1063 Background: Rash develops in approximately 50% of breast cancer patients receiving alpelisib, often requiring dose modifications. Herein, we describe the characteristics of alpelisib-related dermatologic adverse events (dAEs). Methods: A single center retrospective analysis was conducted via review of electronic medical records. We collected clinical, laboratory and management data relevant to patients treated with alpelisib for advanced breast cancer under four different randomized clinical trials or post approval by regulatory agencies from 6/1/2013 to 7/31/2019. Type and severity of dAEs was recorded using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Results: A total of 102 patients (mean age 56 years, range 27-83) receiving alpelisib from 200 to 350 mg daily, most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash [CTCAE grade 1/2 = 22 (21.6%); CTCAE grade 3 = 19, (18.6%)] distributed primarily along the trunk (18, 78%) and developing, on average, within 12.8 +/- 1.5 days of treatment initiation (n = 38). Mean duration of rash was 7.1 +/- 3.8 days; and no grade 4 dAEs were observed. Of 29 patients with documented morphology of alpelisib-related dAEs, the majority (26, 89.7%) had maculopapular rash. Thirteen (68%) of 19 patients with any-grade rash and report of any associated symptoms had pruritus (7, 36%) or burning pain (6, 32%). All-grade dAEs correlated with an increase in serum eosinophils from 2.7% to 4.4% (p < 0.05), and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash onset (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs had interruption of alpelisib, followed by management with antihistamines, topical and/or systemic corticosteroids. We did not observe rash recurrence in 12 (75%) of these 16 patients who re-initiated therapy; and the majority (9, 56.3%) were re-challenged without a dose reduction. Conclusions: Pruritus and increased blood eosinophils occur with maculopapular rash within the first two weeks of initiating alpelisib and persists for approximately seven days. To reduce onset of grade 1/2 rash, non-sedating antihistamines (i.e. cetirizine) are recommended during the first eight weeks. While grade 3 rash leads to interruption of alpelisib, dermatologic improvement is evident with systemic corticosteroids; and most patients can resume therapy at a maintained or reduced dose upon re-challenge.

Rash develops in approximately 50% of patients receiving alpelisib for breast cancer, often requiring dose modifications. Here, we describe the clinicopathologic, laboratory, and management characteristics of alpelisib-related dermatologic adverse events (dAEs). A single center-retrospective analysis was conducted. Data were abstracted from electronic medical records. A total of 102 patients (mean age 56 years, range 27–83) receiving alpelisib most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash distributed primarily along the trunk (78%) and extremities (70%) that developed approximately within two weeks of treatment initiation (mean 12.8 ± 1.5 days) and lasted one-week (mean duration 7.1 ± 0.8 days). Of 29 patients with documented morphology of alpelisib-related dAEs, 26 (89.7%) had maculopapular rash. Histology showed perivascular and interface lymphocytic dermatitis. All-grade rash correlated with an increase in serum eosinophils from 2.7 to 4.4%, p < 0.05, and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs resulted in interruption of alpelisib, which were managed with antihistamines, topical and systemic corticosteroids. We did not observe rash recurrence in 12 (75%) patients who were re-challenged. A maculopapular rash associated with increased blood eosinophils occurs frequently with alpelisib. While grade 3 rash leads to alpelisib therapy interruption, dermatologic improvement is evident with systemic corticosteroids; and most patients can continue oncologic treatment at a maintained or reduced dose upon re-challenge with alpelisib.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Until recently the backbone of therapy against TNBC has been cytotoxic chemotherapy. However, the breast oncology community is now seeing encouraging clinical activity from molecularly targeted approaches to TNBC. Recently, we have seen 3 newly approved targeted therapies for TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation associated breast cancer (gBRCAm-BC) and most recently the checkpoint inhibitor, atezolizumab in combination with nab-paclitaxel for programmed death-ligand 1 (PD-L1+) advanced TNBC. Improved biomarkers are needed to inform better patient selection for treatment with checkpoint inhibition. Higher response rates are seen when checkpoint inhibitors are combined with chemotherapy in the first-line setting and the use of these agents at an earlier stage of the disease does show promise. Antibody-drug conjugates are generating much excitement and may allow re-examination of prior cytotoxics that failed in development due to toxicity. Tumor sequencing is identifying potential molecular targets and ongoing studies are evaluating novel small molecule agents in this field such as AKT inhibition and many others. The treatment paradigm of chemotherapy as “one size fits all” approach for management of TNBC is changing based on molecular subtyping. Soon, the term TNBC may no longer be appropriate, as this heterogenous subtype of breast cancer is further refined by its molecular characteristics and clinical response to a targeted therapeutic approach.

