The rs1800716 variant in CYP2D6 is associated with an increased double endometrial thickness in postmenopausal women on tamoxifen.

BACKGROUND: Tamoxifen remains important in the treatment and prevention of estrogen receptor-positive breast cancer. In postmenopausal women, it can lead to endometrial changes such as cystic appearances, hyperplasia, polyps and endometrial cancer. Tamoxifen is metabolized by cytochrome P450 (CYP450) enzymes to the more active metabolite endoxifen. Several genetic variants in the CYP450 enzymes reduce tamoxifen metabolism, leading to reduced endoxifen levels. We hypothesize that carriers of these variants, which are established poor metabolizers of tamoxifen, do not have the typical tamoxifen-induced increase in endometrial thickness. We test the association between genetic variability in CYP450 enzymes and the increase in double endometrial thickness (DET) as measured through transvaginal ultrasound (TVU). PATIENTS AND METHODS: We carried out a retrospective study on postmenopausal tamoxifen users for which germline DNA was available and at least one DET measurement was made between January 2000 and October 2011. Genotyping of 33 single nucleotide polymorphisms in CYP450 genes involved in tamoxifen metabolism was carried out using Sequenom MassARRAY. The association between these variants and TVU outcome (DET ≥5 mm) was assessed by proportional hazards regression. RESULTS: Data were available for 184 women: 47 with a DET of <5 mm on all ultrasounds and 137 with a DET of ≥5 mm on at least one ultrasound. The rs1800716 variant in CYP2D6 showed a statistically significant association with DET. In particular, mutant carriers of rs1800716 had an increased chance of having a DET of ≥5 mm (P = 0.0022, false discovery rate 0.0179). None of the other variants were associated with DET. CONCLUSION: Although mutant carriers of rs1800716 are characterized by reduced CYP2D6 enzyme activity and by low levels of endoxifen, we observed that mutant alleles of rs1800716 were associated with an increased chance of having a DET of ≥5 mm in postmenopausal women on tamoxifen. We conclude that the increase in endometrial thickness seen under tamoxifen cannot be used as a marker for favorable genotypes. CLINICAL TRIAL NUMBER: B32220084284.

A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI.

Aromatase inhibitor (AI) therapy for estrogen receptor-positive breast cancer is known to induce or enhance musculoskeletal problems. We have previously reported that loss of grip strength is more pronounced in AI-users with extremes in BMI. We here report results from a larger prospective study. Postmenopausal early breast cancer patients scheduled to start AI or tamoxifen therapy were recruited. A functional assessment grip strength test was performed at baseline, 3, 6, and 12 months of therapy. BMI was assessed, and a rheumatologic questionnaire was completed at each visit. 188 patients on an AI and 104 patients on tamoxifen were enrolled. 74 % of AI-users reported new/worsened musculoskeletal complaints compared with 37 % in the tamoxifen group. This was translated in a larger grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints (p = 0.0002). 15 % of AI-users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction versus adherent patients (p = 0.0107). Young age (p = 0.0135), taxane-based chemotherapy (p = 0.0223), and baseline VAS score >4 (p = 0.0155) were predictors for AI-related musculoskeletal pain. In addition, a quadratic trend of BMI with grip strength change (p = 0.0090) and probability of discontinuation was observed (p = 0.0424). Musculoskeletal events were a substantial problem in AI-treated patients and an important reason for treatment discontinuation. The decrease in grip strength was larger in AI- than in tamoxifen-users, with a more pronounced change in symptomatic patients. The inverse relationship between BMI extremes and grip strength change was confirmed in this large group of AI-patients.

An atypical case of necrotizing fasciitis of the breast.

Necrotizing fasciitis is a rare and aggressive soft tissue infection involving the fascia and subcutaneous tissues. It carries a high mortality and morbidity rate. In literature, the few case reports on necrotizing fasciitis of the breast, describe the need for a mastectomy in 90% of the cases. We report on a case of a 72-year old Caucasian women with an atypical presentation of necrotizing fasciitis of the breast in combination with an acute abdomen, successfully treated with breast-conserving debridement and secondary wound closure.

Breast cancer phenotype, nodal status and palpability may be useful in the detection of overdiagnosed screening-detected breast cancers.

BACKGROUND: Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. PATIENTS AND METHODS: A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening-detected breast cancers for distant metastatic and breast cancer-specific survival. RESULTS: We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. CONCLUSION: Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype.

Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data.

