Deep learning based MLC aperture and monitor unit prediction as a warm start for breast VMAT optimisation.

Objective. Automated treatment planning today is focussed on non-exact, two-step procedures. Firstly, dose-volume histograms (DVHs) or 3D dose distributions are predicted from the patient anatomy. Secondly, these are converted in multi-leaf collimator (MLC) apertures and monitor units (MUs) using a generic optimisation to obtain the final treatment plan. In contrast, we present a method to predict volumetric modulated arc therapy (VMAT) MLC apertures and MUs directly from patient anatomy using deep learning. The predicted plan is then provided as initialisation to the optimiser for fine-tuning.Approach. 148 patients (training: 101; validation: 23; test: 24), treated for right breast cancer, are replanned to obtain a homogeneous database of 3-arc VMAT plans (PTVBreast: 45.57 Gy; PTVBoost: 55.86 Gy) according to the clinical protocol, using RapidPlanTMwith automatic optimisation and extended convergence mode (clinical workflow). Projections of the CT and contours are created along the beam's eye view of all control points and given as input to a U-net type convolutional neural networks (CNN). The output are the MLC aperture and MU for all control points, from which a DICOM RTplan is built. This is imported and further optimised in the treatment planning system using automatic optimisation without convergence mode, with clinical PTV objectives and organs-at-risk (OAR) objectives based on the DVHs calculated from the imported plan (CNN workflow).Main results. Mean dose differences between the clinical and CNN workflow over the test set are 0.2 ± 0.5 Gy atD95%and 0.6 ± 0.4 Gy atD0.035ccof PTVBreastand -0.4 ± 0.3 Gy atD95%and 0.7 ± 0.3 Gy atD0.035ccof PTVBoost. For the OAR, they are -0.2 ± 0.2 Gy forDmean,heartand 0.04 ± 0.8 Gy forDmean,ipsilateral lung. The mean computation time is 60 and 25 min respectively.Significance. VMAT optimisation can be initialised by MLC apertures and MUs, directly predicted from patient anatomy using a CNN, reducing planning time with more than half while maintaining clinically acceptable plans. This procedure puts the planner in a supervising role over an AI-based treatment planning workflow.

Clinical evaluation of a deep learning model for segmentation of target volumes in breast cancer radiotherapy.

PURPOSE/OBJECTIVE(S): Precise segmentation of clinical target volumes (CTV) in breast cancer is indispensable for state-of-the art radiotherapy. Despite international guidelines, significant intra- and interobserver variability exists, negatively impacting treatment outcomes. The aim of this study is to evaluate the performance and efficiency of segmentation of CTVs in planning CT images of breast cancer patients using a 3D convolutional neural network (CNN) compared to the manual process. MATERIALS/METHODS: An expert radiation oncologist (RO) segmented all CTVs separately according to international guidelines in 150 breast cancer patients. This data was used to create, train and validate a 3D CNN. The network's performance was additionally evaluated in a test set of 20 patients. Primary endpoints are quantitative and qualitative analysis of the segmentation data generated by the CNN for each level specifically as well as for the total PTV to be irradiated. The secondary endpoint is the evaluation of time efficiency. RESULTS: In the test set, segmentation performance was best for the contralateral breast and the breast CTV and worst for Rotter's space and the internal mammary nodal (IMN) level. Analysis of impact on PTV resulted in non-significant over-segmentation of the primary PTV and significant under-segmentation of the nodal PTV, resulting in slight variations of overlap with OARs. Guideline consistency improved from 77.14% to 90.71% in favor of CNN segmentation while saving on average 24 minutes per patient with a median time of 35 minutes for pure manual segmentation. CONCLUSION: 3D CNN based delineation for breast cancer radiotherapy is feasible and performant, as scored by quantitative and qualitative metrics.

Detection of secondary metastatic breast cancer by measurement of plasma CA 15.3.

