Impact of Electronic Patient-Reported Outcomes on Unplanned Consultations and Hospitalizations in Patients With Cancer Undergoing Systemic Therapy: Results of a Patient-Reported Outcome Study Compared With Matched Retrospective Data.

BACKGROUND: The evaluation of electronic patient-reported outcomes (ePROs) is increasingly being used in clinical studies of patients with cancer and enables structured and standardized data collection in patients' everyday lives. So far, few studies or analyses have focused on the medical benefit of ePROs for patients. OBJECTIVE: The current exploratory analysis aimed to obtain an initial indication of whether the use of the Consilium Care app (recently renamed medidux; mobile Health AG) for structured and regular self-assessment of side effects by ePROs had a recognizable effect on incidences of unplanned consultations and hospitalizations of patients with cancer compared to a control group in a real-world care setting without app use. To analyze this, the incidences of unplanned consultations and hospitalizations of patients with cancer using the Consilium Care app that were recorded by the treating physicians as part of the patient reported outcome (PRO) study were compared retrospectively to corresponding data from a comparable population of patients with cancer collected at 2 Swiss oncology centers during standard-of-care treatment. METHODS: Patients with cancer in the PRO study (178 included in this analysis) receiving systemic therapy in a neoadjuvant or noncurative setting performed a self-assessment of side effects via the Consilium Care app over an observational period of 90 days. In this period, unplanned (emergency) consultations and hospitalizations were documented by the participating physicians. The incidence of these events was compared with retrospective data obtained from 2 Swiss tumor centers for a matched cohort of patients with cancer. RESULTS: Both patient groups were comparable in terms of age and gender ratio, as well as the distribution of cancer entities and Joint Committee on Cancer stages. In total, 139 patients from each group were treated with chemotherapy and 39 with other therapies. Looking at all patients, no significant difference in events per patient was found between the Consilium group and the control group (odds ratio 0.742, 90% CI 0.455-1.206). However, a multivariate regression model revealed that the interaction term between the Consilium group and the factor "chemotherapy" was significant at the 5% level (P=.048). This motivated a corresponding subgroup analysis that indicated a relevant reduction of the risk for the intervention group in the subgroup of patients who underwent chemotherapy. The corresponding odds ratio of 0.53, 90% CI 0.288-0.957 is equivalent to a halving of the risk for patients in the Consilium group and suggests a clinically relevant effect that is significant at a 2-sided 10% level (P=.08, Fisher exact test). CONCLUSIONS: A comparison of unplanned consultations and hospitalizations from the PRO study with retrospective data from a comparable cohort of patients with cancer suggests a positive effect of regular app-based ePROs for patients receiving chemotherapy. These data are to be verified in the ongoing randomized PRO2 study (registered on ClinicalTrials.gov; NCT05425550). TRIAL REGISTRATION: ClinicalTrials.gov NCT03578731; https://www.clinicaltrials.gov/ct2/show/NCT03578731. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/29271.

Comparison of the Real-World Reporting of Symptoms and Well-Being for the HER2-Directed Trastuzumab Biosimilar Ogivri With Registry Data for Herceptin in the Treatment of Breast Cancer: Prospective Observational Study (OGIPRO) of Electronic Patient-Reported Outcomes.