BACKGROUND: Aromatase inhibitors (AIs) frequently lead to the AI-induced musculoskeletal syndrome (AIMSS). Looking into its pathophysiology, 6 months of AI therapy thickens the tendon sheath with intra-articular fluid (IAF) retention and loss of grip strength. We here report 24-month follow-up data. PATIENTS AND METHODS: A prospective cohort study of 33 postmenopausal breast cancer patients received adjuvant endocrine therapy; 27 received an AI and 6 received tamoxifen. At baseline, 6 and 24 months patients had a rheumatologic examination, including a grip strength test, and magnetic resonance imaging of both hands and wrists. The primary end point was tenosynovial changes; secondary end points were changes in morning stiffness, grip strength and IAF. RESULTS: Twenty-three AI and 5 tamoxifen patients completed all investigations. Between month 6 and 24, IAF further increased in AI users (P = 0.04) but not in tamoxifen users, and grip strength further decreased in both groups. The worsened tenosynovial changes were strongly correlated with a decrease in grip strength. At 24 months, morning stiffness continued to be present in over a third of AI users. CONCLUSION: AIMSS represents a substantial problem in breast cancer patients. It is associated with tenosynovial changes, IAF retention, joint stiffness and loss of grip strength that do not improve with prolonged use.

Applying the 2011 St Gallen panel of prognostic markers on a large single hospital cohort of consecutively treated primary operable breast cancers.

BACKGROUND: Many easily measurable and readily available factors are now established as being prognostic in primary operable breast cancer. We here applied the 2011 St Gallen surrogate definition for breast cancer subclassification using tumor grade instead of Ki67. PATIENTS AND METHODS: Four thousand three hundred and eighteen consecutive patients who had surgery for primary operable breast cancer (1 January 2000 and 31 December 2009) in UZ Leuven excluding primary metastastic male breast cancers and those receiving neoadjuvant therapy. Five different surrogate phenotypes were created using the combined expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 together with tumor grade. Disease-free interval (DFI), distant metastastis-free interval (DMFI), locoregional relapse-free interval (LRRFI), breast cancer-specific survival (BCSS) and overall survival (OS) were calculated. RESULTS: Surrogate phenotypes present with significant differences in DFI, DMFI, LRRFI, BCSS and OS. 'Luminal A' tumors presented with the best outcome parameters but the effect weakened at longer follow-up. CONCLUSIONS: The four surrogate markers, agreed upon by the 2011 St Gallen consensus, defined five prognostic surrogate phenotypes in a large series of consecutively treated breast cancer patients. Their prognostic value changed with longer follow-up. The added value of gene expression profile over classical pathological assessment remains to be defined.

Stellate ganglion block for the management of hot flashes and sleep disturbances in breast cancer survivors: an uncontrolled experimental study with 24 weeks of follow-up.

BACKGROUND: We studied the stellate ganglion block (SGB) recently suggested for the treatment of severe vasomotor symptoms and sleep disturbances in breast cancer survivors. Following an initial pilot study, which focused on the acceptability and safety of SGB for this important problem, we evaluated its short- and long-term efficacy. MATERIALS AND METHODS: Postmenopausal breast cancer survivors with severe vasomotor symptoms resistant to standard nonhormonal pharmacological intervention were eligible. Diaries were used to measure daily hot flash scores (frequency and intensity) and sleep quality (Pittsburgh Sleep Quality Index) during scheduled visits at baseline, 1, 4, 12 and 24 weeks following the SGB. Efficacy data were analyzed using longitudinal regression models. RESULTS: Thirty-four patients participated and none refused the SGB procedure. Most patients received more than one SGB. The pilot study found SGB to be safe. In the main study, hot flash scores were reduced from baseline by 64% [95% confidence interval (CI) -74% to -49%] and 47% (95% CI -62% to -27%) at weeks 1 and 24, respectively. The odds ratio of better sleep quality relative to baseline was 3.4 at week 1 (95% CI 1.6-7.2) and 4.3 at week 24 (95% CI 1.9-9.8). CONCLUSION: In the short term, SGB appears to be an effective treatment with acceptable morbidity for some breast cancer survivors with therapy-resistant vasomotor symptoms and/or sleep disturbances. Although sleep quality was maintained out to 24 weeks the efficacy of SGB for hot flashes was reduced over time. A randomized controlled trial is needed to confirm these findings.

Neoadjuvant capecitabine and docetaxel (plus trastuzumab): an effective non-anthracycline-based chemotherapy regimen for patients with locally advanced breast cancer.