BACKGROUND: Most current guidelines do not recommend the serial analysis of tumour marker CA 15.3 in the follow-up of asymptomatic patients treated for early breast cancer (EBC). These guidelines are based on small-scale studies carried out in an era with more limited treatment options than today. In our large academic centre, serial measurements of CA 15.3 are used routinely in the follow-up of EBC, whereas imaging for distant metastases is only carried out on indication. PATIENTS AND METHODS: In this retrospective single-centre study, patients were included if they were treated for EBC between 1 January 2000 and 1 January 2018, diagnosed with secondary metastatic disease at least 6 months after initial surgery and had CA 15.3 available at the time of diagnosis of metastases. The primary objective was to evaluate the proportion of patients in whom metastatic disease was discovered by an increasing CA 15.3. Information on the method of metastases detection, CA 15.3 evolution and survival was collected after approval of the ethics committee. RESULTS: At the moment of diagnosis of metastases, 451 of 730 included patients (62%) had CA 15.3 levels above the upper limit of normal (>30 kU/l). In 269 patients (37%), an increasing CA 15.3 was the first sign that led to the diagnosis of metastases. This was most frequent in luminal A-like tumours (48%) and in liver (45%) and bone (41%) localisation of metastases. By contrast, reported symptoms triggered the diagnosis of metastatic disease in 48% of the patients. Median overall survival was significantly longer when the relapse was discovered by CA 15.3 elevation versus those discovered by another trigger (abnormal clinical examination or history, abnormal laboratory tests or an incidental finding) (35 versus 22 months; P = 0.0027). CONCLUSION: When CA 15.3 is systematically used in the follow-up of EBC patients, the diagnosis of metastatic disease is made in 37% by a CA 15.3 increase.

Features of durable response and treatment efficacy for capecitabine monotherapy in advanced breast cancer: real-world evidence from a large single-centre cohort.

PURPOSE: In metastatic breast cancer (MBC) population treated with capecitabine monotherapy, we investigated clinical-pathological features as possible biomarkers for the oncological outcome. METHODS: Retrospective study of consecutive MBC patients treated at University Hospitals Leuven starting capecitabine between 1999 and 2017. The primary endpoint was the durable response (DR), defined as non-progressive disease for > 52 weeks. Other main endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). RESULTS: We included 506 patients; mean age at primary breast cancer diagnosis was 51.2 years; 18.2% had de novo MBC; 98.8% were pre-treated with taxanes and/or anthracycline. DR was reached in 11.6%. Patients with DR, as compared to those without DR, were more likely oestrogen receptor (ER) positive (91.5% vs. 76.8%, p = 0.010) at first diagnosis, had a lower incidence of lymph node (LN) involvement (35.6% vs. 49.9%, p = 0.039) before starting capecitabine, were more likely to present with metastases limited to ≤ 2 involved sites (54.2% vs. 38.5%, p = 0.020) and time from metastasis to start of capecitabine was longer (mean 3.5 vs. 2.7 years, p = 0.020). ORR was 22%. Median TTP and OS were 28 and 58 weeks, respectively. In multivariate analysis (only performed for TTP), ER positivity (hazard ratio (HR) = 0.529, p < 0.0001), HER2 negativity (HR = 0.582, p = 0.024), absence of LN (HR = 0.751, p = 0.008) and liver involvement (HR = 0.746, p = 0.013), older age at capecitabine start (HR = 0.925, p < 0.0001) and younger age at diagnosis of MBC (HR = 0.935, p = 0.001) were significant features of longer TTP. CONCLUSION: Our data display relevant clinical-pathological features associated with DR and TTP in patients receiving capecitabine monotherapy for MBC.

PROMs following breast-conserving therapy for breast cancer: results from a prospective longitudinal monocentric study.

