Expression of hypoxia-induced proteins in ductal carcinoma in situ and invasive cancer of the male breast

AIMS: The aim of this study was to determine the role of hypoxia in male breast carcinogenesis by evaluating the expression of the hypoxia-related proteins, hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase IX (CAIX) and glucose transporter-1 (Glut-1), in ductal carcinoma in situ (DCIS) of the male breast in relation to invasive cancer (IC). METHODS: Tumour tissue blocks of 18 cases of pure DCIS, 58 DCIS cases adjacent to IC (DCIS-AIC) and the 58 IC cases were stained by immunohistochemistry for HIF-1α, CAIX and Glut-1, and expression frequencies and patterns (diffuse and/or perinecrotic) were noted. RESULTS: HIF-1α overexpression was observed in 61.1% (11/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 36.2% (21/58) of IC cases (not significant (n.s.)). CAIX overexpression was observed in 16.7% (3/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 24.1% (14/58) of IC cases (n.s.). Glut-1 overexpression was observed in 61.1% (11/18) of pure DCIS, in 75.9% (44/58) of DCIS-AIC and in 62.1% (36/58) of IC cases (n.s.). Expression of hypoxia-related proteins was seen around necrosis in a little over one-third of DCIS cases, and often coincided with expression in adjacent IC when present. All these observations indicate that the hypoxia response is already at its maximum in the preinvasive DCIS stage. CONCLUSIONS: In conclusion, male DCIS frequently shows activated hypoxia response, comparable to male IC. This indicates that the activated hypoxia response previously seen in male IC is not a late bystander but likely a genuine carcinogenetic event

[Targeted therapy:the benefit of new oncological tests].

Voor vele kankervormen komen doelgerichte behandelingen beschikbaar, waarvoor op grond van tumoreigenschappen ook rationele keuzes gemaakt kunnen worden.Er is grote behoefte aan adequate biomarkers die het effect van doelgerichte therapie bij individuele kankerpatiënten kunnen voorspellen, om daarmee de juiste oncologische behandeling voor de juiste patiënt te kunnen bepalen. Zo kunnen nutteloze behandelingen en onnodige bijwerkingen vermeden worden, en kosten worden gereduceerd.Bij borstkanker zijn de oestrogeenreceptor (ER) en de humane epidermale groeifactorreceptor 2 (HER2) voorbeelden van gestandaardiseerde, in gerandomiseerde onderzoeken gevalideerde, predictieve testen van behandeleffecten.Voor genexpressieprofielen die samenhangen met tumorgroei worden ook gerandomiseerde onderzoeksdata verwacht.Het kwantificeren van de predictieve waarde van testen op verwachte behandeleffecten in gerandomiseerde studies is kostbaar en tijdrovend. Gezien de toename van doelgerichte medicijnen en diagnostische en prognostische technieken, wordt in allerlei domeinen gezocht naar alternatieve onderzoeksopzetten die kunnen leiden tot snellere en efficiëntere bewijsvoering.An increasing number of targeted drug treatments are becoming available for many types of cancer. There is a great need for adequate biomarkers that can predict the effect of targeted therapy in individual cancer patients, in order to determine the correct oncological treatment per patient. This way, non-effective treatments can be spared, side-effects avoided, and costs reduced. Oestrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2) are examples of standardized tests for breast cancer that have been validated in randomised studies. Data from randomised studies is also expected for gene expression profiles that correlate with tumour growth. Quantifying the predictive value of tests for anticipated treatment effects is costly and time-consuming. Given the increasing availability of targeted agents and diagnostic and prognostic techniques, alternative clinical study designs that can lead to quicker and more efficient verification are being sought in many different domains.</p

Nuclear medicine imaging of multiple myeloma, particularly in the relapsed setting

Multiple myeloma (MM) is characterized by a monoclonal plasma cell population in the bone marrow. Lytic lesions occur in up to 90 % of patients. For many years, whole-body X-ray (WBX) was the method of choice for detecting skeleton abnormalities. However, the value of WBX in relapsing disease is limited because lesions persist post-treatment, which restricts the capacity to distinguish between old, inactive skeletal lesions and new, active ones. Therefore, alternative techniques are necessary to visualize disease activity. Modern imaging techniques such as magnetic resonance imaging, positron emission tomography and computed tomography offer superior detection of myeloma bone disease and extramedullary manifestations. In particular, the properties of nuclear imaging enable the identification of disease activity by directly targeting the specific cellular properties of malignant plasma cells. In this review, an overview is provided of the effectiveness of radiopharmaceuticals that target metabolism, surface receptors and angiogenesis. The available literature data for commonly used nuclear imaging tracers, the promising first results of new tracers, and our pilot work indicate that a number of these radiopharmaceutical applications can be used effectively for staging and response monitoring of relapsing MM patients. Moreover, some tracers can potentially be used for radio immunotherapy