BACKGROUND: To evaluate capecitabine-docetaxel (XT), with trastuzumab (H) in human epidermal growth factor receptor 2 (HER2)-positive disease, in inoperable locally advanced breast cancer (LABC). PATIENTS AND METHODS: Patients received up to six neoadjuvant 21-day cycles of capecitabine 900 mg/m(2) twice daily, days 1-14, plus docetaxel 36 mg/m(2), days 1 and 8. Patients with HER2-positive disease also received trastuzumab 6 mg/kg every 3 weeks. The primary end point was pathologic complete response (pCR) rate, evaluated separately in HER2-negative and HER2-positive cohorts. Secondary end points included clinical response rates and tolerability. RESULTS: The pCR rate was 15% [95% confidence interval (CI) 7-28] in 53 patients receiving XT and 40% (95% CI 26-55) in 50 patients receiving HXT. After neoadjuvant therapy, 50 patients receiving XT and 45 receiving HXT underwent surgery. No unexpected toxicity was observed: the most common grade ≥3 adverse events were diarrhea/mucositis (30% and 20%, respectively) and grade 3 hand-foot syndrome (11% and 6%, respectively). Disease-free survival and overall survival were similar with XT and HXT after median follow-up of 22 months in the XT cohort and 21 months in the HXT cohort. CONCLUSION: Neoadjuvant XT (HXT in HER2-positive disease) is highly effective in inoperable LABC, demonstrating pCR rates of 15% and 40%, respectively. This non-anthracycline-containing regimen offers obvious benefits in early disease, where avoidance of long-term cardiotoxicity is particularly important.

Aromatase inhibitor-induced loss of grip strength is body mass index dependent: hypothesis-generating findings for its pathogenesis.

BACKGROUND: Our preliminary results showed that tenosynovial changes and decrease in grip strength are associated with the aromatase inhibitor-induced musculoskeletal syndrome (AIMSS). Here, we report the final results and assess the relationship between grip strength and body mass index (BMI). PATIENTS AND METHODS: We conducted a prospective study including postmenopausal early breast cancer patients receiving either an aromatase inhibitor (AI) or tamoxifen. Primary end point was change from baseline in tenosynovial abnormalities. Secondary end points were changes from baseline in morning stiffness, intra-articular fluid and grip strength and its association with BMI. RESULTS: After 6 months of therapy, 74% [95% confidence interval (CI) 51% to 89%] of AI-treated patients had worsened tenosynovial abnormalities, 56% (95% CI 34% to 75%) had increased intra-articular fluid, and 22% (95% CI 9% to 45%) had increased morning stiffness. Grip strength decreased 8% for the left hand (95% CI 2% to 21%) and 11% for the right (95% CI 4% to 17%). Regression analysis suggested that grip strength decreased more for subjects with high or with low BMI. CONCLUSIONS: AIMSS is characterized by tenosynovial changes, intra-articular fluid and morning stiffness. We hypothesize that the quadratic association between BMI and loss of grip strength reflects AI-induced changes on the endocrine control of the growth hormone insulin-like growth factor-I pathway.

Lobular and non-lobular breast cancers differ regarding axillary lymph node metastasis: a cross-sectional study on 4,292 consecutive patients.

Invasive lobular carcinoma (ILC) accounts for 8-14% of all breast cancers and carries distinct prognostic and biologic implications. The goal of our study was to investigate the impact of lobular histology on axillary lymph node (ALN) involvement. This is a cross-sectional study of 4,292 consecutive patients surgically treated for breast carcinoma at the University Hospitals Leuven. Logistic regression analysis was used to relate ILC to lymph node involvement while controlling for the following clinicopathologic features: tumor size, multifocal disease, tumor grade, lobular subtype and the combined steroid, and Her-2 status. Odds ratios (ORs) and 95% confidence intervals (CIS) were computed. A subgroup analysis was performed for patients that underwent a sentinel lymph node (SLN) procedure. The observed incidence of ILC was 13%. ILCs were larger, were more often grade II, multifocal, steroid receptor positive and Her-2 negative, and tended to be present in older patients. Incidence of ALN involvement was 42.0% for ILCs versus 38.3% for other tumors (OR 1.17, 95% CI 0.97-1.40). For the SLN subgroup, ILCs were less often ALN positive than non-ILCs (20.5% versus 28.3%, OR 0.66, 95% CI: 0.41-1.00). In the multivariable analysis, the lobular subtype was identified as less likely to have ALN involvement (adjusted OR 0.66, 95% CI 0.53-0.82). The analysis for the SLN subgroup showed comparable results (adjusted OR 0.49, 95% CI 0.30-0.78). This study has demonstrated that the lobular subtype is an independent predictor of lymph node involvement with ILC having a lower incidence of involved lymph nodes. The mildly higher incidence of ALN metastasis in lobular cancers in univariable analysis is not due to the lobular subtype, but due to confounding factors that interact with lymph node involvement.

