Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype.

BACKGROUND: In the adjuvant treatment of hormone receptor-positive (HR+) breast cancer, variables like tumour size, grade and nodal status have great impact on therapy decisions. As most node-positive patients with HR+ breast cancer currently receive adjuvant chemotherapy improved methods for characterization of individuals' metastasis risk are needed to reduce overtreatment. PATIENTS AND METHODS: Tissue specimens from node-positive patients of the ABCSG-8 and ATAC trials who received adjuvant tamoxifen and/or anastrozole were included in this study. Analysing RNA from paraffin blocks using the PAM50 test, the primary objective was to evaluate the prognostic information of the risk of recurrence (ROR) score added to combined clinical standard variables in patients with one positive node (1N+) and in patients with two or three positive nodes (2-3N+), using log-likelihood ratio tests. RESULTS: At a median follow-up of 9.6 years, distant metastases occurred in 97 (18%) of 543 node-positive patients. In a multivariate analysis, the PAM50-derived ROR score provided reliable prognostic information in addition to and beyond established clinical factors for 1N+ (P < 0.0001) and 2-3N+ patients (P = 0.0002). Ten-year distant recurrence risk was significantly increased in the high-risk compared with the low-risk group derived from ROR score for 1N+ [25.5%, 95% confidence interval (CI) 17.5% to 36.1%versus 6.6%, 95% CI 3.3% to 12.8%] and compared with the combined low/intermediate risk group for 2-3N+ patients (33.7%, 95% CI 25.5% to 43.8% versus 12.5%, 95% CI 6.6% to 22.8%). Additionally, the luminal A intrinsic subtype (IS) exhibited significantly lower risk of distant recurrence compared with the luminal B subtype in 1N+ and 2-3N+ patients. CONCLUSION: PAM50 ROR score and IS can identify node-positive patient subgroups with limited risk of metastasis after endocrine therapy, for whom adjuvant chemotherapy can be spared. The PAM50 test is a valuable tool in determining treatment of node-positive early-stage breast cancer patients.

Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.

BACKGROUND: Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months. PATIENTS AND METHODS: Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points. RESULTS: After 94.4-month median follow-up (range, 0-114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60-0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43-1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05-1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. CONCLUSION: These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term. CLINICALTRIALSGOV: NCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).

The multigene signature MammaPrint impacts on multidisciplinary team decisions in ER+, HER2- early breast cancer.

BACKGROUND: Validated multigene signatures (MGS) provide additional prognostic information when evaluating clinical features of ER(+), HER2(-) early breast cancer. We have studied the quantitative and qualitative impact of MGS on multidisciplinary team (MDT) recommendations. METHODS: We prospectively recruited 75 ER(+), HER2(-) breast cancer patients. Inclusion was based on biopsy assessment of grade, hormone receptor status, HER2, clinical tumour and nodal status. A fresh tissue sample was sent for MammaPrint (MP), TargetPrint analysis at surgery. Clinical risk was decided by the MDT in the absence of MP results and repeated following the collection of MP results. Decision changes were recorded and a health technology assessment was undertaken to compare cost effectiveness. RESULTS: The majority of patients were assigned low to intermediate clinical risk by the MDT. According to MP, 76% were low risk. A very high correlation between local IHC and the TargetPrint assessment was shown. In over a third of patients, discordance between clinical and molecular risk was observed. Decision changes were recorded in half of these cases (18.6%) and resulted in two out of three patients not requiring chemotherapy. The use of MP was also found to be more cost effective. CONCLUSIONS: The multigene signature MP revealed clinical and molecular risk discordance in a third of patients. The impact of this on MDT recommendations was most profound in cases where few clinical risk factors were observed and enabled some women to forgo chemotherapy. The use of MGS is unlikely to have an impact in either clinically low-risk women or in patients with more than one relative indication for chemotherapy.

Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24).

BACKGROUND: This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin-docetaxel (ED)±capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors. PATIENTS AND METHODS: Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)±C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery. RESULTS: Five hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P≤0.035) were independent prognostic factors for pCR. Trastuzumab added to ED±C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions. CONCLUSION: These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease. CLINICAL TRIAL NUMBER: NCT00309556, www.clinicaltrials.gov.

Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone.

BACKGROUND: PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence (ROR) score. It has been developed to be carried out in qualified routine hospital pathology laboratories. PATIENTS AND METHODS: One thousand four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer (EBC) treated with tamoxifen or tamoxifen followed by anastrozole from the prospective randomized ABCSG-8 trial were entered into this study. Patients did not receive adjuvant chemotherapy. RNA was extracted from paraffin blocks and analyzed using the PAM50 test. Both intrinsic subtype (luminal A/B, HER2-enriched, basal-like) and ROR score were calculated. The primary analysis was designed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence (DR) over and above standard clinical variables. RESULTS: In all tested subgroups, ROR score significantly adds prognostic information to the clinical predictor (P<0.0001). PAM50 assigns an intrinsic subtype to all cases, and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B (P<0.0001). Significant and clinically relevant discrimination between low- and high-risk groups occurred also within all tested subgroups. CONCLUSION(S): The results of the primary analysis, in combination with recently published results from the ATAC trial, constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC. A 10-year metastasis risk of <3.5% in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome-this finding could help to avoid unwarranted overtreatment. CLINICAL TRIAL NUMBER: ABCSG 8: NCT00291759.

The predictive impact of body mass index on the efficacy of extended adjuvant endocrine treatment with anastrozole in postmenopausal patients with breast cancer: an analysis of the randomised ABCSG-6a trial.

BACKGROUND: We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment. METHODS: The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety. RESULTS: In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P=0.02) and death (HR 0.45; P=0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P=0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P=0.68; distant recurrence-free survival HR 0.91; P=0.78; and OS HR 0.9; P=0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment (P=0.07). CONCLUSION: Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.

Efficacy of tamoxifen ± aminoglutethimide in normal weight and overweight postmenopausal patients with hormone receptor-positive breast cancer: an analysis of 1509 patients of the ABCSG-06 trial.

BACKGROUND: There exists evidence that body mass index (BMI) impacts on the efficacy of aromatase inhibitors in patients with breast cancer. The relationship between BMI and the efficacy of tamoxifen is conflicting. We investigated the impact of BMI on the efficacy of single tamoxifen and tamoxifen plus an aromatase inhibitor in the well-defined prospective study population of the ABCSG-06 trial. METHODS: ABCSG-06 investigated the efficacy of tamoxifen vs tamoxifen plus aminoglutethimide in postmenopausal women with hormone receptor-positive breast cancer. Taking BMI at baseline, patients were classified as normal weight (BMI=18.5-24.9 kg m(-)(2)), overweight (BMI=25-29.9 kg m(-)(2)), and obese (30 kg m(-)(2)) according to WHO criteria. RESULTS: Overweight+obese patients had an increased risk for distant recurrences (hazard ratio (HR): 1.51; Cox P=0·018) and a worse overall survival (OS; HR: 1·49; Cox P=0·052) compared with normal weight patients. Analysing patients treated with single tamoxifen only, no difference between overweight+obese patients and normal weight patients regarding distant recurrence-free survival (HR: 1.35; Cox P=0·24) and OS (HR: 0.99; Cox P=0·97) could be observed. In contrast, in the group of patients treated with the combination of tamoxifen plus aminoglutethimide, overweight+obese patients had an increased risk for distant recurrences (1.67; Cox P=0·03) and a worse OS (1.47; Cox P=0·11) compared with normal weight patients. CONCLUSION: BMI impacts on the efficacy of aromatase inhibitor-based treatment but not single tamoxifen.

The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients.

BACKGROUND: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. METHODS: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis). RESULTS: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. CONCLUSION: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer.

BACKGROUND: In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. PATIENTS AND METHODS: We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan-Meier survival analysis. RESULTS: After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%-61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. CONCLUSION: The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial.

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.

Long-term outcomes after endothoracic sympathetic block at the T4 ganglion for upper limb hyperhidrosis.

