Menopausal status and adjuvant hormonal therapy for breast cancer patients: a practical guideline.

Breast cancer is the most common malignancy amongst women in the developed world. For patients with hormone-sensitive breast cancer eligible for adjuvant hormonal therapy, it is important to know if the ovaries are (still) functional or not. Indeed, the choice for a specific adjuvant hormonal treatment depends on the menopausal status of an individual woman. The currently available measures to determine the menopausal status are conflicting. Until better measures become available, we propose a practical guideline enabling an optimal choice of adjuvant hormonal therapy for women with a hormone receptor positive breast cancer taking into account uncertainties about their menopausal status.

Self-reported cognitive functioning in postmenopausal breast cancer patients before and during endocrine treatment: findings from the neuropsychological TEAM side-study.

OBJECTIVE: This study aimed to evaluate self-reported cognitive functioning of postmenopausal breast cancer patients before and during endocrine treatment compared with healthy female controls, and to investigate associations between self-reported cognitive functioning, cognitive test performance and anxiety/depression, fatigue, and menopausal complaints. METHODS: Self-reported cognitive functioning, anxiety/depression, fatigue, menopausal complaints, and cognitive tests performance were assessed before (T1) and after 1 year (T2) of adjuvant endocrine treatment in postmenopausal chemotherapy-naïve breast cancer patients. Self-reported cognitive functioning was assessed by the cognitive failures questionnaire and interview questions concerning cognitive complaints. Patients participated in the TEAM-trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive breast cancer. Identical information was obtained from healthy postmenopausal volunteers. RESULTS: Two measures for self-reported cognitive functioning provided the distinctive results. At T1 and T2, healthy controls reported a higher frequency of cognitive failures than patients; change over time did not differ between groups. The prevalence of cognitive complaints did not differ between the groups at T1, but change over time regarding attention/concentration complaints differed between groups, due to an increased prevalence in tamoxifen users. Self-reported cognitive functioning showed moderate associations with anxiety/depression, fatigue, and menopausal complaints. Cognitive test performance was not associated with self-reported cognitive functioning, but weakly with anxiety/depression and fatigue. CONCLUSION: Adjuvant therapy with tamoxifen and exemestane did not influence the self-reported frequency of cognitive failures. Increased attention/concentration complaints were observed in tamoxifen users, but not in exemestane users. This latter finding should be confirmed with better validated instruments.

In primary breast cancer the mitotic activity yields similar prognostic information as the histological grade: a study with long-term follow-up.

We evaluated with long-term follow-up, the prognostic value of the mitotic activity index (MAI) and the volume corrected mitotic index (M/V-index) compared with that of the histological grade in breast cancer patients not treated with adjuvant systemic therapy. Of 739 consecutive patients living in the city of Nijmegen, the Netherlands, 477 patients with primary unilateral breast cancer were not treated with adjuvant systemic therapy and eligible for the study. In multivariate survival analyses the MAI and M/V-index showed similar hazard ratios (HRs) compared to HRs of histological grade for overall survival (OS) (HR: 1.45, 1.48, and grade II versus grade I (GII/GI) 1.34, grade III versus grade I (GIII/GI) 1.53, respectively) and for breast cancer specific survival (BCSS) (HR: 1.27, 1.57, and (GII/GI) 1.57 (GIII/GI) 2.32, respectively). Other independent prognostic variables for OS and BCSS were age at diagnosis, tumour size, and number of positive lymph nodes. In the present study with long term follow-up, we compared the prognostic value of mitotic activity with that of histological grade and found no advantage for the mitotic activity in predicting either BCSS or OS and concluded that histological grade and the mitotic activity were equally informative in predicting patient outcome. As histological grade is a well established and widely used prognosticator we do not have arguments to replace the histological grade by the mitotic indices MAI or M/V-index.

Patterns of care in Dutch postmenopausal patients with hormone-sensitive early breast cancer participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.