BACKGROUND: Treatment of breast cancer includes many options and shared decision making is becoming standard practice. Within the context of treatment individualization, the omission of radiotherapy (RT) can be considered. It is thereby of great importance to correctly foresee the side effects attributed to RT. Data from longitudinal studies with contemporary techniques however are sparse. The purpose of the present study was to evaluate patient-reported outcome measures (PROMs) and long-term aesthetic outcome (AO) related to RT in the breast-conserving therapy (BCT) setting for breast cancer over time. METHODS: Patients treated with BCT between April 2015 and April 2016 were prospectively included in the cohort. Evaluations were made at six time points: at baseline (before RT), during and at the end of RT, between 3 and 6 months, 1 year and 2 years after RT. AO was scored by the patient and by the BCCT.core software. Further PROMs were measured with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30/-BR23 and the Body Image after Breast Cancer Questionnaire BIBCQ. Patients were evaluated over 2 years. First, we assessed the evolution in time. Second, we tested the differences in mean scale scores of the PROMs between patients with a favourable and an unfavourable AO. RESULTS: One hundred seventy-five patients were included in the analysis. At baseline, unsatisfactory levels were already present for several scales. Most unsatisfactory PROMs improved up to 1 year after RT. Complaints of fatigue increased at the start but decreased up to a lower level than that at baseline up to 1 year after RT (mean difference (MD) 7.6, - 12.3, respectively). Cognitive functioning showed a small decrease at the start with no further significant decrease (MD - 4.73, - 0.21, respectively). Breast symptoms significantly increased during RT but decreased afterwards up to 2 years after RT to lower values than those at baseline and were then considered satisfactory (MD 15.6, - 19.7, - 4.1, respectively). AO scored as PROM associated with BCCT.core and with the body image measures. CONCLUSIONS: The study suggests that quality of life and body image are temporarily impaired due to RT. Around one third of patients score their long-term AO as unfavourable. These results should be discussed with the patient and could help in the decision making of the treatment plan and in the clarification of the patient's expectations.

Comparison of brachytherapy and external beam radiotherapy boost in breast-conserving therapy: Patient-reported outcome measures and aesthetic outcome.

OBJECTIVE: This study aimed to estimate the probability of an unfavourable aesthetic outcome (AO) 2 years after breast-conserving therapy (BCT) and evaluate the possible influence of brachytherapy (BT) and external beam radiotherapy (EBRT) boost on patient-reported outcomes (PROs) and AO. PATIENTS AND METHODS: Patients treated with BCT starting April 2015 were prospectively included. Selection of the boost technique followed an in-house flowchart based on the depth of the tumour bed. An electron boost was performed for a superficial clinical target volume (maximum 28 mm under the epidermis), a BT boost was proposed in all other cases. Patients were followed-up for 2 years. AO was scored by the BCCT.core software and the patient. Further PROs were measured with the EORTC QLQ-C30, QOL-BR23 and the BIBCQ questionnaires. RESULTS: The analysis included 175 patients, 80 received a BT boost and 95 an EBRT boost. BT patients were significantly older; had a higher breast cup and band size, body mass index and surgical specimen weight of the wide excision; more seroma at baseline and less positive surgical section margins than patients in the EBRT group, and more patients drank alcohol. Cancer- and breast cancer-specific quality of life (QOL) and body image did not differ between the boost techniques over time. Although mean scores for breast symptoms and sexual enjoyment did differ significantly over time (p = 0.05 and < 0.01, respectively), the effect was due to differences before boost administration. Measured with BCCT.core, AO was unfavourable in 28% of patients 2 years after treatment (31% scored by the patient) and results were similar in the BT and EBRT groups. CONCLUSION: Using the presented flowchart (See Verhoeven et al. [16]), AO and PROs on QOL or body image up to 2 years after BCT are not influenced by the boost technique.

Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study.

PURPOSE: Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients. METHODS: We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution's ethical research committee. RESULTS: A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2). CONCLUSIONS: The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

Body mass index, age at breast cancer diagnosis, and breast cancer subtype: a cross-sectional study.