BACKGROUND: The aim of this study was to evaluate long-term results, quality of life, satisfaction and compensatory sweating after endothoracic sympathetic block at T4 (ESB4). METHODS: Patients who underwent an ESB4 procedure for palmar or palmoaxillary hyperhidrosis between 2001 and 2008 were included in a prospective study at a university hospital. Questionnaires devised by Keller and Milanez de Campos were applied to evaluate disease-specific quality of life. RESULTS: A total of 189 patients underwent 374 ESB4 procedures. Of 174 evaluated patients, 54 (31·0 per cent) had palmar and 120 (69·0 per cent) had palmoaxillary hyperhidrosis. Median follow-up was 92 months. In both groups, treatment successfully reduced hyperhidrosis (P < 0·001) and quality of life increased significantly after ESB4 (P < 0·001), remaining stable after 5 years. Overall satisfaction rates decreased owing to the development of compensatory sweating and recurrence during follow-up. Compensatory sweating affected 41 patients (23·6 per cent), and was severe in 11 (6·7 per cent) of 163 patients at 5-year follow-up; eight of these 11 patients had been treated for palmoaxillary sweating. The severity of compensatory sweating did not deteriorate with time. The severe recurrence rate increased to 11·0 per cent during follow-up, and was twice as common in patients treated for palmoaxillary sweating as in those treated for palmar sweating (13·2 versus 6·1 per cent respectively). Nine reoperations (5·2 per cent) were performed for persistent sweating, recurrence or compensatory sweating. CONCLUSION: T4 endothoracic sympathetic clip application is safe and effective in patients with upper limb hyperhidrosis, with stable long-term improvements in quality of life.

Oncologic safety of breast conserving surgery after tumour downsizing by neoadjuvant therapy: a retrospective single centre cohort study.

The objective of this study is to analyse local recurrence rates in patients receiving neoadjuvant chemotherapy (nCT) comparing mastecomized (MX) patients with those undergoing breast conserving therapy (BCT). Patients undergoing breast cancer surgery after nCT (3xCMF or 3-6xED) between 1995 and 2007 at our department were retrospectively analysed. The median follow up was 60 months for 308 patients. Patients who were downsized from MX to BCT with partial or complete response (n = 104) had a similar local recurrence free survival (LRFS) compared to patients who did not experience successful downsizing (n = 67) and finally undergoing MX (LRFS MX-BCT 81% vs. MX-MX 91%; P = 0.79). Uni- and multivariate analyses demonstrated that BCT itself was not an independent prognostic factor for a worse LRFS (P = 0.07 and 0.14). After no pathologic change or progressive disease the risk of local recurrence was increased in patients undergoing BCT (MX-BCT; n = 6 LRFS 66%) compared with MX (n = 44; LRFS 90%; P = 0.04). Overall survival in general was better for the BCT group (n = 197) compared with MX group (n = 111) regardless of clinical response (92% vs. 72%; P < 0.0001). Breast conservation, nodal negativity and low or medium grade histology were prognostic factors for an improved OS (P = 0.02, 0.01, 0.004). In conclusion, our study suggests that BCT is oncologically safe after tumour downsizing by nCT in patients primarily scheduled for mastectomy. These patients, however, should not be treated with breast conservation in the absence of any proven response after nCT.

HER2/neu expression correlates with vascular endothelial growth factor-C and lymphangiogenesis in lymph node-positive breast cancer.