Prediction of lymph node involvement in breast cancer from primary tumor tissue using gene expression profiling and miRNAs.

The aim of this study was to investigate whether lymph node involvement in breast cancer is influenced by gene or miRNA expression of the primary tumor. For this purpose, we selected a very homogeneous patient population to minimize heterogeneity in other tumor and patient characteristics. First, we compared gene expression profiles of primary tumor tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix Human U133 Plus 2.0 microarray chip. A model was built by weighted Least-Squares Support Vector Machines and validated on an internal and external dataset. Next, miRNA profiling was performed on a subset of 82 tumors using Human MiRNA-microarray chips (Illumina). Finally, for each miRNA the number of significant inverse correlated targets was determined and compared with 1000 sets of randomly chosen targets. A model based on 241 genes was built (AUC 0.66). The AUC for the internal dataset was 0.646 and 0. 651 for the external datasets. The model includes multiple kinases, apoptosis-related, and zinc ion-binding genes. Integration of the microarray and miRNA data reveals ten miRNAs suppressing lymph node invasion and one miRNA promoting lymph node invasion. Our results provide evidence that measurable differences in gene and miRNA expression exist between node negative and node positive patients and thus that lymph node involvement is not a genetically random process. Moreover, our data suggest a general deregulation of the miRNA machinery that is potentially responsible for lymph node invasion.

Short- and long-term recovery of upper limb function after axillary lymph node dissection.

All breast cancer patients, suspected with lymph node invasion, need an axillary lymph node dissection. This study investigated the short- and long-term effects of the treatment for breast cancer on shoulder mobility, development of lymphoedema, pain and activities of daily living. Patients who had a modified radical mastectomy (33%) or a breast-conserving procedure (67%) in combination with axillary lymph node dissection were included. Shoulder mobility, lymphoedema, pain and activities of daily living were evaluated at 3 months and at 3.4 years after surgery. At long term, 31% of the patients experienced impaired shoulder mobility, 18% developed lymphoedema, 79% had pain and 51% mentioned impaired daily activities. Between 3 months and 3.4 years after surgery, impaired shoulder mobility decreased from 57% to 31%. The incidence of lymphoedema increased from 4% to 18%. Patients experienced an equal amount of pain but fewer problems with daily activities. At 3.4 years, no significant differences between mastectomy and breast-conserving procedure were found. In conclusion, at long term, significant number of breast cancer survivors still had impaired shoulder mobility, developed lymphoedema, had pain and experienced difficulties during daily activities. Shoulder mobility, pain and daily activities evolved positively, while the incidence of lymphoedema increased.

Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users.

Retrospective studies suggest that single nucleotide polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene predict reduced tamoxifen metabolism, better tolerance and worse treatment outcome. We hypothesized that women with this genotype lack tamoxifen-induced endometrial and biochemical changes in follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). We identified 56 breast cancer patients attending the follow-up clinic with a homozygous mutant (HM) status for the CYP2D6*4 null variant. Here, we report a detailed assessment of tamoxifen activity in 19 CYP2D6 HM women, while they were using tamoxifen either for metastatic (n = 5) or for early disease (n = 14). We assessed response to tamoxifen in metastatic disease. Endometrial appearances and serum levels of FSH and SHBG were assessed from retrospective and prospective testing. Our findings do suggest that the presence of two CYP2D6*4 alleles does not exclude a durable response of tamoxifen in metastatic breast cancer. The transvaginal ultrasonographic appearance of the endometrium in CYP2D6*4/*4 patients on tamoxifen is similar as seen in the normal population of tamoxifen users. The endometrium is increased in thickness with subepithelial cysts and endometrial polyps. Serum levels of FSH and SHBG in CYP2D6*4 HM tamoxifen users were in the range of what would be expected during tamoxifen treatment in the general population. Our findings do show CYP2D6*4/*4 carriers to have activity of tamoxifen on breast cancer, endometrium and serum levels of FSH and SHBG. They support clinical trials prospectively testing the effect of CYP2D6 genetic variability in response to tamoxifen before denying this drug to breast cancer patients only based on their CYP2D6*4 status.

