Radiologic complete response (rCR) in contrast-enhanced magnetic resonance imaging (CE-MRI) after neoadjuvant chemotherapy for early breast cancer predicts recurrence-free survival but not pathologic complete response (pCR).

BACKGROUND: Patients with early breast cancer (EBC) achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) have a favorable prognosis. Breast surgery might be avoided in patients in whom the presence of residual tumor can be ruled out with high confidence. Here, we investigated the diagnostic accuracy of contrast-enhanced MRI (CE-MRI) in predicting pCR and long-term outcome after NACT. METHODS: Patients with EBC, including patients with locally advanced disease, who had undergone CE-MRI after NACT, were retrospectively analyzed (n = 246). Three radiologists, blinded to clinicopathologic data, reevaluated all MRI scans regarding to the absence (radiologic complete remission; rCR) or presence (no-rCR) of residual contrast enhancement. Clinical and pathologic responses were compared categorically using Cohen's kappa statistic. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS) and overall survival (OS). RESULTS: Overall rCR and pCR (no invasive tumor in the breast and axilla (ypT0/is N0)) rates were 45% (111/246) and 29% (71/246), respectively. Only 48% (53/111; 95% CI 38-57%) of rCR corresponded to a pCR (= positive predictive value - PPV). Conversely, in 87% (117/135; 95% CI 79-92%) of patients, residual tumor observed on MRI was pathologically confirmed (= negative predictive value - NPV). Sensitivity to detect a pCR was 75% (53/71; 95% CI 63-84%), while specificity to detect residual tumor and accuracy were 67% (117/175; 95% CI 59-74%) and 69% (170/246; 95% CI 63-75%), respectively. The PPV was significantly lower in hormone-receptor (HR)-positive compared to HR-negative tumors (17/52 = 33% vs. 36/59 = 61%; P = 0.004). The concordance between rCR and pCR was low (Cohen's kappa - 0.1), however in multivariate analysis both assessments were significantly associated with RFS (rCR P = 0.037; pCR P = 0.033) and OS (rCR P = 0.033; pCR P = 0.043). CONCLUSION: Preoperative CE-MRI did not accurately predict pCR after NACT for EBC, especially not in HR-positive tumors. However, rCR was strongly associated with favorable RFS and OS.

Transcatheter aortic valve implantation in a patient with suspected hereditary von Willebrand disease and severe gastrointestinal bleeding - a case report.

INTRODUCTION: von Willebrand disease is the most common hereditary coagulopathy and is characterised by a deficiency in the quantity or quality of the von Willebrand factor. Heyde Syndrome, in contrast, is an acquired form of von Willebrand syndrome (AVWS) due to calcific aortic valve stenosis, characterised by gastrointestinal bleeding from angiodysplasia. CASE PRESENTATION: A 73-year-old patient presented with severe gastrointestinal bleeding and stated that she suffered from hereditary von Willebrand disease. Upon echocardiography, a severe aortic valve stenosis was found, and hence the suspicion of additional AVWS was raised. Since endoscopic interventions and conservative therapeutic approaches did not result in a cessation of the bleeding, transcatheter aortic valve implantation (TAVI) was performed to stop the additional shear stress on von Willebrand factor. This resulted in cessation of the bleeding. CONCLUSION: Retrospectively, this life-threatening gastrointestinal bleeding was a result of severe Heyde Syndrome, which could be alleviated by TAVI. Whether the patient had suffered from inherited von Willebrand disease in the past, remains uncertain. AVWS should be considered in patients with suspected inherited von Willebrand disease and concomitant severe aortic valve stenosis, since it constitutes a treatable cause of a potentially severe bleeding disorder.

Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors.