BACKGROUND: Vascular endothelial growth factor-C (VEGF-C) is the main inducer of lymphangiogenesis. VEGF-C overexpression is associated with lymphovascular tumor cell invasion, an increased rate of lymph node metastasis and adverse prognosis in various human cancers. However, little is known about the upstream inducers of VEGF-C expression. Recent studies have shown that human epidermal growth factor receptor 2 (HER2/neu) overexpression is associated with high VEGF-C levels in human breast cancer cells. In addition to blocking of HER2/neu, tyrosine kinase significantly decreased VEGF-C expression in vitro. PATIENTS AND METHODS: VEGF-C expression, lymphatic microvessel density (LMVD), lymphovascular invasion (LVI) and HER2/neu expression were evaluated with immunohistochemical/FISH methods in a collective of 150 lymph node-positive human breast cancers with long-term follow-up. RESULTS: Cases with 3+ HER2/neu protein expression showed a significantly stronger VEGF-C expression than all others cases (P = 0.006). In addition, we found a significant correlation between VEGF-C expression and LMVD (P = 0.012) and a strong positive association between LMVD and LVI (P < 0.001). CONCLUSION: Our data provide evidence for a clinically relevant association between HER2/neu and VEGF-C expression in human breast cancer. Inhibiting HER2/neu may reduce tumor progression by blocking VEGF-C-mediated tumor cell proliferation and lymphogenic metastasis.

Lymph node ratio after curative surgery for intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is rare but its incidence is rising worldwide. The value of lymph node dissection for ICC is under discussion; the current staging systems do not differentiate between numbers of involved nodes. METHODS: Ninety-three patients who underwent laparotomy for ICC between 1997 and 2007 were identified retrospectively; 46 who underwent curative resection and systematic lymphadenectomy around the hepatoduodenal ligament were analysed further. Univariable and multivariable regression analysis was performed to identify prognostic factors. RESULTS: Tumour size and advanced tumour stage were associated with worse overall and recurrence-free survival in univariable analysis. An increased ratio of positive to total harvested lymph nodes (LNR) was also prognostic for adverse outcome in lymph node-positive patients: crude hazard ratio 8.93 (95 per cent confidence interval (c.i.) 1.52 to 32.50) for overall survival and 8.76 (1.96 to 39.22) for recurrence-free survival. Adjusted hazard ratios for LNR in multivariable regression analysis were 9.81 (1.52 to 43.44) and 10.63 (2.04 to 55.31) respectively. The total number of retrieved lymph nodes was not related to survival or recurrence. CONCLUSION: LNR appears to be a good prognostic factor for survival or recurrence after curative resection for ICC.

Recent developments in breast-conserving surgery for breast cancer patients.

This invited review deals with the latest knowledge regarding breast conserving therapy in breast conserving patients.

Breast cancer chemoprevention - a vision not yet realized.

Despite recent advances in the surgical and medical treatment of breast cancer, the number of patients dying from the disease is still high. In addition to improvements of early diagnosis and treatment, the overall mortality of breast cancer could be reduced by means of preventive intervention in both women with particularly normal and with high risk. Preventing the potentially deadly disease is presumably more effective than treatment, for life quality issues as well as for the economic perspective. Chemoprevention though is still a research field with results from large prevention trials being discussed controversially. For women with a defined increased risk for breast cancer, tamoxifen may be a choice for chemoprevention, balancing carefully benefits against risks. With promising results in adjuvant settings, aromatase inhibitors may deliver better prevention treatment options in the future, nevertheless, more research is needed to reliably predict risk on an individual basis in the future.

New epidemiological aspects of patients with severe hyperhidrosis presenting for sympathetic surgery.

BACKGROUND: Epidemiological data on individuals suffering from severe primary hyperhidrosis are scarce. OBJECTIVE: This study aims to prospectively assess disease-specific characteristics of patients with severe, mostly therapy-resistant hyperhidrosis presenting for sympathetic surgery. METHODS: We evaluated a total of 227 patients (69.6% women) with a mean age of 30 years (standard deviation, 9.5 years) using a standardized questionnaire. Severity of disease was rated on a visual analogue scale (VAS) graded between 0 (no symptoms) and 10 (worst symptom). Age, sex, previous therapies, hormonal therapies and body mass index were analysed for their possible influence on severity of the disease and on hyperhidrosis sites. In addition, allergies were investigated for the first time in this patient population. RESULTS: There was a positive correlation between age of onset and sites of hyperhidrosis. The most commonly affected areas were palmar-axillary-plantar (51.1%) and palmar-plantar (15.0%), with sex-specific differences. Two hundred and twelve patients (93.4%) had previous conservative therapies; 219 patients (96.5%) reported VAS scores between 8 and 10. Female patients stated higher VAS scores for palmar (P = 0.009) and axillary (P = 0.012) sites. Type IV allergies were found to be much higher than in the general Austrian female population. Hormonal therapies and the body mass index had no influence on severity of hyperhidrosis after analysis of VAS scores. CONCLUSION: Sex-dependent aspects can be found in patients strongly affected by primary upper limb hyperhidrosis.