BACKGROUND: Trastuzumab has had a major impact on the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Anti-HER2 biosimilars such as Ogivri have demonstrated safety and clinical equivalence to trastuzumab (using Herceptin as the reference product) in clinical trials. To our knowledge, there has been no real-world report of the side effects and quality of life (QoL) in patients treated with biosimilars using electronic patient-reported outcomes (ePROs). OBJECTIVE: The primary objective of this prospective observational study (OGIPRO study) was to compare the ePRO data related to treatment side effects collected with the medidux app in patients with HER2-positive BC treated with the trastuzumab biosimilar Ogivri (prospective cohort) to those obtained from historical cohorts treated with Herceptin alone or combined with pertuzumab and/or chemotherapy (ClinicalTrials.gov NCT02004496 and NCT03578731). METHODS: Patients were treated with Ogivri alone or combined with pertuzumab and/or chemotherapy and hormone therapy in (neo)adjuvant and palliative settings. Patients used the medidux app to dynamically record symptoms (according to the Common Terminology Criteria for Adverse Events [CTCAE]), well-being (according to the Eastern Cooperative Oncology Group Performance Status scale), QoL (using the EQ-5D-5L questionnaire), cognitive capabilities, and vital parameters over 6 weeks. The primary endpoint was the mean CTCAE score. Key secondary endpoints included the mean well-being score. Data of this prospective cohort were compared with those of the historical cohorts (n=38 patients; median age 51, range 31-78 years). RESULTS: Overall, 53 female patients with a median age of 54 years (range 31-87 years) were enrolled in the OGIPRO study. The mean CTCAE score was analyzed in 50 patients with available data on symptoms, while the mean well-being score was evaluated in 52 patients with available data. The most common symptoms reported in both cohorts included fatigue, taste disorder, nausea, diarrhea, dry mucosa, joint discomfort, tingling, sleep disorder, headache, and appetite loss. Most patients experienced minimal (grade 0) or mild (grade 1) toxicities in both cohorts. The mean CTCAE score was comparable between the prospective and historical cohorts (29.0 and 30.3, respectively; mean difference -1.27, 95% CI -7.24 to 4.70; P=.68). Similarly, no significant difference was found for the mean well-being score between the groups treated with the trastuzumab biosimilar Ogivri and Herceptin (74.3 and 69.8, respectively; mean difference 4.45, 95% CI -3.53 to 12.44; P=.28). CONCLUSIONS: Treatment of patients with HER2-positive BC with the trastuzumab biosimilar Ogivri resulted in equivalent symptoms, adverse events, and well-being as found for patients treated with Herceptin as determined by ePRO data. Hence, integration of an ePRO system into research and clinical practice can provide reliable information when investigating the real-world tolerability and outcomes of similar therapeutic compounds. TRIAL REGISTRATION: ClinicalTrials.gov NCT05234021; https://clinicaltrials.gov/study/NCT05234021.

Metastatic Salivary Duct Carcinoma with ERBB2 Amplification and Sequential Response to Ado-Trastuzumab Emtansine and Neratinib: A Case Report.

Introduction: Salivary duct carcinoma (SDC) is an aggressive and rare subtype of salivary gland carcinoma. Surgical excision and radiotherapy are standard of care for early cancer. Chemotherapies with taxanes and platinum show overall response rates between 39% and 50%. SDCs are often associated with an overexpression of the androgen receptor (AR) and HER2/neu which have recently become druggable targets. Case Presentation: Here, we report on an 84-year-old male patient with metastatic SDC of the right parotid gland. In 2017, he underwent a right total parotidectomy, a right neck dissection, and an infratemporal fossa clearance followed by 6 weeks of radiotherapy. In 2018, due to metastatic spread in the lungs, bones, and pararenal gland, a pathological workup of the tumor tissue was performed and revealed both AR and HER2 overexpression, respectively. Consequently, he underwent androgen deprivation therapy and, due to asymptomatic progression, sequentially human epidermal growth factor receptor 2 (HER-2)-targeted therapy with ado-trastuzumab emtansine and neratinib, which led to stable disease during the course of about 18 months. The electronically captured patient-reported outcome had demonstrated a good tolerance of all three therapeutic lines. Conclusion: In conclusion, since effective standard therapeutic treatment options for SDC may often not be tolerable in older patients, the implementation of personalized and adaptive treatments, especially in patients with rare tumor types, might offer valuable treatment options.

Interference of Herbal Medicine with Axitinib in Metastatic Renal Cell Cancer Treatment: A Case Study.