PURPOSE: Evidence suggests that premenopausal obesity decreases and postmenopausal obesity increases breast cancer risk. Because it is not well known whether this is subtype dependent, we studied the association between body mass index (BMI) and age at breast cancer diagnosis, or the probability of being diagnosed with a specific breast cancer phenotype, by menopausal status. METHODS: All patients with non-metastatic operable breast cancer from the University Hospital Leuven diagnosed between January 1, 2000 and December 31, 2013 were included (n = 7020) in this cross-sectional study. Linear models and logistic regression were used for statistical analysis. Allowing correction for age-related BMI-increase, we used the age-adjusted BMI score which equals the difference between a patient's BMI score and the population-average BMI score corresponding to the patient's age category. RESULTS: The quadratic relationship between the age-adjusted BMI and age at breast cancer diagnosis (p = 0.0207) interacted with menopausal status (p < 0.0001); increased age at breast cancer diagnosis was observed with above-average BMI scores in postmenopausal women, and with below-average BMI scores in premenopausal women. BMI was linearly related to the probabilities of Luminal B and HER2-like breast cancer phenotypes, but only in postmenopausal women. The relative changes in probabilities between both these subtypes mirrored each other. CONCLUSION: BMI associates differently before and after menopause with age at breast cancer diagnosis and with the probability that breast cancer belongs to a certain phenotype. The opposite effect of increasing BMI on relative frequencies of Luminal B and HER2-like breast cancers suggests a common origin.

Omitting radiation therapy in women with triple-negative breast cancer leads to worse breast cancer-specific survival.

PURPOSE: To examine locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) after breast-conserving therapy (BCT) or mastectomy (ME) with or without radiation therapy (RT) in triple-negative breast cancer (TNBC). MATERIAL & METHODS: We identified non-metastatic TNBC cases from a single institution database. BCT, ME with RT (ME + RT) and ME only were compared with respect to LRR and BCSS. Cox regression models were used to analyze the association between prognostic factors and outcome. RESULTS: 439 patients fulfilled the inclusion criteria. Median follow-up was 10.2 years (interquartile range 7.9; 12.4 years). Patients in the BCT (n = 239), ME + RT (n = 116) and ME only (n = 84) group differed with respect to age, pT, pN, lymphovascular invasion, lymph node dissection and chemotherapy administration. Ten-year LRR rates were seven percent, three percent and eight percent for the BCT, ME + RT and ME only group, respectively. pN was associated with LRR. In multivariable analysis LRR were significantly lower in the ME + RT group compared to the BCT and the ME only group (p 0.037 and 0.020, respectively). Ten year BCSS was 87%, 84% and 75% for the BCT, ME + RT and ME only group, respectively. pT, pN, lymph node dissection, lymphovascular invasion and the administration of chemotherapy were associated with BCSS. In multivariable analysis BCSS was significantly lower in the ME only group compared to the BCT group and the ME + RT group (p 0.047 and 0.003, respectively). CONCLUSION: TNBC patients treated with ME without adjuvant RT showed significant lower BCSS compared to patients treated with BCT or ME + RT and significant more LRR compared to ME + RT when corrected for known clinicopathological prognostic factors.

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.

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.

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.

Age interacts with the expression of steroid and HER-2 receptors in operable invasive breast cancer.