Stromal coexpression of uPA/PAI-1 protein predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer.

BACKGROUND: To evaluate whether uPA/PAI-1 protein in hormone receptor-positive (HR+) breast tumor can predict prognosis in early breast cancer (BC). METHODS: 606 women with HR + BC who had ≥5 years of endocrine therapy and in whom tumor tissue was available were included in this analysis. Stromal uPA/PAI-1 protein expression was evaluated by immunohistochemistry and correlated with distant recurrence-free survival (DRFS) and overall survival (OS). RESULTS: Stromal uPA was detected in 292/538 tumors (54.3%) while 269/505 samples (53.3%) exhibited stromal PAI-1. Co-expression of both proteins was found in 163/437 (37.3%) samples. Stromal uPA/PAI-1 co-expression was not associated with tumor size, age, nodal status, grading, or receptor status. Tumor stroma with both uPA and PAI-1 protein expression were more likely to have a shorter DRFS (HR: 1.87; 95%CI 1.18-2.96; p = 0.007) and OS (HR: 1.29; 95%CI 0.93-1.80; p = 0.129) than women without uPA/PAI-1 co-expression. After a median follow-up of 10 years, women with uPA/PAI-1-positive tumors experienced a significantly shorter DRFS (86.5% vs 72.4%; p < 0.001) and OS (70.4% vs 58.9%; p = 0.020) compared to women with uPA/PAI-1 negative tumors. CONCLUSION: Stromal co-expression of uPA and PAI-1 in breast cancer predicts poor DRFS and OS in postmenopausal women with HR + early-stage BC who receive endocrine therapy.

Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials.

BACKGROUND: Several trials have been done to assess treatment of premenopausal breast cancer with luteinising-hormone-releasing hormone (LHRH) agonists, but results have been inconclusive, especially for patients with hormone-receptor-positive cancer. METHODS: We collected individual patients' data from published trials and did analyses focused on women with tumours positive for oestrogen receptor, progesterone receptor, or both. The main endpoints were recurrence and death after recurrence. FINDINGS: We obtained data for 11 906 premenopausal women with early breast cancer randomised in 16 trials. When used as the only systemic adjuvant treatment, LHRH agonists did not significantly reduce recurrence (28.4% relative reduction, 95% CI consistent with 50.5% reduction to 3.5% increase, p=0.08) or death after recurrence (17.8%, 52.8% reduction to 42.9% increase, p=0.49) in hormone-receptor-positive cancers. Addition of LHRH agonists to tamoxifen, chemotherapy, or both reduced recurrence by 12.7% (2.4-21.9, p=0.02); and death after recurrence by 15.1% (1.8-26.7, p=0.03). LHRH agonists showed similar efficacy to chemotherapy (recurrence 3.9% increase, 7.7% reduction to 17.0% increase; death after recurrence 6.7% reduction, 20.7% reduction to 9.6% increase; both not significant). No trials had assessed an LHRH agonist versus chemotherapy with tamoxifen in both arms. LHRH agonists were ineffective in hormone-receptor-negative tumours. INTERPRETATION: LHRH agonists provide an additional class of agents for treatment of premenopausal women with hormone-receptor-positive breast cancer. Optimum duration of use is unknown.

Guidelines on the standards for the training of specialised health professionals dealing with breast cancer.

According to EUSOMA position paper 'The requirements of a specialist breast unit', each breast unit should have a core team made up of health professionals who have undergone specialist training in breast cancer. In this paper, on behalf of EUSOMA, authors have identified the standards of training in breast cancer, to harmonise and foster breast care training in Europe. The aim of this paper is to contribute to the increase in the level of care in a breast unit, as the input of qualified health professionals increases the quality of breast cancer patient care.