Introduction: The awareness and the clinical relevance of the potential interactions between standard and complementary medicine are increasing in medical oncology. Nonetheless, the research and experience of the efficacy, safety, and toxicity of herbal substances are poorly documented. Case Presentation: Here, we report the case of a 68-year-old female patient who had been diagnosed with advanced renal cell cancer with metastasis in the liver and pancreas and had undergone surgical resection with hemi-hepatectomy and resection of metastasis in the pancreas in November 2021. Thereafter, chemotherapy was immediately initiated with three-weekly infusions of pembrolizumab and daily intake of the tyrosine kinase inhibitor axitinib. Surprisingly, 3 months after initiation of systemic treatment, the patient developed early progression and metastasis in the liver, which was then treated with selective internal radiotherapy. Despite continued axitinib and pembrolizumab treatment, a short-term follow-up in November 2022 revealed another metastatic lesion in her pancreas. Due to the presumed lack of response to treatment, the plasma concentration of axitinib was measured and found to demonstrate subtherapeutic levels of exposure. Upon extended anamnesis, the patient reported regular intake of herbal substances prescribed by her oncology acupuncturist for gastrointestinal complaints associated with the primary operation. Conclusion: Further clinical-pharmacological workup strikingly demonstrated a reduction of the therapeutic concentration of axitinib of about 90%, likely caused by herbal drugs such as Dang gui and Bai zhu.

Eribulin as first-line treatment in older patients with advanced breast cancer: A multicenter phase II trial [SAKK 25/14].

INTRODUCTION: Standard-dose eribulin mesylate (1.4 mg/m2 d1 + 8) achieves clinical benefit rates of 26%-52% in patients with metastatic breast cancer (mBC). <10% of patients in the registration trial were ≥ 70 years old; dose reductions were common in these older patients. MATERIALS AND METHODS: This single-arm phase II trial explored the efficacy of reduced starting dosing of first-line eribulin at 1 mg/m2 d1 + 8 q3 weeks in patients with mBC aged ≥70 years. The primary endpoint was a disease control rate (DCR) ≥55%. The secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and patient-reported neurotoxicity. RESULTS: Overall, 77 patients were accrued; their median age was 76 years and Eastern Cooperative Oncology Group performance status was 0-1 in 90%. The DCR was 40% (90% confidence interval [CI]: 31-50); therefore, the primary endpoint was not reached. The overall response rate was 22% (95%CI: 13-33), median PFS 5.4 months (95%CI: 4.5-7.7), and median OS 16.1 months (95%CI: 13.5-26.9). Dose modifications were necessary in 35% of patients. In nine patients, more than fifteen cycles were given; 48 patients (62%) experienced at least one grade 3 toxicity. Median patient-reported neurotoxicity scores remained stable for at least fifteen cycles. The main reason for treatment discontinuation was disease progression (57%). DISCUSSION: We report the first prospective data on first-line eribulin in older patients. The reduced starting dose of 1.1 mg/m2 was safe, with prolonged treatment and DC achieved in a considerable proportion of patients (but less than the 55% assumed), without cumulative neurotoxicity. The reduced dose was apparently within the range of the minimal effective dose, as shown by the efficacy lack in patients requiring further dose reductions. Thus, our results do not support the approach of a reduced starting dose for older patients.

Biomarker dynamics and prognosis in breast cancer after neoadjuvant chemotherapy.

Breast cancer is a biologically diverse disease with treatment modalities selected based on tumor stage and tumor biology. Distinct intrinsic subtypes and surrogate biomarker profiles play a major role for therapeutic decisions. Response rates to systemic and local treatments as well as the interaction with epidemiological risk factors have been validated in clinical trials and translational studies. This retrospective study addresses the question how biomarker profiles and treatment modalities in the neoadjuvant chemotherapy setting have changed during the past 15 years and what prognostic impact these changes implicate. 342 female breast cancer stage I-IV patients receiving neoadjuvant chemotherapy between 2003 and 2017 were analyzed. Overall survival (OS) was correlated with preoperative clinical stage, postoperative pathological stage, treatment modalities and tumor biology before and after chemotherapy. Two subgroups were separated using an arbitrary cut-off year at 2009/2010, due to 2010 when platinum containing regimens were first administered. Median follow-up was 54 months. 57 (17%) patients died; recurrences occurred in 103 of 342 (30%) patients. Nodal stage and intrinsic subtypes (pre- and postoperative) significantly correlated with OS (p < 0.001). Preoperative histological grading lacked prognostic power. When comparing the patient characteristics of the subgroups, we found significant difference in the following characteristics: cT, ypT, ypN, pCR and chemotherapy regimens (p < 0.001). There was no difference in OS when comparing the two subgroups. Pathological complete response (pCR) rates had a significant impact on OS and disease-free survival (DFS) in HER2+ and triple negative subtypes (p = 0.03). In multivariate analysis, high proliferation index (> 30%), clinical metastatic stage and pathological tumor stage had prognostic impact on OS (p < 0.001, p = 0.0001, p = 0.002). Clinico-pathological factors and distinct therapy regiments especially in triple negative and HER2+ subtypes have prognostic impact on pCR, OS and DFS after neoadjuvant chemotherapy.