Opinion statement Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Until recently the backbone of therapy against TNBC has been cytotoxic chemotherapy. However, the breast oncology community is now seeing encouraging clinical activity from molecularly targeted approaches to TNBC. Recently, we have seen 3 newly approved targeted therapies for TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation associated breast cancer (gBRCAm-BC) and most recently the checkpoint inhibitor, atezolizumab in combination with nab-paclitaxel for programmed death-ligand 1 (PD-L1+) advanced TNBC. Improved biomarkers are needed to inform better patient selection for treatment with checkpoint inhibition. Higher response rates are seen when checkpoint inhibitors are combined with chemotherapy in the first-line setting and the use of these agents at an earlier stage of the disease does show promise. Antibody-drug conjugates are generating much excitement and may allow re-examination of prior cytotoxics that failed in development due to toxicity. Tumor sequencing is identifying potential molecular targets and ongoing studies are evaluating novel small molecule agents in this field such as AKT inhibition and many others. The treatment paradigm of chemotherapy as “one size fits all” approach for management of TNBC is changing based on molecular subtyping. Soon, the term TNBC may no longer be appropriate, as this heterogenous subtype of breast cancer is further refined by its molecular characteristics and clinical response to a targeted therapeutic approach.

The mortality from breast cancer has steadily decreased due in part to early detection and advances in therapy. The treatment options for breast cancer vary considerably depending on the histological subtype. There are a number of very effective targeted therapies available for estrogen receptor-positive disease and for human epidermal growth factor receptor 2-positive disease. However, triple-negative breast cancer is a particularly aggressive subtype. This subtype represents an unmet need for improved therapies. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Here we review the recent advances in the treatment of TNBC with emphasis on the many emerging novel targeted therapies.

The treatment landscape for many cancers has dramatically changed with the development of checkpoint inhibitors. This article will review the literature concerning the use of checkpoint inhibitors in breast cancer.

Role of PARP in DNA Damage Repair Cellular function is dependent on the maintenance of genomic integrity. Endogenous and exogenous insults may induce damage to DNA and result in the formation of single-strand DNA breaks (SSBs).1,2 PARP enzymes 1 and 2 are key to the repair of these SSBs. PARP1 binds to the SSBs, which activates its catalytic function and results in PARylation of PARP1. This in turn stimulates the recruitment of DNA repair effectors to the site of DNA damage. AutoPARylation of PARP1 releases PARP1 from the repaired DNA, and cell cycle replication recommences.3 If PARP activity is inhibited, the enzyme appears to be physically “trapped” on the DNA, physically obstructing the progress of replication and introducing significant replication stress. Replication fork stalling occurs with subsequent collapse and the formation of double-strand breaks (DSBs).4 Homologous recombination–directed repair is a highly accurate process for repairing DSBs. Both BRCA1 and BRCA2 are critical to the process of homologous recombination–directed DNA repair. If homologous recombination repair is impaired by the loss of BRCA1 or BRCA2 function, then

PARP enzymes are essential for DNA damage repair. Cancers with defective homologous recombination DNA repair, such has BRCA1- and BRCA2-mutated breast cancers, are targets for PARP inhibitors (PARPi) through the exploitation of synthetic lethality. A number of PARPi are currently undergoing clinical evaluation in breast cancer, with olaparib and talazoparib having demonstrated superior efficacy compared with standard chemotherapy in advanced germline BRCA-mutated cancer. This review describes the biological rationale for PARPi and presents the accumulating data on PARPi use in breast cancer.

