction, and external rotation) of the affected shoulder improved significantly within 10 weeks of training. Group interviews at 6 months follow-up confirmed that patients had appreciated the physical and psychosocial benefits of the intervention. These benefits outweighed the practical disadvantages. Patient selection, assessment and training should take place under (para-)medical supervision and group instructors should have the knowledge and skills to work with a group of recent cancer survivors. Results from this explorative study suggest that Nordic Walking is a feasible and potentially valuable tool in the rehabilitation of patients with breast cancer.

Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial.

BACKGROUND: Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients. METHODS: The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152. FINDINGS: From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. INTERPRETATION: Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. FUNDING: US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

Germline variants in the CYP19A1 gene are related to specific adverse events in aromatase inhibitor users: a substudy of Dutch patients in the TEAM trial.

Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment.

CYP2D6 genotype in relation to hot flashes as tamoxifen side effect in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

In tamoxifen-treated breast cancer patients the occurrence of hot flashes may be associated with effective estrogen receptor antagonism dependent on genetic variations of metabolic enzymes and the estrogen receptor. Early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane within the tamoxifen exemestane adjuvant multinational trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to the occurrence of hot flashes as adverse event during the first year of tamoxifen use (primary aim) and the time to the occurrence of hot flashes as AE during the complete time on tamoxifen (secondary aim). In addition, exploratory analyses on 22 genetic variants of other metabolic enzymes and two common polymorphisms in the estrogen receptor-1 were performed. No association was found between the CYP2D6 genotype/phenotype or any other genetic variant and hot flashes during the first year. Only higher age was related to a lower incidence of hot flashes in the first year (adjusted odds ratio 0.94, 95 % CI 0.92-0.96; p < 0.001). The ESR1 PvuII XbaI CG haplotype was associated with the time to the occurrence of hot flashes during the complete time on tamoxifen (CG/CG vs. CG/other + other/other: adjusted hazard ratio 0.49, 95 % CI 0.25-0.97; p = 0.04). In conclusion, the CYP2D6 genotypes and phenotypes were not associated with the occurrence of hot flashes. Common polymorphisms in the estrogen receptor-1 might predict hot flashes as common tamoxifen side effect, although this finding needs replication.

Factors influencing the effectiveness of scalp cooling in the prevention of chemotherapy-induced alopecia.

The success of scalp cooling in preventing or reducing chemotherapy-induced alopecia (CIA) is highly variable between patients and chemotherapy regimens. The outcome of hair preservation is often unpredictable and depends on various factors. Methods. We performed a structured search of literature published from 1970 to February 2012 for articles that reported on factors influencing the effectiveness of scalp cooling to prevent CIA in patients with cancer. Results. The literature search identified 192 reports, of which 32 studies were considered relevant. Randomized studies on scalp cooling are scarce and there is little information on the determinants of the result. The effectiveness of scalp cooling for hair preservation depends on dose and type of chemotherapy, with less favorable results at higher doses. Temperature seems to be an important determinant. Various studies suggest that a subcutaneous scalp temperature less than 22 °C is required for hair preservation. Conclusions. The effectiveness of scalp cooling for hair preservation varies by chemotherapy type and dose, and probably by the degree and duration of cooling.

Experiences with the FACT-EGFRI-18 instrument in EGFRI-associated mucocutaneous adverse events.

PURPOSE: The functional assessment of cancer therapy epidermal growth factor receptor inhibitor 18 (FACT-EGFRI-18) is a patient-reported outcomes questionnaire developed to assess the effect of EGFRI on health-related quality of life (HRQoL). METHODS: Ten native-speaking residents of The Netherlands who reported EGFRI-associated mucocutaneous adverse events (mcAEs) were administered the questionnaire. Patients were subsequently asked a standardized series of questions about the items' personal relevance. RESULTS: Responses reflected a major negative impact of mcAEs due to EGFRI on physical, social/emotional, and functional domains. In some cases, especially in the social/emotional domain, the responses to the qualitative interview indicated a greater impact on HRQoL than the numerical ratings previously selected for the Dutch FACT-EGFRI-18 questions. CONCLUSIONS: Based on these interviews, we identified that the physical items associated with mcAEs interfere most with HRQoL. The results suggest that the FACT-EGFRI-18 can be applied to measure mcAE-related HRQoL in cancer patients undergoing EGFRI therapy. In addition, patients feel the need to rate their symptom burden, too, and we recommend additional adverse event items to be incorporated into the questionnaire.

Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial.

BACKGROUND: Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). METHODS: The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase 3 trial was conducted in hospitals in nine countries. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. FINDINGS: 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. INTERPRETATION: Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. FUNDING: Pfizer.

Micrometastases or isolated tumor cells and the outcome of breast cancer.

BACKGROUND: The association of isolated tumor cells and micrometastases in regional lymph nodes with the clinical outcome of breast cancer is unclear. METHODS: We identified all patients in The Netherlands who underwent a sentinel-node biopsy for breast cancer before 2006 and had breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in the regional lymph nodes. Patients with node-negative disease were randomly selected from the years 2000 and 2001. The primary end point was disease-free survival. RESULTS: We identified 856 patients with node-negative disease who had not received systemic adjuvant therapy (the node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (the node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (the node-positive, adjuvant-therapy cohort). The median follow-up was 5.1 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95% confidence interval [CI], 1.15 to 1.94); among patients with micrometastases, the adjusted hazard ratio was 1.56 (95% CI, 1.15 to 2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95% CI, 0.45 to 0.73) in the node-positive, adjuvant-therapy cohort, as compared with the node-positive, no-adjuvant-therapy cohort. CONCLUSIONS: Isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. In patients with isolated tumor cells or micrometastases who received adjuvant therapy, disease-free survival was improved.

Impact of chemotherapy-induced nausea and vomiting on quality of life in indonesian patients with gynecologic cancer.

BACKGROUND: Quality of life (QoL) has become a major outcome in the treatment of patients with cancer. This study is aimed at examining the impact of chemotherapy-induced nausea and vomiting on QoL of patients with gynecologic cancer in Indonesia. METHODS: Chemotherapy-naive patients with gynecologic cancer, who were treated with cisplatin at a dosage 50 mg/m or higher as monotherapy or as part of combination chemotherapy regimens, were recruited in the Oncology Department, Dr. Sardjito Hospital, Yogyakarta, Indonesia. Quality of life was assessed by using the Indonesian version of the European Organization for Research and Treatment for Cancer of Quality of Life Questionnaire and Short Form-36, administered immediately before and on day 5 after chemotherapy administration. Patients used a daily diary to record nausea and vomiting during 5 days after chemotherapy. RESULTS: Most (74.9%) of the 179 patients experienced delayed emesis during the 5 days after chemotherapy despite prophylactic use of antiemetics. The delayed nausea and emesis caused significant negative impact on patients' QoL. Nausea in the delayed phase caused negative effects on patients' QoL. CONCLUSIONS: Patients reported a negative impact on the QoL of delayed emesis after chemotherapy. Poor prophylaxis of patients' nausea and vomiting after chemotherapy interferes with patients' QoL. Medical and behavioral interventions may help to alleviate the negative consequences of chemotherapeutic treatment in patients with gynecologic cancers treated with suboptimal antiemetics.