SAKK 21/12: a phase II trial of transdermal CR1447 in breast cancer patients.

Objective: CR1447, a novel transdermal formulation of 4-hydroxytestosterone, has aromatase-inhibiting and androgen receptor (AR)-modulating properties (IC504.4 nM) with antitumor effects against AR-positive tumor cells in vitro. This trial investigated the efficacy and safety of CR1447 for patients with metastatic estrogen receptor-positive (A) and AR-positive triple-negative breast cancers (B). Design and methods: (A) included patients with at most one prior endocrine therapy line without progression ≥6 months, whereas (B) included patients with ≤2 prior chemotherapy lines, all displaying advanced signs of disease. The primary endpoint was disease control at week 24 (DC24). The null hypothesis was DC24 ≤30% (A) and ≤15% (B). Thirty-seven patients were recruited (29 in (A) and 8 in (B)); accrual was stopped following an interim analysis demonstrating futility in (A) and slow accrual in (B). Results: DC24 was attained in 5/21 (95% CI: 8.2-47.2) patients in (A) and none in (B). The median progression-free survival was 5.1 months (95% CI: 2.5-5.6) in (A) and 2.5 months (95% CI: 0.7-2.6) in (B). The median overall survival was 24.6 months (95% CI: 22.9-not applicable) in (A) and 10.8 months (95% CI: 3.3-10.9) in (B). CR1447 had a favorable safety profile without treatment-related grade 3-5 toxicities in (A). Especially no side effects linked to androgenic effects were observed. Conclusions: Despite this trial being negative, the 24% DC24 rate in a second-line setting, and the prolonged partial response experienced by a patient, indicate activity. Further evaluation of CR1447 in endocrine-sensitive patients or combination trials appears warranted.

The Effect of Collaborative Reviews of Electronic Patient-Reported Outcomes on the Congruence of Patient- and Clinician-Reported Toxicity in Cancer Patients Receiving Systemic Therapy: Prospective, Multicenter, Observational Clinical Trial.

BACKGROUND: Electronic patient-reported outcomes (ePRO) are a relatively novel form of data and have the potential to improve clinical practice for cancer patients. In this prospective, multicenter, observational clinical trial, efforts were made to demonstrate the reliability of patient-reported symptoms. OBJECTIVE: The primary objective of this study was to assess the level of agreement κ between symptom ratings by physicians and patients via a shared review process in order to determine the future reliability and utility of self-reported electronic symptom monitoring. METHODS: Patients receiving systemic therapy in a (neo-)adjuvant or noncurative intention setting captured ePRO for 52 symptoms over an observational period of 90 days. At 3-week intervals, randomly selected symptoms were reviewed between the patient and physician for congruency on severity of the grading of adverse events according to the Common Terminology Criteria of Adverse Events (CTCAE). The patient-physician agreement for the symptom review was assessed via Cohen kappa (κ), through which the interrater reliability was calculated. Chi-square tests were used to determine whether the patient-reported outcome was different among symptoms, types of cancer, demographics, and physicians' experience. RESULTS: Among the 181 patients (158 women and 23 men; median age 54.4 years), there was a fair scoring agreement (κ=0.24; 95% CI 0.16-0.33) for symptoms that were entered 2 to 4 weeks before the intended review (first rating) and a moderate agreement (κ=0.41; 95% CI 0.34-0.48) for symptoms that were entered within 1 week of the intended review (second rating). However, the level of agreement increased from moderate (first rating, κ=0.43) to substantial (second rating, κ=0.68) for common symptoms of pain, fever, diarrhea, obstipation, nausea, vomiting, and stomatitis. Similar congruency levels of ratings were found for the most frequently entered symptoms (first rating: κ=0.42; second rating: κ=0.65). The symptom with the lowest agreement was hair loss (κ=-0.05). With regard to the latency of symptom entry into the review, hardly any difference was demonstrated between symptoms that were entered from days 1 to 3 and from days 4 to 7 before the intended review (κ=0.40 vs κ=0.39, respectively). In contrast, for symptoms that were entered 15 to 21 days before the intended review, no congruency was demonstrated (κ=-0.15). Congruency levels seemed to be unrelated to the type of cancer, demographics, and physicians' review experience. CONCLUSIONS: The shared monitoring and review of symptoms between patients and clinicians has the potential to improve the understanding of patient self-reporting. Our data indicate that the integration of ePRO into oncological clinical research and continuous clinical practice provides reliable information for self-empowerment and the timely intervention of symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT03578731; https://clinicaltrials.gov/ct2/show/NCT03578731.