531 Background: A subset of triple negative breast cancer (TNBC) is characterized by androgen receptor (AR) expression and dependence on AR signaling (Doane Oncogene 2006; Gucalp CCR 2013). Enzalutamide (ENZA), an AR-antagonist, has a clinical benefit rate of 33% in evaluable patients(pts) with metastatic AR+ TNBC (Traina et al, JCO 2018). This study tests the feasibility of 1 year (y) of adjuvant ENZA for the treatment (tx) of early stage, AR+ TNBC (NCT02750358). We now report safety data observed in our phase II trial. Methods: Eligible pts have centrally confirmed, Stage I-III, ER/PR < 1%, HER2(-) AR ≥1% BC and completed all planned tx (surgery, (neo)adjuvant chemotherapy and radiation) within 6 months of study start. Tx consists of ENZA 160mg orally daily for 1y with option for 2y at pt discretion. Toxicity assessment per NCI CTCAEv4 every 4 weeks for 12 weeks, then every 3 months. Primary endpoint: feasibility of 1y ENZA, measured as the tx discontinuation rate due to toxicity, withdrawal of consent or tolerability. 46 evaluable pts are required to discriminate between feasibility of 50% and 70%, with type I error 5% and 88% power. Secondary endpoints: feasibility rate at 1y in adherent pts, safety of extended duration ENZA and 3y DFS and OS. Exploratory endpoints: pt reported outcomes and biomarker development. Results: Between 5/2016-1/2018, 38 pts on tx, with complete accrual planned by 6/2018. Pt characteristics: median age 53y(32-80), Stage I/II 81%, III 19%, Grade 2 21%, Grade 3 79%. 35(92%) received chemo: Neo 49%, Adj 51%; Anthracycline/Taxane-based 29 (83%), Platinum 2 (6%), Other 6 (17%). 5(14%) received adjuvant capecitabine for lack of pCR. 79% received XRT. AR > 10% in 24 pts(63.2%) and AR ≤10% in 14(36.8%). Any grade (gr) AE possibly attributed to ENZA: fatigue (31.5%), hot flashes (21%), reduced white blood cells (7.9%), nausea (5.3%) and increased alkaline phosphatase (5.3%). The only ENZA-related gr ≥3 AE was fatigue (1pt, 3%). No seizures were observed. 3 pts had dose reduction due to AE. Conclusions: ENZA administered in the adjuvant setting is well tolerated following definitive locoregional tx and standard of care chemotherapy. No new safety signals were observed. Clinical trial information: NCT02750358.

Emerging evidence has identified the androgen receptor (AR) pathway as a potential driver for breast cancer (BC) carcinogenesis. The prevalence of AR expression differs across breast cancer subtypes, and its prognostic role in BC is not clear. Triple-negative breast cancer (TNBC) is a heterogeneously diverse disease, which includes a subset that may be androgen driven. This review will discuss the role of AR across the differing subtypes of BC and summarize the most recent clinical trial data for the use of androgen-directed therapy in the treatment of AR+ breast cancer, with a particular emphasis on TNBC.

The poor prognosis for patients with esophagogastric cancers (EGC) requires the development of newer more effective therapies to further improve the treatment outcomes for this disease. Immunotherapy is a novel treatment strategy that is dramatically changing the treatment landscape for several types of cancers. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death the programmed death (PD)-1/PD-ligand are essential immune checkpoint inhibitors that suppress T cell activation. Targeting of these immune checkpoints with monoclonal antibodies has shown clinical efficacy in several solid tumors which has led to their approval and use in routine clinical practice. In EGC early phase evaluation of immune checkpoint inhibitors has yielded encouraging results with multiple phase 3 studies currently ongoing. In this review, the biological rationale for the use of immune checkpoint inhibitors in cancer will briefly be described and the accumulating data concerning their use in EGC will be presented.

The poor prognosis for patients with esophagogastric cancers (EGC) has resulted in an increased focus on the use of targeted agents in this disease. Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), MET, poly (ADP-ribose) polymerase (PARP) and claudin 18.2 (CLDN18.2). Trastuzumab, an anti-Her2 antibody, was approved by the U.S. FDA in 2010 as first-line therapy in combination with chemotherapy for Her2-positive disease. Since then, strategies targeting Her2 that have been successful in Her2-positive breast cancer, have failed in EGC. The one remaining study, the phase III Jacob study with pertuzumab, has yet to be presented. The anti-VEGF receptor 2 antibody, ramucirumab has been investigated as second-line therapy in 2 phase III trials, which resulted in improved survival, with subsequent FDA approval of ramucirumab in the second-line setting. Therapies targeting EGFR have been evaluated in a number of phase III studies, all of which have been negative. Phase III investigation of an mTOR inhibitor did not improve survival, although biomarker studies are awaited which may identify subgroups of patients that may benefit from its use. The results of the trials targeting MET in EGC have been disappointing, raising doubts about the usefulness of further testing agents that inhibit the MET pathway. PARP inhibition with olaparib, warrants further investigation, possibly in combination with other targeted therapies or immune checkpoint inhibition and in a biomarker-selected population. The identification of CLDN18.2 and its targeting with claudiximab is very promising and will be further investigated in a phase III study.