OBJECTIVES: Resistance to MET inhibition occurs inevitably in MET-dependent non-small cell lung cancer and the underlying mechanisms are insufficiently understood. We describe resistance mechanisms in patients with MET exon 14 skipping mutation (METΔex14), MET amplification, and MET fusion and report treatment outcomes after switching therapy from type I to type II MET inhibitors. MATERIALS AND METHODS: Pre- and post-treatment biopsies were analysed by NGS (next generation sequencing), digital droplet PCR (polymerase chain reaction), and FISH (fluorescense in situ hybridization). A patient-derived xenograft model was generated in one case. RESULTS: Of 26 patients with MET tyrosine kinase inhibitor treatment, eight had paired pre- and post-treatment biopsies (Three with MET amplification, three with METΔex14, two with MET fusions (KIF5B-MET and PRKAR2B-MET).) In six patients, mechanisms of resistance were detected, whereas in two cases, the cause of resistance remained unclear. We found off-target resistance mechanisms in four cases with KRAS mutations and HER2 amplifications appearing. Two patients exhibited second-site MET mutations (p.D1246N and p. Y1248H). Three patients received type I and type II MET tyrosine kinase inhibitors sequentially. In two cases, further progressive disease was seen hereafter. The patient with KIF5B-MET fusion received three different MET inhibitors and showed long-lasting stable disease and a repeated response after switching therapy, respectively. CONCLUSION: Resistance to MET inhibition is heterogeneous with on- and off-target mechanisms occurring regardless of the initial MET aberration. Switching therapy between different types of kinase inhibitors can lead to repeated responses in cases with second-site mutations. Controlled clinical trials in this setting with larger patient numbers are needed, as evidence to date is limited to preclinical data and case series.

Transferring MINDACT to Daily Routine: Implementation of the 70-Gene Signature in Luminal Early Breast Cancer - Results from a Prospective Registry of the Austrian Group Medical Tumor Therapy (AGMT).

Background: For hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC), adjuvant chemotherapy (ACT) is recommended in the case of high-risk features only. The MINDACT trial showed that patients with high clinical risk (CR) but low genomic risk (GR) defined by the 70-gene signature (MammaPrint®; 70-GS) did not benefit from ACT. In this registry, we investigated the frequency and feasibility of 70-GS and concurrent 80-gene subtyping (BluePrint®) use in HR-positive, HER2-negative EBC. Furthermore, we recorded the frequency of ACT recommendation and the adherence to it when the "MINDACT strategy" was used. Methods: This prospective registry included patients from 2 Austrian cancer centers. Similar to MINDACT, a modified version of Adjuvant!Online was used to determine CR, and 70-GC was used to determine GR in high-CR patients. ACT was recommended to patients with high CR and high GR. Results: Of 224 enrolled patients, 76 (33.9%) had high CR and 67 (88.2%) received genomic testing. Of those, 43 (64.2%) were classified as low and 24 (35.8%) as high GR, respectively. All 24 patients with high CR and GR (10.7% of all patients) received the recommendation for ACT, but ACT was started in only 15 patients (62.5%). The median time from surgery to the start of ACT was 45 days (range 32-68), and the median time from test decision to the test result was 15 days (range 9-56). Conclusion: We showed that the results of the MINDACT trial are reproducible in an Austrian population. Incorporating 70-GS into the daily clinical routine is feasible and mostly accepted by physicians for the guidance of treatment recommendations.

Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer.

Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAFV600E and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAFV600E mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients.

Low Expression of miR-20a-5p Predicts Benefit to Bevacizumab in Metastatic Breast Cancer Patients Treated within the TANIA Phase III Trial.

BACKGROUND: In metastatic breast cancer (MBC) patients, no biomarker predicting benefit to a bevacizumab-containing therapy has been established yet. MicroRNAs (miRNAs) are involved in angiogenesis and treatment resistance and therefore could be of predictive value. METHODS: Profiling of 754 miRNAs was performed in tumor samples of 58 MBC patients treated with a bevacizumab-containing first-line regimen (learning set). Based on progression-free survival (PFS), patients were divided into responders (R) and non-responders (NR). Differentially expressed miRNAs between R and NR were analyzed in a cohort of 57 patients treated with first-line chemotherapy without bevacizumab (control set), to exclude miRNAs providing prognostic information. MiRNA candidates significantly associated with PFS in multivariate analysis were further validated in tumor samples of 203 patients treated within the phase III trial TANIA randomizing between chemotherapy either alone or with bevacizumab after progression on first-line bevacizumab. RESULTS: Low expression of miR-20a-5p (multivariate p = 0.035) and miR-21-5p (multivariate p = 0.004) were significantly associated with longer PFS in the learning set, but not in the control set. In samples from the TANIA trial, low expression of miR-20a-5p was also significantly associated with longer PFS (hazard ration (HR) 0.60; 95%-CI 0.37-0.89; p = 0.012) and longer overall survival (OS; HR 0.54; 95%-CI 0.32-0.83; p = 0.007) in the bevacizumab arm but not in the chemotherapy-only arm (PFS: HR 0.73, p = 0.119; OS: HR 1.01; p = 0.964). For miR-21-5p no significant association with PFS or OS in both treatment arms was observed. CONCLUSION: MiR-20a-5p expression in breast cancer tissue was predictive for a greater benefit from bevacizumab-containing therapy in two independent cohorts.

Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations.

BACKGROUND: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach. METHODS: Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy. RESULTS: We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment. CONCLUSION: Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.

Baseline Absolute Lymphocyte Count and ECOG Performance Score Are Associated with Survival in Advanced Non-Small Cell Lung Cancer Undergoing PD-1/PD-L1 Blockade.

Immune-checkpoint blockade in front-line or second-line treatment improves survival in advanced non-small cell lung cancer (aNSCLC) when compared with chemotherapy alone. However, easily applicable predictive parameters are necessary to guide immune-checkpoint inhibition in clinical practice. In this retrospective bi-centric analysis, we investigated the impact of baseline patient and tumor characteristics on clinical outcome in aNSCLC patients treated with programmed cell death protein 1(PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors. Between May 2015 and January 2018, 142 unselected consecutive NSCLC patients received PD-1/PD-L1 inhibitors during the course of disease. In multivariate analysis, we identified the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG > 1 versus ECOG ≤ 1, HR: 3.23, 95%CI: 1.58-6.60, P = 0.001), baseline absolute lymphocyte count (ALC; high: >0.93 × 109/L versus low: ≤ 0.93 × 109/L, HR: 0.38, 95%CI: 0.23-0.62, P < 0.001), prior or concomitant anti-vascular endothelial growth factor (VEGF) targeting therapy (yes versus no, HR: 2.18, 95%CI: 1.15-4.14, P = 0.017) and TNM stage (IV versus III, HR: 4.18, 95%CI: 1.01-17.36, P = 0.049) as the most relevant parameters for survival. Neither antibiotic exposure (antibiotic-positive versus antibiotic-negative, HR: 0.90, 95%CI: 0.56-1.45, P = 0.675), nor PD-L1 expression on tumor cells (≥1% versus <1%, HR: 0.68, 95%CI: 0.41-1.13, P = 0.140) was associated with survival. Baseline ECOG performance status and ALC were associated with survival in aNSCLC patients treated with PD-1/PD-L1 inhibitors and assessment of these parameters could be suitable in clinical practice.

Cure in metastatic breast cancer.

Oligometastatic disease characterizes a distinct subgroup of metastatic breast cancer patients that might benefit from different treatment strategies to achieve long-lasting remission and potentially cure. Those long-lasting remissions are reported after locoregional treatment of the primary tumor and all metastatic sites in several case series; however, unlike other tumor entities, prospective data are lacking. Furthermore, tumor eradication by excellent systemic anticancer therapy with novel chemotherapies and targeted agents can lead to long-term survival. In addition, reactivation of the host immune defense by immuno-oncologic drugs can achieve long-lasting tumor control. So far, unfortunately, checkpoint inhibitors as monotherapy have led to responses only in a small percentage of patients with metastatic breast cancer. This short review summarizes available data on long-lasting remissions and potential cure in metastatic breast cancers. It describes and discusses data on locoregional treatment, chemo-, antibody- and immunotherapy and tries to select individual patients for whom a multidisciplinary treatment approach with curative intention might be an option to achieve long-term survival.

Impact of antibiotic treatment on immune-checkpoint blockade efficacy in advanced non-squamous non-small cell lung cancer.

INTRODUCTION: Despite durable responses from immune-checkpoint blockade (ICB) in a subset of patients with advanced non-small cell lung cancer (NSCLC), the majority of patients do not derive benefit from this treatment. In this analysis we evaluated the impact of concomitant administration of antibiotics during initiation of ICB on clinical outcome. METHODS: Advanced non-squamous NSCLC patients receiving ICB as second- or later line between 2015 and 2017 at our tertiary cancer center in Salzburg (Austria) were included. Concomitant use of antibiotics was defined as administration of antibiotics within a time frame of one month before or one month after initiation of ICB (AB+-group). RESULTS: Of the 30 patients included, 11 (36.7%) received antibiotics one month before or one month after start of ICB (AB+-group). Median PFS on ICB was in favor of the AB--group (AB-: 3.1 months [95%CI: 3.0-16.3]; AB+: 2.9 months, [95%CI: 1.9-NA]; HR=0.46 [95%CI: 0.12-0.90], p=0.031). Furthermore, median OS was significantly longer in the AB--group (AB-: 15.1 months [95%CI: 11.1-NA]; AB+: 7.5 months [95%CI: 6.3-NA]; HR=0.31 [95%CI: 0.02-0.78], p=0.026). In a multivariate analysis, the antibiotic treatment status was identified as the only parameter statistically significantly associated with PFS (p=0.028) and OS (p=0.026). CONCLUSIONS: Stratification of patients according to the antibiotic treatment status is warranted in future trials investigating ICB.