Treatment of older breast cancer patients:de-escalation in oncology

De prognose van borstkankerpatiënten is in de afgelopen decennia sterk verbeterd. Innovaties in beeldvormende technieken en pathologisch onderzoek, geoptimaliseerde chirurgische en radiotherapeutische technieken hebben daaraan bijgedragen. Een groot deel van de verbetering komt door de uitbreiding van het scala aan effectieve systemische middelen en de gestage uitbreiding van de indicatie hiervoor. Verruiming van de richtlijnen met betrekking tot aanvullende behandelingen maakt echter dat de absolute winst steeds kleiner wordt. De balans tussen effectiviteit en bijwerkingen kan hierdoor in het gedrang komen. Dat is een stimulans om te zoeken naar mogelijkheden om bepaalde aanvullende behandelingen achterwege te laten, ter preventie van de potentiële schade van die behandelingen, zonder het individuele risico op terugkeer van ziekte onnodig te vergroten. Een patiëntengroep bij wie dit momenteel onderzocht wordt in Nederland zijn oudere vrouwen met borstkanker.The prognosis of breast cancer patients has greatly improved in recent decades. Innovations in imaging techniques, pathological assessment, optimized surgical and radiotherapy techniques have contributed to this. Much of the improvement is due to the increase of the range of effective systemic treatment and the continual expansion of the indication for this purpose. However, broadening the guidelines for adjuvant systemic treatments, results in a smaller absolute gain. The balance between effectiveness and side-effects could therefore be compromised, which is an incentive to search for possibilities for de-escalation to prevent potential damage, without unnecessarily increasing the risk of recurrence. Currently, in The Netherlands this is being investigated in older breast cancer patients.</p

Positron emission tomography of tumour [18F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Purpose Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Upregulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16 alpha-[F-18] fluoro-17 beta-oestradiol (F-18-FES) as potential marker to select breast cancer patients for oestradiol therapy. Methods Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after >= 2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent F-18-FES-PET/CT imaging at baseline. Tumour F-18-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUVmax). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression >= 24 weeks. Results F-18-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value PPV/NPV) of F-18-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUVmax >1.5. Conclusion F-18-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy

Assessing the role of tumour-associated macrophage subsets in breast cancer subtypes using digital image analysis

Purpose: The number of M1-like and M2-like tumour-associated macrophages (TAMs) and their ratio can play a role in breast cancer development and progression. Early clinical trials using macrophage targeting compounds are currently ongoing. However, the most optimal detection method of M1-like and M2-like macrophage subsets and their clinical relevance in breast cancer is still unclear. We aimed to optimize the assessment of TAM subsets in different breast cancer subtypes, and therefore related TAM subset numbers and ratio to clinicopathological characteristics and clinical outcome. Methods: Tissue microarrays of 347 consecutive primary Luminal-A, Luminal-B, HER2-positive and triple-negative tumours of patients with early-stage breast cancer were serially sectioned and immunohistochemically stained for the pan-macrophage marker CD68 and the M2-like macrophage markers CD163, CSF-1R and CD206. TAM numbers were quantified using a digital image analysis algorithm. M1-like macrophage numbers were calculated by subtracting M2-like TAM numbers from the total TAM number. Results: M2-like markers CD163 and CSF-1R showed a moderate positive association with each other and with CD68 (r ≥ 0.47), but only weakly with CD206 (r ≤ 0.06). CD68 + , CD163 + and CSF-1R + macrophages correlated with tumour grade in Luminal-B tumours (P < 0.001). Total or subset TAM numbers did not correlate with disease outcome in any breast cancer subtype. Conclusion: In conclusion, macrophages and their subsets can be detected by means of a panel of TAM markers and are related to unfavourable clinicopathological characteristics in Luminal-B breast cancer. However, their impact on outcome remains unclear. Preferably, this should be determined in prospective series