AimsThe assessment of B-raf proto-oncogene, serine/threonine kinase (BRAF) gene status is now standard practice in patients diagnosed with metastatic melanoma with its presence predicting a clinical response to treatment with BRAF inhibitors. The gold standard in determining BRAF status is currently by DNA-based methods. More recently, a BRAF V600E antibody has been developed. We aim to investigate whether immunohistochemical detection of BRAF mutation is a suitable alternative to molecular testing by polymerase chain reaction (PCR).MethodsWe assessed the incidence of BRAF mutation in our cohort of 132 patients, as determined by PCR, as well as examining clinical and histopathological features. We investigated the sensitivity and specificity of the anti-BRAF V600E VE1 clone antibody in detecting the presence of the BRAF V600E mutation in 122 cases deemed suitable for testing.ResultsThe incidence of BRAF mutation in our cohort was 28.8% (38/132). Patients with the BRAF mutation were found to be significantly younger at age of diagnosis. BRAF-mutated melanomas tended to be thinner and more mitotically active. The antibody showed a sensitivity of 86.1% with a specificity of 96.9%. The positive predictive value was 96.9%; the negative predictive value was 94.4%. The concordance rate between PCR and immunohistochemical BRAF status was 95.1% (116/122).ConclusionsThe rate of BRAF mutation in our cohort (28.8%) was lower than international published rates of 40%–60%. This may reflect ethnic or geographic differences within population cohorts. The high concordance rate of PCR and immunohistochemical methods in determining BRAF status suggests that immunohistochemistry is potentially a viable, cost-effective alternative to PCR testing and suitable as a screening test for the BRAF mutation.

e21076 Background: Activating BRAF V600 mutations have been shown to occur in 40%–60% of melanomas, although the mutation rate among the Irish melanoma population has been reported to be lower (30%). The current standard for determining BRAF mutation status is with the use of the Cobas 4800 PCR test. IHC analysis to determine BRAF mutation status has been made possible by the development of monoclonal antibodies directed at mutant BRAF protein expression, which may be of use as an alternative to molecular testing. Methods: We identified 132 patients with metastatic melanoma between 2011 and 2014 at our institution that had tumour tested for BRAF mutation using PCR. Of these, 122 cases were suitable for IHC. Tissue samples were obtained and tested with the BRAF V600E antibody. IHC was assessed as 0 (negative), 1, 2 or 3 based on intensity of cytoplasmic staining. We assessed the incidence of BRAF mutation, investigated the sensitivity and specificity of the BRAF V600E antibody in detecting the presence of the BRAF V600E mutation. Clinical response to BRAF inhibitor therapy as per RECIST was correlated to BRAF mutation status by PCR and to IHC expression. Results: The incidence of BRAF mutation as assessed by PCR was 28.8% (38/132). The antibody showed a sensitivity of 86.1% with a specificity of 96.9%. The positive predictive value was 96.9%; the negative predictive value was 94.4%. The concordance rate between PCR and IHC was 95.1% (116/122). One false positive case and five false negative cases were observed. The results of clinical outcomes for the PCR positive cohort and the IHC level of expression cohorts are shown in the table. Conclusions: The high concordance rate of PCR and IHC methods in determining BRAF status and predicting response to therapy suggests that antibody testing is a viable and cost effective alternative to PCR testing. The BRAF V600E antibody may be suitable as a screening test for the BRAF mutation, with all negative cases being submitted for PCR testing to identify variant BRAF mutations not detected by IHC. Response Rate (%) Median Duration of Response (months) Median Overall Survival (months) PCR (n = 25) 92 7 12 IHC 3+ (n = 10) 83 9.5 12 IHC 2+ (n = 4) 100 7 10 IHC 1+ (n = 1) 100 18 31 IHC 0 (n = 5) 100 6 8

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent’s University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m2 and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m2. Median Dox dose was 240 mg/m2 [225–298]; 92 patients (59.7 %) received ≤240 mg/m2 and 62 (40.3 %) > 240 mg/m2. Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9–36.5] and 21.1 pg/ml [9.8–37.7] in those without LVD and 61.5 pg/ml [50–68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