BACKGROUND: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial investigates the efficacy and safety of adjuvant exemestane alone and in sequence after tamoxifen in postmenopausal women with hormone-sensitive early breast cancer. As there was a nationwide participation in The Netherlands, we studied the variations in patterns of care in the Comprehensive Cancer Centre Regions (CCCRs) and compliance with national guidelines. METHODS: Clinicopathological characteristics, carried out local treatment strategies and adjuvant chemotherapy data were collected. RESULTS: From 2001 to January 2006, 2754 Dutch patients were randomised to the study. Mean age of patients was 65 years (standard deviation 9). Tumours were < or =2 cm in 46% (within CCCRs 39%-50%), node-negative disease varied from 25% to 45%, and PgR status was determined in 75%-100% of patients. Mastectomy was carried out in 55% (45%-70%), sentinel lymph node procedure in 68% (42%-79%) and axillary lymph node dissections in 77% (67%-83%) of patients, all different between CCCRs (P < 0.0001). Adjuvant chemotherapy was given in 15%-70% of eligible patients (P < 0.001). DISCUSSION: In spite of national guidelines, breast cancer treatment on specific issues widely varied between the various Dutch regions. These data provide valuable information for breast cancer organisations indicating (lack of) guideline adherence and areas for breast cancer care improvement.

Cognitive functioning of postmenopausal breast cancer patients before adjuvant systemic therapy, and its association with medical and psychological factors.

PURPOSE: This study aimed to identify medical and psychological predictors for cognitive performance of breast cancer (BC) patients before the start of adjuvant systemic treatment and to compare cognitive performance between BC patients and healthy controls adjusting for medical and psychological variables. MATERIAL: 205 postmenopausal BC patients underwent pre-treatment neuropsychological tests and provided medical and psychological data. 124 healthy controls underwent the same assessment. RESULTS: 'Treatment for diabetes mellitus' and/or 'hypertension', 'less hours spent on cognitively stimulating activities', 'fewer days since surgery' and 'more reproductive years' were associated with worse cognitive performance in the BC patients, independent of age and IQ. Cognitive differences between BC patients and healthy controls could partly be explained by the evaluated variables. CONCLUSION: The results stress the need for adjustment for pre-treatment cognitive differences between study groups, and also indicate that further research into pre-treatment cognitive dysfunction is warranted.

Timely withdrawal of G-CSF reduces the occurrence of thrombocytopenia during dose-dense chemotherapy.

BACKGROUND: Post chemotherapy Granulocyte colony stimulating factor (G-CSF) reduces leucopenia, while G-CSF priming shortly before chemotherapy increases myelotoxicity. We performed a trial with a two-schedule crossover design to determine the optimal G-CSF schedule for densified 2-weekly chemotherapy. METHODS: During 2-weekly chemotherapy days 1 and 2, G-CSF was given on days 3-10, with a G-CSF-free interval before the next chemotherapy cycle of 5 days, or on days 3-13, with a G-CSF-free interval of 2 days. In schedule A, cycle II was preceded by a 5 days, cycle III and IV by a 2 days and cycle V by a 5 days G-CSF free interval. In schedule B, this was 2, 5, 5, and 2 days, respectively. RESULTS: Intra-patient comparison for cycles II versus III and cycles IV versus V showed that platelet (PLT) nadir count was significantly lower for cycles preceded by a 2-days compared to a 5-days G-CSF free interval: mean difference 45.7 x 10(9)/l (95% CI 33.2-58.2, p = 0.0001). Neutrophil count did not differ significantly (p = 0.85). CONCLUSION: Timely withdrawal of G-CSF in dose-dense chemotherapy reduces chemotherapy-related thrombocytopenia. Leucopenia was not aggravated, reflecting a protective effect of post-chemotherapy G-CSF.

Cost-effectiveness of new guidelines for adjuvant systemic therapy for patients with primary breast cancer.

BACKGROUND: In this study, the potential impact of a new national guideline for adjuvant systemic therapy in breast cancer (introduced in The Netherlands in 1998) was assessed, as well as the modifications of this guideline, issued in 2001. Both the change in total number of patients eligible for adjuvant therapy, as well as the cost-effectiveness of the changed clinical management of these patients were analysed. PATIENTS AND METHODS: Percentages of patients who would be eligible for adjuvant therapy in 1994, 1998 and 2001 were estimated, based on clinical data from 127 patients, who were operated on in 1994. Ten-year overall survival rates were used as a measure of effectiveness, based on the two most recent EBCTCG meta-analyses. Actual resource costs were calculated. With a decision analytic model, the incremental cost-effectiveness ratios (1998 versus 1994, and 2001 versus 1998) were calculated. RESULTS: The introduction of the 1998 guideline resulted in a relative increase of 80% in the total number of patients eligible for adjuvant therapy, compared with 1994 (from 40% to 72% of all patients with primary breast cancer). With an estimated absolute increase of 10-year overall survival of 2%, the 1998 guideline was found to have an expected incremental cost-effectiveness ratio of about 4837 per life-year gained. CONCLUSIONS: Introduction of the new guideline considerably affected the number of patients eligible for adjuvant systemic therapy for breast cancer. The associated incremental cost-effectiveness ratio is well within the range of values that are generally considered acceptable.

