Safety and efficacy analysis of neoadjuvant pertuzumab, trastuzumab and standard chemotherapy for HER2-positive early breast cancer: real-world data from NeoPowER study.

BACKGROUND: The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P + H + CT in a real-world population. METHODS: We retrospectively reviewed the medical records of stage II-III, HER2 + BC patients treated with NaT: who received P + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables. RESULTS: 260 patients were included, 48% received P + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% (P + H + CT) and 40% (H + CT) (p = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05,p = 0.047). Preoperative use of anthracyclines (OR = 1.81,p = 0.03) and duration of NaT (OR = 1.18,p = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23,p = 0.009). CONCLUSIONS: Adding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes.

Tremelimumab and durvalumab in the treatment of unresectable, advanced hepatocellular carcinoma.

Liver cancer is the third most common cause of cancer-related mortality worldwide, with over 780,000 deaths in 2018. About 90% of liver cancer cases are hepatocellular carcinoma (HCC), a prototype of inflammation-driven cancer, leading to a robust rationale for the exploration of immune therapy. Previously approved agents for first-line therapy, such as sorafenib, lenvatinib and bevacizumab combined with atezolizumab, have focused on angiogenesis. HIMALAYA was the first trial to demonstrate the benefit of dual immune checkpoint inhibitors, representing a new treatment option in this scenario.

Liver cancer is the third most common cause of cancer-related mortality worldwide, with over 780,000 deaths in 2018. About 90% of liver cancer cases originate in liver cells and are referred to as hepatocellular carcinoma (HCC). Systemic treatment (medications) is the mainstay for patients with advanced disease who are not suitable for resection or liver transplant and aims to improve survival and quality of life. HIMALAYA was the first study to demonstrate the benefit of using a combination of two immunotherapy medications for initial treatment.

Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis.

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human ß2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.

Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies.

Hepatocellular carcinoma (HCC) is a common cancer globally and a leading cause of cancer-related deaths. Although early-stage disease may be curable by resection, liver transplantation or ablation, many patients present with unresectable disease and have a poor prognosis. Combination treatment with atezolizumab (targeting PD-L1) and bevacizumab (targeting VEGF) in the recent IMbrave150 study was shown to be effective with an acceptable safety profile in patients with unresectable HCC. Herein, we discuss this novel combination in the context of the liver immune environment, summarize the mechanism and pharmacokinetics of atezolizumab and bevacizumab, and examine recent data on other immune checkpoint inhibitor combination strategies as well as future directions in the treatment of patients with advanced HCC.

Lay abstract Cancer of the liver is common worldwide and is one of the main causes of death from cancer. If caught early, liver cancer can be treated successfully, but most patients are diagnosed when their cancer has already spread and are less likely to survive. A new treatment method using two kinds of antibodies, atezolizumab and bevacizumab, has recently been shown in a clinical trial to be safe and to have a good effect in patients with advanced liver cancer. In this review, we look at how this new treatment works and discuss the results of other clinical trials using similar treatments. We also look ahead to how patients with advanced liver cancer might be treated in the future.

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers.

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11-1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT+CD8+ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43-3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36-2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10-2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT+CD8+ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.

Reversion of cardiovascular remodelling in renovascular hypertensive 2K-1C rats by renin-angiotensin system inhibitors.

OBJECTIVES: Evaluate whether the RAS dual blockade would induce additional beneficial effects on cardiovascular remodelling when compared to monotherapy in renal hypertensive two kidneys-one clip (2K-1C) rats. METHODS: Hypertensive 2K-1C and normotensive (2K) rats were treated for 14 days with submaximal doses of losartan (LOS), enalapril (ENA), losartan plus enalapril (LOS + ENA) or vehicle (water). Blood pressure and some parameters of cardiovascular remodelling were evaluated. RESULTS: Systolic blood pressure (SBP) was higher in 2K-1C (209 ± 3 mm Hg, P < .05) than in 2K (113 ± 1 mm Hg) rats. There was an additional effect in 2K-1C treated with LOS + ENA (153 ± 9 mm Hg) on lowering SBP when compared to LOS (184 ± 12 mm Hg) or ENA (177 ± 9 mm Hg). None of the treatments had effect on SBP in 2K rats. In 2K-1C, cardiomyocyte hypertrophy was reduced by all treatments, although the cardiac hypertrophy indexes remained unchanged. 2K-1C aortas presented medial thickening that was partially reduced by the treatments. Intimal hyperplasia observed in 2K-1C (15.56 ± 0.89 µm vs 8.24 ± 0.80 µm) was reversed by ENA (9.52 ± 0.45 µm) or LOS + ENA (8.17 ± 0.53 µm). Collagen deposition was increased in 2K-1C hearts (1.77 ± 0.16 vs 1.28 ± 0.09) and aortas (8.1 ± 0.6 vs 5.2 ± 0.2). Treatment with LOS reduced (1.12 ± 0.14%) and ENA (0.81 ± 0.11%) or LOS + ENA (0.86 ± 0.11%) additionally diminished collagen only in 2K-1C hearts. CONCLUSIONS: Submaximal doses of ACEi and/or ARB have inhibitory actions on cardiac remodelling and vascular hypertrophy not entirely dependent on their effects on blood pressure normalization in renovascular hypertensive rats. Combined therapy produced additional reduction in blood pressure than monotherapy despite a similar inhibition on cardiovascular remodelling.