Supervised versus autonomous exercise training in breast cancer patients: A multicenter randomized clinical trial.

BACKGROUND: There is a well-known correlation between obesity, sedentary lifestyle, and breast cancer incidence and outcome. The Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) exercise study was a multicenter, randomized clinical trial and assessed the feasibility and efficacy of physical training in 50 breast cancer patients undergoing aromatase inhibitor treatment. METHODS: Postmenopausal, estrogen receptor-positive breast cancer patients under aromatase inhibitor treatment were randomized 1:1 to counseling and unsupervised training for 48 weeks (unsupervised arm) or counseling and a sequential training (supervised arm) with a supervised phase (24 weeks) followed by unsupervised physical training (further 24 weeks). Primary endpoint was the individual maximum power output on a cycle ergometer after 24 weeks of exercise. A key secondary endpoint was the feasibility of achieving 12 METh/week (metabolic equivalent of task hours per week). RESULTS: Twenty-three patients (92%) in the unsupervised arm and 19 patients (76%) in the supervised arm with early-stage breast cancer completed the study. After 24 weeks, the supervised arm achieved a significantly higher maximum output in watt (mean 132 ±  standard deviation [SD] 34; 95% confidence interval [CI] 117-147) compared to baseline (107 ± 25; 95%CI 97-117; P = 0.012) with a numerically higher output than the unsupervised arm (week 24 115 ± 25; 95%CI 105-125; P = 0.059). Significantly higher METh/week was reported in the supervised arm compared to the unsupervised arm during the whole study period (week 1-24 unsupervised: 18.3 (7.6-58.3); supervised: 28.5 (6.7-40.1); P = 0.043; week 25-48; P = 0.041)). CONCLUSION: This trial indicates that patients in an exercise program achieve higher fitness levels during supervised than unsupervised training.

Antiangiogenic therapy in breast cancer.

Based on a strong rationale for anti-VEGF (vascular endothelial growth factor) treatment in breast cancer and promising preclinical data, great hopes have been placed on the anti-VEGF antibody bevacizumab. Clinical trials, however, reported conflicting results. In metastatic human epidermal growth factor receptor 2(HER2)-negative breast cancer, the addition of bevacizumab to standard chemotherapy improved consistently progression-free survival (PFS), however, without effect on overall survival (OS). In early breast cancer bevacizumab increased the pathologic complete response rate (pCR) after neoadjuvant therapy, but adjuvant trials did not demonstrate an effect on long-term survival. Unfortunately, despite extensive research, there is still no biomarker for bevacizumab efficacy available, making patient selection difficult. This review summarizes all phase III trials investigating efficacy and toxicity of bevacizumab in early, locally advanced and metastatic breast cancer. It recapitulates the main toxicities, gives an overview on biomarker studies and discusses the role and future aspects of antiangiogenic therapy in breast cancer.

Adjuvant medical treatment for breast cancer in elderly and old women.

The probability of developing breast cancer increases with age. Therefore, more than 50 % of women with breast cancer are older than 65 years at the time of diagnosis. However, elderly patients are often undertreated and clinical trials for elderly patients in the adjuvant setting are lacking. Elderly patients who are otherwise fit should receive the standard treatment regimen independent of age. Endocrine therapy should not be withheld from patients by age alone. Thus, there are more adverse events in the elderly population. The decision on adjuvant chemotherapy should be made taking into consideration the patient's comorbidities and frailty. A less toxic single-agent regimen may influence overall survival, but are associated with much less toxicity. Trastuzumab has a similar effect in elderly patients to that in younger patients. The risk of cardiotoxicity should be carefully considered in each patient.