Response to Vemurafenib in Metastatic Triple-Negative Breast Cancer Harbouring a BRAF V600E Mutation: A Case Report and Electronically Captured Patient-Reported Outcome.

Effective treatment options are still scarce for metastatic triple-negative breast cancers. An increasing interest in the mutational landscape of this disease will facilitate novel therapeutic strategies in a variety of cancers. Here we report the case of a 38-year-old female patient who developed multiple lung metastasis of a triple-negative breast cancer 2 years after the completion of local therapy. When she progressed after two palliative chemotherapy lines and local electroporation, a next-generation sequencing revealed a BRAF V600E mutation for which we initiated therapy with the BRAF inhibitor vemurafenib. Radiological improvement was already evident after 3 months and has been ongoing for 19 months so far with very few side effects, as is demonstrated by electronically captured patient-reported outcomes. To our knowledge, this is the first published case where a BRAF V600E-mutated advanced triple-negative breast cancer was successfully treated with vemurafenib.

Die Bedeutung der Ethik bei der Nutzung Künstlicher emotionaler Intelligenz in der Psychiatrie ­ ein ethischer Diskurs.

The ethical discourse addresses the following aspects: What do we need ethics for? Man's disposition to morality, natural ethics. Morality as a social norm. Morality to maintain an inhuman, superhuman power structure. Morality as an artifact of the brain, as a hindrance to new developments. Unity of ethics and aesthetics. "Zoon politikon", "Robinson Crusoe". Does Artificial Intelligence (AI) need new ethics? Characteristics of an AI, developed for loneliness, as a servant or with Christian software, group ability, own emotions, awareness and own ethics, as a supplement. Should AI be expected to have human emotions? Emotional intelligence, language as a mediator of emotions and empathy, the ability to mentalize, artificial (general) emotional intelligence, "Terminator", "L'Eve future".

Effect of Collaborative Review of Electronic Patient-Reported Outcomes for Shared Reporting in Breast Cancer Patients: Descriptive Comparative Study.

BACKGROUND: Digital monitoring of treatment-related symptoms and self-reported patient outcomes is important for the quality of care among cancer patients. As mobile devices are ubiquitous nowadays, the collection of electronic patient-reported outcomes (ePROs) is gaining momentum. So far, data are lacking on the modalities that contribute to the quantity and quality of ePROs. OBJECTIVE: The objective of our study was to compare the utilization of two versions of a subsequently employed mobile app for electronic monitoring of PROs and to test our hypothesis that a shared review of symptoms in patient-physician collaboration has an impact on the number of data entries. METHODS: The Consilium Care app engages cancer patients to standardize reporting of well-being and treatment-related symptoms in outpatient settings. For descriptive comparison of the utilization of two slightly different app versions, data were obtained from an early breast cancer trial (version 1 of the app, n=86) and an ongoing study including patients with advanced disease (version 2 of the app, n=106). In both app versions, patients and doctors were allowed to share the information from data entries during consultations. Version 2 of the app, however, randomly selected symptoms that required a detailed and shared regular patient-doctor review in order to focus on the collection and appropriate interpretation regarding awareness and guidance for severity grading. The numbers and types of symptom entries, satisfaction with both app versions, and patients' perceived effects during consultations were included for analysis. RESULTS: Symptom severity grading was performed according to the Common Terminology Criteria for Adverse Events (CTCAE) using a horizontal slider and was indicated in descriptive terminology in both apps, while a graphical display facilitated the illustration of symptom history charts. In total, 192 patients electronically reported 11,437 data entries on well-being and 33,380 data entries on individual symptoms. Overall, 628 (of 872 intended) requested patient-doctor symptom reviews were performed in version 2 of the app. Both the amount of data entries per patient and day for well-being (version 1 vs version 2: 0.3 vs 1.0; P<.001) and symptoms (version 1 vs version 2: 1.3 vs 1.9; P=.04) appeared significantly increased in version 2 of the app. Overall satisfaction with both app versions was high, although version 2 of the app was perceived to be more helpful in general. CONCLUSIONS: Version 2 of the app showed much better results than version 1 of the app. A request for collaborative patient-doctor symptom review is likely to affect the number of digital symptom data entries. This app shows high potential to improve the patient-doctor experience. TRIAL REGISTRATION: ClinicalTrials.gov NCT02004496; https://clinicaltrials.gov/ct2/show/NCT02004496 and ClinicalTrials.gov NCT03578731; https://clinicaltrials.gov/ct2/show/NCT03578731.