Stereotactic Radiation and Dual Human Epidermal Growth Factor Receptor 2 Blockade with Trastuzumab and Pertuzumab in the Treatment of Breast Cancer Brain Metastases: A Single Institution Series.

(1) Background: This study aims to assess the safety and efficacy of fractionated SRT (fSRT) and pertuzumab-trastuzumab (PT) in patients with breast cancer brain metastases (BCBM). (2) Methods: Patients with HER2+ BCBM who received FSRT from 2015 to 2019 were identified. Patients were included if they were treated with fSRT within 21 days of receiving PT. All lesions were treated with LINAC-based fSRT to a total dose of 27 Gy delivered in three consecutive fractions. All patients received concurrent PT. Patients were evaluated 4-6 weeks after SRS and subsequently every 2-3 months with MRI re-imaging (3) Results: A total of 49 patients with HER2+ brain metastases were identified. Of these patients, a total of 10 patients with 32 HER2+ BCBM were treated with concurrent SRT and PT and included in the analysis. No local progression was observed. Overall response rate was 68.7%. Only one patient developed asymptomatic radionecrosis. Median time to BM occurrence was 15.6 (range: 1-40.5 months). Distant intracranial failure occurred in 4/10 patients (40.0%). Overall BCBM median survival was 33.9 months (95%CI 24.1-43.6). Mean duration of PT treatment was 27.9 months (range: 10.1-53.7 months). (4) Conclusions: In our single institution experience, fSRT and PT showed to be a safe treatment for patients with BCBM with an adequate overall response rate.

Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFß and PD-1/PD-L1.

INTRODUCTION: In solid tumor immunotherapy, less than 20% of patients respond to anti-programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) agents. The role of transforming growth factor ß (TGFß) in diverse immunity is well-established; however, systemic blockade of TGFß is associated with toxicity. Accumulating evidence suggests the role of crosstalk between TGFß and PD-1/PD-L1 pathways. AREAS COVERED: We focus on TGFß and PD-1/PD-L1 signaling pathway crosstalk and the determinant role of TGFß in the resistance of immune checkpoint blockade. We provide the rationale for combination anti-TGFß and anti-PD-1/PD-L1 therapies for solid tumors and discuss the current status of dual blockade therapy in preclinical and clinical studies. EXPERT OPINION: The heterogeneity of tumor microenvironment across solid tumors complicates patient selection, treatment regimens, and response and toxicity assessment for investigation of dual blockade agents. However, clinical knowledge from single-agent studies provides infrastructure to translate dual blockade therapies. Dual TGFß and PD-1/PD-L1 blockade results in enhanced T-cell infiltration into tumors, a primary requisite for successful immunotherapy. A bifunctional fusion protein specifically targets TGFß in the tumor microenvironment, avoiding systemic toxicity, and prevents interaction of PD-1+ cytotoxic cells with PD-L1+ tumor cells.

Correlation Between Preoperative Radiological and Postoperative Pathological Tumor Size in Patients With HER2+ Breast Cancer After Neoadjuvant Chemotherapy Plus Trastuzumab and Pertuzumab.