Vascular endothelial growth factor levels do not predict efficacy of systemic adjuvant treatment as assessed in 1127 breast cancer patients.

The vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and has proven to be of prognostic value in patients with primary breast cancer. In this study we investigated whether VEGF is of predictive value with regard to the efficacy of adjuvant systemic therapy in primary invasive breast cancer. In 1127 tumors of patients with invasive breast cancer the cytosolic levels of VEGF were measured using a quantitative enzyme-linked immunosorbent assay. These patients were followed for a median follow-up time of 59 months (range 2-268 months) after primary surgery. Correlations with well-known prognostic factors, and univariate and multivariate survival analyses were performed. The VEGF levels showed a positive correlation with age, menopausal status and tumor size. In addition, VEGF levels were inversely correlated with estrogen and progesterone receptor levels. A high VEGF level predicted an early relapse in the univariate relapse-free survival (RFS) analysis for all patients (P=0.010), but not in the multivariate analysis. Furthermore, there were no statistically significant interactions between the levels of VEGF and the use of adjuvant endocrine therapy or chemotherapy in the RFS analysis. We conclude that tumor levels of VEGF do not predict the efficacy of adjuvant endocrine therapy or chemotherapy in patients with primary breast cancer.

Adherence to the guidelines of the CCCE in the treatment of node-positive breast cancer patients.

Guidelines are tools to improve the quality of care in daily practice. To accomplish adherence, active implementation is needed. The effect of audit, group-oriented feedback and educational activities to increase guideline adherence were investigated in this study. Treatment according to a guideline for premenopausal node-positive breast cancer patients from 1988 to 1992 (P1) and from 1996 to 1998 (P2) was assessed using the following indicators: percentage of patients with breast-conserving surgery, secondary surgery, > or = 10 reported resected axillary lymph nodes, reported tumour differentiation grade, reported hormonal receptor status, chemotherapy received (CT), start of CT < or = 28 days after surgery, Dose Intensity (DI) > or = 85% and completion of CT < or = 1 week beyond the ideal duration of CT. Data were audited from patients' records. The first audit resulted in a quality programme with feedback focused on the delivery of chemotherapy and resected axillary lymph nodes and educational sessions. A Fisher's exact test was used to estimate significant differences between the two time periods. In P1, 323 patients and in P2, 155 patients were eligible for treatment according to the guideline. The percentage of patients with > or = 10 lymph nodes improved from 65.3 to 81.3% (P=0.0004), as did the percentage with a reported oestrogen receptor (ER) status, from 84.8 to 96.8% (P=0.00004), progesterone receptor (PR) status from 82.3% to 97.4% (P<0.000001) and with a DI > or = 85%, from 74.9 to 93.9% (P=0.000003). Adherence varied between the hospitals. In conclusion, significant improvements were observed for the indicators of resected axillary lymph nodes and DI of chemotherapy, which may be attributed to the quality programme. Repeated assessment of the adherence to the guideline is important to observe changes and interhospital variations in order to remain focused on areas for improvement.

Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome.

Here, we set out to assess CA9 expression levels by real-time quantitative RT-PCR in breast cancer tissue samples obtained from 253 patients, and correlated those with relapse-free (RFS) survival. The median follow-up time was 75 months (range 2-168 months). CA9 expression was mainly found in high-grade, steroid receptor negative cancer tissues. CA9 levels were not significantly associated with RFS (P=0.926, hazard ratio (HR)=0.99, 95% CI=0.80-1.22) in the total cohort of 253 patients. In multivariate analysis with other clinicopathological factors, CA9 (P=0.018, HR=0.77, 95% CI=0.62-0.96), the interaction of adjuvant chemotherapy with CA9 (P=0.009, HR=1.31, 95% CI=1.07-1.61) and the interaction of adjuvant endocrine therapy with CA9 (P<0.001, HR=1.41, 95% CI=1.20-1.66) all contributed significantly to the final model. These results indicate that patients with low CA9 levels benefit more from adjuvant treatment than do patients with high levels. Thus, the determination of CA9 levels could aid in the selection of patients who will not benefit from adjuvant therapy, and whose prognosis will more likely improve with other treatment modalities.