Differential prognostic value of positive HER2 status determined by immunohistochemistry or fluorescence in situ hybridization in breast cancer.

PURPOSE: Human epidermal growth factor-receptor-2 (HER2) is a membrane-tyrosine-kinase that is amplified/overexpressed up to 20% in breast cancer. HER2 positive status is associated with faster disease progression, higher metastatic potential, and shorter disease-free/overall survival and also has emerged as an important therapeutic target in breast cancer. HER2 status can be determined by in-situ-hybridization (ISH) or immunohistochemistry (IHC). Although the concordance rate between ISH and IHC is well-known, the prognostic power of both technologies if tested in parallel on the same tumor has not been studied extensively. METHODS: In this study we retrospectively analyzed a large HER2 positive breast cancer cohort tested both with fluorescence labeled ISH (FISH) and IHC in parallel on each case. We stratified HER2 positive results by FISH and IHC with long-term overall survival, 5-year survival and metastases/recurrence rates. Positive HER2 status both FISH and IHC was available in 364 patients. RESULTS: The number of HER2 FISH-positive and FISH-negative patients was 342 and 22, respectively. The number of HER2 IHC 0/1 + , IHC 2 + , and IHC 3 + patients was 12, 42, and 310, respectively. Among the patients with IHC 3 + status, 288 were FISH-positive and 22 FISH-negative. HER2 status determined by FISH correlated with clinical outcomes (overall survival and with metastases/recurrence, p = 0.036, p = 0.039), whereas HER2 status determined by IHC did not. CONCLUSION: Our results indicate that prognostic information in HER2 positive breast cancer also depends on the methodology of how positivity was determined. In our cohort, FISH was superior to IHC based positive HER2 status.

Consilium Smartphone App for Real-World Electronically Captured Patient-Reported Outcome Monitoring in Cancer Patients Undergoing anti-PD-L1-Directed Treatment.

Digital patient monitoring gains importance for quality of clinical cancer care. Our case report provides insight into usability and acceptance of a smartphone app for monitoring of electronically captured patient-reported outcomes in patients undergoing immunotherapy. During 3 months, 6 patients with advanced or metastatic PD-L1-positive cancer of the lung, prostate, and bladder who underwent checkpoint immunotherapy were using the Consilium app for standardized and structured electronic reporting of symptoms and therapy side effects. We evaluated the number and quality of symptom entries as well as usability and safety of shared reporting between the patient and the treating physician. Duration of anti-PD-L1-directed immunotherapy in the 6 patients ranged from 4 to 10 months and comprised a total of 21 anti-PD-L1-directed immunotherapy cycles. Patients reported between 4 and 16 different symptoms, of which the most frequent (57%) were dry cough, fatigue, shortness of breath, fever, and appetite loss. Overall, 1,279 symptom entries were counted, corresponding to 2.4 symptom entries per patient per day. Symptom severity grading ranged from 0.1 (very slight symptoms) to 7.8 (severe symptoms), which triggered prespecified alerts in 4 of the 6 patients. No unplanned visits were noted, and no safety issues occurred. Satisfaction with the app usability was high, as was the beneficial effect on consultation. Usability and reviewed data entries indicate high shared reporting efforts of patients and treating physicians and overall satisfaction with electronically reported patient outcomes.