It has been recognised that up to 25% of breast cancer overexpresses the transmembrane human epidermal growth factor receptor 2 (HER2), which, in the absence of treatment, is associated with an adverse prognosis for patients Hudis, 2007Hudis C.A. Trastuzumab: mechanism of action and use in clinical practice.N. Engl. J. Med. 2007; 357: 39-51Crossref PubMed Scopus (1846) Google Scholar. The monoclonal antibody trastuzumab, which targets the HER2 receptor, has significantly improved both overall and disease-free survival for patients with advanced and early stage disease Slamon et al., 2001Slamon D.J. Leyland-Jones B. Shak S. et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N. Engl. J. Med. 2001; 344: 783-792Crossref PubMed Scopus (9169) Google Scholar, Moja et al., 2012Moja L. Tagliabue L. Balduzzi S. et al.Trastuzumab containing regimens for early breast cancer.Cochrane Database Syst. Rev. 2012; 4Google Scholar. However, an unexpected finding during the clinical trials of trastuzumab was the development of cardiotoxicity, mostly manifested as a decline in left ventricular ejection fraction (LVEF) and, more rarely, congestive heart failure. Despite extensive research, the mechanisms underlying trastuzumab-related cardiotoxicity remain poorly understood. Against this background, the article in this issue of EBioMedicine by Reijers et al. Reijers and Burggraaf, 2015Reijers J.A.A. Burggraaf J. Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled Trial.EBio. Med. 2015; : 949-955Google Scholar, investigated the effects of trastuzumab administration on a group of healthy male volunteers and its impact on cardiac function. This report focuses, in part, on a clinical trial, in which a developmental trastuzumab drug product was shown to have bio-equivalence to the currently approved formulation of trastuzumab (Herceptin®) Wisman et al., 2014Wisman L.A. De Cock E.P. Reijers J.A. et al.A phase I dose-escalation and bio-equivalence study of a trastuzumab biosimilar in healthy male volunteers.Clin. Drug Invest. 2014; 34: 887-894Crossref PubMed Scopus (30) Google Scholar. As part of this study, volunteers (n = 118) underwent serial measurements of body weight and biomarkers, including haemoglobin, haematocrit, albumin, total protein, cardiac Troponin (cTn)-T and N-terminal pro-peptide of B-type natriuretic peptide (NT-proBNP), along with assessments of cardiac function by echocardiography. The current report focuses more narrowly on cardiac function in 54/118 men who received either trastuzumab (n = 46) or placebo (n = 8). Mean haemoglobin (−0.3 mM), haematocrit (−0.013 L/L), total protein (−2 g/dL) and albumin (−2 g/dL) all significantly decreased post exposure to trastuzumab compared with placebo. There was also a corresponding increase in body weight (+0.4 kg), although this result was not statistically significant (p = 0.226) and the time for change to return to baseline was not reported. There was no detectable increase in the cardiac specific blood parameters, NT-proBNP and cTn-T in either trastuzumab-treated volunteers (n = 46) or those who received placebo (n = 6). In a further subset analysis, there was no significant difference in LVEF in volunteers who received trastuzumab (n = 9) compared to placebo (n = 8) at either 4 or 63 days. No cardiac events were reported in the study, which is not unexpected, given the small number of subjects and exposure to trastuzumab was only a single dose. The major strength of this report by Reijers et al. is the fact that the population were all healthy, with no comorbidities and had never been exposed to chemotherapy. In fact, many patients with HER2 positive breast cancer receive anthracyclines, which are also associated with a risk of cardiotoxicity. Hence the interpretation of the mechanisms underlying cardiotoxicity in this population is more challenging, and the current study represents a relatively homogeneous cohort, without the confounding effects of potentially cardiotoxic chemotherapy. The most interesting observation in this study was that trastuzumab was associated with an immediate, transient increase in body weight. The authors suggested that there was haemodilution caused by fluid retention post trastuzumab administration, and that this observation might provide some insight into the cardiovascular effect of trastuzumab. Furthermore, it was postulated that this might have been a direct consequence of cardiac myocyte stress induced by exposure to trastuzumab. However, the small placebo group (as comparator) limits this study and cautious interpretation of the findings is recommended. Although the authors concluded that monitoring of biomarkers and measuring body weight as used in the study might contribute to establishing a patient's risk of trastuzumab-induced haemodynamic alterations, the lack of a significant change in LVEF and the lack of correlation between haemodynamic alterations and cardiotoxicity, argues against the routine use of these measurements in clinical practice. As noted, many patients with HER2 positive breast cancer receive anthracyclines, which can cause oxidative damage to cardiac myocytes. Those cells sustaining sufficient damage undergo apoptosis leading to cardiotoxicity, while other cells can repair the damage from these processes. If trastuzumab is then introduced, it binds to the damaged myocytes and inhibits cell repair thereby resulting in an even higher incidence of cardiac dysfunction Ewer and Ewer, 2010Ewer M.S. Ewer S.M. Troponin I provides insight into cardiotoxicity and the anthracycline–trastuzumab interaction.J. Clin. Oncol. 2010; 28: 3901-3904Crossref PubMed Scopus (60) Google Scholar. Trastuzumab also can cause cardiotoxicity when administered as a single agent or with a non-anthracycline chemotherapeutic agent, albeit at a much lower incidence. The mechanism differs to that of anthracycline-related cardiotoxicity, evidenced by the evaluation of cardiac biopsy specimens after trastuzumab exposure, which do not show typical anthracycline ultrastructural changes Ewer et al., 2005Ewer M.S. Vooletich M.T. Durand J.B. et al.Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment.J. Clin. Oncol. 2005; 23: 7820-7826Crossref PubMed Scopus (565) Google Scholar. In addition, withdrawal of trastuzumab can reverse the cardiac effects, with LVEF improving in most patients and trastuzumab rechallenge often possible Guarneri et al., 2006Guarneri V. Lenihan D.J. Valero V. et al.Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience.J. Clin. Oncol. 2006; 24: 4107-4115Crossref PubMed Scopus (315) Google Scholar. However, LVEF recovery is not universal and some patients will be left with significant cardiac dysfunction. Therefore, a major focus of ongoing research is the development of biomarkers to identify those patients at most risk. Research into potential biomarkers to predict risk of cardiotoxicity in patients treated with trastuzumab, including the study by Reijers et al., has focused on cTns, which are relatively specific for myocardial damage. However, results from clinical studies have been conflicting. Cardinale et al. identified a subgroup of patients treated with trastuzumab and elevated cTnI, who were more likely to develop trastuzumab-induced cardiotoxicity, less likely to recover fully and who had a 25-fold increase in risk for major adverse cardiac event Cardinale et al., 2010Cardinale D. Colombo A. Torrisi R. et al.Trastuzumab-induced cardiotoxicity: clinical and prognostic implication of troponin I elevation.J. Clin. Oncol. 2010; 28: 3910-3916Crossref PubMed Scopus (461) Google Scholar. In contrast, in a prospective study investigating cTnI in patients treated with chemotherapy, trastuzumab and the oral anti-HER2 agent lapatinib, there was no association between elevations in cTnI and LVEF decline Morris et al., 2011Morris P. Chen C. Steingart R. et al.Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib.Clin. Cancer Res. 2011; 17: 3490-3499Crossref PubMed Scopus (118) Google Scholar. Similarly, in the present study by Reijers et al., there was no increase in NT-proBNP and troponin-T post exposure to trastuzumab and no link to cardiotoxicity. In short, the clinical utility of these cardiac biomarkers in predicting trastuzumab-related toxicity is currently unclear. Trastuzumab-induced cardiotoxicity remains an important clinical concern for all patients undergoing therapy for HER2 positive breast cancer. As evidence accumulates we are developing a clearer understanding of the pathophysiology of this important clinical problem. However, further research is needed to discover potential biomarkers, which will allow identification of those people at risk of developing cardiotoxicity and thereby, tailoring therapy (both anticancer and cardioprotective) to ensure that our patients achieve the optimal benefit of trastuzumab without the potential long term toxicity. The authors declare no conflicts of interest. Trastuzumab Induces an Immediate, Transient Volume Increase in Humans: A Randomised Placebo-Controlled TrialSingle dose administration of trastuzumab in humans is associated with an immediate, transient extracellular volume increase, either as a primary or secondary (compensatory) response, which can be detected easily using routine clinical assessments. Echocardiographic changes, both short and long term, could not be found after single dose administration to drug-naive patients. Full-Text PDF Open Access