Clinicopathological features of inflammatory versus noninflammatory locally advanced nonmetastatic breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer. It is mainly a clinical diagnosis. The aim of this study was to compare IBC to clinically diagnosed noninflammatory locally advanced nonmetastatic breast cancer, also called cLABC. MATERIAL AND METHODS: One hundred and eight patients were studied: 49 with IBC and 59 with cLABC. The following features were analyzed: age at diagnosis, body mass index (BMI), axillary lymph node status (cN), estrogen receptor status (ER), progesterone receptor status (PR), HER2 status, histological tumor grade and subtype. Short-term disease-free (DFS) and overall survival (OS) were also assessed in both groups. RESULTS: Compared with cLABC, IBC was less often PR positive (41.7 vs. 66.1%, p = 0.01) and showed a trend to be more often HER2 positive (34.7 vs. 19.3%, p = 0.07). The 3-year DFS was 63 and 77%, respectively, for IBC and cLABC (p = 0.01); these figures were 83 and 85% for OS (p = 0.17). No significant differences in age at diagnosis, ER, cN, BMI, histological tumor grade or subtype were demonstrated. CONCLUSION: Compared to cLABC, IBC are more frequently PR negative, have a worse DFS, and have a tendency to be more often HER2 positive. These data reinforce the idea of IBC being a distinct biological entity compared to noninflammatory breast cancer.

Radiation-induced sarcoma: analysis of 46 cases.

A retrospective analysis was performed of 46 cases of sarcoma treated in our institution between 1989 and 2007 that occurred in a previously irradiated area. Eight male and 38 female patients had received radiotherapy, mainly for breast cancer and genitourinary tumours. The interval between irradiation and the diagnosis of sarcoma ranged from 1 to 54 years (median 15 y). The most common clinical findings were a mass, pain and skin dislocation. Angiosarcoma and sarcoma non-otherwise-specified were the most common histological types. Surgical resection was performed in 34 patients (74%) and 5-year survival was 45% when a radical resection was obtained. No 5-year survival was noticed after non-radical resection and in the absence of surgery. Stage and location of the sarcoma were other prognostic factors. Overall 5-year survival was 27% for the whole group.

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.

Inter-rater reliability of shoulder measurements in middle-aged women.

OBJECTIVES: To investigate inter-rater reliability of a set of shoulder measurements including inclinometry [shoulder range of motion (ROM)], acromion-table distance and pectoralis minor muscle length (static scapular positioning), upward rotation with two inclinometers (scapular kinematics) and pain pressure thresholds (muscle tenderness) in middle-aged women. DESIGN: Observational study. PARTICIPANTS: Thirty symptom-free middle-aged women (first cohort) were measured by two raters. All measurements with an intraclass correlation coefficient (ICC) below 0.75 were retested after an additional training period in a second cohort of 30 symptom-free middle-aged women. MAIN OUTCOME MEASURES: Inter-rater reliability of all variables was measured with the ICC (95% confidence interval) and standard error of measurement (SEM). RESULTS: Acromion-table distance (ICC=0.91, SEM 0.22 to 0.28% of body length), pectoralis minor muscle length (ICC=0.91, SEM 0.16% of body length), pain pressure thresholds (ICC=0.78 to 0.85, SEM 0.39 to 0.70kg) and abduction ROM (ICC=0.77, SEM 5°) showed good to excellent inter-rater reliability in the first cohort. After an additional training period, forward flexion ROM showed good inter-rater reliability (ICC=0.83, SEM 5°), scapular upward rotation in resting position showed moderate reliability (ICC=0.52, SEM 2°), and other scaption angles showed weak reliability (ICC=0.26 to 0.43, SEM 3 to 8°). CONCLUSIONS: In a battery of clinical tools to evaluate factors contributing to shoulder pain, static scapular positioning and pressure pain thresholds were found to have good to excellent inter-rater reliability in middle-aged women. Additional training is recommended for measurements with a gravity inclinometer.

Plasma gelatinase levels in patients with primary breast cancer in relation to axillary lymph node status, Her2/neu expression and other clinicopathological variables.