Efficacy of a CDK4/6 Inhibitor in a Patient with Breast Cancer and Liposarcoma: A Case Report and Review of the Literature.

BACKGROUND: The cyclin D/cyclin-dependent kinase (CDK)4/6 inhibitor of the CDK4 (INK4)/retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression. Selective CDK4/6 inhibitors specifically target a variety of tumors, with the main focus on hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative breast cancer (BC). CASE REPORT: We report on the efficacy of neoadjuvant palbociclib and letrozole application in a patient suffering from invasive estrogen receptor (ER)+/HER2- BC and concurrent well-differentiated and dedifferentiated liposarcoma (WD-DDLPS) of the thigh. Clinical and histological workup upon surgery revealed significant regressive changes in both the liposarcoma and the BC. The 24-month follow-up shows no signs of disease. CONCLUSION: CDK4/6 inhibitors exhibit a high therapeutic potential, although reliable prognostic markers need to be identified.

SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial.

BACKGROUND: Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in metastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/bevacizumab compared with paclitaxel/bevacizumab. METHODS: This multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily oral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. The primary endpoint was the incidence of selected grade 3-5 adverse events (AE) including: febrile neutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response rate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was registered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010. RESULTS: Between September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of primary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15-35 %) and arm B (24 % [16/68]; 95 % CI 13-34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46-0.69) and 50 % (37/74; 95 % CI 0.39-0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7-11.3) in arm A and 8.5 months (95 % CI 6.5-11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different between study arms. The only statistically significant differences in QoL were less hair loss and less numbness in arm B. Treatment costs between the two arms were equivalent. CONCLUSION: This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3-5 AEs with metronomic bevacizumab, cyclophosphamide and capecitabine.

A Mobile App to Stabilize Daily Functional Activity of Breast Cancer Patients in Collaboration With the Physician: A Randomized Controlled Clinical Trial.

BACKGROUND: The well-being of breast cancer patients and reporting of adverse events require close monitoring. Mobile apps allow continuous recording of disease- and medication-related symptoms in patients undergoing chemotherapy. OBJECTIVE: The aim of the study was to evaluate the effects of a mobile app on patient-reported daily functional activity in a supervised and unsupervised setting. METHODS: We conducted a randomized controlled study of 139 breast cancer patients undergoing chemotherapy. Patient status was self-measured using Eastern Cooperative Oncology Group scoring and Common Terminology Criteria for Adverse Events. Participants were randomly assigned to a control group, an unsupervised group that used a mobile app to record data, or a supervised group that used the app and reviewed data with a physician. Primary outcome variables were change in daily functional activity and symptoms over three outpatient visits. RESULTS: Functional activity scores declined in all groups from the first to second visit. However, from the second to third visit, only the supervised group improved, whereas the others continued to decline. Overall, the supervised group showed no significant difference from the first (median 90.85, IQR 30.67) to third visit (median 84.76, IQR 18.29, P=.72). Both app-using groups reported more distinct adverse events in the app than in the questionnaire (supervised: n=1033 vs n=656; unsupervised: n=852 vs n=823), although the unsupervised group reported more symptoms overall (n=4808) in the app than the supervised group (n=4463). CONCLUSIONS: The mobile app was associated with stabilized daily functional activity when used under collaborative review. App-using participants could more frequently report adverse events, and those under supervision made fewer and more precise entries than unsupervised participants. Our findings suggest that patient well-being and awareness of chemotherapy adverse effects can be improved by using a mobile app in collaboration with the treating physician. CLINICALTRIAL: ClinicalTrials.gov NCT02004496; https://clinicaltrials.gov/ct2/show/NCT02004496 (Archived by WebCite at http://www.webcitation.org/6k68FZHo2).

HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy.