Hintergrund: Ipilimumab kann nachweislich das Gesamtüberleben bei Patienten mit metastasiertem Melanom verbessern; vollständige Remissionen (CRs) bewirkt es jedoch selten. Immunologische Nebenwirkungen betreffen meist die Haut oder den Gastrointestinaltrakt. Neurologische Ereignisse treten weniger häufig auf, sind aber umfassend beschrieben. Fallbericht: Wir berichten hier über den Fall eines 58-jährigen Mannes mit metastasiertem Melanom, bei dem nach einer spinalen Dekompression und Bestrahlung eine Behandlung mit Ipilimumab begonnen wurde. Nach dem 2. Zyklus entwickelte er eine Colitis, und das Ipilimumab wurde abgesetzt. Die Bildgebung zeigte jedoch eine radiologische CR. Acht Wochen später traten bei dem Patienten, trotz weiterhin bestehender CR, eine Paraplegie und Myelitis auf. Die Anwendung von Steroiden bewirkte eine gewisse radiologische Verbesserung, jedoch keine klinische. Schlussfolgerung: Wir berichten über Myelitis mit nachfolgender Paraplegie als potenzielle neurologische, immunvermittelte Nebenwirkung von Ipilimumab. Hierbei beschreiben wir einen Patienten mit einer CR nach 2 Zyklen Ipilimumab im Zusammenhang mit einer Bestrahlung.