BACKGROUND: Neoadjuvant chemotherapy (NAC) in combination with anti-HER2 treatment is standard of care in patients with early HER2 positive breast cancer. Preoperative radiological evaluation is mandatory for defining the extent of surgery. In this study, we evaluated the correlation between preoperative radiological and postoperative pathological tumor size in early HER2 positive patients after neoadjuvant chemotherapy in combination with trastuzumab and pertuzumab. In a patient population with HER2 positive breast cancer, who received neoadjuvant chemotherapy and anti-HER2 treatment, the correlation between preoperative radiological and postoperative pathological tumor size was performed. Concordance of radiological and pathological tumor size was found in 55.7%, leading to more extensive breast surgery as required in 7 cases and to the underestimation of 6 neoplastic lesions before surgery, respectively. PATIENTS AND METHODS: Seventy early HER2 positive breast cancer patients were included and retrospectively analysed. All preoperative radiological assessments as well as the tumor board decision on surgical extent and pathological evaluation were completed at the Medical University of Vienna. Preoperative radiological assessment of tumor size and lymph node status were compared with final histopathological findings. The correlation between different radiological modalities regarding tumor size was investigated. RESULTS: Concordance of radiological and pathological tumor size was found in 55.7 % (50% by sonography and 66.7% by MRI, respectively) of patients with a nonsignificant correlation of r = 0.31 (P = .08). Of the 39 patients with pathologic complete remission (pCR), 16 were also classified as radiological complete response (rCR) while 23 of those showed a radiological stable disease or partial response. In 6 patients, radiological assessment showed a CR but invasive cancer with a tumor size range from 7 to 36 mm was found in histopathological examination. Neither menopausal status (P= .69) nor BMI (P = .60) and age (P = .50) had an impact on the correlation between radiological and histopathological tumor size. Regarding lymph node status, a statistically significant association and clinically relevant correlation between radiological and histopathological evaluation was found (r = 0.66, P < .001). CONCLUSION: Concordance between radiology and histopathology was low regarding tumor size after NAC in combination with trastuzumab and pertuzumab, but significant regarding lymph node status.

Effect of Sequential Nephron Blockade versus Dual Renin-Angiotensin System Blockade Plus Bisoprolol in the Treatment of Resistant Hypertension, a Randomized Controlled Trial (Resistant Hypertension on Treatment - ResHypOT).

Introduction: Hypertension is the most important modifiable risk factor for cardiovascular disease and a leading public health concern. Objectives: The primary aim was to compare sequential nephron blockade (SNB) versus dual renin-angiotensin system blockade (DRASB) plus bisoprolol in patients with resistant hypertension to observe reductions in systolic and diastolic blood pressure (SBP and DBP) levels after 20 weeks of treatment. Material and Methods: This trial was an open-label, prospective, randomized, parallel-group, clinical study with optional drug up-titration. Participants were evaluated during five visits at 28-day intervals. Results: The mean age was 55.5 years in the SNB and 58.4 years in the DRASB + bisoprolol group (p=NS). Significant office BP reductions were observed in both groups. SNB group, SBP decreased from 174.5±21.0 to 127.0±14.74 mmHg (p<0.0001), and DBP decreased from 105.3±15.5 to 78.11±9.28 mmHg (p<0.0001). DRASB group, SBP decreased from 178.4±21.08 to 134.4 ± 23.25 mmHg (p<0.0001) and DBP decreased from 102.7±11.07 to 77.33±13.75 mmHg (p<0.0001). Ambulatory blood pressure monitoring (ABPM) showed also significant SBP and DBP reductions in both groups (p<0.0001). Conclusion: In patients with RHTN adherent to treatment, SNB and DRASB plus bisoprolol showed excellent therapeutic efficacy, although SNB was associated with earlier SBP reduction.

The Dual Blockade of the TIGIT and PD-1/PD-L1 Pathway as a New Hope for Ovarian Cancer Patients.

The prognosis for ovarian cancer (OC) patients is poor and the five-year survival rate is only 47%. Immune checkpoints (ICPs) appear to be the potential targets in up-and-coming OC treatment. However, the response of OC patients to immunotherapy based on programmed cell death pathway (PD-1/PD-L1) inhibitors totals only 6-15%. The promising approach is a combined therapy, including other ICPs such as the T-cell immunoglobulin and ITIM domain/CD155/DNAX accessory molecule-1 (TIGIT/CD155/DNAM-1) axis. Preclinical studies in a murine model of colorectal cancer showed that the dual blockade of PD-1/PD-L1 and TIGIT led to remission in the whole studied group vs. the regression of the tumors with the blockade of a single pathway. The approach stimulates the effector activity of T cells and NK cells, and redirects the immune system activity against the tumor. The understanding of the synergistic action of the TIGIT and PD-1/PD-L1 blockade is, however, poor. Thus, the aim of this review is to summarize the current knowledge about the mode of action of the dual TIGIT and PD-1/PD-L1 blockade and its potential benefits for OC patients. Considering the positive impact of this combined therapy in malignancies, including lung and colorectal cancer, it appears to be a promising approach in OC treatment.

Genomic Sequencing for Bladder Urothelial Carcinoma and Its Clinical Implications for Immunotherapy.