BACKGROUND: Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS). METHODS: Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007-2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression. RESULTS: A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23-89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic impact was detected for tumor size (p = 0.02), nodal status (p<0.01), proliferation index (p<0.01), level (≥20%) of estrogen receptor expression (p = 0.03) and neoadjuvant therapeutic setting (p = 0.03), respectively. Importantly, univariate and multivariable analysis revealed that standard trastuzumab containing chemotherapy resulted in impaired disease free survival among tumors with FISH ratio >8 (p<0.01). Although less pronounced, a similar association was found also with respect to high HER2 gene copy numbers (>12) and DFS (p = 0.01). CONCLUSIONS: In early BC patients, tumors with high HER2 amplification ratios (>8), may less likely respond to standard trastuzumab-containing therapies. Although, we obtained a similar effect for high HER2 gene copy numbers, this provides only an indirect speculation and not a proof that high HER2/CEP17 ratios may induce HER2 resistance.

Bevacizumab specifically decreases elevated levels of circulating KIT+CD11b+ cells and IL-10 in metastatic breast cancer patients.

BACKGROUND: Whether bevacizumab exerts its anti-tumor properties through systemic effects beyond local inhibition of angiogenesis and how these effects can be monitored in patients, remain largely elusive. To address these questions, we investigated bone marrow-derived cells and cytokines in the peripheral blood of metastatic breast cancer patients undergoing therapy with bevacizumab. METHODS: Circulating endothelial cells (CEC), circulating endothelial progenitor (CEP) and circulating CD11b+ cells in metastatic breast cancer patients before and during therapy with paclitaxel alone (n = 11) or in combination with bevacizumab (n = 10) were characterized using flow cytometry, real time PCR and RNASeq. Circulating factors were measured by ELISA. Aged-matched healthy donors were used as baseline controls (n = 12). RESULTS: Breast cancer patients had elevated frequencies of CEC, CEP, TIE2+CD11b+ and KIT+CD11b+ cell subsets. CEC decreased during therapy, irrespective of bevacizumab, while TIE2+CD11b+ remained unchanged. KIT+CD11b+ cells decreased in response to paclitaxel with bevacizumab, but not paclitaxel alone. Cancer patients expressed higher mRNA levels of the M2 polarization markers CD163, ARG1 and IL-10 in CD11b+ cells and increased levels of the M2 cytokines IL-10 and CCL20 in plasma. M1 activation markers and cytokines were low or equally expressed in cancer patients compared to healthy donors. Chemotherapy with paclitaxel and bevacizumab, but not with paclitaxel alone, significantly decreased IL-10 mRNA in CD11b+ cells and IL-10 protein in plasma. CONCLUSIONS: This pilot study provides evidence of systemic immunomodulatory effects of bevacizumab and identified circulating KIT+CD11b+ cells and IL-10 as candidate biomarkers of bevacizumab activity in metastatic breast cancer patients.

The use of granulocyte colony stimulating factor (G-CSF) and management of chemotherapy delivery during adjuvant treatment for early-stage breast cancer--further observations from the IMPACT solid study.

OBJECTIVE: To investigate the use and impact of granulocyte colony-stimulating factors (G-CSF) on chemotherapy delivery and neutropenia management in breast cancer in a clinical practice setting. METHODS: IMPACT Solid was an international, prospective observational study in patients with a physician-assessed febrile neutropenia (FN) risk of ≥20%. This analysis focused on stages I-III breast cancer patients who received a standard chemotherapy regimen for which the FN risk was published. Chemotherapy delivery and neutropenia-related outcomes were reported according to the FN risk of the regimen and intent of G-CSF use. RESULTS: 690 patients received a standard chemotherapy regimen; 483 received the textbook dose/schedule with a majority of these regimens (84%) having a FN risk ≥10%. Patients receiving a regimen with a FN risk ≥10% were younger with better performance status than those receiving a regimen with a FN risk <10%. Patients who received higher-risk regimens were more likely to receive G-CSF primary prophylaxis (48% vs 22%), complete their planned chemotherapy (97% vs 88%) and achieve relative dose intensity ≥85% (93% vs 86%) than those receiving lower-risk regimens. Most first FN events (56%) occurred in cycles not supported with G-CSF primary prophylaxis. CONCLUSION: Physicians generally recommend standard adjuvant chemotherapy regimens and were more likely to follow G-CSF guidelines for younger, good performance status patients in the curative setting, and often modify standard regimens in more compromised patients. However, G-CSF support is not optimal, indicated by G-CSF primary prophylaxis use in <50% of high-risk patients and observation of FN without G-CSF support.