Continuing chemotherapy or not after the induction treatment in advanced breast cancer patients. clinical outcomes and oncologists' preferences.

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment failure, overall survival and using a Q-TWiST analysis. The treating physician's opinion was asked. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group conducted a randomised trial in 204 non-progressing metastatic breast cancer patients after induction chemotherapy (CMF) to stop or continue treatment. Progression-free (PFS) and overall survival (OS) were studied. To gain more insight into the burden of treatment-related side-effects, Q-TWiST was analysed. In addition, we asked for oncologists' preferences as patients are likely to be influenced by their physicians' opinion. Continuation of CMF had a significantly longer time to treatment failure (TTF) 5.2 versus 3.5 months (P=0.011). There was no overall survival (OS) difference 14.0 versus 14.4 months (P=0.77). Mean quality-adjusted survival time was equal to 8.4 months for no further treatment and decreased to 7.9 months for continuation of CMF (95% Confidence Interval (CI) of difference equals 0.5+/-2.5 months). Almost half of the oncologists said they would favour continuous treatment for a 3-month gain in time to progression-a difference which was not found in this study. Based on these data, an interruption of chemotherapy (CMF), if this is the wish of the patient, is justified.

The prognostic value of the mitotic activity index in patients with primary breast cancer who were not treated with adjuvant systemic therapy.

BACKGROUND: At the St Gallen meeting of 2001 it was agreed to select high-risk patients for adjuvant systemic therapy by lymph node status, tumor size, age, hormone receptor status, and histological grade. In The Netherlands it was chosen to use either the histological grade or the mitotic activity index (MAI). The aim of this study was to retrospectively evaluate the independent prognostic value of the MAI in primary breast cancer patients, who were not treated with adjuvant systemic therapy, on relapse-free survival (RFS) and overall survival (OS). PATIENTS AND METHODS: The data of 137 systemically untreated patients with primary breast cancer diagnosed between 1992 and 1996, of whom MAI was assessed, were retrospectively collected. The MAI was correlated to classical prognostic factors and we determined the prognostic value of the MAI, the histological grade and other prognostic factors. RESULTS: The median observation time was 4.2 years. The MAI showed a positive correlation to lymph node status (P < 0.001) and a negative correlation to age (P = 0.005), menopausal status (P < 0.001) and the ER and PgR status (r(s) = -0.390 [ER], r(s) = -0.440 [PgR], both P < 0.001). A high MAI (> or = 15) predicted a reduced RFS and OS in the Kaplan-Meier analysis (P = 0.0070 and P = 0.0017, respectively). Also in the multivariate analysis, the MAI showed to be an independent predictor of poor RFS (P = 0.035), in addition to lymph node status. However, the MAI did not predict for OS, in contrast to tumor size and lymph node status. CONCLUSION: The present study confirms that the MAI is an independent prognostic factor for RFS, but not for OS and may be useful for daily clinical practice.

The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy.

The growth and metastasising capacity of solid tumours are dependent on angiogenesis. Vascular endothelial growth factor is a mediator of angiogenesis. In this study we investigated whether vascular endothelial growth factor is associated with the natural course of the disease in primary invasive breast cancer. In 574 tumours of patients with node-negative invasive breast cancer the cytosolic levels of vascular endothelial growth factor were measured using a quantitative enzyme-linked immunosorbent assay. These patients did not receive adjuvant systemic therapy and were followed for a median follow-up time of 61 months (range 2-155 months) after the primary diagnosis. Correlations with well-known prognostic factors, and univariate and multivariate survival analyses were performed. Vascular endothelial growth factor level was positively associated with age and tumour size (P=0.042 and P=0.029, respectively). In addition, vascular endothelial growth factor level was inversely, but weakly correlated with progesterone receptor levels (PgR) (r(s)=-0.090, P=0.035). A high vascular endothelial growth factor level (equal or above the median level of 0.53 ng mg(-1) protein) predicted a reduced relapse-free survival and overall survival in the univariate survival rate analysis (for both P=0.005). In the multivariate analysis as well, vascular endothelial growth factor showed to be an independent predictor of poor relapse-free survival and overall survival (P=0.045 and P=0.029, respectively), in addition to age, tumour size and PgR. The results show that cytosolic levels of vascular endothelial growth factor in tumour tissue samples are independently indicative of prognosis for patients with node-negative breast cancer who were not treated with adjuvant systemic therapy. This implies that vascular endothelial growth factor is related with the natural course of breast cancer progression.