Matrix metalloproteinases (MMPs), in particular the gelatinases MMP2 and MMP9, are important mediators of tumour invasion and metastasis. We examined whether plasma gelatinase levels could predict lymph node metastasis in breast cancer patients. Further, we investigated the relationship of plasma gelatinase levels with Her2/neu expression, recently acknowledged as an important prognostic factor for recurrence, and with various clinicopathological factors. Preoperative plasma samples from 81 breast cancer patients were collected. Total and active gelatinase levels were measured by enzyme immunoassays and activity assays, respectively. Neither total nor active plasma MMP2 levels correlated with nodal status or with any of the classical clinicopathological factors including histological tumour type, tumour size and grade and hormone receptor status. Patients with Her2/neu overexpressing tumours showed an increase of 27% (P=0.007) in plasma MMP2 activity, but not in total MMP2, compared with patients without overexpression. MMP9 levels, total and active, did not correlate with any of the investigated variables. In contrast to MMP9, total MMP2 levels correlated significantly with active MMP2 levels. In summary, total and active plasma gelatinase levels failed to identify high risk for axillary lymph node metastasis. Active plasma MMP2 was significantly increased in patients with Her2/neu overexpressing tumours, suggesting a role for Her2/neu in the signalling pathways of MMP2 activation in carcinogenesis. However, this increase was too small to be of clinical use. Furthermore, no relationship was found between plasma gelatinase levels, total or active, and any of the clinicopathological prognostic factors.

Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer.

AIMS: To investigate the association between tumour characteristics and HER-2/neu by immunohistochemistry in primary operable breast cancer. METHODS: The association between HER-2/neu and other clinicopathological factors was evaluated in 1362 consecutive patients with primary breast cancer treated between 2000 and July 2003 in one centre. Microscopic tumour size, tumour grade, lymph node status, patient's age, oestrogen receptor (ER), progesterone receptor (PR), and joint ER/PR status were evaluated, using the chi2 test for univariate analysis and logistic regression for multivariate analysis. The hormone receptors and HER-2/neu were studied immunohistochemically. Using the HER-2/neu DAKO scoring system, scores of 0, 1+, or 2+ were defined as negative and 3+ as positive. Data for DAKO scores 2+/3+ versus 0/1+ are also presented. RESULTS: Hormone receptor negative breast cancers were more often HER-2/neu positive than hormone receptor positive cancers, both for ER (28.7% v 6.8%) and PR (19.9% v 5.9%). In multivariate analysis, both ER, PR, and tumour grade were independently associated with HER-2/neu. In ER+ tumours, HER-2/neu overexpression was significantly lower in PR+ than in PR- cases (11.5% v 5.4%). HER-2/neu overexpression (2.7%) was lowest in the large subgroup of ER+PR+ tumours with low tumour grade (grade 1-2), comprising 46.1% of all patients. CONCLUSIONS: ER, PR, and tumour grade are independent predictors for HER-2/neu overexpression in women with primary operable breast cancer. ER and PR are negatively associated with HER-2/neu, whereas tumour grade is positively associated with HER-2/neu. In women with ER+ tumours, PR status also affects the likelihood of HER-2/neu expression.

Comparison of the surgical procedures for breast conserving treatment of early breast cancer in seven EORTC centres.

The aim of this study was to develop a standardised surgical report for breast-conserving procedures, supporting the systematic documentation of the different aspects of the surgery. The surgical procedure for tumourectomy and axillary clearance was translated into a series of steps that could be quantitatively documented. This description was submitted twice to a group of surgeons from different departments to ensure that all steps that are considered to have relevance for outcome were included and that no superfluous data were collected. After two corrective phases, a first test format was developed. Between February 1993 and May 1994, seven surgical departments, participating in EORTC trials, completed this questionnaire for a number of their patients. The data collected related to general information on the department, the tumour excision itself, the axillary dissection and, in a later phase, on pathology. 269 questionnaires (264 tumour excisions, 259 axillary dissections and 189 pathology reports) were collected and analysed. Even though the participating departments were involved in a single trial on breast-conserving surgery and had previously developed regular contacts about the practical aspects of treatment, many differences were detected. In general, variations were found in the waiting time between treatment prescription and execution, experience of the surgeon, duration of the procedure, and the use of prophylactic antibiotics. Also, in the practical execution of the procedure, major variations in the type of incision, width of tumour excision, closure of the breast tissue and skin, the use of frozen sections and the extent of the axillary dissection were found. The most relevant differences and their possible consequences are discussed. It has been proven possible and feasible to document quantitatively a surgical procedure. The fact that within a group of surgeons participating in the same clinical trials, many differences in the surgical techniques are observed, stresses the need to reach a consensus on a stricter set of guidelines for breast-conserving procedures and their documentation, especially when conducting clinical trials.