PURPOSE: This study aimed to explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI). MATERIALS AND METHODS: We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, programmed death-ligand 1 (PD-L1) expression was evaluated in a subset of patients (n=57) including those treated with ICI (n=8). RESULTS: We identified frequent molecular dysregulations in chromatin regulatory genes (KDM6A, ARID1A, MLL2, and STAG2) and recurrent copy number alterations. Thirty-five samples (54.7%) were PD-L1-positive (PD-L1 combined positive score ≥ 1) with a significantly higher exonic tumor mutational burden (TMB) compared to PD-L1-negative BC samples (p=0.010). We observed that various immune-responsive pathways, including the PD-L1 signaling pathway, were enriched significantly in PD-L1-positive BCs. Interestingly, genes in the CTLA4 pathway were enriched significantly in PD-L1-positive BC as well. Among eight patients who received ICI, progressive disease was confirmed in one patient, whose tumor had low exonic TMB, negative PD-L1 status, and a relatively colder microenvironment. CONCLUSION: Gaining new insights into the molecular landscape of BC will improve treatment strategies. Our analysis suggests a rationale for studying dual checkpoint inhibition against BC.

Dual Blockade of the Renin-Angiotensin System: A Strategy that Should Be Reconsidered in Cardiorenal Diseases?

Studies on pharmacological mechanisms demonstrated that a strategy of dual renin-angiotensin system (RAS) blockade may have a synergistic effect in the treatment of cardiorenal diseases and may reduce adverse reactions. However, some previous clinical studies reported that dual RAS blockade did not significantly benefit many patients with cardiorenal diseases and increased the risk of hyperkalemia, hypotension and renal function damage. Therefore, the current clinical guidelines suggest that the combined use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should be used with caution in the clinic. However, these studies enrolled older patients with cardiovascular risk factors, and the results of these trials may not be generalized to the overall population. Some clinical evidence suggests that the combination of low-dose ACEIs and ARBs leads to more effective RAS blockade with few adverse effects. The advent of new RAS inhibitors with superior pharmacological effects provides a more suitable drug choice for individualized therapy for dual RAS blockade. Therefore, the choice of appropriate ARBs/ACEIs for individualized therapy based on patient condition may be a better way to improve the efficiency and safety of the dual RAS blockade strategy.

Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab.

BACKGROUND: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown. METHODS: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into 'TP', 'other-HER2-targeted therapy' and 'no-HER2-targeted therapy' according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM). RESULTS: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%. CONCLUSION: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.

Association between pertuzumab-associated diarrhoea and rash and survival outcomes in patients with HER2-positive metastatic breast cancer: Exploratory analysis from the CLEOPATRA trial.

BACKGROUND: Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit. METHODS: This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used. RESULTS: Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48-0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30-0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46-0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts. CONCLUSIONS: In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit.

Contextualizing pertuzumab approval in the treatment of HER2-positive breast cancer patients.

The use of adjuvant pertuzumab in HER2-positive early-stage breast cancer has recently been approved by the EMA on the basis of data from the APHINITY trial. Accordingly, we have produced this opinion article with the aim of putting the study data in perspective against other add-on therapeutic strategies, to clarify methodological or statistical doubts about the study, and to define the population of high-risk patients with hormone receptor-negative breast cancer that we agree, in general, should be treated. With this approval, physicians must be well prepared to place the APHINITY study data in context. It is now up to each country to ratify the EMA-approved indications and to agree on reimbursement, and doctors must optimize their use based on knowledge and discussion with patients.

Detrimental effect of renin-angiotensin blockade on progression of chronic kidney disease at later stages: A matter of dosage adjustment? / Efecto negativo del bloqueo del sistema renina-angiotensina sobre la progresión de la enfermedad renal crónica avanzada: ¿una cuestión de ajuste de dosis?