Wir berichteten in einer fruheren Arbeit, dass S-777469 [1-([6-Ethyl-1-(4-Fluorbenzyl)-5-Methyl-2-Oxo-1,2-Dihydropyridin-3-Carbonyl]amino)-Cyclohexancarboxylsaure], ein neuartiger Agonist des Cannabin

Hintergrund: Nahrungsmittel-Allergien auf Lupinen werden häufig bei Patienten festgestellt, die auch allergisch auf Erdnüsse oder Soja reagieren; eine Kreuzreaktivität zwischen diesen Hülsenfrüchten ist bekannt. Darüber hinaus ist von respiratorischen Allergien gegen Lupinen nach einer Inhalation, meist am Arbeitsplatz, berichtet worden. Unser Ziel war es, die Häufigkeit der Sensibilisierung auf Lupine bei europäischen Bäckern mit Verdacht auf Bäckerallergie zu untersuchen. Zudem erforschten wir Assoziationen zwischen der Sensibilisierung gegenüber Lupine und anderen Pflanzenallergenen. Methoden: 116 Bäcker mit arbeitsassoziierten allergischen Symptomen, jedoch ohne bekannte Nahrungsmittel-Allergien wurden untersucht. Spezifische IgE-Antikörper (sIgE) gegen Weizenmehl, Roggenmehl, Lupine, Erdnuss, Soja sowie das rekombinante Einzelbirkenprotein rBet v 1 wurden quantifiziert. Ausgewählte Seren wurden mittels ImmunoCAP-Inhibition und ISAC-Microarrays auf Kreuzreaktivität untersucht. Ergebnisse: Während 67% der Bäcker eine Sensibilisierung auf Weizen- und/oder Roggenmehl zeigten, hatten 35% sIgE gegen Erdnuss und 33% gegen Lupine. Alle lupinepositiven Bäcker hatten zugleich auch sIgE entweder gegen Weizenmehl (89%) und/oder gegen Erdnuss (92%), und Lupine-sIgE korrelierten signifikant mit sIgE gegen Erdnuss, Soja, Weizen- und Roggenmehl. Als Inhibitor eingesetzt hemmte Weizenmehl die IgE-Bindung an Lupine in 4 von 8 Seren, was auf eine Kreuzreaktivität hindeutet. In Microarrays zeigten die Seren IgE-Bindungen an Lipid-Transferproteine, Profiline und/oder kreuzreaktive Kohlenhydrat-Determinanten. Weitere Inhibitionsversuche deuten darauf hin, dass diese Einzelallergene an der Kreuzreaktivität beteiligt sind. Schlussfolgerung: Ein Drittel der 116 Bäcker mit Symptomen wiesen sIgE gegen Lupine auf. Zumindest teilweise basierten diese Sensibilisierungen auf einer Kreuzreaktivität zwischen Lupine und Weizenmehl. Allerdings könnte die erhebliche Sensibilisierungsrate auch ein Zeichen dafür sein, dass die Verwendung von Lupinenmehl in Bäckereien von beruflicher Relevanz ist. Übersetzung aus van Kampen V, et al: IgE sensitization to lupine in bakers - cross-reactivity or co-sensitization to wheat flour? Int Arch Allergy Immunol 2015;166:63-70 (DOI: 10.1159/000375238)