Effects of quality of treatment on prognosis in primary breast cancer patients treated in daily practice.

UNLABELLED: Information on treatment outcome outside clinical trials is sparse. This is the first study that relates surgical and medical quality of care in daily practice with outcome. BACKGROUND: In a previous study we showed, that the quality of chemotherapy as described by a guideline and given in daily practice to premenopausal primary breast cancer patients was suboptimal with only 68% and 53% of the patients receiving chemotherapy with a dose intensity (DI) and relative dose intensity (RDI) of > or = 85%, respectively. Many invalid reasons for delay and dose reductions were identified. PATIENTS AND METHODS: Premenopausal node-positive primary breast cancer patients treated from 1988 to 1992 were traced using two national registries. Relevant data were collected from their records. The following treatment-related variables were correlated with prognosis: type of surgery, number of investigated lymph nodes, radiotherapy, chemotherapy, interval between surgery and start of chemotherapy, DI, duration, delays and dose adjustments of chemotherapy and hospital size. RESULTS: Twenty-four of the 254 traced patients did not receive any chemotherapy, 230 received the recommended schedule of cyclophosphamide (C), methotrexate (M) and 5-fluorouracil (F). The median time of follow-up was 6.7 (range 0.9-10.2) years. The 5-year disease-free survival (DFS) and overall survival (OS) was 61% and 77%, respectively. In an univariate analysis DI < 65% correlated with a worse DFS and OS (p=0.05 and p=0.03, respectively). The use of chemotherapy correlated with a better DFS (p=0.03) than no use. In a multivariate analysis DI between 65 and 85% resulted in a better DFS (p=0.02) than DI > or = 85% and DI < 65%. CONCLUSION: The prognosis of the breast cancer patients in this population was comparable with the results of randomised trials using adjuvant CMF. The only treatment related variable of value for prognosis was DI. Unexpectedly DI between 65% and 85% resulted in the best prognosis in this population. The relevance of this observation remains unclear and warrants further investigation.

Repeated mammographic screening reduces breast cancer mortality along the continuum of age.

OBJECTIVE: The optimal age boundaries for breast cancer screening are still under debate. A case-referent design was used to describe the effect of mammographic screening on breast cancer mortality along the continuum of age, based on a 20 year follow up period. SETTING: The population based breast cancer screening programme in Nijmegen, The Netherlands, which has biennially invited women over 35 years since 1975. METHODS: Cases, defined as women who died from primary breast cancer between 1987 and 1997, were selected from the group of women who received at least one invitation to the screening programme. For 157 cases, 785 women from the same group were selected as referents. Information on the index screening (the screening examination preceding diagnosis of the case) was collected for both cases and referents. The risk of dying from breast cancer was calculated per 10 year moving age group for women who had attended the index screening versus those who had not. RESULTS: The youngest 10 year age group showing an effect in our study were women aged 45-54 at their index screening. Breast cancer mortality for women in this group who attended the index screening was 32% lower, although not significant, than for women who did not (odds ratio (OR) 0.68, 95% confidence interval (95% CI) 0.33 to 1.41). This reduction in risk was not explained solely by an effect in women over 50 because the OR in women aged 45-49 was 0.56 (95% CI 0.20 to 1.61). Reductions in mortality became smaller with increasing age. Nevertheless, for women over 60 at index screening, participation in screening over a maximum 4 year period before diagnosis of the case yielded protective effects at least up to an age around 80. CONCLUSIONS: Although our results are based on a relatively small number of cases, they suggest that even in a programme with a 2 year screening interval there may be a benefit of starting screening around age 45. Also older women who participate at least once every 4 years still have much to gain from screening.