INTRODUCTION: The renoprotective effect of renin-angiotensin (RAS) blockers (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) has been questioned in patients with advanced chronic kidney disease (CKD). Moreover, combination therapy (dual RAS blockade) can further accelerate renal function decline in some populations at risk. However, it is unknown whether this adverse outcome is due to a dose-dependent effect or if it can be attributed more specifically to a drug interaction. Aim This study aims to investigate if the rate of renal function decline in advanced CKD patients is associated to the doses of RAS blockers, and if dual RAS blockade worsens renal function independently of major confounding factors. MATERIAL AND METHODS: Retrospective, observational study in an incident cohort of adult patients with CKD stage 4 or 5 not on dialysis, treated with RAS blockers for at least 3 months prior to the study inclusion. Inclusion criteria were: having at least three consecutive measurements of estimated glomerular filtration rate (eGFR) in a follow-up period >3 months. Decline in renal function was estimated as the slope of the individual linear regression line of eGFR over follow-up time. Equipotent doses of RAS blockers were normalised for a body weight of 70kg or a body surface area of 1.73m2 (END-RASI). Associations of END-RASI or dual RAS blockade with the rate of renal function decline were analysed by uni- or multivariate linear regression models, accounting for major confounding variables. RESULTS: The study group consisted of 813 patients (mean age 64±14 years, 430 males) with a mean eGFR 14.9±4.2ml/min/1.73m2; 729 patients were on RAS blockade monotherapy and 84 on dual RAS blockade. Median END-RASI in the whole group was 0.91 (I.Q. ranges: 0.69-1.20). Patients on dual RAS blockade had significantly higher END-RASI than the rest of study patients (1.52±0.49 vs. 0.93±0.44; p<0.0001). In univariate linear regression, END-RASI were significantly correlated with eGFR decline (R=-0.149; p<0.0001). Patients on dual RAS blockade showed a significantly faster decline of renal function than the rest of the study patients (-6.19±5.57 vs. -3.04±5.37ml/min/1.73m2/year, p<0.0001). By multivariate linear regression, while dual RAS blockade remained independent and significantly associated with faster renal function decline (beta=-0.094; p=0.005), END-RASI (normalised either for body weight or surface area) did not reach statistical significance. CONCLUSION: END-RASI are significantly associated with the rate of renal function decline in advanced CKD patients. However, the detrimental effect of dual RAS blockade on CKD progression seems to be independent of END-RASI and other major confounding factors.

The Dual Blockade in the Neoadjuvant Setting of HER-2 Positive Early-Stage Breast Cancer.

Patients with positive Her-2/neu breast cancer and a high risk of recurrence are known to benefit from the addition of the dual blockade of Her-2/neu with Trastuzumab and Pertuzumab to the neoadjuvant chemotherapy, a combination which has been demonstrated to give a higher rate of a complete pathologic response in the breast and in the axilla. The purpose of this review is to outline the efficacy of the dual blockade with Trastuzumab and Pertuzumab in the neoadjuvant treatment of high-risk Her-2 positive breast cancer. Electronic databases (Pubmed, Medline, and Cochrane Database of Systematic Reviews) were searched for English- and German-language studies, which were published in the last ten years. The search has been focused on neoadjuvant clinical trials as well as on the data presented in the abstracts published at the San Antonio Breast Cancer Symposium as well as at the annual meeting of the American Society of Clinical Oncology. The results reported in the published clinical trials demonstrated a higher pathologic complete response rate in breast and lymph nodes after using targeted therapy with two anti-Her-2/neu agents - Trastuzumab and Pertuzumab in combination with neoadjuvant chemotherapy for early-stage Her-2/neu positive breast cancers. The pathologic complete response rate is the most important prognostic marker in Her-2/neu positive tumors, a higher pathologic complete response rate being demonstrated to be associated with a better survival outcome in terms of higher overall survival and disease-free survival rates.

Effects of dual blockade in heart failure and renal dysfunction: Systematic review and meta-analysis.

OBJECTIVE: The effect of dual renin-angiotensin system (RAS) inhibition in heart failure (HF) is still controversial. Systematic reviews have shown that dual RAS blockade may reduce mortality and hospitalizations, yet it has been associated with the increased risk of renal dysfunction (RD). Surprisingly, although RD in patients with HF is frequent, the effect of combining RAS inhibitors in HF patients with RD has never been studied in a meta-analysis. METHODS: A systematic review and meta-analysis of randomized clinical trials involving HF patients with RD who received dual blockade analyzing death, cardiovascular (CV) death or HF hospitalization, and adverse events. RESULTS: Out of 2258 screened articles, 12 studies were included (34,131 patients). Compared with monotherapy, dual RAS inhibition reduced hazard ratio of death to 0.94 (p=0.07) and significantly reduced CV death or HF hospitalization to 0.89 (p=0.0006) in all individuals, and to 0.86 (p=0.005) in patients with RD and to 0.91 (p=0.04) without RD. Nevertheless, dual RAS blockade significantly increased the risk of renal impairment (40%), hyperkalemia (44%), and hypotension (42%), although discontinuation of treatment occurs only in 3.68% versus 2.19% (p=0.00001). CONCLUSIONS: Dual RAS inhibition therapy reduces the risk of CV death or HF hospitalization. However, cautions monitoring for specific adverse events may be warranted.