BACKGROUND: The negative association between the oestrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER-2) in breast cancer travels in both directions. ER+ tumours are less likely HER-2+ and HER-2+ tumours are less likely ER+. METHODS: We studied the age-related immunohistochemical (IHC) expression of ER, progesterone receptor (PR) and HER-2 in 2,227 tumours using age as a continuous variable. Steroid receptors were considered positive for any nuclear staining of invasive cancer cells and for HER-2, either for strong expression by IHC (score 3+) or gene amplification by fluorescence in situ hybridisation (FISH). Based on nonparametric regression, the age-related association between steroid receptors and HER-2 was presented as likelihood curves. RESULTS: The association between ER or PR and HER-2 is age-related. The age-related expression of ER and PR is HER-2 dependent. In HER-2(-) cases, the odds ratio (OR) for being ER+ was 2.594 (95% CI = 1.874-3.591) up to age 50 and age-independent thereafter; for PR-expression the OR was 2.687 (95% CI = 1.780-4.057) up to age 45 and 0.847 (95% CI = 0.761-0.942) thereafter. In HER-2+ cases, the OR was 0.806 (95% CI = 0.656-0.991) to be ER+ and 0.722 (95% CI = 0.589-0.886) to be PR+. The age-related OR for breast cancers to be HER-2+ is steroid receptor dependent. Taking together, ER+PR+HER-2+ breast cancers appear on average 5.4 years earlier than breast cancers of any other ER/PR/HER-2 phenotype (95% CI = 3.3-7.5; P < 0.0001). CONCLUSION: There is a qualitative interaction between age and expression of steroid and HER-2 receptors. Our findings suggest a strong age-related selective growth advantage for breast tumour cells belonging to the ER+PR+HER-2+ subgroup.

Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients.

BACKGROUND: Tamoxifen may induce uterine abnormalities of clinical concern. Our aim was to compare early uterine changes occurring in postmenopausal breast cancer patients treated in first-line with tamoxifen or third generation aromatase inhibitors. We also assessed the effect of aromatase inhibitors on tamoxifen-induced uterine changes. PATIENTS AND METHODS: Seventy-seven consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. Transvaginal ultrasonography (TVUS) was carried out before and after 3 months of therapy. No interventions were done on pre-existing asymptomatic uterine abnormalities seen on baseline sonography. RESULTS: After 3 months of therapy, tamoxifen significantly increased endometrial thickness and uterine volume. Additionally, tamoxifen induced endometrial cysts and polyps, and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathologies seen under tamoxifen. Furthermore, aromatase inhibitors decreased endometrial thickness and uterine volume in patients previously treated with tamoxifen. CONCLUSIONS: Our study demonstrates that tamoxifen induces uterine abnormalities from as early as 3 months of therapy. In contrast, these abnormalities are not seen in patients on aromatase inhibitors. Furthermore, our data indicate that tamoxifen therapy followed by an aromatase inhibitor may lead to a reduction in endometrial pathologies associated with tamoxifen.

Interobserver variations in gross tumor volume delineation of brain tumors on computed tomography and impact of magnetic resonance imaging.

PURPOSE: (1) To assess the interobserver variability of brain tumor delineation on computed tomography (CT). (2) To assess the impact of the addition of magnetic resonance imaging (MRI) information. METHODS: Nine physicians were asked to delineate the gross tumor volume (GTV) of five patients with supratentorial inoperable brain tumors on CT scans and 2 weeks (or more) later on MRIs. The delineations were performed on a computer screen. During delineation on MRI, the registered CT images (without delineation) were displayed on the screen (MRI+CT). RESULTS: A high interobserver variability in GTV delineation on CT is found: the ratio of the largest to the smallest defined volumes varies for the five patients by factors of resp. 2.8, 1.8, 1.8, 1.9 and 1.7. The interobserver variability is as large on MRI+CT as on CT alone (ratio largest/smallest volume: 2.4, 1.7, 1.9, 2.7 and 1.5). Volumes delineated on MRI+CT (mean: 69.6 cm(3)) are larger than on CT alone (mean: 59.5 cm(3)). Residual volumes (volume delineated on one image modality but not on the other) are >0 for CT alone and for MRI+CT. CONCLUSIONS: A large interobserver variability in GTV delineation of brain tumors is demonstrated. The addition of MRI to CT does not reduce interobserver variability. GTVs delineated on MRI+CT are larger than on CT alone, but some volumes are delineated on CT and not on MRI. Therefore, a combination of the two image modalities is recommended for brain tumor delineation for treatment planning.